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Tecemotide: An antigen-specific cancer immunotherapy a
a
b
Gregory T. Wurz , Chiao-Jung Kao , Michael Wolf & Michael W. DeGregorio
a
a
University of California, Davis, Department of Internal Medicine, Division of Hematology and Oncology, Sacramento, CA 95817 USA b
Department of ImmunoOncology, Merck Serono Research, Merck KGaA, Darmstadt, Germany Accepted author version posted online: 01 Nov 2014.
Click for updates To cite this article: Gregory T. Wurz, Chiao-Jung Kao, Michael Wolf & Michael W. DeGregorio (2014): Tecemotide: An antigenspecific cancer immunotherapy, Human Vaccines & Immunotherapeutics, DOI: 10.4161/hv.29836 To link to this article: http://dx.doi.org/10.4161/hv.29836
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Tecemotide: An Antigen-Specific Cancer Immunotherapy Gregory T. Wurz1, Chiao-Jung Kao1, Michael Wolf2, Michael W. DeGregorio1* 1
University of California, Davis, Department of Internal Medicine, Division of Hematology and
Oncology, Sacramento, CA 95817 USA. Department of ImmunoOncology, Merck Serono Research, Merck KGaA, Darmstadt, Germany.
Keywords:
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2
Tecemotide; MUC1; Non-Small Cell Lung Cancer; Immunotherapy; Chemo-
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*To whom correspondence should be addressed:
Dr. Michael W. DeGregorio, Professor of Medicine, University of California, Davis, Department
an
of Internal Medicine, Division of Hematology and Oncology, 4501 X Street Suite 3016, Sacramento, CA 95817 USA, E-mail: [email protected]
ADT
Androgen deprivation therapy
APC
ed
M
Abbreviations
Antigen presenting cell
BSC
CI
Best supportive care Carcinoembryonic antigen
ce
CEA
Active specific immunotherapy
pt
ASI
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radiotherapy.
Confidence interval
CONSORT
Consolidated standards of reporting trials
CPA
Cyclophosphamide
CRT
Chemoradiotherapy
CTL
Cytotoxic T-lymphocyte
DMPG
Dimyristoyl phosphatidylglycerol
1
DTH
Delayed-type hypersensitivity
ECOG
Eastern cooperative oncology group
ELISpot
Enzyme-linked immunosorbent spot
FACT-L
Functional assessment of cancer therapy-lung
Gy
Gray
HLA
Human lymphocyte antigen
HR
Hazard ratio
IFN-
Interferon gamma
IgG
Immunoglobulin G
IL-2
Interleukin 2
INSPIRE
Stimuvax trial in Asian NSCLC patients: stimulating immune response
ITT
Intent to treat
i.v.
ed
cr us
pt
Keyhole limpet hemocyanin L-BLP25 in colorectal cancer Locoregional
ce
LICC LR
an
M
Intravenous
KLH
MAP
ip t
Dipalmitoyl phosphatidylcholine
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DPPC
Multiple antigenic peptide
MHC
Major histocompatibility complex
MMT
MUC1-expressing mammary tumor
MPLA
Monophosphoryl lipid A
MUC1
Mucin 1
MUC1.Tg
MUC1 transgenic
2
OH-BBN
N-butyl-N-(4-hydroxybutyl)nitrosamine
OS
Overall survival
PBL
Peripheral blood lymphocytes
PCR
Pathological complete remission
PSA
Prostate specific antigen
PyV-mT
Polyomavirus middle-T
QOL
Quality of life
RCB
Residual cancer burden
RECIST
Response evaluation criteria in solid tumors
RTX
Radiotherapy
START
Stimulating targeted antigenic responses to NSCLC
TAA
Tumor associated antigen
TGF-
ed
M
an
us
cr
ip t
Non-small cell lung cancer
Transforming growth factor beta T-helper type I
TH2
pt
TH1
T-helper type II Tumor necrosis factor alpha
ce
TNFTOI
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NSCLC
VNTR
Trial outcome index Variable number of tandem repeats
Abstract
The identification of tumor-associated antigens (TAA) has made possible the development of antigen-specific cancer immunotherapies such as tecemotide. One of those is mucin 1 (MUC1), a cell membrane glycoprotein expressed on some epithelial tissues such as breast and lung. In
3
cancer, MUC1 becomes overexpressed and aberrantly glycosylated, exposing the immunogenic tandem repeat units in the extracellular domain of MUC1. Designed to target tumor associated MUC1, tecemotide is being evaluated in Phase III clinical trials for treatment of unresectable stage IIIA/IIIB non-small cell lung cancer (NSCLC) as maintenance therapy following
ip t
chemoradiotherapy. Additional Phase II studies in other indications are ongoing. This review discusses the preclinical and clinical development of tecemotide, ongoing preclinical studies of
cr
us
potential application of these models for optimizing the timing of chemoradiotherapy and
an
tecemotide immunotherapy to achieve the best treatment outcome for patients.
Introduction
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The development of antigen-specific cancer immunotherapies has been made possible by the identification of tumor-associated antigens (TAA), of which a vast number have now been
ed
discovered.1, 2 One of the best characterized TAAs is mucin 1 (MUC1), which is overexpressed
pt
and aberrantly glycosylated in over 90% of adenocarcinomas such as breast and lung cancer.3, 4 While MUC1 is a self-antigen expressed in a number of different epithelial tissues, the normal
ce
glycosylation pattern shields the peptide core from immune surveillance.
The aberrant
underglycosylation of MUC1 in cancer leads to the exposure of the immunogenic tandem repeat regions of the core peptide, which had made MUC1 an attractive target for immunotherapies.2, 5-8
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tecemotide in human MUC1 transgenic mouse models of breast and lung cancer, and the
Both cellular and humoral immune responses to MUC1 have been observed in many patients with lung, breast and other adenocarcinomas, but the native immune response is insufficient in controlling tumor growth, which is due to existing tolerance and the development of multiple mechanisms of immune evasion.4, 9-11 Tecemotide, a MUC1-specific cancer immunotherapy, is
4
currently being evaluated in Phase III clinical trials as maintenance therapy following chemoradiotherapy (CRT) for the treatment of unresectable stage IIIA/IIIB non-small cell lung cancer (NSCLC).
Recently published clinical trials results suggest that the timing of
chemotherapy, radiation, and tecemotide immunotherapy is important with respect to treatment
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outcome.12
Tecemotide, formerly known as L-BLP25 or Stimuvax®, has been developed for the treatment of
cr
us
family. Tecemotide is designed to elicit an antigen-specific cellular immune response against MUC1, which was one of the first TAAs identified by human tumor-specific T-cells.8 It is
of
aberrantly
glycosylated,
an
broadly distributed on the apical surface of most simple epithelial tissues, but strong expression tumor-associated
MUC1
has
been
observed
in
most
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adenocarcinomas, including lung, breast, stomach, pancreas, colon, prostate, and ovary as well as hematological malignancies such as multiple myeloma. On tumor cells polarity is lost and
ed
MUC1 is expressed on the entire cell surface.13 The extracellular domain of MUC1 consists of a
pt
variable number of tandem repeats (VNTR) of a characteristic 20-amino acid sequence (PDTRPAPGSTAPPAHGVTSA) that is aberrantly glycosylated in tumor tissues.14-17
The
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resulting underglycosylation of MUC1 facilitates peptide processing and loading onto human lymphocyte antigen (HLA) molecules, which results in the exposure of a novel and large epitope
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adenocarcinomas that express MUC1, a member of the membrane-bound O-glycoprotein mucin
repertoire bound to HLA molecules that can be recognized by MUC1-specific cytotoxic Tlymphocytes (CTLs).18, 19 It has been shown that immunization of cancer patients with MUC1 peptides results in the generation of both anti-MUC1 antibodies and CTL responses.20
In
addition, MUC1 was found to be expressed on activated T cells, exhibiting both immunostimulatory and immunosuppressive functions.21 Several MUC1-based immunotherapy
5
approaches such as tecemotide,12, 22-25 TG4010,26-28 and PANVAC™,29-31 have been evaluated in clinical trials for a variety of malignancies including NSCLC, metastatic breast cancer, renal cell carcinoma, ovarian cancer and metastatic colorectal carcinoma. The purpose of this review is to discuss the preclinical and clinical development of
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tecemotide and to highlight ongoing research in human MUC1 transgenic mouse models of breast32 and lung cancer33, 34 that are being utilized with the goal of optimizing the timing of
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for patients.35 As there are presently no effective maintenance therapies for stage III NSCLC
overall treatment outcomes.36 Preclinical Development of Tecemotide
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BP16
an
following CRT, immunotherapies such as tecemotide offer a potential method of improving
ed
Early preclinical research into the development of MUC1 immunotherapy strategies was conducted using various synthetic peptides from the tandem repeat region of the MUC1 core
pt
peptide.37 Mice were immunized with peptides of various lengths conjugated to either dendritic multiple antigenic peptide (MAP-4) or keyhole limpet hemocyanin (KLH) as a carrier molecule
ce
and using DETOX, which contains monophosphoryl lipid A (MPLA) and mycobacterial cell wall, as an adjuvant. Each of the peptides tested contained the B and T cell epitope PDTRP in
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chemotherapy, radiation, and tecemotide immunotherapy to achieve the best treatment outcome
various configurations, along with portions of the 20-amino acid sequence from the MUC1 tandem repeat region. The SP1-16 peptide additionally contained two MUC1 tandem repeats plus a universal T-cell epitope from tetanus toxin. Following immunization, antibody, delayed type hypersensitivity (DTH), and antitumor responses were evaluated. To assess DTH and antitumor responses, immunized mice were challenged with 410.4 mouse mammary tumor cells
6
that had been transfected with human MUC1.38 Delayed type hypersensitivity responses were also assessed by peptide challenge in immunized mice.
The results showed that peptides
conjugated to either KLH (SP1-7-KLH) or MAP-4 (SP1-5 and SP1-6) proved to be the most immunogenic.37
The SP1-6 peptide additionally contained a 19-amino acid sequence
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(EKKIAKMEKASSVFNVVNS) from the CST-3 peptide of Plasmodium falciparum, which is a universal T-helper epitope.
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only in response to challenge with the same or similar peptide, which shows specificity of response. When challenged with mammary tumor cells, immunized mice had DTH responses
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only when injected with cells that had been transfected with human MUC1. The antitumor effects of these peptides were evaluated in both preventive (immunization) and treatment (active
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specific immunotherapy or ASI) settings. Whether used prophylactically or as ASI, significant tumor growth inhibition was seen with the MAP-4 conjugated peptides and the KLH-conjugated
ed
peptide SP1-7, a 16-mer (GVTSAPDTRPAPGSTA), in particular.37 Active specific
pt
immunotherapy with the three most promising peptides in this study, SP1-5, a 22-mer (APDTRPAPGSTAPPAHGVTSAP-MAP4), SP1-6, an 8-mer (SAPDTRPA-CST-MAP4) and
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SP1-7-KLH, was most effective when mice were pretreated with cyclophosphamide (CPA), which is thought to reduce the number and immunosuppressive functionality of T-regulatory cells,39-43 thereby augmenting the response to immunotherapy.44, 45 Some interesting differences
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Mice that had been immunized displayed DTH reactions, indicative of cellular immunity,
were observed in this study with respect to immune response. Peptides that induced strong antibody and DTH responses were inferior with respect to antitumor effects compared to those that were poor inducers of antibody response. This result is consistent with the hypothesis that
7
for an effective antitumor response, a TH1 or cellular immune response is superior to a TH2 or humoral antibody immune response.37 BP24 Based on the results obtained with the SP1-7 peptide (BP16) by Ding et al. in 1993, additional
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studies were performed using a newer peptide, BP24 (TAPPAHGVTSAPDTRPAPGSTAPP),
which was synthesized to include additional T-cell epitopes compared to BP16.46 Because there
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and MUC1 is highly expressed in breast cancer, Agrawal et al. evaluated the proliferation of peripheral blood lymphocytes (PBL) from men and multiparous and nulliparous women in 48
These investigators found that CD4+ T cells from
an
response to exposure to BP24.47,
multiparous women, but not nulliparous women or men, proliferated specifically in response to
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BP24 as well as BP16, the sequence of which is contained within BP24.
No significant
ed
proliferation was noted in response to a negative control peptide. Proliferative responses were noted in the lymphocytes from several different HLA types in an MHC class II-restricted
pt
fashion.47 In a follow-up experiment using T lymphocyte cell lines established from the PBLs of multiparious donors, MUC1-specific MHC class I-restricted CTLs were induced by stimulation
ce
with autologous antigen-presenting cells (APCs) that had been loaded with BP24 peptide.48 This result is consistent with Domenech et al., who showed MHC class I-restricted binding of a nine amino acid peptide (STAPPAHGV) to HLA-A1, HLA-A2.1, HLA-A3 and HLA-A11,49 although
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is strong evidence suggesting that multiple pregnancies provide protection against breast cancer,
BP24 does not fully contain this peptide sequence. This latter experiment was performed under conditions that favored peptide binding to MHC class I molecules, whereas conditions in the earlier study favored MHC class II binding, and no CTL response was observed.47
8
Liposomal BP24 In order to improve cellular or TH1 type immune responses, the BP24 peptide was prepared in a liposomal formulation, using MPLA as the adjuvant, and then evaluated for immunogenicity and antitumor activity.46 Compared to BP16-KLH, the immune response to liposomal BP24 was
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predominantly TH1, as assessed by immunizing non-tumor-bearing mice. Mice treated with
BP16-KLH showed a much stronger IgG antibody response compared to the BP24-treated mice,
cr
The
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antitumor activity of liposomal BP24 was evaluated in intravenous, subcutaneous and artificial metastasis tumor models using a human MUC1 transfected mouse mammary carcinoma cell line
an
(410.4). Following intravenous tumor challenge after immunization, mice treated with liposomal BP24 survived significantly longer and formed significantly fewer lung metastases.
Mice
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immunized with liposomal BP24 showed complete protection following subcutaneous tumor
ed
challenge with MUC1 transfected cells, while immunization provided no protection against nontransfected cells, indicating specificity of immune response. The artificial metastasis model
pt
showed that BP24 immunization again showed complete protection with respect to the formation of lung tumor foci. When used as ASI, BP24-treated mice developed far fewer lung tumor foci
ce
compared to control mice or mice treated with empty liposomes containing MPLA. Results of cytokine and antibody analyses in tumor-bearing mice were consistent with a TH1-polarized immune response.46
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suggesting a poorer CTL cellular immune response to the KLH-conjugated peptide.
Liposomal BLP25 To further augment the MUC1 immune response, a serine residue was added to BP24, yielding BP25 (STAPPAHGVTSAPDTRPAPGSTAPP), also known as BLP25.50,
51
This synthetic
MUC1 peptide was synthesized to introduce HLA class I epitopes49 to complement the HLA
9
class II epitopes that had already been demonstrated for the MUC1 peptide BP24, the sequence of which is completely contained within BP25.47 The first experiments with liposomal BP25 (BLP25) examined the generation of MUC1-specific CD4+ and CD8+ T-cell responses in vitro in unprimed lymphocytes from the PBL of human donors.50 T cells cultured in the presence of
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autologous APCs pulsed with liposome-encapsulated BLP25 showed marked proliferation
compared to those cultured with APCs that had been pulsed with soluble BLP25. When T-cell
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to liposomal BLP25, with weak responses to liposomal BLP24 and soluble BLP25 and BP24. These lymphocyte responses were found to be TH1 type based on increased IFN-
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minimal IL-4. The lymphocyte subtypes proliferating in response to BLP25 were identified as CD4+ and CD8+ T cells based on flow cytometric analysis and the lack of proliferation in the
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presence of anti-CD4 and anti-CD8 antibodies. The T cells stimulated by autologous APCs pulsed with BLP25 were able to lyse targets pulsed with HLA class I 9-mer MUC1 peptide
ed
epitopes, confirming cytotoxic activity.50
pt
As pointed out above, early studies performed by Agrawal et al. on liposomal BLP25 showed that T cells cultured with autologous APCs pulsed with liposomal BLP25 showed
ce
marked proliferation compared to T cells cultured with APCs pulsed with soluble BLP25.50 This finding is consistent with the results of a study by Guan et al. that showed physical association of
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proliferation was assessed for antigen specificity, T cells proliferated most strongly in response
the peptide with liposomes, either through encapsulation or surface exposure, is required for a Tcell proliferative response. Peptide alone or peptide combined with empty liposomes failed to elicit an antigen-specific T-cell response in immunized mice.51 This study also found that the nature of the physical association had a significant effect on the humoral immune response to the BLP25 peptide. Compared to liposomal BLP25, only those mice that were immunized with
10
surface-exposed peptide liposomes developed MUC1-specific antibodies, which suggests that different liposome formulations can produce different immune responses.51
Tecemotide in Transgenic Tumor-Bearing Mouse Models
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Breast Cancer
An immune-intact transgenic breast cancer mouse model that expresses human MUC1 as a self-
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developed to study MUC1-specific immunotherapy.4 To develop this model, MUC1 transgenic (MUC1.Tg) C57BL/6 mice52 were crossed with mice transgenic for polyomavirus middle T
an
(PyV-mT) driven by the MMTV promoter.53 The resulting double transgenic MUC1-expressing mammary tumor (MMT) mice spontaneously develop breast cancer that expresses human
M
MUC1. Using this model, Mukherjee et al. evaluated the effects of liposomal BLP25, now
ed
known as tecemotide.4 In this study, mice that had been immunized with tecemotide developed MUC1 antigen-specific T-cell responses and CTLs that were cytotoxic in vitro against mouse
pt
breast cancer cells that had been transfected with human MUC1. The T cells that developed in immunized mice expressed intracellular IFN- , consistent with a TH1 immune response, and
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were reactive with an MHC class I MUC1 tetramer. Although immunization with tecemotide generated MUC1-specific CTLs, this did not result in a durable antitumor response.
A
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antigen under the control of its own promoter in a pattern consistent with humans52 was
significantly lower tumor burden at 18 weeks was observed in immunized mice compared to controls; however, no significant differences in tumor burden were seen at 24 weeks. Mukherjee et al. found evidence suggesting that tumor evasion mechanisms may have been responsible. Specifically, the expression of transforming growth factor beta (TGF-
which can create an
immunosuppressive tumor microenvironment,54 was found to increase as tumors progressed, an
11
effect supported by decreasing numbers of T cells expressing interferon gamma (IFN-
. In
addition, the surface expression of MHC class I molecules, required for CTL immune recognition, decreased as tumor burden increased.4 Furthermore, immune tolerance may also have contributed to the lack of significant antitumor effects in this study.52
ip t
The MMT breast cancer model was later used to show that tecemotide combined with
letrozole, an aromatase inhibitor used in the treatment of breast cancer, had additive antitumor
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preclinical study to demonstrate additive antitumor activity and survival benefits following hormonal therapy combined with immunotherapy. Also assessed in this study were the effects of
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tamoxifen combined with tecemotide immunotherapy, but this combination resulted in no added antitumor or survival benefits compared to tamoxifen monotherapy, which was not unexpected
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given previously published results regarding the effects of tamoxifen on immunity.55-59 Mehta et
ed
al. showed that hormonal therapy did not interfere with the immune response to tecemotide and demonstrated a TH1 immune response as well as the generation of CTLs specific for human
pt
MUC1 in their study.32 The antitumor effect of tecemotide was not seen in the study conducted by Mukherjee et al.,4 but the timing of tecemotide immunotherapy may have played a role. It is
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known that cancer specific immunotherapy is most effective with minimal tumor burden.60-62 In the study by Mukherjee et al., tecemotide immunotherapy began at seven weeks of age, when
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effects and significantly increased survival compared to tecemotide alone.32 This was the first
tumors were already detectable, and CPA pretreatment was not employed in that study. When Mehta et al. began tecemotide immunotherapy combined with hormonal therapy after tumors had become established, no significant effects of treatment on tumor burden or survival were noted, in agreement with the results of Mukherjee et al.32
12
Lung Cancer As tecemotide has primarily been evaluated clinically in lung cancer, a human MUC1.Tg, immune intact, lung tumor-bearing mouse model34 has been developed to evaluate the effects of tecemotide in a preclinical or “postclinical” setting to refine the protocols of clinical trials, e.g.
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the Phase III START trial of tecemotide as maintenance therapy following CRT.12 Using the
chemical carcinogen urethane to induce the development of lung tumors, this mouse model was
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After 10 weekly doses of 0.75 mg/g urethane, mice were administered either one or two cycles of tecemotide, each consisting of eight weekly 10-µg doses. Three days prior to the first dose of
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tecemotide in each cycle, each mouse received a single 100-mg/kg dose of CPA as pretreatment. The results showed that pretreatment with CPA potentiated the tecemotide-induced TH1 cytokine
M
responses, and proinflammatory cytokines were increased with distinctive kinetics. Two cycles of tecemotide immunotherapy administered during tumor progression resulted in a significant
ed
reduction in the number of lung tumor foci, whereas single cycle treatment was ineffective.34
pt
Clinically, a primary cycle of tecemotide immunotherapy consisting of eight weekly doses is given, followed by maintenance doses every six weeks until disease progression. In light of the
ce
findings in the preclinical lung cancer mouse model, the continued dosing of tecemotide appears to be necessary.
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developed in human MUC1.Tg C57BL/6 mice and used to assess the efficacy of tecemotide.34
This urethane-induced human MUC1.Tg lung cancer mouse model has also been used in
preliminary studies examining the effects of cisplatin chemotherapy, radiotherapy, and the combination of cisplatin and tecemotide immunotherapy. These studies were designed to lay the groundwork for future studies that will address the optimal timing of CRT and tecemotide immunotherapy.
As detailed below, results of the Phase III START trial revealed some
13
important differences in overall survival in patients who received concurrent CRT followed by tecemotide immunotherapy compared to those who received sequential CRT.12
Preclinical
studies utilizing the lung cancer mouse model developed by Wurz et al.34 showed that the combination of two cycles of tecemotide immunotherapy concurrent with four cycles of cisplatin
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chemotherapy resulted in a significant and additive reduction in the number of lung tumor foci,
with elevated IFN-γ levels and MUC1-specific immune responses. Moreover, neither cisplatin
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relevance of this observed modest reduction in lung tumor foci is unclear, the results of these studies were important in that tecemotide did not interfere with the activity of cisplatin, a key
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first-line chemotherapeutic used in the treatment of NSCLC, and that the immune response to tecemotide was sustained during concurrent radiation treatment.33 Kao et al. recently discussed
Bladder Cancer
ed
CRT followed by tecemotide.35
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the use of this lung tumor model in addressing the differences between concurrent and sequential
pt
A human MUC1.Tg mouse model of invasive transitional cell bladder carcinoma was developed in immune intact C57BL/6 mice for the purpose of immunotherapy development.63 In this
ce
model, bladder cancer is induced using the bladder carcinogen N-butyl-N-(4-hydroxybutyl)nitrosamine (OH-BBN), and the bladder tumors that develop are positive for the expression of human
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nor radiation interfered with the immune response to tecemotide. Although the translational
MUC1. Although not specifically evaluated for antitumor effects in this model, tecemotide treatment resulted in a TH1 polarized serum cytokine profile and a MUC1-specific T cell response as assessed by enzyme-linked immunosorbent spot (ELISpot) immunoassay.63 As bladder cancer, particularly transitional cell carcinoma, is another epithelial cell cancer that expresses MUC1 at a high level,64-66 this disease, where high rates of recurrence are seen despite
14
the best treatments available, is thus a logical candidate for MUC1-targeted immunotherapies such as tecemotide. Clinical Development of Tecemotide The clinical development of tecemotide began in the late 1990s, and the results of the first Phase
ip t
I study were published in 2001. As of July 2013, a total of 14 clinical trials of tecemotide against
a variety of cancers, including NSCLC, prostate cancer, colorectal carcinoma, and breast
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beginning with an early clinical trial of BP16-KLH in breast cancer patients. Research on BP16KLH led to the development of liposome encapsulated MUC1 peptides, culminating in liposomal Completed clinical trials are summarized in Table 1,
an
BLP25, now known as tecemotide.
Early Clinical Development
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whereas Table 2 summarizes all ongoing clinical trials of tecemotide.
ed
Based on the preclinical results seen with BP1-7-KLH (also known as BP16-KLH),37 which is an ASI with MUC1 used as a vaccine construct, a Phase I study was conducted in 16 metastatic
pt
breast cancer patients treated with the BP16-KLH vaccine plus the adjuvant DETOX-B. This vaccine, which was the precursor to tecemotide (BLP25) now in Phase III clinical trials,
ce
employed a synthetic 16-amino acid peptide derived from MUC1 conjugated to KLH as the immunogenic carrier protein. Patients received a total of four 10-µg doses of BP16-KLH by
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carcinoma had been initiated or completed. Results of the published studies are discussed below,
subcutaneous injection. One week prior to the first and third doses, each patient received a single, low dose of CPA (300 mg/m2). The use of CPA is thought to enhance antitumor immunity through increasing DTH humoral and cellular immune responses and inhibiting Tsuppressor function.67 Only three of the 16 patients developed weak anti-MUC1 IgG responses, in contrast to strong IgG antibody responses against KLH in all of the patients. Using PBLs
15
isolated from 11 patients, seven developed HLA class I (HLA-A2, HLA-A1, and HLA-A11)restricted CTL effectors capable of killing MUC1-expressing human breast cancer cell line targets after only a single in vitro stimulation with synthetic BP16 MUC1 peptide. No safety concerns were noted in this study.68
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During the course of early clinical studies with BP16-KLH, development of liposomal
vaccine formulations based on a longer MUC1 peptide (BLP25), which contains epitopes with
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and HLA-A1, was begun in order to provide stronger protection against tumor cell challenge and to increase cellular immune responses.50 The development of BLP25 was built on liposomal
an
BP24, which contains epitopes that bind to HLA class II molecules. The final vaccine product, tecemotide, is comprised of BLP25 lipopeptide encapsulated with MPLA and three different cholesterol,
dimyristoyl
phosphatidylglycerol
M
lipids:
(DMPG)
and
dipalmitoyl
ed
phosphatidylcholine (DPPC) in multilamellar liposomes. Tecemotide is designed to facilitate uptake by APCs such as dendritic cells so that the peptide is processed and presented via class I
response.
ce
Phase I
pt
and class II HLA molecules, thereby eliciting a CTL-mediated MUC1-specific cellular immune
The safety and immunogenicity of two dose levels of tecemotide (20 and 200 µg) were evaluated
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the capacity to bind to several HLA class I molecules including HLA-A11, HLA-A3, HLA-A2.1
in 17 patients with unresectable stage IIIB or IV NSCLC in an uncontrolled Phase I clinical trial.24 In this trial, the 12 patients who completed the treatment protocol received four doses of either 20 µg or 200 µg tecemotide administered in weeks 0, 2, 5, and 9, followed by maintenance vaccinations at 12-week intervals. Three days prior to initiating ASI with tecemotide, each patient received a single dose of CPA 300 mg/m2 (maximum dose 600 mg). Although no
16
antitumor responses were observed, median survival time was 5.4 months in patients receiving 20 μg compared to 14.6 months in patients treated with 200 μg tecemotide, a difference that was not statistically significant due to the small number of patients.
As expected, tecemotide
treatment induced primarily a cellular immune response. Among the 12 evaluable patients, five
ip t
developed CTL responses against MUC1-positive tumor cell lines, and no significant humoral
immune responses were noted in any of the patients. Another five patients out of the 12
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immunotherapy and were not included in the group of patients considered positive for CTL activity following tecemotide immunization. This trial demonstrated that tecemotide can be
an
safely administered and is well tolerated in stage IIIB and stage IV NSCLC patients.24 A second, non-randomized, open-label Phase I study, conducted as part of a Phase I/II
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study, assessed the safety of tecemotide in Japanese patients following primary CRT for stage III
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NSCLC.69 Tecemotide at a dose of 1000 µg was administered by subcutaneous injection weekly for eight weeks, with 1000-µg maintenance doses administered every six weeks thereafter until
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disease progression. Three days prior to the first dose of tecemotide, each patient received a single 300-mg/m2 dose of CPA intravenously. Adverse events considered related to tecemotide
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treatment were arthralgia, myalgia, and nausea. No serious adverse events were observed.69 This trial showed that tecemotide is well tolerated in Japanese NSCLC patients, with a safety
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evaluable were found to have preexisting MUC1-specific CTLs prior to tecemotide
profile consistent with previous clinical trials. The immunogenicity of tecemotide was not studied in this trial.
17
Phase II Following completion of the Phase I safety trial, two early Phase II studies were conducted in previously treated stage IIIB and stage IV NSCLC patients to establish the tecemotide dose and treatment schedule.70 In the first study, performed in eight patients, a higher dose and more
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frequent immunization schedule (1000 µg weekly x 8 weeks) compared to the Phase I study were employed, in addition to maintenance immunizations every six weeks. Compared to baseline
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responses following tecemotide immunization. A MUC1-specific cytokine response was also detected in these six patients, as shown by intracellular tumor necrosis factor alpha (TNF- ).
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Median survival in this trial was 9.6 months.70 In the other early Phase II trial, a total of 18 patients were administered the 1000-µg dose of tecemotide in combination with two different
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doses of liposomal IL-2, an immune modulator. A MUC1-specific T-cell proliferative response
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was seen in two of the 10 patients given the lower dose of IL-2, one of whom had TNF- expressing CD4+ T cells.
Of the eight patients who received the higher dose of IL-2 in
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combination with tecemotide, six showed MUC1-specific T-cell proliferative responses, and four of these six demonstrated TNF- -expressing CD4+ T cells. In this latter early Phase II study,
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median survival was 8.7 months for those patients who received the lower dose of IL-2 and 17.8 months for patients who were given the higher dose of IL-2 in combination with tecemotide.70
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measurements, six of the eight patients showed significant, MUC1-specific T-cell proliferative
Based on the promising results of the two early Phase II studies, a multicenter, open-label, randomized Phase IIB trial was conducted in a total of 171 patients with stage IIIB or stage IV NSCLC.23 Patients were randomized to receive either best supportive care (BSC) (83 patients) or tecemotide plus BSC (88 patients). As in previous clinical studies, patients randomized to the
18
tecemotide arm received a single 300-mg/m2 dose of CPA prior to the first dose of tecemotide. Tecemotide was administered by subcutaneous injection weekly for eight weeks at a dose of 1000 µg spread over four anatomic sites, and then every six weeks thereafter as maintenance therapy. Overall median survival time was 4.4 months longer with tecemotide plus BSC (17.4
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months) compared with BSC alone (13.0 months).23 The greatest difference in median survival
was seen in the subset of patients with stage IIIB locoregional (LR) disease, where median
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Although this difference did not reach the level of statistical significance, it was definitely worthy of further study. Quality of life, as assessed by the Functional Assessment of Cancer
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Therapy-Lung (FACT-L) questionnaire and the Trial Outcome Index (TOI), was maintained longer in patients who received tecemotide compared to those who received only BSC.23 Of the
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88 patients who received tecemotide, T-cell immune responses were assessed in 78. MUC1-
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specific proliferative T-cell responses as a result of tecemotide immunotherapy were observed in 16 patients, only two of whom had stage IIIB LR disease. Among the tecemotide-treated
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patients with a positive T-cell proliferative response, median survival was 27.6 months compared to 16.7 months in those patients with a negative proliferative response.23 In confirmation of the
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initial analysis, an updated survival analysis showed that the overall three-year survival rate was 31% with tecemotide plus BSC compared to 17% with BSC alone. In patients with stage IIIB
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survival was 13.3 months with BSC alone and 30.6 months with tecemotide plus BSC. 22,
LR disease, three-year survival was 49% with tecemotide and 27% with BSC alone, but this difference was not quite statistically significant.22 No significant safety issues were encountered in this study.23 Another open-label Phase II trial in 22 patients with unresectable stage IIIA/IIIB NSCLC evaluated the safety of a new formulation of tecemotide.71 Patient survival was the secondary
19
endpoint of this study. Tecemotide liposomes contain MPLA as the adjuvant, and while this was not changed in the new formulation, changes in the manufacturing process resulted in changes to the MPLA chain composition. The design of this study was as described for the Phase IIB study. Results of this trial showed that the new tecemotide formulation was well tolerated, had a safety
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profile similar to the original formulation,71 and the two-year survival rate was comparable to
that reported by Butts et al. for patients with LR stage IIIB NSCLC.22 The new tecemotide
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A Phase II pilot study of tecemotide in prostate cancer was performed in 16 patients who had experienced prostate specific antigen (PSA) failure following radical prostatectomy.72 All
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patients received CPA pretreatment followed by weekly tecemotide (1000 µg) for eight weeks, followed by tecemotide maintenance dosing every six weeks for up to one year. A total of 15
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patients completed the primary treatment period and 10 completed the maintenance period.
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After eight weeks treatment, eight patients experienced stable or decreased PSA; however, by the end of the maintenance period, only one patient had stable PSA, with all others progressing.
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Interestingly, six of the 15 patients who completed the primary treatment experienced a more than 50% increase in their PSA doubling time compared to their baseline measurements. The
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most common adverse events were nausea, fatigue and injection site reactions. These results suggest that tecemotide may be useful in prolonging PSA doubling time, potentially delaying the start of hormone deprivation therapy in this patient population.72
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formulation was thus considered safe for use in Phase III clinical development.
Phase III
The first Phase III clinical trial of tecemotide, designated START (stimulating targeted antigenic responses to NSCLC), was a randomized, placebo-controlled, double-blind trial conducted in 1,513 patients from 33 different countries.12 The START trial, the results of which were recently
20
published, assessed the safety, efficacy and tolerability of tecemotide in patients with unresectable, locally advanced stage IIIA/IIIB NSCLC who had not progressed after initial concurrent or sequential CRT. Patients were randomized 2:1 to treatment with tecemotide or placebo. Patients assigned to the tecemotide arm received CPA pretreatment (300 mg/m2 to a
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maximum of 600 mg) followed by 806 µg tecemotide weekly for eight weeks and then every six
weeks thereafter until disease progression or withdrawal. A total of 829 tecemotide-treated and
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of tecemotide, including the START trial, were put on hold for enrollment and treatment after a case of encephalitis occurred in a Phase II trial of tecemotide for multiple myeloma. Subsequent
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investigations of this patient, an overall safety analysis of the use of tecemotide in NSCLC, and introduction of safety measures by protocol amendment led to the clinical hold being lifted in
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June 2010. As a result, the sample size of the START trial was adjusted and 274 excluded
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patients were replaced, so that 1,200 patients were needed to observe the anticipated number of events in the modified intention-to-treat (ITT) analyses for efficacy.
The modified ITT
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population did not introduce bias to the statistical analysis. The U.S. FDA under Special Protocol Assistance and several European regulatory authorities approved the amendment and
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modification of the ITT population before the analysis. For a detailed consolidated standards of reporting trials (CONSORT) diagram and description of the population, as well as for details on the clinical hold impact, please refer to the respective recent publication.12 The primary endpoint
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410 placebo-treated patients were included in the efficacy analysis. In March 2010, clinical trials
of overall survival prolongation in patients who received CPA and tecemotide was not significantly different compared to those who received saline and placebo (HR 0.88 [95% CI 0.76-1.03]; p=0.126). However, a favorable effect of tecemotide was observed in a prospectively planned analysis of the predefined subgroup of patients receiving initial concurrent CRT (HR
21
0.78 [95% CI 0.64-0.95]; p=0.016), with a 10.2-month improvement in median overall survival (from 20.6 months to 30.8 months), whereas no survival benefit of tecemotide was seen in the sequential CRT subgroup. The improved OS outcome in patients receiving initial concurrent CRT appeared to be consistent across respective patient subsets.12
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In the START trial, the safety analysis set consisted of 1,024 patients who received
tecemotide, 372 (36%) of whom received it for more than 52 weeks. These analyses confirmed
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differences between tecemotide and placebo for any adverse event reported. Adverse events of special interest such as injection-site reactions or flu-like symptoms were reported to be
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infrequent and rarely greater than grade 2. Potential immune-related diseases or events were seen in less than 3% of patients and with similar frequency in the two groups.12
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While the reason for the difference in survival outcome between concurrent and sequential CRT is unknown, it suggests that the timing of chemotherapy, radiotherapy, and
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tecemotide immunotherapy is important. The studies recently reported by Kao et al.33 have laid
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the groundwork for future studies that will address the optimal timing of CRT and tecemotide immunotherapy as discussed by Kao et al.35 and DeGregorio et al.36 In order to verify the results
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of the START trial showing a significant increase in overall survival in patients receiving concurrent CRT followed by tecemotide, a new Phase III trial (START2) has been initiated to study tecemotide maintenance therapy after concurrent CRT.36
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the favorable safety and tolerability profile of tecemotide. There were no clinically concerning
Ongoing Clinical Trials Phase III The recently initiated pivotal phase III study START273 intends to confirm the results observed
22
in the predefined subset of 806 patients treated with concurrent CRT who experienced improved overall survival (OS; adjusted HR 0.78, 95% CI 0.64–0.95; p=0.016) in the START trial.12 The START2 study is a global, randomized, double-blind, placebo-controlled Phase III trial investigating tecemotide in patients with unresectable stage III NSCLC who did not progress
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after completing first-line concurrent CRT 4-12 weeks before randomization. Concurrent CRT is defined as ≥2 cycles of platinum-based chemotherapy that overlaps with radiotherapy (total
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exclusion criterion. Patients will be stratified by response to CRT (stable disease or objective response) and region (North America and Australia; Western Europe; Rest of World), and
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randomized on a 1:1 basis to tecemotide (806 μg lipopeptide) or placebo. A single dose of CPA (300 mg/m2) or saline will be given i.v. three days prior to the first dose of tecemotide or Eight weekly subcutaneous injections will be administered initially,
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placebo, respectively.
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followed by maintenance injections every six weeks thereafter until disease progression or discontinuation. The primary objective is OS. Secondary objectives are time to symptom
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progression (Lung Cancer Symptom Scale), progression-free survival, time to progression, and safety. Approximately 1,002 patients will be enrolled. Sample size was calculated for a hazard
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ratio of 0.77 corresponding to an increase in median OS from 20 to 26 months in the placebo/tecemotide arm, respectively, a power of 90%, and one-sided significance level of 2.5%.
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tumor dose ≥60 Gy, single fraction dose ≥1.8 Gy); any other therapy for NSCLC constitutes an
The START2 trial will be conducted in more than 20 countries worldwide, excluding Asia. The study started recruiting in 2014.73 While the START and START2 trials have focused on patients with a Caucasian background, parallel studies had been initiated to investigate tecemotide in patients with Asian genetic background. There are currently two ongoing clinical trials of tecemotide in Asian
23
patients with unresectable stage III NSCLC, one Phase II study in Japan69 and one Phase III study in China, Hong Kong, South Korea, Singapore, and Taiwan.25 In both studies, the same treatment regimens used in the START trial are being employed. The tecemotide dose reported for earlier clinical trials was 1000 µg, but patients were found to have actually received about
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930 µg or 806 µg based on an updated density determination of tecemotide prior to lyophilization and the respective applied syringe types for reconstitution. It was decided that the
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subsequent Phase III trial START2. However, the 930-µg dose was maintained unchanged for the Asian trial INSPIRE.25
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The multinational Phase III clinical trial INSPIRE (tecemotide trial in Asian NSCLC patients: stimulating immune response) is designed to assess the efficacy of tecemotide plus
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BSC, compared to placebo plus BSC, on overall survival time in patients of East Asian ethnicity
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with locally advanced, unresectable stage III NSCLC who had documented stable disease or an objective response following completion of primary CRT based on Response Evaluation Criteria Secondary objectives include time to symptom
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in Solid Tumors (RECIST) criteria.25
progression, time to progression, progression-free survival time, time to treatment failure and
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safety. Patients will be randomized 2:1 to treatment with tecemotide plus BSC or placebo plus BSC. The results of the START trial have led to the modification of the INSPIRE trial to exclude sequential therapies and concentrate on concurrent therapy options.36 The projected
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dose actually applied in the Phase III study START (806 µg) would be carried forward into the
enrollment is 420 patients.25 Phase II Several Phase II studies are ongoing in colorectal cancer, rectal cancer, prostate cancer, breast cancer, and lung cancer. In a randomized, double-blind, placebo-controlled Phase II trial (L-
24
BLP25 In Colorectal Cancer, or LICC), a total of 159 patients with stage IV colorectal adenocarcinoma following curative resection of hepatic metastases will be randomized 2:1 to receive treatment with tecemotide or placebo. Tecemotide is being administered at a dose of 930 µg weekly for eight weeks, followed by maintenance dosing every six weeks thereafter for the
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first two years and every 12 weeks in the third year until recurrence. The primary endpoint is recurrence-free survival, and the secondary endpoints are overall survival, safety, and
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In rectal cancer, the multi-center, randomized, three-arm, open-label, Phase II mechanistic trial, designated SPRINT (NCT01507103), is designed to investigate the immune
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response to tecemotide treatment in rectal cancer patients undergoing neoadjuvant CRT.76 The immune response to tecemotide (primary endpoint) will be evaluated based on the local response
In this three-arm study (1:1:1 randomization) 24 subjects per arm receive either
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blood.
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in the tumor and the MUC1- and carcinoembryonic antigen (CEA)-specific response tested in
tecemotide (806 µg weekly for eight weeks) concomitant with standard CRT with or without a
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prior single dose of CPA (300 mg/m2), or standard CRT alone. This study has completed recruitment and results are expected in 2015.76
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In breast cancer, the randomized, two-arm, controlled, open-label Phase-II study
(Austrian Breast & Colorectal Cancer Study Group-34) is investigating tecemotide in the preoperative treatment of women with primary breast cancer.77 A total of 400 patients will
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tolerability.74, 75
receive either standard chemotherapy or standard hormonal therapy, with or without tecemotide. The primary objective is assessment of histopathological response to preoperative standard of care treatment with or without tecemotide immunotherapy when measured by Residual Cancer Burden (RCB0/I versus RCBII/III) at the time of surgery.
25
Secondary objectives include
assessment of pathological complete remission (pCR; an absence of invasive cancer cells in surgical specimen) at the time of surgery, immunological parameters, quality of life and safety.77 Triggered by encouraging Phase I data in prostate cancer, a randomized, controlled Phase II study of tecemotide in combination with standard androgen deprivation therapy (ADT) and
Cancer Institute (NCT01496131).78
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RTX for newly diagnosed, high-risk prostate cancer patients was initiated at the U.S. National
A total of 48 patients will receive RTX/ADT with or
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Secondary outcomes include time to progression, further
immune-related parameters and safety.78
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and six months after radiation).
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immune parameters (change from baseline in the ELISpot level of MUC1-specific T cells at two
In lung cancer, the ongoing Phase II Japanese study mentioned earlier had included 168
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patients with unresectable stage III NSCLC following primary CRT who were randomized 2:1 to
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treatment with either BSC alone or BSC plus tecemotide weekly for eight weeks followed by maintenance dosing every six weeks thereafter until disease progression. More than 90% of
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patients had received concurrent CRT pretreatment. The primary endpoint of this study is overall survival. This event-driven study is in the follow-up phase and results are expected in
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2015.69
Finally, the ongoing open-label, Eastern Cooperative Oncology Group (ECOG) Phase II
study (NCT00828009)79 is investigating the combination of tecemotide and bevacizumab after
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without combined tecemotide treatment (1:1 randomization). Primary outcome will be to assess
CRT in a total of 55 patients with newly diagnosed stage IIIA or stage IIIB unresectable NSCLC. The primary endpoint of this interventional study is to determine the safety of this combination treatment. Secondary endpoints are overall survival and progression-free survival in patients treated with this combination regimen.79
26
Conclusions Tecemotide is liposome-based, antigen-specific cancer immunotherapy designed to elicit a cellular immune response against MUC1, a TAA that is overexpressed and aberrantly glycosylated in epithelial cancers such as lung, breast and prostate cancer. Tecemotide has been
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in clinical development for over 13 years, and clinical trials have shown very promising results
in regard to prolongation of overall survival and improvement in quality of life in patients with
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Phase III clinical trial were disappointing in that overall survival was not significantly increased with tecemotide following primary CRT compared to placebo, a notable survival benefit was
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observed in the predefined subset of patients treated with concurrent CRT followed by tecemotide compared to those patients treated with sequential CRT.
Safety analyses of
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tecemotide studies have revealed an overall favorable safety and tolerability profile. In the START study, as yet the largest controlled study of tecemotide, there were no clinically relevant
ed
differences between tecemotide and placebo observed with respect to safety and tolerability.12 A
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new Phase III trial (START2) will address concurrent CRT regimens followed by tecemotide maintenance therapy, while an ongoing Phase III trial in Asian patients has been modified to
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focus on concurrent CRT options. A number of Phase II clinical trials are ongoing and may provide additional mechanistic insights as well as potential activity signals in indications other
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locally advanced, unresectable stage IIIA/IIIB NSCLC. While results of the first and largest
than lung cancer. Studies utilizing an immune-intact, MUC1 transgenic lung cancer mouse model are currently underway that seek to address the mechanisms underlying the differences between concurrent and sequential CRT so that the optimal timing of chemotherapy, radiotherapy and tecemotide immunotherapy may be defined to achieve the most beneficial treatment outcome for patients.
Tecemotide remains a very promising maintenance
27
immunotherapy for unresectable stage III NSCLC, and the results of ongoing Phase III trials are eagerly awaited. Tecemotide may also prove to be useful in the treatment of many other types of cancer, including breast, prostate, rectal and colorectal carcinoma, for which Phase II clinical trials are currently ongoing.
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Acknowledgments
The authors would like to thank Drs. Martin Picard, Christoph Bogedain, Samir Henni, Martin
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Conflicts of Interest
GTW and CJK declare no conflicts. MW is an employee of Merck KGaA, and MWD is
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principal investigator of a research grant received from Merck KGaA.
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Falk, and Christoph Helwig of Merck KGaA for their critical review of the manuscript.
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Longenecker BM. Anti-MUC1 class I restricted CTLs in metastatic breast cancer patients
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immunized with a synthetic MUC1 peptide. Int J Cancer 1998; 76:817-23. 69. Ohyanagi F, Horai T, Sekine I, Yamamoto N, Nakagawa K, Nishio M, Senger S, Morsli N,
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Tamura T. Safety of BLP25 liposome vaccine (L-BLP25) in Japanese patients with unresectable stage III NSCLC after primary chemoradiotherapy: preliminary results from a
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Phase I/II study. Jpn J Clin Oncol 2011; 41:718-22. 70. North S, Butts C. Vaccination with BLP25 liposome vaccine to treat non-small cell lung and
ce
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prostate cancers. Expert Rev Vaccines 2005; 4:249-57. 71. Butts C, Murray RN, Smith CJ, Ellis PM, Jasas K, Maksymiuk A, Goss G, Ely G, Beier F, Soulieres D. A multicenter open-label study to assess the safety of a new formulation of
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68. Reddish M, MacLean GD, Koganty RR, Kan-Mitchell J, Jones V, Mitchell MS,
BLP25 liposome vaccine in patients with unresectable stage III non-small-cell lung cancer. Clin Lung Cancer 2010; 11:391-5.
72. North SA, Graham K, Bodnar D, Venner P. A pilot study of the liposomal MUC1 vaccine BLP25 in prostate specific antigen failures after radical prostatectomy. J Urol 2006; 176:915.
39
73. Ramalingam S, Mitchell P, Vansteenkiste J, Debus J, Curran W, Socinski MA, Helwig C, Falk M, Butts C. START2: Tecemotide in unresectable stage III NSCLC after first-line concurrent chemoradiotherapy. Abstract TPS7608. 50th Annual Meeting of the American Society of Clinical Oncology May 30-June 3, 2014. Chicago, Illinois: American Society of
ip t
Clinical Oncology, 2014.
cr
us
Becker S, von Wichert G, Vohringer M, Heike M, et al. LICC: L-BLP25 in patients with colorectal carcinoma after curative resection of hepatic metastases: a randomized, placebo-
an
controlled, multicenter, multinational, double-blinded phase II trial. BMC Cancer 2012; 12:144.
M
75. Kasper S. A randomized, double-blind, placebo-controlled, multicenter, binational, phase II trial of immunotherapy with L-BLP25 (tecemotide) in patients with colorectal carcinoma
ed
following R0/R1 hepatic metastasectomy. Abstract TPS3658. 50th Annual Meeting of the
pt
American Society of Clinical Oncology. Chicago, Illinois: American Society of Clinical
ce
Oncology, 2014. 76. NIH.
Tecemotide
(L-BLP25)
in
Rectal
Cancer
(SPRINT)
NCT01507103.
http://www.clinicaltrials.gov/ct2/show/NCT01507103?term=NCT01507103&rank=1.
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74. Schimanski CC, Mohler M, Schon M, van Cutsem E, Greil R, Bechstein WO, Hegewisch-
ClinicalTrials.gov. May 30, 2014.
77. ICTRP. An open, randomized, phase-II study of a therapeutic cancer vaccine (L-BLP25, Stimuvax®) in the pre-operative treatment of women with primary breast cancer. http://apps.who.int/trialsearch/Trial.aspx?TrialID=EUCTR2011-004822-85-AT. International Clinical Trials Registry Platform. May 30, 2014.
40
78. NIH.
L-BLP25
(Stimuvax)
in
Prostate
Cancer
NCT01496131.
http://www.clinicaltrials.gov/ct2/show/NCT01496131?term=NCT01496131&rank=1. ClinicalTrials.gov. May 30, 2014.
ip t
79. NIH. BLP25 Liposome Vaccine and Bevacizumab after Chemotherapy and Radiation Therapy in Treating Patients with Newly Diagnosed Stage IIIA or Stage IIIB Non-Small Cancer
that
cannot
be
Removed
by
Surgery
NCT00828009.
cr
Lung
us
http://www.clinicaltrials.gov/ct2/show/NCT00828009?term=NCT00828009&rank=1.
ce
pt
ed
M
an
ClinicalTrials.gov. May 30, 2014.
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Cell
41
Table 1. Completed Clinical Trials of Tecemotide
Phase l randomized open-label safety and dose comparison study.
17
24
8
70
ip t
Phase II open-label safety and immunogenicity study. Phase II open-label, dose-escalation study to determine safety and immunogenicity of tecemotide in combination with liposomal IL-2.
70
cr
18
Phase IIB open-label, randomized study to test safety and efficacy of tecemtotide plus BSC compared to BSC alone.
171
22, 23
22
71
1513
12
16
72
34
In preparation
us
an
Phase II open-label study to assess safety of tecemotide made with a new formulation of the immunoadjuvant MPL®.
A multicenter randomized double-blind placebo-controlled Phase III trial of tecemotide versus placebo in patients with unresectable stage III NSCLC. Phase II open-label trial to test safety and efficacy of tecemotide in patients with rising PSA values following radical prostatectomy. Phase II open-label, dose-escalation study to determine safety and efficacy of L-BLP25 in multiple myeloma, either chemotherapy naïve, slowly progressive and asymptomatic or with stage II/III in stable response/plateau following antitumor therapy.
ce
pt
NCT01094548 EMR 63325-008 Multiple myeloma
Reference
M
EMR 63325-007 Prostate cancer
Patients Enrolled
ed
EMR 63325-002 Stage IIIB or IV NSCLC EMR 63325-003 Stage IIIB or IV NSCLC EMR 63325-004 Stage IIIB or IV NSCLC NCT00157209 EMR 63325-005 Stage IIIB or IV NSCLC NCT00157196 EMR 63325-006 Unresectable stage III NSCLC NCT00409188 EMR 63325-001 (START) Unresectable stage III NSCLC
Description
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Study Identifier Indication
42
Table 2. Ongoing Clinical Trials of Tecemotide. Description
Patients Planned
Reference
Closed to enrollment
Combined Phase I/II study in Japanese subjects with stage III unresectable NSCLC following primary chemotherapy.
205
69
Open to enrollment*
Phase II study of tecemotide and bevacizumab in unresectable stage IIIA and IIIB NSCLC after definitive CRT.
Open to enrollment*
cr
55
420
us
Open to enrollment*
Phase III clinical trial of tecemotide in Asian subjects with stage III, unresectable, NSCLC who have demonstrated either stable disease or objective response following primary CRT. A multicenter randomized double-blind placebo-controlled Phase III trial of tecemotide versus placebo in patients with completed concurrent CRT for unresectable stage III NSCLC.
ip t
Status
79
25, 36
73
262
—
124
76
48
78
159
74, 75
Open to enrollment*
400
77
Open to enrollment*
Open to enrollment*
ce
NCT01462513 EMR 63325-602 (LICC) Colorectal cancer EMR 63325-603 (ABCSG 34) Breast cancer
M
Closed to enrollment*
Open label trial to collect long-term data on subjects who have received tecemotide in previous clinical trials. Multi-center, randomized, open-label, mechanistic trial of the biological effects of tecemotide in rectal cancer subjects undergoing neoadjuvant CRT. A randomized Phase II study of tecemotide in combination with standard ADT and RTX for newly diagnosed, high-risk prostate cancer. Multicenter, multinational, randomized (2:1), double-blind, placebo-controlled Phase II trial in colorectal carcinoma after curative resection of hepatic metastases. Multicenter, randomized (1:1), open label, 2-arm trial in the pre-operative treatment of women with primary breast cancer.
ed
NCT01496131 EMR 63325-015 Prostate cancer
Enrollment on invitation
an
1002
pt
NCT00960115 EMR 63325-009 Unresectable stage III NSCLC NCT00828009 EMR 63325-600 (ECOG 6508) Unresectable stage III NSCLC NCT01015443 EMR 63325-012 (INSPIRE) Unresectable stage III NSCLC NCT02049151 EMR 63325-021 (START2) Unresectable stage III NSCLC NCT01423760 EMR 63325-011 Tumor type as per feeder trial NCT01507103 EMR 63325-013 (SPRINT) Rectal cancer
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Study Identifier Indication
*as of June 2014.
43
Human Vaccines & Immunotherapeutics Publication details, including instructions for authors and subscription information: http://www.tandfonline.com/loi/khvi20
Tecemotide: An antigen-specific cancer immunotherapy a
a
b
Gregory T. Wurz , Chiao-Jung Kao , Michael Wolf & Michael W. DeGregorio
a
a
University of California, Davis, Department of Internal Medicine, Division of Hematology and Oncology, Sacramento, CA 95817 USA b
Department of ImmunoOncology, Merck Serono Research, Merck KGaA, Darmstadt, Germany Accepted author version posted online: 01 Nov 2014.
Click for updates To cite this article: Gregory T. Wurz, Chiao-Jung Kao, Michael Wolf & Michael W. DeGregorio (2014): Tecemotide: An antigenspecific cancer immunotherapy, Human Vaccines & Immunotherapeutics, DOI: 10.4161/hv.29836 To link to this article: http://dx.doi.org/10.4161/hv.29836
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Tecemotide: An Antigen-Specific Cancer Immunotherapy Gregory T. Wurz1, Chiao-Jung Kao1, Michael Wolf2, Michael W. DeGregorio1* 1
University of California, Davis, Department of Internal Medicine, Division of Hematology and
Oncology, Sacramento, CA 95817 USA. Department of ImmunoOncology, Merck Serono Research, Merck KGaA, Darmstadt, Germany.
Keywords:
ip t
2
Tecemotide; MUC1; Non-Small Cell Lung Cancer; Immunotherapy; Chemo-
cr us
*To whom correspondence should be addressed:
Dr. Michael W. DeGregorio, Professor of Medicine, University of California, Davis, Department
an
of Internal Medicine, Division of Hematology and Oncology, 4501 X Street Suite 3016, Sacramento, CA 95817 USA, E-mail: [email protected]
ADT
Androgen deprivation therapy
APC
ed
M
Abbreviations
Antigen presenting cell
BSC
CI
Best supportive care Carcinoembryonic antigen
ce
CEA
Active specific immunotherapy
pt
ASI
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radiotherapy.
Confidence interval
CONSORT
Consolidated standards of reporting trials
CPA
Cyclophosphamide
CRT
Chemoradiotherapy
CTL
Cytotoxic T-lymphocyte
DMPG
Dimyristoyl phosphatidylglycerol
1
DTH
Delayed-type hypersensitivity
ECOG
Eastern cooperative oncology group
ELISpot
Enzyme-linked immunosorbent spot
FACT-L
Functional assessment of cancer therapy-lung
Gy
Gray
HLA
Human lymphocyte antigen
HR
Hazard ratio
IFN-
Interferon gamma
IgG
Immunoglobulin G
IL-2
Interleukin 2
INSPIRE
Stimuvax trial in Asian NSCLC patients: stimulating immune response
ITT
Intent to treat
i.v.
ed
cr us
pt
Keyhole limpet hemocyanin L-BLP25 in colorectal cancer Locoregional
ce
LICC LR
an
M
Intravenous
KLH
MAP
ip t
Dipalmitoyl phosphatidylcholine
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DPPC
Multiple antigenic peptide
MHC
Major histocompatibility complex
MMT
MUC1-expressing mammary tumor
MPLA
Monophosphoryl lipid A
MUC1
Mucin 1
MUC1.Tg
MUC1 transgenic
2
OH-BBN
N-butyl-N-(4-hydroxybutyl)nitrosamine
OS
Overall survival
PBL
Peripheral blood lymphocytes
PCR
Pathological complete remission
PSA
Prostate specific antigen
PyV-mT
Polyomavirus middle-T
QOL
Quality of life
RCB
Residual cancer burden
RECIST
Response evaluation criteria in solid tumors
RTX
Radiotherapy
START
Stimulating targeted antigenic responses to NSCLC
TAA
Tumor associated antigen
TGF-
ed
M
an
us
cr
ip t
Non-small cell lung cancer
Transforming growth factor beta T-helper type I
TH2
pt
TH1
T-helper type II Tumor necrosis factor alpha
ce
TNFTOI
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NSCLC
VNTR
Trial outcome index Variable number of tandem repeats
Abstract
The identification of tumor-associated antigens (TAA) has made possible the development of antigen-specific cancer immunotherapies such as tecemotide. One of those is mucin 1 (MUC1), a cell membrane glycoprotein expressed on some epithelial tissues such as breast and lung. In
3
cancer, MUC1 becomes overexpressed and aberrantly glycosylated, exposing the immunogenic tandem repeat units in the extracellular domain of MUC1. Designed to target tumor associated MUC1, tecemotide is being evaluated in Phase III clinical trials for treatment of unresectable stage IIIA/IIIB non-small cell lung cancer (NSCLC) as maintenance therapy following
ip t
chemoradiotherapy. Additional Phase II studies in other indications are ongoing. This review discusses the preclinical and clinical development of tecemotide, ongoing preclinical studies of
cr
us
potential application of these models for optimizing the timing of chemoradiotherapy and
an
tecemotide immunotherapy to achieve the best treatment outcome for patients.
Introduction
M
The development of antigen-specific cancer immunotherapies has been made possible by the identification of tumor-associated antigens (TAA), of which a vast number have now been
ed
discovered.1, 2 One of the best characterized TAAs is mucin 1 (MUC1), which is overexpressed
pt
and aberrantly glycosylated in over 90% of adenocarcinomas such as breast and lung cancer.3, 4 While MUC1 is a self-antigen expressed in a number of different epithelial tissues, the normal
ce
glycosylation pattern shields the peptide core from immune surveillance.
The aberrant
underglycosylation of MUC1 in cancer leads to the exposure of the immunogenic tandem repeat regions of the core peptide, which had made MUC1 an attractive target for immunotherapies.2, 5-8
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tecemotide in human MUC1 transgenic mouse models of breast and lung cancer, and the
Both cellular and humoral immune responses to MUC1 have been observed in many patients with lung, breast and other adenocarcinomas, but the native immune response is insufficient in controlling tumor growth, which is due to existing tolerance and the development of multiple mechanisms of immune evasion.4, 9-11 Tecemotide, a MUC1-specific cancer immunotherapy, is
4
currently being evaluated in Phase III clinical trials as maintenance therapy following chemoradiotherapy (CRT) for the treatment of unresectable stage IIIA/IIIB non-small cell lung cancer (NSCLC).
Recently published clinical trials results suggest that the timing of
chemotherapy, radiation, and tecemotide immunotherapy is important with respect to treatment
ip t
outcome.12
Tecemotide, formerly known as L-BLP25 or Stimuvax®, has been developed for the treatment of
cr
us
family. Tecemotide is designed to elicit an antigen-specific cellular immune response against MUC1, which was one of the first TAAs identified by human tumor-specific T-cells.8 It is
of
aberrantly
glycosylated,
an
broadly distributed on the apical surface of most simple epithelial tissues, but strong expression tumor-associated
MUC1
has
been
observed
in
most
M
adenocarcinomas, including lung, breast, stomach, pancreas, colon, prostate, and ovary as well as hematological malignancies such as multiple myeloma. On tumor cells polarity is lost and
ed
MUC1 is expressed on the entire cell surface.13 The extracellular domain of MUC1 consists of a
pt
variable number of tandem repeats (VNTR) of a characteristic 20-amino acid sequence (PDTRPAPGSTAPPAHGVTSA) that is aberrantly glycosylated in tumor tissues.14-17
The
ce
resulting underglycosylation of MUC1 facilitates peptide processing and loading onto human lymphocyte antigen (HLA) molecules, which results in the exposure of a novel and large epitope
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adenocarcinomas that express MUC1, a member of the membrane-bound O-glycoprotein mucin
repertoire bound to HLA molecules that can be recognized by MUC1-specific cytotoxic Tlymphocytes (CTLs).18, 19 It has been shown that immunization of cancer patients with MUC1 peptides results in the generation of both anti-MUC1 antibodies and CTL responses.20
In
addition, MUC1 was found to be expressed on activated T cells, exhibiting both immunostimulatory and immunosuppressive functions.21 Several MUC1-based immunotherapy
5
approaches such as tecemotide,12, 22-25 TG4010,26-28 and PANVAC™,29-31 have been evaluated in clinical trials for a variety of malignancies including NSCLC, metastatic breast cancer, renal cell carcinoma, ovarian cancer and metastatic colorectal carcinoma. The purpose of this review is to discuss the preclinical and clinical development of
ip t
tecemotide and to highlight ongoing research in human MUC1 transgenic mouse models of breast32 and lung cancer33, 34 that are being utilized with the goal of optimizing the timing of
cr
us
for patients.35 As there are presently no effective maintenance therapies for stage III NSCLC
overall treatment outcomes.36 Preclinical Development of Tecemotide
M
BP16
an
following CRT, immunotherapies such as tecemotide offer a potential method of improving
ed
Early preclinical research into the development of MUC1 immunotherapy strategies was conducted using various synthetic peptides from the tandem repeat region of the MUC1 core
pt
peptide.37 Mice were immunized with peptides of various lengths conjugated to either dendritic multiple antigenic peptide (MAP-4) or keyhole limpet hemocyanin (KLH) as a carrier molecule
ce
and using DETOX, which contains monophosphoryl lipid A (MPLA) and mycobacterial cell wall, as an adjuvant. Each of the peptides tested contained the B and T cell epitope PDTRP in
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chemotherapy, radiation, and tecemotide immunotherapy to achieve the best treatment outcome
various configurations, along with portions of the 20-amino acid sequence from the MUC1 tandem repeat region. The SP1-16 peptide additionally contained two MUC1 tandem repeats plus a universal T-cell epitope from tetanus toxin. Following immunization, antibody, delayed type hypersensitivity (DTH), and antitumor responses were evaluated. To assess DTH and antitumor responses, immunized mice were challenged with 410.4 mouse mammary tumor cells
6
that had been transfected with human MUC1.38 Delayed type hypersensitivity responses were also assessed by peptide challenge in immunized mice.
The results showed that peptides
conjugated to either KLH (SP1-7-KLH) or MAP-4 (SP1-5 and SP1-6) proved to be the most immunogenic.37
The SP1-6 peptide additionally contained a 19-amino acid sequence
ip t
(EKKIAKMEKASSVFNVVNS) from the CST-3 peptide of Plasmodium falciparum, which is a universal T-helper epitope.
cr
us
only in response to challenge with the same or similar peptide, which shows specificity of response. When challenged with mammary tumor cells, immunized mice had DTH responses
an
only when injected with cells that had been transfected with human MUC1. The antitumor effects of these peptides were evaluated in both preventive (immunization) and treatment (active
M
specific immunotherapy or ASI) settings. Whether used prophylactically or as ASI, significant tumor growth inhibition was seen with the MAP-4 conjugated peptides and the KLH-conjugated
ed
peptide SP1-7, a 16-mer (GVTSAPDTRPAPGSTA), in particular.37 Active specific
pt
immunotherapy with the three most promising peptides in this study, SP1-5, a 22-mer (APDTRPAPGSTAPPAHGVTSAP-MAP4), SP1-6, an 8-mer (SAPDTRPA-CST-MAP4) and
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SP1-7-KLH, was most effective when mice were pretreated with cyclophosphamide (CPA), which is thought to reduce the number and immunosuppressive functionality of T-regulatory cells,39-43 thereby augmenting the response to immunotherapy.44, 45 Some interesting differences
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Mice that had been immunized displayed DTH reactions, indicative of cellular immunity,
were observed in this study with respect to immune response. Peptides that induced strong antibody and DTH responses were inferior with respect to antitumor effects compared to those that were poor inducers of antibody response. This result is consistent with the hypothesis that
7
for an effective antitumor response, a TH1 or cellular immune response is superior to a TH2 or humoral antibody immune response.37 BP24 Based on the results obtained with the SP1-7 peptide (BP16) by Ding et al. in 1993, additional
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studies were performed using a newer peptide, BP24 (TAPPAHGVTSAPDTRPAPGSTAPP),
which was synthesized to include additional T-cell epitopes compared to BP16.46 Because there
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and MUC1 is highly expressed in breast cancer, Agrawal et al. evaluated the proliferation of peripheral blood lymphocytes (PBL) from men and multiparous and nulliparous women in 48
These investigators found that CD4+ T cells from
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response to exposure to BP24.47,
multiparous women, but not nulliparous women or men, proliferated specifically in response to
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BP24 as well as BP16, the sequence of which is contained within BP24.
No significant
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proliferation was noted in response to a negative control peptide. Proliferative responses were noted in the lymphocytes from several different HLA types in an MHC class II-restricted
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fashion.47 In a follow-up experiment using T lymphocyte cell lines established from the PBLs of multiparious donors, MUC1-specific MHC class I-restricted CTLs were induced by stimulation
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with autologous antigen-presenting cells (APCs) that had been loaded with BP24 peptide.48 This result is consistent with Domenech et al., who showed MHC class I-restricted binding of a nine amino acid peptide (STAPPAHGV) to HLA-A1, HLA-A2.1, HLA-A3 and HLA-A11,49 although
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is strong evidence suggesting that multiple pregnancies provide protection against breast cancer,
BP24 does not fully contain this peptide sequence. This latter experiment was performed under conditions that favored peptide binding to MHC class I molecules, whereas conditions in the earlier study favored MHC class II binding, and no CTL response was observed.47
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Liposomal BP24 In order to improve cellular or TH1 type immune responses, the BP24 peptide was prepared in a liposomal formulation, using MPLA as the adjuvant, and then evaluated for immunogenicity and antitumor activity.46 Compared to BP16-KLH, the immune response to liposomal BP24 was
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predominantly TH1, as assessed by immunizing non-tumor-bearing mice. Mice treated with
BP16-KLH showed a much stronger IgG antibody response compared to the BP24-treated mice,
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antitumor activity of liposomal BP24 was evaluated in intravenous, subcutaneous and artificial metastasis tumor models using a human MUC1 transfected mouse mammary carcinoma cell line
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(410.4). Following intravenous tumor challenge after immunization, mice treated with liposomal BP24 survived significantly longer and formed significantly fewer lung metastases.
Mice
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immunized with liposomal BP24 showed complete protection following subcutaneous tumor
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challenge with MUC1 transfected cells, while immunization provided no protection against nontransfected cells, indicating specificity of immune response. The artificial metastasis model
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showed that BP24 immunization again showed complete protection with respect to the formation of lung tumor foci. When used as ASI, BP24-treated mice developed far fewer lung tumor foci
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compared to control mice or mice treated with empty liposomes containing MPLA. Results of cytokine and antibody analyses in tumor-bearing mice were consistent with a TH1-polarized immune response.46
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suggesting a poorer CTL cellular immune response to the KLH-conjugated peptide.
Liposomal BLP25 To further augment the MUC1 immune response, a serine residue was added to BP24, yielding BP25 (STAPPAHGVTSAPDTRPAPGSTAPP), also known as BLP25.50,
51
This synthetic
MUC1 peptide was synthesized to introduce HLA class I epitopes49 to complement the HLA
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class II epitopes that had already been demonstrated for the MUC1 peptide BP24, the sequence of which is completely contained within BP25.47 The first experiments with liposomal BP25 (BLP25) examined the generation of MUC1-specific CD4+ and CD8+ T-cell responses in vitro in unprimed lymphocytes from the PBL of human donors.50 T cells cultured in the presence of
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autologous APCs pulsed with liposome-encapsulated BLP25 showed marked proliferation
compared to those cultured with APCs that had been pulsed with soluble BLP25. When T-cell
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to liposomal BLP25, with weak responses to liposomal BLP24 and soluble BLP25 and BP24. These lymphocyte responses were found to be TH1 type based on increased IFN-
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minimal IL-4. The lymphocyte subtypes proliferating in response to BLP25 were identified as CD4+ and CD8+ T cells based on flow cytometric analysis and the lack of proliferation in the
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presence of anti-CD4 and anti-CD8 antibodies. The T cells stimulated by autologous APCs pulsed with BLP25 were able to lyse targets pulsed with HLA class I 9-mer MUC1 peptide
ed
epitopes, confirming cytotoxic activity.50
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As pointed out above, early studies performed by Agrawal et al. on liposomal BLP25 showed that T cells cultured with autologous APCs pulsed with liposomal BLP25 showed
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marked proliferation compared to T cells cultured with APCs pulsed with soluble BLP25.50 This finding is consistent with the results of a study by Guan et al. that showed physical association of
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proliferation was assessed for antigen specificity, T cells proliferated most strongly in response
the peptide with liposomes, either through encapsulation or surface exposure, is required for a Tcell proliferative response. Peptide alone or peptide combined with empty liposomes failed to elicit an antigen-specific T-cell response in immunized mice.51 This study also found that the nature of the physical association had a significant effect on the humoral immune response to the BLP25 peptide. Compared to liposomal BLP25, only those mice that were immunized with
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surface-exposed peptide liposomes developed MUC1-specific antibodies, which suggests that different liposome formulations can produce different immune responses.51
Tecemotide in Transgenic Tumor-Bearing Mouse Models
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Breast Cancer
An immune-intact transgenic breast cancer mouse model that expresses human MUC1 as a self-
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developed to study MUC1-specific immunotherapy.4 To develop this model, MUC1 transgenic (MUC1.Tg) C57BL/6 mice52 were crossed with mice transgenic for polyomavirus middle T
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(PyV-mT) driven by the MMTV promoter.53 The resulting double transgenic MUC1-expressing mammary tumor (MMT) mice spontaneously develop breast cancer that expresses human
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MUC1. Using this model, Mukherjee et al. evaluated the effects of liposomal BLP25, now
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known as tecemotide.4 In this study, mice that had been immunized with tecemotide developed MUC1 antigen-specific T-cell responses and CTLs that were cytotoxic in vitro against mouse
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breast cancer cells that had been transfected with human MUC1. The T cells that developed in immunized mice expressed intracellular IFN- , consistent with a TH1 immune response, and
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were reactive with an MHC class I MUC1 tetramer. Although immunization with tecemotide generated MUC1-specific CTLs, this did not result in a durable antitumor response.
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antigen under the control of its own promoter in a pattern consistent with humans52 was
significantly lower tumor burden at 18 weeks was observed in immunized mice compared to controls; however, no significant differences in tumor burden were seen at 24 weeks. Mukherjee et al. found evidence suggesting that tumor evasion mechanisms may have been responsible. Specifically, the expression of transforming growth factor beta (TGF-
which can create an
immunosuppressive tumor microenvironment,54 was found to increase as tumors progressed, an
11
effect supported by decreasing numbers of T cells expressing interferon gamma (IFN-
. In
addition, the surface expression of MHC class I molecules, required for CTL immune recognition, decreased as tumor burden increased.4 Furthermore, immune tolerance may also have contributed to the lack of significant antitumor effects in this study.52
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The MMT breast cancer model was later used to show that tecemotide combined with
letrozole, an aromatase inhibitor used in the treatment of breast cancer, had additive antitumor
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preclinical study to demonstrate additive antitumor activity and survival benefits following hormonal therapy combined with immunotherapy. Also assessed in this study were the effects of
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tamoxifen combined with tecemotide immunotherapy, but this combination resulted in no added antitumor or survival benefits compared to tamoxifen monotherapy, which was not unexpected
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given previously published results regarding the effects of tamoxifen on immunity.55-59 Mehta et
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al. showed that hormonal therapy did not interfere with the immune response to tecemotide and demonstrated a TH1 immune response as well as the generation of CTLs specific for human
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MUC1 in their study.32 The antitumor effect of tecemotide was not seen in the study conducted by Mukherjee et al.,4 but the timing of tecemotide immunotherapy may have played a role. It is
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known that cancer specific immunotherapy is most effective with minimal tumor burden.60-62 In the study by Mukherjee et al., tecemotide immunotherapy began at seven weeks of age, when
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effects and significantly increased survival compared to tecemotide alone.32 This was the first
tumors were already detectable, and CPA pretreatment was not employed in that study. When Mehta et al. began tecemotide immunotherapy combined with hormonal therapy after tumors had become established, no significant effects of treatment on tumor burden or survival were noted, in agreement with the results of Mukherjee et al.32
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Lung Cancer As tecemotide has primarily been evaluated clinically in lung cancer, a human MUC1.Tg, immune intact, lung tumor-bearing mouse model34 has been developed to evaluate the effects of tecemotide in a preclinical or “postclinical” setting to refine the protocols of clinical trials, e.g.
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the Phase III START trial of tecemotide as maintenance therapy following CRT.12 Using the
chemical carcinogen urethane to induce the development of lung tumors, this mouse model was
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After 10 weekly doses of 0.75 mg/g urethane, mice were administered either one or two cycles of tecemotide, each consisting of eight weekly 10-µg doses. Three days prior to the first dose of
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tecemotide in each cycle, each mouse received a single 100-mg/kg dose of CPA as pretreatment. The results showed that pretreatment with CPA potentiated the tecemotide-induced TH1 cytokine
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responses, and proinflammatory cytokines were increased with distinctive kinetics. Two cycles of tecemotide immunotherapy administered during tumor progression resulted in a significant
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reduction in the number of lung tumor foci, whereas single cycle treatment was ineffective.34
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Clinically, a primary cycle of tecemotide immunotherapy consisting of eight weekly doses is given, followed by maintenance doses every six weeks until disease progression. In light of the
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findings in the preclinical lung cancer mouse model, the continued dosing of tecemotide appears to be necessary.
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developed in human MUC1.Tg C57BL/6 mice and used to assess the efficacy of tecemotide.34
This urethane-induced human MUC1.Tg lung cancer mouse model has also been used in
preliminary studies examining the effects of cisplatin chemotherapy, radiotherapy, and the combination of cisplatin and tecemotide immunotherapy. These studies were designed to lay the groundwork for future studies that will address the optimal timing of CRT and tecemotide immunotherapy.
As detailed below, results of the Phase III START trial revealed some
13
important differences in overall survival in patients who received concurrent CRT followed by tecemotide immunotherapy compared to those who received sequential CRT.12
Preclinical
studies utilizing the lung cancer mouse model developed by Wurz et al.34 showed that the combination of two cycles of tecemotide immunotherapy concurrent with four cycles of cisplatin
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chemotherapy resulted in a significant and additive reduction in the number of lung tumor foci,
with elevated IFN-γ levels and MUC1-specific immune responses. Moreover, neither cisplatin
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relevance of this observed modest reduction in lung tumor foci is unclear, the results of these studies were important in that tecemotide did not interfere with the activity of cisplatin, a key
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first-line chemotherapeutic used in the treatment of NSCLC, and that the immune response to tecemotide was sustained during concurrent radiation treatment.33 Kao et al. recently discussed
Bladder Cancer
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CRT followed by tecemotide.35
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the use of this lung tumor model in addressing the differences between concurrent and sequential
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A human MUC1.Tg mouse model of invasive transitional cell bladder carcinoma was developed in immune intact C57BL/6 mice for the purpose of immunotherapy development.63 In this
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model, bladder cancer is induced using the bladder carcinogen N-butyl-N-(4-hydroxybutyl)nitrosamine (OH-BBN), and the bladder tumors that develop are positive for the expression of human
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nor radiation interfered with the immune response to tecemotide. Although the translational
MUC1. Although not specifically evaluated for antitumor effects in this model, tecemotide treatment resulted in a TH1 polarized serum cytokine profile and a MUC1-specific T cell response as assessed by enzyme-linked immunosorbent spot (ELISpot) immunoassay.63 As bladder cancer, particularly transitional cell carcinoma, is another epithelial cell cancer that expresses MUC1 at a high level,64-66 this disease, where high rates of recurrence are seen despite
14
the best treatments available, is thus a logical candidate for MUC1-targeted immunotherapies such as tecemotide. Clinical Development of Tecemotide The clinical development of tecemotide began in the late 1990s, and the results of the first Phase
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I study were published in 2001. As of July 2013, a total of 14 clinical trials of tecemotide against
a variety of cancers, including NSCLC, prostate cancer, colorectal carcinoma, and breast
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beginning with an early clinical trial of BP16-KLH in breast cancer patients. Research on BP16KLH led to the development of liposome encapsulated MUC1 peptides, culminating in liposomal Completed clinical trials are summarized in Table 1,
an
BLP25, now known as tecemotide.
Early Clinical Development
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whereas Table 2 summarizes all ongoing clinical trials of tecemotide.
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Based on the preclinical results seen with BP1-7-KLH (also known as BP16-KLH),37 which is an ASI with MUC1 used as a vaccine construct, a Phase I study was conducted in 16 metastatic
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breast cancer patients treated with the BP16-KLH vaccine plus the adjuvant DETOX-B. This vaccine, which was the precursor to tecemotide (BLP25) now in Phase III clinical trials,
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employed a synthetic 16-amino acid peptide derived from MUC1 conjugated to KLH as the immunogenic carrier protein. Patients received a total of four 10-µg doses of BP16-KLH by
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carcinoma had been initiated or completed. Results of the published studies are discussed below,
subcutaneous injection. One week prior to the first and third doses, each patient received a single, low dose of CPA (300 mg/m2). The use of CPA is thought to enhance antitumor immunity through increasing DTH humoral and cellular immune responses and inhibiting Tsuppressor function.67 Only three of the 16 patients developed weak anti-MUC1 IgG responses, in contrast to strong IgG antibody responses against KLH in all of the patients. Using PBLs
15
isolated from 11 patients, seven developed HLA class I (HLA-A2, HLA-A1, and HLA-A11)restricted CTL effectors capable of killing MUC1-expressing human breast cancer cell line targets after only a single in vitro stimulation with synthetic BP16 MUC1 peptide. No safety concerns were noted in this study.68
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During the course of early clinical studies with BP16-KLH, development of liposomal
vaccine formulations based on a longer MUC1 peptide (BLP25), which contains epitopes with
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and HLA-A1, was begun in order to provide stronger protection against tumor cell challenge and to increase cellular immune responses.50 The development of BLP25 was built on liposomal
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BP24, which contains epitopes that bind to HLA class II molecules. The final vaccine product, tecemotide, is comprised of BLP25 lipopeptide encapsulated with MPLA and three different cholesterol,
dimyristoyl
phosphatidylglycerol
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lipids:
(DMPG)
and
dipalmitoyl
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phosphatidylcholine (DPPC) in multilamellar liposomes. Tecemotide is designed to facilitate uptake by APCs such as dendritic cells so that the peptide is processed and presented via class I
response.
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Phase I
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and class II HLA molecules, thereby eliciting a CTL-mediated MUC1-specific cellular immune
The safety and immunogenicity of two dose levels of tecemotide (20 and 200 µg) were evaluated
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the capacity to bind to several HLA class I molecules including HLA-A11, HLA-A3, HLA-A2.1
in 17 patients with unresectable stage IIIB or IV NSCLC in an uncontrolled Phase I clinical trial.24 In this trial, the 12 patients who completed the treatment protocol received four doses of either 20 µg or 200 µg tecemotide administered in weeks 0, 2, 5, and 9, followed by maintenance vaccinations at 12-week intervals. Three days prior to initiating ASI with tecemotide, each patient received a single dose of CPA 300 mg/m2 (maximum dose 600 mg). Although no
16
antitumor responses were observed, median survival time was 5.4 months in patients receiving 20 μg compared to 14.6 months in patients treated with 200 μg tecemotide, a difference that was not statistically significant due to the small number of patients.
As expected, tecemotide
treatment induced primarily a cellular immune response. Among the 12 evaluable patients, five
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developed CTL responses against MUC1-positive tumor cell lines, and no significant humoral
immune responses were noted in any of the patients. Another five patients out of the 12
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immunotherapy and were not included in the group of patients considered positive for CTL activity following tecemotide immunization. This trial demonstrated that tecemotide can be
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safely administered and is well tolerated in stage IIIB and stage IV NSCLC patients.24 A second, non-randomized, open-label Phase I study, conducted as part of a Phase I/II
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study, assessed the safety of tecemotide in Japanese patients following primary CRT for stage III
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NSCLC.69 Tecemotide at a dose of 1000 µg was administered by subcutaneous injection weekly for eight weeks, with 1000-µg maintenance doses administered every six weeks thereafter until
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disease progression. Three days prior to the first dose of tecemotide, each patient received a single 300-mg/m2 dose of CPA intravenously. Adverse events considered related to tecemotide
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treatment were arthralgia, myalgia, and nausea. No serious adverse events were observed.69 This trial showed that tecemotide is well tolerated in Japanese NSCLC patients, with a safety
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evaluable were found to have preexisting MUC1-specific CTLs prior to tecemotide
profile consistent with previous clinical trials. The immunogenicity of tecemotide was not studied in this trial.
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Phase II Following completion of the Phase I safety trial, two early Phase II studies were conducted in previously treated stage IIIB and stage IV NSCLC patients to establish the tecemotide dose and treatment schedule.70 In the first study, performed in eight patients, a higher dose and more
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frequent immunization schedule (1000 µg weekly x 8 weeks) compared to the Phase I study were employed, in addition to maintenance immunizations every six weeks. Compared to baseline
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responses following tecemotide immunization. A MUC1-specific cytokine response was also detected in these six patients, as shown by intracellular tumor necrosis factor alpha (TNF- ).
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Median survival in this trial was 9.6 months.70 In the other early Phase II trial, a total of 18 patients were administered the 1000-µg dose of tecemotide in combination with two different
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doses of liposomal IL-2, an immune modulator. A MUC1-specific T-cell proliferative response
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was seen in two of the 10 patients given the lower dose of IL-2, one of whom had TNF- expressing CD4+ T cells.
Of the eight patients who received the higher dose of IL-2 in
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combination with tecemotide, six showed MUC1-specific T-cell proliferative responses, and four of these six demonstrated TNF- -expressing CD4+ T cells. In this latter early Phase II study,
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median survival was 8.7 months for those patients who received the lower dose of IL-2 and 17.8 months for patients who were given the higher dose of IL-2 in combination with tecemotide.70
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measurements, six of the eight patients showed significant, MUC1-specific T-cell proliferative
Based on the promising results of the two early Phase II studies, a multicenter, open-label, randomized Phase IIB trial was conducted in a total of 171 patients with stage IIIB or stage IV NSCLC.23 Patients were randomized to receive either best supportive care (BSC) (83 patients) or tecemotide plus BSC (88 patients). As in previous clinical studies, patients randomized to the
18
tecemotide arm received a single 300-mg/m2 dose of CPA prior to the first dose of tecemotide. Tecemotide was administered by subcutaneous injection weekly for eight weeks at a dose of 1000 µg spread over four anatomic sites, and then every six weeks thereafter as maintenance therapy. Overall median survival time was 4.4 months longer with tecemotide plus BSC (17.4
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months) compared with BSC alone (13.0 months).23 The greatest difference in median survival
was seen in the subset of patients with stage IIIB locoregional (LR) disease, where median
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Although this difference did not reach the level of statistical significance, it was definitely worthy of further study. Quality of life, as assessed by the Functional Assessment of Cancer
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Therapy-Lung (FACT-L) questionnaire and the Trial Outcome Index (TOI), was maintained longer in patients who received tecemotide compared to those who received only BSC.23 Of the
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88 patients who received tecemotide, T-cell immune responses were assessed in 78. MUC1-
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specific proliferative T-cell responses as a result of tecemotide immunotherapy were observed in 16 patients, only two of whom had stage IIIB LR disease. Among the tecemotide-treated
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patients with a positive T-cell proliferative response, median survival was 27.6 months compared to 16.7 months in those patients with a negative proliferative response.23 In confirmation of the
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initial analysis, an updated survival analysis showed that the overall three-year survival rate was 31% with tecemotide plus BSC compared to 17% with BSC alone. In patients with stage IIIB
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survival was 13.3 months with BSC alone and 30.6 months with tecemotide plus BSC. 22,
LR disease, three-year survival was 49% with tecemotide and 27% with BSC alone, but this difference was not quite statistically significant.22 No significant safety issues were encountered in this study.23 Another open-label Phase II trial in 22 patients with unresectable stage IIIA/IIIB NSCLC evaluated the safety of a new formulation of tecemotide.71 Patient survival was the secondary
19
endpoint of this study. Tecemotide liposomes contain MPLA as the adjuvant, and while this was not changed in the new formulation, changes in the manufacturing process resulted in changes to the MPLA chain composition. The design of this study was as described for the Phase IIB study. Results of this trial showed that the new tecemotide formulation was well tolerated, had a safety
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profile similar to the original formulation,71 and the two-year survival rate was comparable to
that reported by Butts et al. for patients with LR stage IIIB NSCLC.22 The new tecemotide
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A Phase II pilot study of tecemotide in prostate cancer was performed in 16 patients who had experienced prostate specific antigen (PSA) failure following radical prostatectomy.72 All
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patients received CPA pretreatment followed by weekly tecemotide (1000 µg) for eight weeks, followed by tecemotide maintenance dosing every six weeks for up to one year. A total of 15
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patients completed the primary treatment period and 10 completed the maintenance period.
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After eight weeks treatment, eight patients experienced stable or decreased PSA; however, by the end of the maintenance period, only one patient had stable PSA, with all others progressing.
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Interestingly, six of the 15 patients who completed the primary treatment experienced a more than 50% increase in their PSA doubling time compared to their baseline measurements. The
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most common adverse events were nausea, fatigue and injection site reactions. These results suggest that tecemotide may be useful in prolonging PSA doubling time, potentially delaying the start of hormone deprivation therapy in this patient population.72
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formulation was thus considered safe for use in Phase III clinical development.
Phase III
The first Phase III clinical trial of tecemotide, designated START (stimulating targeted antigenic responses to NSCLC), was a randomized, placebo-controlled, double-blind trial conducted in 1,513 patients from 33 different countries.12 The START trial, the results of which were recently
20
published, assessed the safety, efficacy and tolerability of tecemotide in patients with unresectable, locally advanced stage IIIA/IIIB NSCLC who had not progressed after initial concurrent or sequential CRT. Patients were randomized 2:1 to treatment with tecemotide or placebo. Patients assigned to the tecemotide arm received CPA pretreatment (300 mg/m2 to a
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maximum of 600 mg) followed by 806 µg tecemotide weekly for eight weeks and then every six
weeks thereafter until disease progression or withdrawal. A total of 829 tecemotide-treated and
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of tecemotide, including the START trial, were put on hold for enrollment and treatment after a case of encephalitis occurred in a Phase II trial of tecemotide for multiple myeloma. Subsequent
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investigations of this patient, an overall safety analysis of the use of tecemotide in NSCLC, and introduction of safety measures by protocol amendment led to the clinical hold being lifted in
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June 2010. As a result, the sample size of the START trial was adjusted and 274 excluded
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patients were replaced, so that 1,200 patients were needed to observe the anticipated number of events in the modified intention-to-treat (ITT) analyses for efficacy.
The modified ITT
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population did not introduce bias to the statistical analysis. The U.S. FDA under Special Protocol Assistance and several European regulatory authorities approved the amendment and
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modification of the ITT population before the analysis. For a detailed consolidated standards of reporting trials (CONSORT) diagram and description of the population, as well as for details on the clinical hold impact, please refer to the respective recent publication.12 The primary endpoint
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410 placebo-treated patients were included in the efficacy analysis. In March 2010, clinical trials
of overall survival prolongation in patients who received CPA and tecemotide was not significantly different compared to those who received saline and placebo (HR 0.88 [95% CI 0.76-1.03]; p=0.126). However, a favorable effect of tecemotide was observed in a prospectively planned analysis of the predefined subgroup of patients receiving initial concurrent CRT (HR
21
0.78 [95% CI 0.64-0.95]; p=0.016), with a 10.2-month improvement in median overall survival (from 20.6 months to 30.8 months), whereas no survival benefit of tecemotide was seen in the sequential CRT subgroup. The improved OS outcome in patients receiving initial concurrent CRT appeared to be consistent across respective patient subsets.12
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In the START trial, the safety analysis set consisted of 1,024 patients who received
tecemotide, 372 (36%) of whom received it for more than 52 weeks. These analyses confirmed
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differences between tecemotide and placebo for any adverse event reported. Adverse events of special interest such as injection-site reactions or flu-like symptoms were reported to be
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infrequent and rarely greater than grade 2. Potential immune-related diseases or events were seen in less than 3% of patients and with similar frequency in the two groups.12
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While the reason for the difference in survival outcome between concurrent and sequential CRT is unknown, it suggests that the timing of chemotherapy, radiotherapy, and
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tecemotide immunotherapy is important. The studies recently reported by Kao et al.33 have laid
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the groundwork for future studies that will address the optimal timing of CRT and tecemotide immunotherapy as discussed by Kao et al.35 and DeGregorio et al.36 In order to verify the results
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of the START trial showing a significant increase in overall survival in patients receiving concurrent CRT followed by tecemotide, a new Phase III trial (START2) has been initiated to study tecemotide maintenance therapy after concurrent CRT.36
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the favorable safety and tolerability profile of tecemotide. There were no clinically concerning
Ongoing Clinical Trials Phase III The recently initiated pivotal phase III study START273 intends to confirm the results observed
22
in the predefined subset of 806 patients treated with concurrent CRT who experienced improved overall survival (OS; adjusted HR 0.78, 95% CI 0.64–0.95; p=0.016) in the START trial.12 The START2 study is a global, randomized, double-blind, placebo-controlled Phase III trial investigating tecemotide in patients with unresectable stage III NSCLC who did not progress
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after completing first-line concurrent CRT 4-12 weeks before randomization. Concurrent CRT is defined as ≥2 cycles of platinum-based chemotherapy that overlaps with radiotherapy (total
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exclusion criterion. Patients will be stratified by response to CRT (stable disease or objective response) and region (North America and Australia; Western Europe; Rest of World), and
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randomized on a 1:1 basis to tecemotide (806 μg lipopeptide) or placebo. A single dose of CPA (300 mg/m2) or saline will be given i.v. three days prior to the first dose of tecemotide or Eight weekly subcutaneous injections will be administered initially,
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placebo, respectively.
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followed by maintenance injections every six weeks thereafter until disease progression or discontinuation. The primary objective is OS. Secondary objectives are time to symptom
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progression (Lung Cancer Symptom Scale), progression-free survival, time to progression, and safety. Approximately 1,002 patients will be enrolled. Sample size was calculated for a hazard
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ratio of 0.77 corresponding to an increase in median OS from 20 to 26 months in the placebo/tecemotide arm, respectively, a power of 90%, and one-sided significance level of 2.5%.
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tumor dose ≥60 Gy, single fraction dose ≥1.8 Gy); any other therapy for NSCLC constitutes an
The START2 trial will be conducted in more than 20 countries worldwide, excluding Asia. The study started recruiting in 2014.73 While the START and START2 trials have focused on patients with a Caucasian background, parallel studies had been initiated to investigate tecemotide in patients with Asian genetic background. There are currently two ongoing clinical trials of tecemotide in Asian
23
patients with unresectable stage III NSCLC, one Phase II study in Japan69 and one Phase III study in China, Hong Kong, South Korea, Singapore, and Taiwan.25 In both studies, the same treatment regimens used in the START trial are being employed. The tecemotide dose reported for earlier clinical trials was 1000 µg, but patients were found to have actually received about
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930 µg or 806 µg based on an updated density determination of tecemotide prior to lyophilization and the respective applied syringe types for reconstitution. It was decided that the
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subsequent Phase III trial START2. However, the 930-µg dose was maintained unchanged for the Asian trial INSPIRE.25
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The multinational Phase III clinical trial INSPIRE (tecemotide trial in Asian NSCLC patients: stimulating immune response) is designed to assess the efficacy of tecemotide plus
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BSC, compared to placebo plus BSC, on overall survival time in patients of East Asian ethnicity
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with locally advanced, unresectable stage III NSCLC who had documented stable disease or an objective response following completion of primary CRT based on Response Evaluation Criteria Secondary objectives include time to symptom
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in Solid Tumors (RECIST) criteria.25
progression, time to progression, progression-free survival time, time to treatment failure and
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safety. Patients will be randomized 2:1 to treatment with tecemotide plus BSC or placebo plus BSC. The results of the START trial have led to the modification of the INSPIRE trial to exclude sequential therapies and concentrate on concurrent therapy options.36 The projected
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dose actually applied in the Phase III study START (806 µg) would be carried forward into the
enrollment is 420 patients.25 Phase II Several Phase II studies are ongoing in colorectal cancer, rectal cancer, prostate cancer, breast cancer, and lung cancer. In a randomized, double-blind, placebo-controlled Phase II trial (L-
24
BLP25 In Colorectal Cancer, or LICC), a total of 159 patients with stage IV colorectal adenocarcinoma following curative resection of hepatic metastases will be randomized 2:1 to receive treatment with tecemotide or placebo. Tecemotide is being administered at a dose of 930 µg weekly for eight weeks, followed by maintenance dosing every six weeks thereafter for the
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first two years and every 12 weeks in the third year until recurrence. The primary endpoint is recurrence-free survival, and the secondary endpoints are overall survival, safety, and
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In rectal cancer, the multi-center, randomized, three-arm, open-label, Phase II mechanistic trial, designated SPRINT (NCT01507103), is designed to investigate the immune
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response to tecemotide treatment in rectal cancer patients undergoing neoadjuvant CRT.76 The immune response to tecemotide (primary endpoint) will be evaluated based on the local response
In this three-arm study (1:1:1 randomization) 24 subjects per arm receive either
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blood.
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in the tumor and the MUC1- and carcinoembryonic antigen (CEA)-specific response tested in
tecemotide (806 µg weekly for eight weeks) concomitant with standard CRT with or without a
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prior single dose of CPA (300 mg/m2), or standard CRT alone. This study has completed recruitment and results are expected in 2015.76
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In breast cancer, the randomized, two-arm, controlled, open-label Phase-II study
(Austrian Breast & Colorectal Cancer Study Group-34) is investigating tecemotide in the preoperative treatment of women with primary breast cancer.77 A total of 400 patients will
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tolerability.74, 75
receive either standard chemotherapy or standard hormonal therapy, with or without tecemotide. The primary objective is assessment of histopathological response to preoperative standard of care treatment with or without tecemotide immunotherapy when measured by Residual Cancer Burden (RCB0/I versus RCBII/III) at the time of surgery.
25
Secondary objectives include
assessment of pathological complete remission (pCR; an absence of invasive cancer cells in surgical specimen) at the time of surgery, immunological parameters, quality of life and safety.77 Triggered by encouraging Phase I data in prostate cancer, a randomized, controlled Phase II study of tecemotide in combination with standard androgen deprivation therapy (ADT) and
Cancer Institute (NCT01496131).78
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RTX for newly diagnosed, high-risk prostate cancer patients was initiated at the U.S. National
A total of 48 patients will receive RTX/ADT with or
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Secondary outcomes include time to progression, further
immune-related parameters and safety.78
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and six months after radiation).
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immune parameters (change from baseline in the ELISpot level of MUC1-specific T cells at two
In lung cancer, the ongoing Phase II Japanese study mentioned earlier had included 168
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patients with unresectable stage III NSCLC following primary CRT who were randomized 2:1 to
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treatment with either BSC alone or BSC plus tecemotide weekly for eight weeks followed by maintenance dosing every six weeks thereafter until disease progression. More than 90% of
pt
patients had received concurrent CRT pretreatment. The primary endpoint of this study is overall survival. This event-driven study is in the follow-up phase and results are expected in
ce
2015.69
Finally, the ongoing open-label, Eastern Cooperative Oncology Group (ECOG) Phase II
study (NCT00828009)79 is investigating the combination of tecemotide and bevacizumab after
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without combined tecemotide treatment (1:1 randomization). Primary outcome will be to assess
CRT in a total of 55 patients with newly diagnosed stage IIIA or stage IIIB unresectable NSCLC. The primary endpoint of this interventional study is to determine the safety of this combination treatment. Secondary endpoints are overall survival and progression-free survival in patients treated with this combination regimen.79
26
Conclusions Tecemotide is liposome-based, antigen-specific cancer immunotherapy designed to elicit a cellular immune response against MUC1, a TAA that is overexpressed and aberrantly glycosylated in epithelial cancers such as lung, breast and prostate cancer. Tecemotide has been
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in clinical development for over 13 years, and clinical trials have shown very promising results
in regard to prolongation of overall survival and improvement in quality of life in patients with
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Phase III clinical trial were disappointing in that overall survival was not significantly increased with tecemotide following primary CRT compared to placebo, a notable survival benefit was
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observed in the predefined subset of patients treated with concurrent CRT followed by tecemotide compared to those patients treated with sequential CRT.
Safety analyses of
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tecemotide studies have revealed an overall favorable safety and tolerability profile. In the START study, as yet the largest controlled study of tecemotide, there were no clinically relevant
ed
differences between tecemotide and placebo observed with respect to safety and tolerability.12 A
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new Phase III trial (START2) will address concurrent CRT regimens followed by tecemotide maintenance therapy, while an ongoing Phase III trial in Asian patients has been modified to
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focus on concurrent CRT options. A number of Phase II clinical trials are ongoing and may provide additional mechanistic insights as well as potential activity signals in indications other
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locally advanced, unresectable stage IIIA/IIIB NSCLC. While results of the first and largest
than lung cancer. Studies utilizing an immune-intact, MUC1 transgenic lung cancer mouse model are currently underway that seek to address the mechanisms underlying the differences between concurrent and sequential CRT so that the optimal timing of chemotherapy, radiotherapy and tecemotide immunotherapy may be defined to achieve the most beneficial treatment outcome for patients.
Tecemotide remains a very promising maintenance
27
immunotherapy for unresectable stage III NSCLC, and the results of ongoing Phase III trials are eagerly awaited. Tecemotide may also prove to be useful in the treatment of many other types of cancer, including breast, prostate, rectal and colorectal carcinoma, for which Phase II clinical trials are currently ongoing.
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Acknowledgments
The authors would like to thank Drs. Martin Picard, Christoph Bogedain, Samir Henni, Martin
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Conflicts of Interest
GTW and CJK declare no conflicts. MW is an employee of Merck KGaA, and MWD is
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principal investigator of a research grant received from Merck KGaA.
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Falk, and Christoph Helwig of Merck KGaA for their critical review of the manuscript.
28
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http://www.clinicaltrials.gov/ct2/show/NCT01496131?term=NCT01496131&rank=1. ClinicalTrials.gov. May 30, 2014.
ip t
79. NIH. BLP25 Liposome Vaccine and Bevacizumab after Chemotherapy and Radiation Therapy in Treating Patients with Newly Diagnosed Stage IIIA or Stage IIIB Non-Small Cancer
that
cannot
be
Removed
by
Surgery
NCT00828009.
cr
Lung
us
http://www.clinicaltrials.gov/ct2/show/NCT00828009?term=NCT00828009&rank=1.
ce
pt
ed
M
an
ClinicalTrials.gov. May 30, 2014.
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Cell
41
Table 1. Completed Clinical Trials of Tecemotide
Phase l randomized open-label safety and dose comparison study.
17
24
8
70
ip t
Phase II open-label safety and immunogenicity study. Phase II open-label, dose-escalation study to determine safety and immunogenicity of tecemotide in combination with liposomal IL-2.
70
cr
18
Phase IIB open-label, randomized study to test safety and efficacy of tecemtotide plus BSC compared to BSC alone.
171
22, 23
22
71
1513
12
16
72
34
In preparation
us
an
Phase II open-label study to assess safety of tecemotide made with a new formulation of the immunoadjuvant MPL®.
A multicenter randomized double-blind placebo-controlled Phase III trial of tecemotide versus placebo in patients with unresectable stage III NSCLC. Phase II open-label trial to test safety and efficacy of tecemotide in patients with rising PSA values following radical prostatectomy. Phase II open-label, dose-escalation study to determine safety and efficacy of L-BLP25 in multiple myeloma, either chemotherapy naïve, slowly progressive and asymptomatic or with stage II/III in stable response/plateau following antitumor therapy.
ce
pt
NCT01094548 EMR 63325-008 Multiple myeloma
Reference
M
EMR 63325-007 Prostate cancer
Patients Enrolled
ed
EMR 63325-002 Stage IIIB or IV NSCLC EMR 63325-003 Stage IIIB or IV NSCLC EMR 63325-004 Stage IIIB or IV NSCLC NCT00157209 EMR 63325-005 Stage IIIB or IV NSCLC NCT00157196 EMR 63325-006 Unresectable stage III NSCLC NCT00409188 EMR 63325-001 (START) Unresectable stage III NSCLC
Description
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Study Identifier Indication
42
Table 2. Ongoing Clinical Trials of Tecemotide. Description
Patients Planned
Reference
Closed to enrollment
Combined Phase I/II study in Japanese subjects with stage III unresectable NSCLC following primary chemotherapy.
205
69
Open to enrollment*
Phase II study of tecemotide and bevacizumab in unresectable stage IIIA and IIIB NSCLC after definitive CRT.
Open to enrollment*
cr
55
420
us
Open to enrollment*
Phase III clinical trial of tecemotide in Asian subjects with stage III, unresectable, NSCLC who have demonstrated either stable disease or objective response following primary CRT. A multicenter randomized double-blind placebo-controlled Phase III trial of tecemotide versus placebo in patients with completed concurrent CRT for unresectable stage III NSCLC.
ip t
Status
79
25, 36
73
262
—
124
76
48
78
159
74, 75
Open to enrollment*
400
77
Open to enrollment*
Open to enrollment*
ce
NCT01462513 EMR 63325-602 (LICC) Colorectal cancer EMR 63325-603 (ABCSG 34) Breast cancer
M
Closed to enrollment*
Open label trial to collect long-term data on subjects who have received tecemotide in previous clinical trials. Multi-center, randomized, open-label, mechanistic trial of the biological effects of tecemotide in rectal cancer subjects undergoing neoadjuvant CRT. A randomized Phase II study of tecemotide in combination with standard ADT and RTX for newly diagnosed, high-risk prostate cancer. Multicenter, multinational, randomized (2:1), double-blind, placebo-controlled Phase II trial in colorectal carcinoma after curative resection of hepatic metastases. Multicenter, randomized (1:1), open label, 2-arm trial in the pre-operative treatment of women with primary breast cancer.
ed
NCT01496131 EMR 63325-015 Prostate cancer
Enrollment on invitation
an
1002
pt
NCT00960115 EMR 63325-009 Unresectable stage III NSCLC NCT00828009 EMR 63325-600 (ECOG 6508) Unresectable stage III NSCLC NCT01015443 EMR 63325-012 (INSPIRE) Unresectable stage III NSCLC NCT02049151 EMR 63325-021 (START2) Unresectable stage III NSCLC NCT01423760 EMR 63325-011 Tumor type as per feeder trial NCT01507103 EMR 63325-013 (SPRINT) Rectal cancer
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Study Identifier Indication
*as of June 2014.
43
