Cancer Chemother Pharmacol DOI 10.1007/s00280-014-2467-z
Original Article
A phase 1 and dose‑finding study of LY2523355 (litronesib), an Eg5 inhibitor, in Japanese patients with advanced solid tumors Hiroshi Wakui · Noboru Yamamoto · Satoru Kitazono · Hidenori Mizugaki · Shinji Nakamichi · Yutaka Fujiwara · Hiroshi Nokihara · Yasuhide Yamada · Kohei Suzuki · Hironori Kanda · Shiro Akinaga · Tomohide Tamura
Received: 21 March 2014 / Accepted: 8 April 2014 © Springer-Verlag Berlin Heidelberg 2014
Abstract Purpose Eg5, a mitotic motor kinesin protein, plays an essential role in bipolar spindle formation in the M phase of the cell cycle. LY2523355 (litronesib) is an allosteric inhibitor of Eg5. This phase 1 and dose-finding study aimed to assess the safety, pharmacokinetics (PK), recommended dose for further studies, and preliminary efficacy in Japanese patients with advanced solid tumors. Methods LY2523355 was given on days 1, 2, and 3 every 3 weeks at one of three dose levels: 2, 4, and 5 mg/m2/day. Toxicity was assessed according to NCI-CTCAE version 4.0, and tumor response according to RECIST version 1.1. granulocyte colony-stimulating factor (G-CSF) was used only for grade 4 neutropenia or grade 3 febrile neutropenia. Results Twelve patients were treated at doses of 2 (n = 3), 4 (n = 3), and 5 (n = 6) mg/m2/day. Most frequent treatment-related adverse events were neutropenia and leukopenia (100 %). Grade 4 neutropenia was observed in 83 %, but all recovered to above 500 neutrophils/μl within 7 days. All patients at 4 and 5 mg/m2/day required G-CSF support. No dose-limiting toxicities were reported up to 5 mg/m2/day. In PK analysis, LY2523355 exposure increased in a dose-dependent manner. The PK parameters H. Wakui · N. Yamamoto · S. Kitazono · H. Mizugaki · S. Nakamichi · Y. Fujiwara · H. Nokihara · T. Tamura (*) Department of Thoracic Oncology, National Cancer Center Hospital, 5‑1‑1, Tsukiji, Chuo‑ku, Tokyo 104‑0045, Japan e-mail: [email protected] Y. Yamada Department of Gastrointestinal Oncology, National Cancer Center Hospital, 5‑1‑1, Tsukiji, Chuo‑ku, Tokyo 104‑0045, Japan K. Suzuki · H. Kanda · S. Akinaga Development Division, Kyowa Hakko Kirin Co., Ltd, 1‑6‑1, Ohtemachi, Chiyoda‑ku, Tokyo 100‑8185, Japan
for LY2523355 were similar to those observed in Western populations. No objective tumor responses were observed. Conclusions The recommended dose of LY2523355 with therapeutic G-CSF use for further studies was determined to be 5 mg/m2/day in Japanese patients with advanced solid tumors. Keywords LY2523355 · Litronesib · Eg5 inhibitor · Phase 1 study · Solid tumor
Introduction Eg5, also known as kinesin spindle protein, is a mitosisspecific motor protein that hydrolyzes ATP to produce force and moves along microtubules. It is essential for bipolar spindle formation and subsequent chromosome separation in the M phase [1]. Since Eg5 is not expressed in post-mitotic neurons and is likely to act only in dividing cells [2], inhibition of Eg5 may not cause any neuropathic adverse events as opposed to traditional tubulin-binding agents such as vinca alkaloids and taxanes. Importantly, some researchers have reported that Eg5 inhibitors induce mitotic arrest and cell death in taxane-resistant and/or taxane-sensitive cancer cells [3, 4]. Interestingly, Eg5 is overexpressed in tumor cells relative to normal cells [5, 6], and the positive correlation between Eg5 expression and the response of non-small-cell lung cancer to antimitotic agents has been reported [7]. Thus, Eg5 is a particularly attractive target for novel anticancer therapies [2], and recent efforts have been increased to develop Eg5 inhibitors since the development of ispinesib began. LY2523355 (litronesib) is a specific, ATP-uncompetitive, allosteric, and potent small-molecule inhibitor of Eg5 that has been shown to prevent centrosome separation and
13
mitotic spindle assembly. This leads to the formation of monopolar spindles, activation of spindle checkpoint proteins, mitotic arrest, and eventually cell death. LY2523355 has demonstrated promising anticancer activity across a broad range of solid tumors in vitro and in vivo [8]. In parallel with the present study, several clinical studies on LY2523355, the second highest number following ispinesib, have already been conducted in several countries [9, 10]. In addition to the fact that some patients experienced partial response with an acceptable tolerability profile, evidence of the formation of monopolar spindles as a proof of mechanism in a clinical setting has been presented [9]. Pharmacodynamics data from skin and tumor biopsies demonstrated an LY2523355 exposure-dependent response in phosphohistone H3, which is a specific marker for mitosis [9]. The most frequent-related adverse events were hematologic such as neutropenia [9, 10]. Eventually, LY2523355 administration for three consecutive days with prophylactic granulocyte colony-stimulating factor (G-CSF) support has been adapted as a best-dose schedule for the phase 2 clinical investigation. There were no prior clinical reports of LY2523355 administration in Japanese patients. In fact, a phase 1 study of this compound in Asian patients had yet to be conducted. We therefore conducted the first phase 1 clinical trial in Japanese patients with advanced or metastatic solid tumors to evaluate the tolerability and safety of LY2523355 administered on days 1, 2, and 3 to determine the recommended dose for further studies. The need for therapeutic G-CSF use not prophylactic G-CSF support was tested in the population.
Patients and methods Patient eligibility Eligible patients possessed histologically or cytologically confirmed advanced or metastatic solid tumors that were refractory to standard treatment. Eligibility criteria also included the following: age ≥20 years at informed consent; Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0–1; life expectancy >3 months; adequate hematologic [absolute neutrophil count (ANC) ≥1,500/μl; platelet count ≥100,000/μl; hemoglobin ≥9 g/dl], hepatic [total bilirubin ≤1.5 × upper limit of normal (ULN); alanine and aspartate aminotransferase ≤98 IU/l], and renal functions (serum creatinine ≤1.5 mg/dl); and no previous chemotherapy, radiation therapy, hormonal therapy, or surgery within 4 weeks before treatment with LY2523355 (6 weeks for previous treatment with nitrosoureas and mitomycin C). Any toxicity related to prior therapy must have recovered to ≤grade 1.
13
Cancer Chemother Pharmacol
Exclusion criteria included the following: previous treatment with LY2523355 therapy; active infections requiring treatment; symptomatic brain metastasis; current acute or chronic leukemia; a history of an autologous or allogenic hematopoietic stem cell transplantation; uncontrolled or significant cardiovascular or pulmonary disease; hepatic B or C virus or human immunodeficiency virus infection; and pregnancy, lactation, or possibility of pregnancy. Written informed consent was obtained from all patients. This study was conducted in accordance with the Declaration of Helsinki and the applicable guidelines on good clinical practice, and the protocol and the informed consent received institutional review board/independent ethics committee approval. Study design This was an open-label, single-center, dose-escalation, phase 1 study in Japanese patients (Clinicaltrials.gov Identifier: NCT01358019). The primary objective was to evaluate the safety and pharmacokinetics (PK) of LY2523355 in Japanese patients with advanced solid tumors. Secondary objectives were to determine a recommended dose for Japanese studies and to obtain a preliminary assessment of tumor response. Drug administration and dose‑escalation procedure Eligible patients were treated with LY2523355 by 60-min IV administration on days 1, 2, and 3 every 3 weeks at one of three dose levels: 2, 4, and 5 mg/m2/day. Cycles were repeated until disease progression, unacceptable toxicity, or until the patient or the investigator requested therapy discontinuation. Dose was escalated by a classic 3 + 3 design. Dose-limiting toxicities (DLTs) were evaluated from the initial dose to cycle 1 day 21. Patients were hospitalized during the DLT evaluation period. DLTs were defined as any of the following toxicities assessed to have a causal relationship with the study drug: (1) grade 4 thrombocytopenia or grade 3 thrombocytopenia requiring blood transfusion; (2) grade 4 neutropenia that lasted >7 days; (3) a neutrophil count of 2 days; (4) grade 3 or worse non-hematologic toxicities except for nausea, vomiting, or diarrhea without maximal supportive treatment, and except for a transient electrolyte abnormality. G-CSF was used only for grade 4 neutropenia or grade 3 febrile neutropenia. Safety assessments Treatment-emergent adverse events were assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE version 4.0)
Cancer Chemother Pharmacol
throughout the treatment period until 30 days after the last dose. PS was examined prior to study entry, before each cycle, and at the end of the study. Vital signs were assessed prior to study entry, at days 1, 2, 3, 8, 15, and 22 of cycle 1, at days 1 and 8 of each cycle from the following cycle, and at the end of the study. Twelve-lead electrocardiograms were performed prior to study entry, at days 1, 3, and 8 of cycles 1 and 2, before every cycle from cycle 3, and at the end of the study. Cerebellar function was tested per each dose during cycle 1, and at days 1 and 3 of each cycle from the following cycle. Clinical laboratory tests were examined prior to study entry, at days 1, 4, 8, 11, 15, and 22 of cycle 1, at days 1 and 8 of each cycle from the following cycle (plus at days 15–22 of cycle 2 for hematology), and at the end of the study. Urinalysis was performed prior to study entry, at days 1, 8, and 22 of cycle 1, before each cycle from the following cycle, and at the end of the study. A pregnancy test was performed prior to study entry and before even numbered cycles.
Table 1 Patient characteristics
Pharmacokinetic analyses
Prior therapy [n (%)] Chemotherapy Median number of chemotherapy regimens (range) Surgery Radiotherapy
Plasma samples for PK evaluation were collected during cycle 1, on day 1 prior to dose and at 0, 1, 2, 4, and 8 h after the completing of infusion, on day 2 prior to dose, on day 3 prior to dose and at 0, 1, 2, 4, and 8 h after the completing of infusion, and on days 4, 5, and 8 at the same hour as the start of infusion on day 3. Additional samples were collected on day 1 prior to dose and immediately after the completing of infusion, and on day 3 immediately after the completing of infusion during cycle 2. LY2523355 was extracted from plasma samples and then analyzed by liquid chromatography–tandem mass spectrometry (LC–MS/MS). PK parameters of LY2523355 and its active metabolite, M1, included maximum concentration (Cmax), area under concentration–time curve from 0 to 24 h (AUC0–24), clearance (CL), time to Cmax (tmax), terminal half-life (t1/2), intracycle accumulation ratio (Ra), and metabolic ratio. Tumor response Tumor response was assessed with Response Evaluation Criteria in Solid Tumors (RECIST version 1.1). Baseline radiologic tumor assessments were performed within 14 days prior to study entry, and subsequent tumor evaluations were performed on days 15–22 of cycle 1 and subsequent even numbered cycles, and at the end of the study. The minimum period of stable disease was defined as 36 days. Statistical analyses Descriptive statistics was used to summarize safety, PK parameters, and tumor response from all dosed patients.
Characteristics
n = 12
Age (years) Median (range)
61.5 (36–71)
Gender [n (%)] Male Female
7 (58 %) 5 (42 %)
ECOG PS [n (%)] 0 1
7 (58 %) 5 (42 %)
Tumor type [n (%)] Colorectal Non-small-cell lung Small-cell lung Angiosarcoma Breast Esophageal Gastric Ovarian
3 (25 %) 2 (17 %) 2 (17 %) 1 (8 %) 1 (8 %) 1 (8 %) 1 (8 %) 1 (8 %)
Hormonal therapy
12 (100 %) 4 (1–8) 10 (83 %) 3 (25 %) 1 (8 %)
Results Patient characteristics Twelve patients were enrolled at the National Cancer Center Hospital, Tokyo, Japan, from June 2011 to May 2012, and received at least one dose of LY2523355 at doses of 2 (n = 3), 4 (n = 3), and 5 (n = 6) mg/m2/day. Patient characteristics are listed in Table 1. The median age was 61.5 years (range 36–71), and seven patients (58 %) were men. Seven patients had an ECOG PS of 0, and five had a PS of 1. Tumor types included colorectal cancer (3), non-small-cell lung cancer (2), small-cell lung cancer (2), angiosarcoma (1), breast cancer (1), esophageal cancer (1), gastric cancer (1), and ovarian cancer (1). All patients had received previous chemotherapy for their cancer. The median number of prior chemotherapy regimens (range) was 4 (1–8). Safety and tolerability The most frequent treatment-emergent adverse events occurring in ≥25 % of patients throughout the study are shown in Table 2. The most common toxicities noted were hematologic such as neutropenia and leukopenia (100 %),
13
Cancer Chemother Pharmacol
Table 2 Treatment-emergent adverse events of any grade reported in three or more patients (≥25 % of patients), all cycles Patients with treatment-emergent adverse events, n (%) LY2523355 dose 2 mg/m2/day (n = 3)
4 mg/m2/day (n = 3)
5 mg/m2/day (n = 6)
Total (n = 12)
Neutropenia Leukopenia Lymphopenia Febrile neutropenia
3 (100) 3 (100) 3 (100) 0
3 (100) 3 (100) 3 (100) 2 (67)
6 (100) 6 (100) 5 (83) 6 (100)
12 (100) 12 (100) 11 (92) 8 (67)
Anemia Alkaline phosphatase increased Hyponatremia Diarrhea γ-glutamyl transpeptidase increased Hypercalcemia Pruritus Stomatitis Fatigue Alanine aminotransferase increased Aspartate aminotransferase increased Thrombocytopenia Loss of body weight Hyperglycemia Hypoalbuminemia
1 (33) 2 (67) 1 (33) 1 (33) 0 0 2 (67) 0 0 0 1 (33) 1 (33) 1 (33) 0 0
1 (33) 1 (33) 1 (33) 1 (33) 1 (33) 1 (33) 2 (67) 0 2 (67) 1 (33) 1 (33) 0 1 (33) 2 (67) 1 (33)
3 (50) 2 (33) 3 (50) 2 (33) 3 (50) 3 (50) 0 3 (50) 1 (17) 2 (33) 1 (17) 2 (33) 1 (17) 1 (17) 2 (33)
5 (42) 5 (42) 5 (42) 4 (33) 4 (33) 4 (33) 4 (33) 3 (25) 3 (25) 3 (25) 3 (25) 3 (25) 3 (25) 3 (25) 3 (25)
Oropharyngeal pain
0
1 (33)
2 (33)
3 (25)
Table 3 Grade 3 and higher treatment-emergent adverse events by dose level, all cycles
Patients with treatment-emergent adverse events, n (%) LY2523355 dose
Neutropenia Leukopenia Febrile neutropenia Lymphopenia Ileal perforation Peritonitis Alkaline phosphatase increased Hyponatremia
4 mg/m2 (n = 3)
5 mg/m2 (n = 6)
Grade 3
Grade 4
Grade 3
Grade 3
1 (33)
1 (33) 2 (67) 2 (67) 1 (33)
Grade 4 3 (100) 1 (33)
4 (67) 6 (100) 1 (17)
Grade 4 6 (100) 2 (33)
1 (33) 1 (33) 1 (17) 1 (17)
Diabetic mellitus (worsening) Hyperuricemia
1 (17) 1 (17)
Hemoptysis
1 (17)
lymphopenia (92 %), febrile neutropenia (67 %), consistent with the toxicities predicted from the preclinical animal data and the Western phase 1 [9, 10] and phase 2 studies. Neutropenia was the CTCAE grade ≥3 event most commonly reported, both during cycle 1 and throughout the study [overall, n = 11 (92 %)]. Ten of 12 (83 %) patients experienced grade 4 neutropenia (Table 3) requiring G-CSF therapy. The
13
2 mg/m2 (n = 3)
neutropenia nadir occurred at 8–11 days after the infusion of LY2523355, but all recovered to above 500 neutrophils/μl within 7 days. Grade 3 or 4 leukopenia occurred in nine patients (three at the 4 mg/m2/day and six at the 5 mg/m2/ day dose levels). Also, grade 3 febrile neutropenia occurred in eight patients (two at the 4 mg/m2/day and six at the 5 mg/ m2/day dose levels). Two patients experienced a fever over
Cancer Chemother Pharmacol Fig. 1 Plasma concentration– time profiles for LY2523355 (a) and M1 (b) (mean + standard deviation)
38.5 °C, but it decreased ≤2 days with antibiotic treatment in addition to G-CSF therapy. Other than the events described above, it should be noted that even though the severity of stomatitis observed in two patients at the 5 mg/m2/day dose level was grade 2, the events required some treatment such as oral rinse, dexamethasone ointment, and fluid. There was no increase in preexisting neuropathy and no new significant neuropathy. No clinically significant treatment-emergent changes in physical findings, vital signs, or electrocardiograms were reported. Four serious adverse events were reported in three patients: ileus, ileal perforation, hemoptysis, and constipation. Only the constipation event was considered to be possibly related to the study treatment. Two patients discontinued LY2523355 treatment due to disease progression and the investigator’s discretion (switching to another therapy on disease progression). There were no deaths during the study. No DLTs were reported in this study. The maximum tolerated dose was not defined in this population, and the 5 mg/m2/day dose level was expanded to six patients to establish the preliminary safety profile of the study agent.
Pharmacokinetics All patients had evaluable PK data obtained after the administration of LY252335 on days 1 and 3 of cycle 1, three patients each at the 2 and 4 mg/m2/day dose levels, and six patients at the 5 mg/m2/day dose level. The mean plasma concentrations of LY2523355 and M1, a main metabolite of LY2523355, increased in a dose-dependent manner and declined in a biphasic pattern (Fig. 1). The PK parameters of LY2523355 and M1 on days 1 and 3 of cycle 1 are presented in Tables 4 and 5, respectively. The Cmax and AUC0–24 of LY2523355 and M1 increased approximately dose-proportionally over the dose range from 2 to 5 mg/m2/day. The t1/2 and CL of LY2523355 were dose-independent, ranging from 17.5 to 22.9 h and 11.1 to 14.2 L/h/m2, respectively. The t1/2 of M1 ranged from 20.8 to 31.1 h. The metabolic ratio was stable across all doses investigated. There was no accumulation of LY2523355 and M1 among cycles. The PK parameters for LY2523355 were similar to those observed in Western populations [9].
13
Table 4 PK parameters for LY2523355 and active metabolite of LY2523355, M1, following dosing on day 1 of cycle 1
CV, coefficient of variation; Metabolic ratio, AUC0–24, M1/AUC0–24, LY2523355 Table 5 PK parameters for LY2523355 and active metabolite of LY2523355, M1, following dosing on day 3 of cycle 1
Cancer Chemother Pharmacol Parameter, mean (CV %)
LY2523355 dose 2 mg/m2/day (n = 3)
5 mg/m2/day (n = 6)
LY2523355 Cmax (ng/ml) AUC0–24 (ng h/ml) M1
65.30 (7.43)
122.2 (30.3)
160.6 (33.3)
139.80 (15.58)
252.66 (89.94)
384.66 (156.51)
tmax (h) Cmax (ng/ml) AUC0–24 (ng h/ml)
2.03 (0.00)
1.32 (0.62)
1.68 (0.52)
1.835 (0.673)
4.256 (1.511)
4.869 (1.234)
15.71 (6.54)
28.22 (11.73)
39.83 (12.32)
0.11 (0.04)
0.11 (0.01)
0.11 (0.03)
Metabolic ratio
Parameter, mean (CV %)
LY2523355 dose 2 mg/m2/day (n = 3)
4 mg/m2/day (n = 3)
5 mg/m2/day (n = 6)
LY2523355 Cmax (ng/ml) AUC0–24 (ng h/ml) t1/2 (h) CL (L/h/m2) Ra, Cmax
69.30 (7.2)
132.9 (21.9)
192.6 (31.2)
175.77 (7.6) 17.5 (17.4) 11.4 (7.5) 0.94 (4.8)
306.12 (35.4) 19.8 (38.5) 14.2 (33.9) 0.93 (15.4)
534.05 (53.7) 22.9 (30.3) 11.1 (36.2) 0.86 (13.9)
0.79 (6.9)
0.83 (12.7)
0.76 (12.9)
1.34 (44.9)
1.35 (46.6)
1.52 (37.5)
Ra, AUC M1
CV, coefficient of variation; Ra, Cmax, Cmax on day 1/Cmax on day 3; Ra, AUC, AUC0–24 on day 1/AUC0–24 on day 3; Metabolic ratio, AUC0–24, M1/AUC0–24,
4 mg/m2/day (n = 3)
tmax (h) Cmax (ng/ml) AUC0–24 (ng h/ml) t1/2 (h)
2.332 (42.8)
4.681 (22.5)
5.816 (41.6)
Ra, Cmax
23.33 (43.7) 20.8 (21.8) 0.80 (8.4)
42.31 (42.9) 25.3 (27.3) 0.94 (44.4)
55.58 (37.6) 31.1 (57.3) 0.89 (21.2)
Ra, AUC
0.68 (10.7)
0.70 (30.7)
0.74 (18.0)
Metabolic ratio
0.13 (43.9)
0.13 (15.6)
0.12 (41.9)
LY2523355
Tumor response No objective tumor responses were observed. The best overall response was stable disease (SD) in two patients. The longest duration of SD was 52 days, reported in both patients at the 4 mg/m2/day dose level. Five patients displayed progressive disease (PD). Another five patients were not evaluated.
Discussion From this phase 1 and dose-finding study of LY2523355 in Japanese patients with advanced or metastatic solid tumors, it was concluded that the recommended dose with a manageable safety profile of LY2523355 with therapeutic G-CSF use for further studies was 5 mg/m2/day on days 1–3 every 3 weeks. Initially, we planned four dose levels: 2, 4, 5, and 6 mg/m2/day. At the 5 mg/m2/day
13
dose level, however, grade 3 febrile neutropenia occurred in all patients with therapeutic G-CSF use. Dose escalation was halted at 5 mg/m2/day due to these safety concerns in addition to the fact that a dosage of 5 mg/m2/day with prophylactic G-CSF support was used in the parallel overseas phase 2 studies (ClinicalTrials.gov Identifier: NCT01025284; NCT01416389; NCT01059643). Even with G-CSF and/or antibiotic therapy, higher doses may not be tolerated considering the toxicity profile, particularly the occurrence of febrile neutropenia and grade 2 stomatitis requiring some treatment such as oral rinse, dexamethasone ointment, and fluid. Stomatitis and/or mucositis might be among the important and typical toxicities caused by Eg5 inhibition, as reported for other inhibitors [11–15]. The toxicity profile observed in this study was similar to that observed in overseas phase 1 studies of LY2523355 [9, 10]. The most common toxicities were hematologic, and the most common grade ≥3 toxicities thought to be attributable to LY2523355 treatment were neutropenia,
ST
ST, lymp
4SC-205
EMD534085
44 pts; 27–86 y
46 pts; -
43 pts; 23–75 y 48 pts; 28–82 y
Every 21 days
Days 1, 8, or days 1,4, 8, 11; 21-day cycle
Every 21 days Weekly
Days 1, 2, 15, 16; 28-day cycle + carfilzomib Days 1, 2, 15, 16, or days 1, 15; 28-day cycle + Bortezomib Every 21 days Every 2 weeks
Day 1 or days 1, 3, 5 per cycle
Days 1, 2; every 2 weeks
Days 1,4, 8, 11; 21-day cycle Days 1, 2, 3; 2-week cycle
Every 21 days + docetaxel Every 21 days + capecitabine Days 1, 8, 15; 28-day cycle Days 1, 8, 15; 28-day cycle
Days 1, 8, 15; 28-day cycle
Days 1, 2, 3; 21-day cycle Days 1, 8, 15; 28-day cycle Days 1, 15; 28-day cycle
2 –3 doses; 21-day cycle
Dosing schedule
Neutropenia, Acute coronary syndrome
Neutropenia (major DLT) Hepatic failure leading to death, Thrombocytopenia, Hypokalemia Neutropenia Fatigue, Intravascular hemolysis, Nausea, Headache, Peripheral sensory neuropathy Neutropenia, Stomatitis (main side effects)
None (higher dose)
Neutropenia, Febrile neutropenia (main DLTs) Febrile neutropenia (main DLT) Neutropenia Increased aspartate and alanine aminotransferases Neutropenia, hyperbilirubinemia, elevated aspartate and alanine aminotransferases Neutropenia, febrile neutropenia Neutropenia Neutropenia, febrile neutropenia Neutropenia, pulmonary embolism, mucosal inflammation, febrile neutropenia Neutropenia Stomatitis, hyperbilirubinemia, Palmarplantar erythrodysesthesia syndrome Neutropenia, febrile neutropenia, mucositis, corneal disorder Mucositis, exfoliative rash, hand-foot syndrome, hyperbilirubinemia Pneumonia and parainfluenza
DLT or main side effects
SD ≥4 mo: 10/44 pts (23 %)
-
SD ≥4 cycles: 6/41 pts (15 %) 1 CR; No PD (includes 1CR) > 4 mo: 7/37 pts (19 %) SD ≥5 mo: 4/22 pts (18 %) SD > 4 mo: 6/29 pts (21 %)
≥PR: 8/19 pts (42 %); 2 MR
1 near CR, 6 PR, 5 MR
13
3 CR; 1 MR; SD ≥10 mo: 4/31 pts (13 %) 1 PR; SD: 10/34 pts (29 %)
29
15
27 28
25 26
24
23
14
22 12
19 20 21 11
18
9 16 17
10
Ref.
SD ≥12 weeks: 2/16 pts (13 %) No remissions or responses
SD ≥18 weeks: 7 pts SD: 8/16 pts (50 %) SD ≥8 weeks: 5/16 pts (31 %) SD ≥12 weeks: 7/41 pts (17 %)
SD ≥4 cycles: 3/24 pts (13 %)
2 PR; SD ≥3 cycles: 13 pts SD ≥6 cycles: 6/30 pts (20 %) 3 PR; SD ≥90 days: 4/15 pts (27 %)
SD ≥6 cycles: 5 pts
Activity
Ref references, ST solid tumors, Lymp lymphoma, AML acute myeloid leukemia, MDS myelodysplastic syndrome, pts patients, y years, mo months, CR complete remission, PR partial response, MR minimal response, SD stable disease, PD progressive disease, - unknown
ST ST
MK-0731 ARQ621
44 pts; 32–80 y 41 pts; 34–78 y
28 pts; 31–79 y
Multiple myeloma
ST, lymp ST
20 pts; 43–80 y
Multiple myeloma
SB-743921 ALN-VSP02
ARRY-520 36 pts; 21–88 y
62 pts; 44–77 y 30 pts; 23–84 y
ST, lymp AML
AZD4877
AML, MDS
24 pts; 41–76 y 16 pts; 36–75 y 18 pts; 45–75 y 43 pts; 39–83 y
ST ST ST ST
31 pts; 43–79 y
24 pts; 1–19 y
ST
Multiple myeloma
54 pts; ≥18 y 30 pts; ≥18 y 16 pts; 26–82 y
ST, other ST Breast cancer
Ispinesib (SB-715992)
51 pts; >16 y
ST, other
LY2523355
Number of patients; Age
Disease
Compound
Table 6 Summary of Eg5 inhibitors in clinical phase I studies
Cancer Chemother Pharmacol
13
leukopenia, and febrile neutropenia. These toxicities were manageable with appropriate supportive care measures such as the use of G-CSF and antibiotics. Significant nonhematologic toxicities, particularly neurotoxicities that are typically seen with microtubule-targeting agents, were not observed. The results support evidence that Eg5 inhibitors are not inherently neurotoxic. A number of Eg5 inhibitors have been examined for their potential use as anticancer agents [9–29]. An analysis of phase 1 studies of Eg5 inhibitors has shown neutropenia as the major dose-limiting toxicity as shown in Table 6. Bone marrow suppression, in particular neutropenia, was also seen in our study and seems to be the class effect of Eg5 inhibitors in general. Neutropenia could be considered as a pharmacodynamics marker of pharmacological effect of Eg5 inhibitors. Thus, numerous early clinical trial data indicate that they are generally well tolerated at biologically active doses, with neutropenia being dose-limiting and showing little evidence of neurotoxicity. LY2523355 Cmax and AUC increase approximately proportionally to the dose administered, supporting an approximately linear PK profile. The PK parameters for LY2523355 in Japanese patients were comparable with those reported in Western patients [9]. Interestingly, the AUC0–24 and Cmax following 5 mg/m2/day of LY2523355 in the present study were comparable with the calculated LY2523355 AUC0–∞ and Cmax at which 50 % of maximum achievable pharmacodynamics effect in tumor biopsies obtained in the overseas phase 1 study [9]. This suggests that the drug may have reached its target pharmacological dose. Despite the fact that LY2523355 exhibits promising preclinical activity, this trial did not show a clinical benefit. The result is consistent with what has been reported in the phase 1 trials with most other Eg5 inhibitors [9–29] as shown in Table 6. This suggests that cancer in humans is a complex disease although it is impossible to conclude anything based on the result from phase 1 studies because the population is comprised of heavily pretreated patients and only a small number of patients were evaluated. Recently, however, some potential reasons for marginal efficacy of inhibitors targeting mitosis have been discussed. For example, reduced spindle assembly checkpoint activity in some cancer cells, or increased slippage rate, may reduce sensitivity to killing by spindle-perturbing drugs [30]. KomlodiPasztor et al. [31, 32] reported that the majority of human tumors do not divide rapidly enough to be susceptible to such drugs, and more importantly, they divide much slower than vulnerable marrow elements. This is supported by the fact that there was expected neutropenia in human subjects. They also reported that microtubule-targeting agents kill cancer cells in patients principally by interfering with interphase microtubule functions, for example, intracellular trafficking, not by disrupting mitosis.
13
Cancer Chemother Pharmacol
In summary, LY2523355 was well tolerated up to 5 mg/m2/day without DLTs in Japanese patients with advanced solid tumors. PK profiles for LY2523355 in Japanese patients were similar to those observed in Western populations. Acknowledgments We thank the patients, their families and caregivers, and all personnel who contributed to patient care and data collection. This study was sponsored by Kyowa Hakko Kirin Co., Ltd.
References 1. Blangy A, Lane HA, d’Hérin P, Harper M, Kress M, Nigg EA (2005) Phosphorylation by p34cdc2 regulates spindle association of human Eg5, a kinesin-related motor essential for bipolar spindle formation in vivo. Cell 83:1159–1169 2. Sakowicz R, Finer JT, Beraud C, Crompton A, Lewis E, Fritsch A, Lee Y, Mak J, Moody R, Turincio R, Chabala JC, Gonzales P, Roth S, Weitman S, Wood KW (2004) Antitumor activity of a kinesin inhibitor. Cancer Res 64:3276–3280 3. Marcus AI, Peters U, Thomas SL, Garrett S, Zelnak A, Kapoor TM, Giannakakou P (2005) Mitotic kinesin inhibitors induce mitotic arrest and cell death in Taxol-resistant and -sensitive cancer cells. J Biol Chem 280:11569–11577 4. Wiltshire C, Singh BL, Stockley J, Fleming J, Doyle B, Barnetson R, Robson CN, Kozielski F, Leung HY (2010) Docetaxel-resistant prostate cancer cells remain sensitive to S-trityl-l-cysteine– Mediated Eg5 inhibition. Mol Cancer Ther 9:1730–1739 5. Hedge P, Cogswell J, Carrick K, Jackson JR, Wood KW, Eng WK, Brawner M, Huang PS, Bergsma D (2003) Differential gene expression analysis of kinesin spindle protein in human solid tumors. Proc Am Soc Clin Oncol 22:abst 535 6. Carter BZ, Mak DH, Shi Y, Schober WD, Wang RY, Konopleva M, Koller E, Dean NM, Andreeff M (2006) Regulation and targeting of Eg5, a mitotic motor protein in blast crisis CML: overcoming imatinib resistance. Cell Cycle 5:2223–2229 7. Saijo T, Ishii G, Ochiai A, Yoh K, Goto K, Nagai K, Kato H, Nishiwaki Y, Saijo N (2006) Eg5 expression is closely correlated with the response of advanced non-small cell lung cancer to antimitotic agents combined with platinum chemotherapy. Lung Cancer 54:217–225 8. Ye XS, Fan L, Van Horn R, Yin T, Nakai R, Ohta Y, Credille K, Donoho G, Akinaga S, Murakata C, Perkins E, Ocheltree S, Yamashita Y, Blanchard K, Westin E (2009) A novel Eg5 inhibitor that causes mitotic arrest leading to rapid cancer cell death shows broad-spectrum antitumor activity in preclinical xenograft tumor models. In: Proceedings of the 2009 AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2009 Nov 15–19; Boston, MA: AACR; Mol Cancer Ther 8(12 Suppl 1): Abstract nr A62 9. Verschraegen C, Cohen RB, Olszanski AJ, Shaheen M, Nishida Y, Bauman J, Li L, Brandt JT, Nasir A, Hynes SM, Leohr JK, McGlothlin A, Westin EH (2011) A phase 1 study of LY2523355, an Eg5 inhibitor, administered on Days 1, 2, and 3 with or without pegfilgrastim in patients with advanced malignancy (NCT01214642). In: Proceedings of the 2011 AACR-NCIEORTC International Conference on Molecular Targets and Cancer Therapeutics; 2011 Nov 12–16; San Francisco, California. Philadelphia (PA): AACR; Mol Cancer Ther 10(11 Suppl): Abstract nr A86 10. Shih KC, Infante JR, Papadopoulos KP, Bendell JC, Tolcher AW, Burris HA, Beeram M, Jackson L, Arcos R, Westin EH,
Cancer Chemother Pharmacol Farrington D, McGlothlin A, Hynes S, Leohr J, Brandt JT, Nasir A, Patnaik A (2011) A phase I dose-escalation study of LY2523355, an Eg5 inhibitor, administered either on days 1, 5, and 9; days 1 and 8; or days 1 and 5 with pegfilgrastim (peg) every 21 days (NCT01214642). J Clin Oncol 29:(suppl; abstr 2600) 11. Infante JR, Kurzrock R, Spratlin J, Burris HA, Eckhardt SG, Li J, Wu K, Skolnik JM, Hylander-Gans L, Osmukhina A, Huszar D, Herbst RS (2012) A Phase I study to assess the safety, tolerability, and pharmacokinetics of AZD4877, an intravenous Eg5 inhibitor in patients with advanced solid tumors. Cancer Chemother Pharmacol 69:165–172 12. Kantarjian HM, Padmanabhan S, Stock W, Tallman MS, Curt GA, Li J, Osmukhina A, Wu K, Huszar D, Borthukar G, Faderl S, Garcia-Manero G, Kadia T, Sankhala K, Odenike O, Altman JK, Minden M (2012) Phase I/II multicenter study to assess the safety, tolerability, pharmacokinetics and pharmacodynamics of AZD4877 in patients with refractory acute myeloid leukemia. Invest New Drugs 30:1107–1115 13. Shah JJ, Zonder J, Cohen A, Orlowski RZ, Alexanian R, Thomas SK, Weber D, Kaufman JL, Harvey RD, Walker D, Litwiler K, Karan S, Hilder B, Ptaszynski AM, Lonial S (2011) ARRY-520 shows Durable responses in patients with relapsed/refractory multiple myeloma in a phase 1 dose-escalation study. Blood 118:2011 (ASH Annual Meeting; abstract 1860) 14. Khoury HJ, Garcia-Manero G, Borthakur G, Kadia T, Foudray MC, Arellano M, Langston A, Bethelmie-Bryan B, Rush S, Litwiler K, Karan S, Simmons H, Marcus AI, Ptaszynski M, Kantarjian H (2012) A phase 1 dose-escalation study of ARRY-520, a kinesin spindle protein inhibitor, in patients with advanced myeloid leukemias. Cancer 118:3556–3564 15. 4SC (2012) Press release: 4SC reports positive data from clinical Phase I trial with 4SC-205 in cancer patients and initiates study amendment. http://www.4sc.de/news-media/corporatenews/2012. Accessed 12 Feb 2014 16. Burris HA 3rd, Jones SF, Williams DD, Kathman SJ, Hodge JP, Pandite L, Ho PT, Boerner SA, Lorusso P (2011) A phase I study of ispinesib, a kinesin spindle protein inhibitor, administered weekly for three consecutive weeks of a 28-day cycle in patients with solid tumors. Invest New Drugs 29:467–472 17. Gomez HL, Philco M, Pimentel P, Kiyan M, Monsalvo ML, Conlan MG, Saikali KG, Chen MM, Seroogy JJ, Wolff AA, Escandon RD (2012) Phase I dose-escalation and pharmacokinetic study of ispinesib, a kinesin spindle protein inhibitor, administered on days 1 and 15 of a 28-day schedule in patients with no prior treatment for advanced breast cancer. Anticancer Drugs 23:335–341 18. Souid AK, Dubowy RL, Ingle AM, Conlan MG, Sun J, Blaney SM, Adamson PC (2010) A pediatric phase I trial and pharmacokinetic study of ispinesib: a Children’s Oncology Group phase I consortium study. Pediatr Blood Cancer 55:1323–1328 19. Blagden SP, Molife LR, Seebaran A, Payne M, Reid AH, Protheroe AS, Vasist LS, Williams DD, Bowen C, Kathman SJ, Hodge JP, Dar MM, de Bono JS, Middleton MR (2008) A phase I trial of ispinesib, a kinesin spindle protein inhibitor, with docetaxel in patients with advanced solid tumours. Br J Cancer 98:894–899 20. Calvo E, Chu Q, Til E, Rowinsky E, Patnaik A, Takimoto C, Kathman S, Williams D, Bowen C, Hodge J, Dar M, Tolcher A (2005) Phase I Study Of Ispinesib In Combination With Capecitabine in Patients With Advanced Solid Tumors. AACR-NCIEORTC, November 2005
21. Esaki T, Seto T, Ariyama H, Arita S, Fujimoto C, Tsukasa K, Kometani T, Nosaki K, Hirai F, Yagawa K (2011) Phase I study to assess the safety, tolerability and pharmacokinetics of AZD4877 in Japanese patients with solid tumors. Arch Drug Inf 4:23–31 22. Gerecitano JF, Stephenson JJ, Lewis NL, Osmukhina A, Li J, Wu K, You Z, Huszar D, Skolnik JM, Schwartz GK (2013) A Phase I trial of the kinesin spindle protein (Eg5) inhibitor AZD4877 in patients with solid and lymphoid malignancies. Invest New Drugs 31:355–362 23. Shah JJ, Feng L, Thomas SK, Weber DM, Wang M, Hilder B, Alexanian R, Orlowski RZ (2013) Phase 1 study of the novel kinesin spindle protein inhibitor ARRY-520 (Filanesib) + Carfilzomib (Car) in patients with relapsed and/or refractory multiple myeloma (RRMM). Annual Meeting of ASH: abstract 1982 24. Chari A, Htut M, Zonder J, Fay JW, Jakubowiak AJ, Harrison B, Lau K, Hilder B, Ptaszynski A, Rush SA, Kaufman JL, Burt SM (2013) A phase 1 study of ARRY-520 (Filanesib) with bortezomib (BTZ) and dexamethasone (dex) in relapsed or refractory multiple myeloma (RRMM). Annual Meeting of ASH: abstract 1938 25. Holen KD, Belani CP, Wilding G, Ramalingam S, Volkman JL, Ramanathan RK, Vasist LS, Bowen CJ, Hodge JP, Dar MM, Ho PT (2011) A first in human study of SB-743921, a kinesin spindle protein inhibitor, to determine pharmacokinetics, biologic effects and establish a recommended phase II dose. Cancer Chemother Pharmacol 67:447–454 26. Tabernero J, Shapiro GI, Lorusso PM, Cervantes A, Schwartz GK, Weiss GJ, Paz-Ares L, Cho DC, Infante JR, Alsina M, Gounder MM, Falzone R, Harrop J, White AC, Toudjarska I, Bumcrot D, Meyers RE, Hinkle G, Svrzikapa N, Hutabarat RM, Clausen VA, Cehelsky J, Nochur SV, Gamba-Vitalo C, Vaishnaw AK, Sah DW, Gollob JA, Burris HA 3rd (2013) First-in-humans trial of an RNA interference therapeutic targeting VEGF and KSP in cancer patients with liver involvement. Cancer Discov 3:406–417 27. Holen K, DiPaola R, Liu G, Tan AR, Wilding G, Hsu K, Agrawal N, Chen C, Xue L, Rosenberg E, Stein M (2012) A phase I trial of MK-0731, a kinesin spindle protein (KSP) inhibitor, in patients with solid tumors. Invest New Drugs 30:1088–1095 28. Rosen L, Chen L, Iyengar T, Goldman J, Lahr S, Savage R, Wang Y, Kazakin J, Chan TCK, Schwartz B, Abbadessa G, Von Hoff D (2011) First in human study with ARQ 621, a novel inhibitor of Eg5: final results. Annual Meeting of ASCO: abstract 3076 29. Hollebecque A, Deutsch E, Massard C, Gomez-Roca C, Bahleda R, Ribrag V, Bourgier C, Lazar V, Lacroix L, Gazzah A, Varga A, de Baere T, Beier F, Kroesser S, Trang K, Zenke FT, Klevesath M, Soria JC (2013) A phase I, dose-escalation study of the Eg5inhibitor EMD 534085 in patients with advanced solid tumors or lymphoma. Invest New Drugs. doi:10.1007/s10637-013-0026-9 30. Huang HC, Shi J, Orth JD, Mitchison TJ (2009) Evidence that mitotic exit is a better cancer therapeutic target than spindle assembly. Cancer Cell 16:347–358 31. Komlodi-Pasztor E, Sackett D, Wilkerson J, Fojo T (2011) Mitosis is not a key target of microtubule agents in patient tumors. Nat Rev Clin Oncol 8:244–250 32. Komlodi-Pasztor E, Sackett DL, Fojo AT (2012) Inhibitors targeting mitosis: tales of how great drugs against a promising target were brought down by a flawed rationale. Clin Cancer Res 18:51–63
13
Original Article
A phase 1 and dose‑finding study of LY2523355 (litronesib), an Eg5 inhibitor, in Japanese patients with advanced solid tumors Hiroshi Wakui · Noboru Yamamoto · Satoru Kitazono · Hidenori Mizugaki · Shinji Nakamichi · Yutaka Fujiwara · Hiroshi Nokihara · Yasuhide Yamada · Kohei Suzuki · Hironori Kanda · Shiro Akinaga · Tomohide Tamura
Received: 21 March 2014 / Accepted: 8 April 2014 © Springer-Verlag Berlin Heidelberg 2014
Abstract Purpose Eg5, a mitotic motor kinesin protein, plays an essential role in bipolar spindle formation in the M phase of the cell cycle. LY2523355 (litronesib) is an allosteric inhibitor of Eg5. This phase 1 and dose-finding study aimed to assess the safety, pharmacokinetics (PK), recommended dose for further studies, and preliminary efficacy in Japanese patients with advanced solid tumors. Methods LY2523355 was given on days 1, 2, and 3 every 3 weeks at one of three dose levels: 2, 4, and 5 mg/m2/day. Toxicity was assessed according to NCI-CTCAE version 4.0, and tumor response according to RECIST version 1.1. granulocyte colony-stimulating factor (G-CSF) was used only for grade 4 neutropenia or grade 3 febrile neutropenia. Results Twelve patients were treated at doses of 2 (n = 3), 4 (n = 3), and 5 (n = 6) mg/m2/day. Most frequent treatment-related adverse events were neutropenia and leukopenia (100 %). Grade 4 neutropenia was observed in 83 %, but all recovered to above 500 neutrophils/μl within 7 days. All patients at 4 and 5 mg/m2/day required G-CSF support. No dose-limiting toxicities were reported up to 5 mg/m2/day. In PK analysis, LY2523355 exposure increased in a dose-dependent manner. The PK parameters H. Wakui · N. Yamamoto · S. Kitazono · H. Mizugaki · S. Nakamichi · Y. Fujiwara · H. Nokihara · T. Tamura (*) Department of Thoracic Oncology, National Cancer Center Hospital, 5‑1‑1, Tsukiji, Chuo‑ku, Tokyo 104‑0045, Japan e-mail: [email protected] Y. Yamada Department of Gastrointestinal Oncology, National Cancer Center Hospital, 5‑1‑1, Tsukiji, Chuo‑ku, Tokyo 104‑0045, Japan K. Suzuki · H. Kanda · S. Akinaga Development Division, Kyowa Hakko Kirin Co., Ltd, 1‑6‑1, Ohtemachi, Chiyoda‑ku, Tokyo 100‑8185, Japan
for LY2523355 were similar to those observed in Western populations. No objective tumor responses were observed. Conclusions The recommended dose of LY2523355 with therapeutic G-CSF use for further studies was determined to be 5 mg/m2/day in Japanese patients with advanced solid tumors. Keywords LY2523355 · Litronesib · Eg5 inhibitor · Phase 1 study · Solid tumor
Introduction Eg5, also known as kinesin spindle protein, is a mitosisspecific motor protein that hydrolyzes ATP to produce force and moves along microtubules. It is essential for bipolar spindle formation and subsequent chromosome separation in the M phase [1]. Since Eg5 is not expressed in post-mitotic neurons and is likely to act only in dividing cells [2], inhibition of Eg5 may not cause any neuropathic adverse events as opposed to traditional tubulin-binding agents such as vinca alkaloids and taxanes. Importantly, some researchers have reported that Eg5 inhibitors induce mitotic arrest and cell death in taxane-resistant and/or taxane-sensitive cancer cells [3, 4]. Interestingly, Eg5 is overexpressed in tumor cells relative to normal cells [5, 6], and the positive correlation between Eg5 expression and the response of non-small-cell lung cancer to antimitotic agents has been reported [7]. Thus, Eg5 is a particularly attractive target for novel anticancer therapies [2], and recent efforts have been increased to develop Eg5 inhibitors since the development of ispinesib began. LY2523355 (litronesib) is a specific, ATP-uncompetitive, allosteric, and potent small-molecule inhibitor of Eg5 that has been shown to prevent centrosome separation and
13
mitotic spindle assembly. This leads to the formation of monopolar spindles, activation of spindle checkpoint proteins, mitotic arrest, and eventually cell death. LY2523355 has demonstrated promising anticancer activity across a broad range of solid tumors in vitro and in vivo [8]. In parallel with the present study, several clinical studies on LY2523355, the second highest number following ispinesib, have already been conducted in several countries [9, 10]. In addition to the fact that some patients experienced partial response with an acceptable tolerability profile, evidence of the formation of monopolar spindles as a proof of mechanism in a clinical setting has been presented [9]. Pharmacodynamics data from skin and tumor biopsies demonstrated an LY2523355 exposure-dependent response in phosphohistone H3, which is a specific marker for mitosis [9]. The most frequent-related adverse events were hematologic such as neutropenia [9, 10]. Eventually, LY2523355 administration for three consecutive days with prophylactic granulocyte colony-stimulating factor (G-CSF) support has been adapted as a best-dose schedule for the phase 2 clinical investigation. There were no prior clinical reports of LY2523355 administration in Japanese patients. In fact, a phase 1 study of this compound in Asian patients had yet to be conducted. We therefore conducted the first phase 1 clinical trial in Japanese patients with advanced or metastatic solid tumors to evaluate the tolerability and safety of LY2523355 administered on days 1, 2, and 3 to determine the recommended dose for further studies. The need for therapeutic G-CSF use not prophylactic G-CSF support was tested in the population.
Patients and methods Patient eligibility Eligible patients possessed histologically or cytologically confirmed advanced or metastatic solid tumors that were refractory to standard treatment. Eligibility criteria also included the following: age ≥20 years at informed consent; Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0–1; life expectancy >3 months; adequate hematologic [absolute neutrophil count (ANC) ≥1,500/μl; platelet count ≥100,000/μl; hemoglobin ≥9 g/dl], hepatic [total bilirubin ≤1.5 × upper limit of normal (ULN); alanine and aspartate aminotransferase ≤98 IU/l], and renal functions (serum creatinine ≤1.5 mg/dl); and no previous chemotherapy, radiation therapy, hormonal therapy, or surgery within 4 weeks before treatment with LY2523355 (6 weeks for previous treatment with nitrosoureas and mitomycin C). Any toxicity related to prior therapy must have recovered to ≤grade 1.
13
Cancer Chemother Pharmacol
Exclusion criteria included the following: previous treatment with LY2523355 therapy; active infections requiring treatment; symptomatic brain metastasis; current acute or chronic leukemia; a history of an autologous or allogenic hematopoietic stem cell transplantation; uncontrolled or significant cardiovascular or pulmonary disease; hepatic B or C virus or human immunodeficiency virus infection; and pregnancy, lactation, or possibility of pregnancy. Written informed consent was obtained from all patients. This study was conducted in accordance with the Declaration of Helsinki and the applicable guidelines on good clinical practice, and the protocol and the informed consent received institutional review board/independent ethics committee approval. Study design This was an open-label, single-center, dose-escalation, phase 1 study in Japanese patients (Clinicaltrials.gov Identifier: NCT01358019). The primary objective was to evaluate the safety and pharmacokinetics (PK) of LY2523355 in Japanese patients with advanced solid tumors. Secondary objectives were to determine a recommended dose for Japanese studies and to obtain a preliminary assessment of tumor response. Drug administration and dose‑escalation procedure Eligible patients were treated with LY2523355 by 60-min IV administration on days 1, 2, and 3 every 3 weeks at one of three dose levels: 2, 4, and 5 mg/m2/day. Cycles were repeated until disease progression, unacceptable toxicity, or until the patient or the investigator requested therapy discontinuation. Dose was escalated by a classic 3 + 3 design. Dose-limiting toxicities (DLTs) were evaluated from the initial dose to cycle 1 day 21. Patients were hospitalized during the DLT evaluation period. DLTs were defined as any of the following toxicities assessed to have a causal relationship with the study drug: (1) grade 4 thrombocytopenia or grade 3 thrombocytopenia requiring blood transfusion; (2) grade 4 neutropenia that lasted >7 days; (3) a neutrophil count of 2 days; (4) grade 3 or worse non-hematologic toxicities except for nausea, vomiting, or diarrhea without maximal supportive treatment, and except for a transient electrolyte abnormality. G-CSF was used only for grade 4 neutropenia or grade 3 febrile neutropenia. Safety assessments Treatment-emergent adverse events were assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE version 4.0)
Cancer Chemother Pharmacol
throughout the treatment period until 30 days after the last dose. PS was examined prior to study entry, before each cycle, and at the end of the study. Vital signs were assessed prior to study entry, at days 1, 2, 3, 8, 15, and 22 of cycle 1, at days 1 and 8 of each cycle from the following cycle, and at the end of the study. Twelve-lead electrocardiograms were performed prior to study entry, at days 1, 3, and 8 of cycles 1 and 2, before every cycle from cycle 3, and at the end of the study. Cerebellar function was tested per each dose during cycle 1, and at days 1 and 3 of each cycle from the following cycle. Clinical laboratory tests were examined prior to study entry, at days 1, 4, 8, 11, 15, and 22 of cycle 1, at days 1 and 8 of each cycle from the following cycle (plus at days 15–22 of cycle 2 for hematology), and at the end of the study. Urinalysis was performed prior to study entry, at days 1, 8, and 22 of cycle 1, before each cycle from the following cycle, and at the end of the study. A pregnancy test was performed prior to study entry and before even numbered cycles.
Table 1 Patient characteristics
Pharmacokinetic analyses
Prior therapy [n (%)] Chemotherapy Median number of chemotherapy regimens (range) Surgery Radiotherapy
Plasma samples for PK evaluation were collected during cycle 1, on day 1 prior to dose and at 0, 1, 2, 4, and 8 h after the completing of infusion, on day 2 prior to dose, on day 3 prior to dose and at 0, 1, 2, 4, and 8 h after the completing of infusion, and on days 4, 5, and 8 at the same hour as the start of infusion on day 3. Additional samples were collected on day 1 prior to dose and immediately after the completing of infusion, and on day 3 immediately after the completing of infusion during cycle 2. LY2523355 was extracted from plasma samples and then analyzed by liquid chromatography–tandem mass spectrometry (LC–MS/MS). PK parameters of LY2523355 and its active metabolite, M1, included maximum concentration (Cmax), area under concentration–time curve from 0 to 24 h (AUC0–24), clearance (CL), time to Cmax (tmax), terminal half-life (t1/2), intracycle accumulation ratio (Ra), and metabolic ratio. Tumor response Tumor response was assessed with Response Evaluation Criteria in Solid Tumors (RECIST version 1.1). Baseline radiologic tumor assessments were performed within 14 days prior to study entry, and subsequent tumor evaluations were performed on days 15–22 of cycle 1 and subsequent even numbered cycles, and at the end of the study. The minimum period of stable disease was defined as 36 days. Statistical analyses Descriptive statistics was used to summarize safety, PK parameters, and tumor response from all dosed patients.
Characteristics
n = 12
Age (years) Median (range)
61.5 (36–71)
Gender [n (%)] Male Female
7 (58 %) 5 (42 %)
ECOG PS [n (%)] 0 1
7 (58 %) 5 (42 %)
Tumor type [n (%)] Colorectal Non-small-cell lung Small-cell lung Angiosarcoma Breast Esophageal Gastric Ovarian
3 (25 %) 2 (17 %) 2 (17 %) 1 (8 %) 1 (8 %) 1 (8 %) 1 (8 %) 1 (8 %)
Hormonal therapy
12 (100 %) 4 (1–8) 10 (83 %) 3 (25 %) 1 (8 %)
Results Patient characteristics Twelve patients were enrolled at the National Cancer Center Hospital, Tokyo, Japan, from June 2011 to May 2012, and received at least one dose of LY2523355 at doses of 2 (n = 3), 4 (n = 3), and 5 (n = 6) mg/m2/day. Patient characteristics are listed in Table 1. The median age was 61.5 years (range 36–71), and seven patients (58 %) were men. Seven patients had an ECOG PS of 0, and five had a PS of 1. Tumor types included colorectal cancer (3), non-small-cell lung cancer (2), small-cell lung cancer (2), angiosarcoma (1), breast cancer (1), esophageal cancer (1), gastric cancer (1), and ovarian cancer (1). All patients had received previous chemotherapy for their cancer. The median number of prior chemotherapy regimens (range) was 4 (1–8). Safety and tolerability The most frequent treatment-emergent adverse events occurring in ≥25 % of patients throughout the study are shown in Table 2. The most common toxicities noted were hematologic such as neutropenia and leukopenia (100 %),
13
Cancer Chemother Pharmacol
Table 2 Treatment-emergent adverse events of any grade reported in three or more patients (≥25 % of patients), all cycles Patients with treatment-emergent adverse events, n (%) LY2523355 dose 2 mg/m2/day (n = 3)
4 mg/m2/day (n = 3)
5 mg/m2/day (n = 6)
Total (n = 12)
Neutropenia Leukopenia Lymphopenia Febrile neutropenia
3 (100) 3 (100) 3 (100) 0
3 (100) 3 (100) 3 (100) 2 (67)
6 (100) 6 (100) 5 (83) 6 (100)
12 (100) 12 (100) 11 (92) 8 (67)
Anemia Alkaline phosphatase increased Hyponatremia Diarrhea γ-glutamyl transpeptidase increased Hypercalcemia Pruritus Stomatitis Fatigue Alanine aminotransferase increased Aspartate aminotransferase increased Thrombocytopenia Loss of body weight Hyperglycemia Hypoalbuminemia
1 (33) 2 (67) 1 (33) 1 (33) 0 0 2 (67) 0 0 0 1 (33) 1 (33) 1 (33) 0 0
1 (33) 1 (33) 1 (33) 1 (33) 1 (33) 1 (33) 2 (67) 0 2 (67) 1 (33) 1 (33) 0 1 (33) 2 (67) 1 (33)
3 (50) 2 (33) 3 (50) 2 (33) 3 (50) 3 (50) 0 3 (50) 1 (17) 2 (33) 1 (17) 2 (33) 1 (17) 1 (17) 2 (33)
5 (42) 5 (42) 5 (42) 4 (33) 4 (33) 4 (33) 4 (33) 3 (25) 3 (25) 3 (25) 3 (25) 3 (25) 3 (25) 3 (25) 3 (25)
Oropharyngeal pain
0
1 (33)
2 (33)
3 (25)
Table 3 Grade 3 and higher treatment-emergent adverse events by dose level, all cycles
Patients with treatment-emergent adverse events, n (%) LY2523355 dose
Neutropenia Leukopenia Febrile neutropenia Lymphopenia Ileal perforation Peritonitis Alkaline phosphatase increased Hyponatremia
4 mg/m2 (n = 3)
5 mg/m2 (n = 6)
Grade 3
Grade 4
Grade 3
Grade 3
1 (33)
1 (33) 2 (67) 2 (67) 1 (33)
Grade 4 3 (100) 1 (33)
4 (67) 6 (100) 1 (17)
Grade 4 6 (100) 2 (33)
1 (33) 1 (33) 1 (17) 1 (17)
Diabetic mellitus (worsening) Hyperuricemia
1 (17) 1 (17)
Hemoptysis
1 (17)
lymphopenia (92 %), febrile neutropenia (67 %), consistent with the toxicities predicted from the preclinical animal data and the Western phase 1 [9, 10] and phase 2 studies. Neutropenia was the CTCAE grade ≥3 event most commonly reported, both during cycle 1 and throughout the study [overall, n = 11 (92 %)]. Ten of 12 (83 %) patients experienced grade 4 neutropenia (Table 3) requiring G-CSF therapy. The
13
2 mg/m2 (n = 3)
neutropenia nadir occurred at 8–11 days after the infusion of LY2523355, but all recovered to above 500 neutrophils/μl within 7 days. Grade 3 or 4 leukopenia occurred in nine patients (three at the 4 mg/m2/day and six at the 5 mg/m2/ day dose levels). Also, grade 3 febrile neutropenia occurred in eight patients (two at the 4 mg/m2/day and six at the 5 mg/ m2/day dose levels). Two patients experienced a fever over
Cancer Chemother Pharmacol Fig. 1 Plasma concentration– time profiles for LY2523355 (a) and M1 (b) (mean + standard deviation)
38.5 °C, but it decreased ≤2 days with antibiotic treatment in addition to G-CSF therapy. Other than the events described above, it should be noted that even though the severity of stomatitis observed in two patients at the 5 mg/m2/day dose level was grade 2, the events required some treatment such as oral rinse, dexamethasone ointment, and fluid. There was no increase in preexisting neuropathy and no new significant neuropathy. No clinically significant treatment-emergent changes in physical findings, vital signs, or electrocardiograms were reported. Four serious adverse events were reported in three patients: ileus, ileal perforation, hemoptysis, and constipation. Only the constipation event was considered to be possibly related to the study treatment. Two patients discontinued LY2523355 treatment due to disease progression and the investigator’s discretion (switching to another therapy on disease progression). There were no deaths during the study. No DLTs were reported in this study. The maximum tolerated dose was not defined in this population, and the 5 mg/m2/day dose level was expanded to six patients to establish the preliminary safety profile of the study agent.
Pharmacokinetics All patients had evaluable PK data obtained after the administration of LY252335 on days 1 and 3 of cycle 1, three patients each at the 2 and 4 mg/m2/day dose levels, and six patients at the 5 mg/m2/day dose level. The mean plasma concentrations of LY2523355 and M1, a main metabolite of LY2523355, increased in a dose-dependent manner and declined in a biphasic pattern (Fig. 1). The PK parameters of LY2523355 and M1 on days 1 and 3 of cycle 1 are presented in Tables 4 and 5, respectively. The Cmax and AUC0–24 of LY2523355 and M1 increased approximately dose-proportionally over the dose range from 2 to 5 mg/m2/day. The t1/2 and CL of LY2523355 were dose-independent, ranging from 17.5 to 22.9 h and 11.1 to 14.2 L/h/m2, respectively. The t1/2 of M1 ranged from 20.8 to 31.1 h. The metabolic ratio was stable across all doses investigated. There was no accumulation of LY2523355 and M1 among cycles. The PK parameters for LY2523355 were similar to those observed in Western populations [9].
13
Table 4 PK parameters for LY2523355 and active metabolite of LY2523355, M1, following dosing on day 1 of cycle 1
CV, coefficient of variation; Metabolic ratio, AUC0–24, M1/AUC0–24, LY2523355 Table 5 PK parameters for LY2523355 and active metabolite of LY2523355, M1, following dosing on day 3 of cycle 1
Cancer Chemother Pharmacol Parameter, mean (CV %)
LY2523355 dose 2 mg/m2/day (n = 3)
5 mg/m2/day (n = 6)
LY2523355 Cmax (ng/ml) AUC0–24 (ng h/ml) M1
65.30 (7.43)
122.2 (30.3)
160.6 (33.3)
139.80 (15.58)
252.66 (89.94)
384.66 (156.51)
tmax (h) Cmax (ng/ml) AUC0–24 (ng h/ml)
2.03 (0.00)
1.32 (0.62)
1.68 (0.52)
1.835 (0.673)
4.256 (1.511)
4.869 (1.234)
15.71 (6.54)
28.22 (11.73)
39.83 (12.32)
0.11 (0.04)
0.11 (0.01)
0.11 (0.03)
Metabolic ratio
Parameter, mean (CV %)
LY2523355 dose 2 mg/m2/day (n = 3)
4 mg/m2/day (n = 3)
5 mg/m2/day (n = 6)
LY2523355 Cmax (ng/ml) AUC0–24 (ng h/ml) t1/2 (h) CL (L/h/m2) Ra, Cmax
69.30 (7.2)
132.9 (21.9)
192.6 (31.2)
175.77 (7.6) 17.5 (17.4) 11.4 (7.5) 0.94 (4.8)
306.12 (35.4) 19.8 (38.5) 14.2 (33.9) 0.93 (15.4)
534.05 (53.7) 22.9 (30.3) 11.1 (36.2) 0.86 (13.9)
0.79 (6.9)
0.83 (12.7)
0.76 (12.9)
1.34 (44.9)
1.35 (46.6)
1.52 (37.5)
Ra, AUC M1
CV, coefficient of variation; Ra, Cmax, Cmax on day 1/Cmax on day 3; Ra, AUC, AUC0–24 on day 1/AUC0–24 on day 3; Metabolic ratio, AUC0–24, M1/AUC0–24,
4 mg/m2/day (n = 3)
tmax (h) Cmax (ng/ml) AUC0–24 (ng h/ml) t1/2 (h)
2.332 (42.8)
4.681 (22.5)
5.816 (41.6)
Ra, Cmax
23.33 (43.7) 20.8 (21.8) 0.80 (8.4)
42.31 (42.9) 25.3 (27.3) 0.94 (44.4)
55.58 (37.6) 31.1 (57.3) 0.89 (21.2)
Ra, AUC
0.68 (10.7)
0.70 (30.7)
0.74 (18.0)
Metabolic ratio
0.13 (43.9)
0.13 (15.6)
0.12 (41.9)
LY2523355
Tumor response No objective tumor responses were observed. The best overall response was stable disease (SD) in two patients. The longest duration of SD was 52 days, reported in both patients at the 4 mg/m2/day dose level. Five patients displayed progressive disease (PD). Another five patients were not evaluated.
Discussion From this phase 1 and dose-finding study of LY2523355 in Japanese patients with advanced or metastatic solid tumors, it was concluded that the recommended dose with a manageable safety profile of LY2523355 with therapeutic G-CSF use for further studies was 5 mg/m2/day on days 1–3 every 3 weeks. Initially, we planned four dose levels: 2, 4, 5, and 6 mg/m2/day. At the 5 mg/m2/day
13
dose level, however, grade 3 febrile neutropenia occurred in all patients with therapeutic G-CSF use. Dose escalation was halted at 5 mg/m2/day due to these safety concerns in addition to the fact that a dosage of 5 mg/m2/day with prophylactic G-CSF support was used in the parallel overseas phase 2 studies (ClinicalTrials.gov Identifier: NCT01025284; NCT01416389; NCT01059643). Even with G-CSF and/or antibiotic therapy, higher doses may not be tolerated considering the toxicity profile, particularly the occurrence of febrile neutropenia and grade 2 stomatitis requiring some treatment such as oral rinse, dexamethasone ointment, and fluid. Stomatitis and/or mucositis might be among the important and typical toxicities caused by Eg5 inhibition, as reported for other inhibitors [11–15]. The toxicity profile observed in this study was similar to that observed in overseas phase 1 studies of LY2523355 [9, 10]. The most common toxicities were hematologic, and the most common grade ≥3 toxicities thought to be attributable to LY2523355 treatment were neutropenia,
ST
ST, lymp
4SC-205
EMD534085
44 pts; 27–86 y
46 pts; -
43 pts; 23–75 y 48 pts; 28–82 y
Every 21 days
Days 1, 8, or days 1,4, 8, 11; 21-day cycle
Every 21 days Weekly
Days 1, 2, 15, 16; 28-day cycle + carfilzomib Days 1, 2, 15, 16, or days 1, 15; 28-day cycle + Bortezomib Every 21 days Every 2 weeks
Day 1 or days 1, 3, 5 per cycle
Days 1, 2; every 2 weeks
Days 1,4, 8, 11; 21-day cycle Days 1, 2, 3; 2-week cycle
Every 21 days + docetaxel Every 21 days + capecitabine Days 1, 8, 15; 28-day cycle Days 1, 8, 15; 28-day cycle
Days 1, 8, 15; 28-day cycle
Days 1, 2, 3; 21-day cycle Days 1, 8, 15; 28-day cycle Days 1, 15; 28-day cycle
2 –3 doses; 21-day cycle
Dosing schedule
Neutropenia, Acute coronary syndrome
Neutropenia (major DLT) Hepatic failure leading to death, Thrombocytopenia, Hypokalemia Neutropenia Fatigue, Intravascular hemolysis, Nausea, Headache, Peripheral sensory neuropathy Neutropenia, Stomatitis (main side effects)
None (higher dose)
Neutropenia, Febrile neutropenia (main DLTs) Febrile neutropenia (main DLT) Neutropenia Increased aspartate and alanine aminotransferases Neutropenia, hyperbilirubinemia, elevated aspartate and alanine aminotransferases Neutropenia, febrile neutropenia Neutropenia Neutropenia, febrile neutropenia Neutropenia, pulmonary embolism, mucosal inflammation, febrile neutropenia Neutropenia Stomatitis, hyperbilirubinemia, Palmarplantar erythrodysesthesia syndrome Neutropenia, febrile neutropenia, mucositis, corneal disorder Mucositis, exfoliative rash, hand-foot syndrome, hyperbilirubinemia Pneumonia and parainfluenza
DLT or main side effects
SD ≥4 mo: 10/44 pts (23 %)
-
SD ≥4 cycles: 6/41 pts (15 %) 1 CR; No PD (includes 1CR) > 4 mo: 7/37 pts (19 %) SD ≥5 mo: 4/22 pts (18 %) SD > 4 mo: 6/29 pts (21 %)
≥PR: 8/19 pts (42 %); 2 MR
1 near CR, 6 PR, 5 MR
13
3 CR; 1 MR; SD ≥10 mo: 4/31 pts (13 %) 1 PR; SD: 10/34 pts (29 %)
29
15
27 28
25 26
24
23
14
22 12
19 20 21 11
18
9 16 17
10
Ref.
SD ≥12 weeks: 2/16 pts (13 %) No remissions or responses
SD ≥18 weeks: 7 pts SD: 8/16 pts (50 %) SD ≥8 weeks: 5/16 pts (31 %) SD ≥12 weeks: 7/41 pts (17 %)
SD ≥4 cycles: 3/24 pts (13 %)
2 PR; SD ≥3 cycles: 13 pts SD ≥6 cycles: 6/30 pts (20 %) 3 PR; SD ≥90 days: 4/15 pts (27 %)
SD ≥6 cycles: 5 pts
Activity
Ref references, ST solid tumors, Lymp lymphoma, AML acute myeloid leukemia, MDS myelodysplastic syndrome, pts patients, y years, mo months, CR complete remission, PR partial response, MR minimal response, SD stable disease, PD progressive disease, - unknown
ST ST
MK-0731 ARQ621
44 pts; 32–80 y 41 pts; 34–78 y
28 pts; 31–79 y
Multiple myeloma
ST, lymp ST
20 pts; 43–80 y
Multiple myeloma
SB-743921 ALN-VSP02
ARRY-520 36 pts; 21–88 y
62 pts; 44–77 y 30 pts; 23–84 y
ST, lymp AML
AZD4877
AML, MDS
24 pts; 41–76 y 16 pts; 36–75 y 18 pts; 45–75 y 43 pts; 39–83 y
ST ST ST ST
31 pts; 43–79 y
24 pts; 1–19 y
ST
Multiple myeloma
54 pts; ≥18 y 30 pts; ≥18 y 16 pts; 26–82 y
ST, other ST Breast cancer
Ispinesib (SB-715992)
51 pts; >16 y
ST, other
LY2523355
Number of patients; Age
Disease
Compound
Table 6 Summary of Eg5 inhibitors in clinical phase I studies
Cancer Chemother Pharmacol
13
leukopenia, and febrile neutropenia. These toxicities were manageable with appropriate supportive care measures such as the use of G-CSF and antibiotics. Significant nonhematologic toxicities, particularly neurotoxicities that are typically seen with microtubule-targeting agents, were not observed. The results support evidence that Eg5 inhibitors are not inherently neurotoxic. A number of Eg5 inhibitors have been examined for their potential use as anticancer agents [9–29]. An analysis of phase 1 studies of Eg5 inhibitors has shown neutropenia as the major dose-limiting toxicity as shown in Table 6. Bone marrow suppression, in particular neutropenia, was also seen in our study and seems to be the class effect of Eg5 inhibitors in general. Neutropenia could be considered as a pharmacodynamics marker of pharmacological effect of Eg5 inhibitors. Thus, numerous early clinical trial data indicate that they are generally well tolerated at biologically active doses, with neutropenia being dose-limiting and showing little evidence of neurotoxicity. LY2523355 Cmax and AUC increase approximately proportionally to the dose administered, supporting an approximately linear PK profile. The PK parameters for LY2523355 in Japanese patients were comparable with those reported in Western patients [9]. Interestingly, the AUC0–24 and Cmax following 5 mg/m2/day of LY2523355 in the present study were comparable with the calculated LY2523355 AUC0–∞ and Cmax at which 50 % of maximum achievable pharmacodynamics effect in tumor biopsies obtained in the overseas phase 1 study [9]. This suggests that the drug may have reached its target pharmacological dose. Despite the fact that LY2523355 exhibits promising preclinical activity, this trial did not show a clinical benefit. The result is consistent with what has been reported in the phase 1 trials with most other Eg5 inhibitors [9–29] as shown in Table 6. This suggests that cancer in humans is a complex disease although it is impossible to conclude anything based on the result from phase 1 studies because the population is comprised of heavily pretreated patients and only a small number of patients were evaluated. Recently, however, some potential reasons for marginal efficacy of inhibitors targeting mitosis have been discussed. For example, reduced spindle assembly checkpoint activity in some cancer cells, or increased slippage rate, may reduce sensitivity to killing by spindle-perturbing drugs [30]. KomlodiPasztor et al. [31, 32] reported that the majority of human tumors do not divide rapidly enough to be susceptible to such drugs, and more importantly, they divide much slower than vulnerable marrow elements. This is supported by the fact that there was expected neutropenia in human subjects. They also reported that microtubule-targeting agents kill cancer cells in patients principally by interfering with interphase microtubule functions, for example, intracellular trafficking, not by disrupting mitosis.
13
Cancer Chemother Pharmacol
In summary, LY2523355 was well tolerated up to 5 mg/m2/day without DLTs in Japanese patients with advanced solid tumors. PK profiles for LY2523355 in Japanese patients were similar to those observed in Western populations. Acknowledgments We thank the patients, their families and caregivers, and all personnel who contributed to patient care and data collection. This study was sponsored by Kyowa Hakko Kirin Co., Ltd.
References 1. Blangy A, Lane HA, d’Hérin P, Harper M, Kress M, Nigg EA (2005) Phosphorylation by p34cdc2 regulates spindle association of human Eg5, a kinesin-related motor essential for bipolar spindle formation in vivo. Cell 83:1159–1169 2. Sakowicz R, Finer JT, Beraud C, Crompton A, Lewis E, Fritsch A, Lee Y, Mak J, Moody R, Turincio R, Chabala JC, Gonzales P, Roth S, Weitman S, Wood KW (2004) Antitumor activity of a kinesin inhibitor. Cancer Res 64:3276–3280 3. Marcus AI, Peters U, Thomas SL, Garrett S, Zelnak A, Kapoor TM, Giannakakou P (2005) Mitotic kinesin inhibitors induce mitotic arrest and cell death in Taxol-resistant and -sensitive cancer cells. J Biol Chem 280:11569–11577 4. Wiltshire C, Singh BL, Stockley J, Fleming J, Doyle B, Barnetson R, Robson CN, Kozielski F, Leung HY (2010) Docetaxel-resistant prostate cancer cells remain sensitive to S-trityl-l-cysteine– Mediated Eg5 inhibition. Mol Cancer Ther 9:1730–1739 5. Hedge P, Cogswell J, Carrick K, Jackson JR, Wood KW, Eng WK, Brawner M, Huang PS, Bergsma D (2003) Differential gene expression analysis of kinesin spindle protein in human solid tumors. Proc Am Soc Clin Oncol 22:abst 535 6. Carter BZ, Mak DH, Shi Y, Schober WD, Wang RY, Konopleva M, Koller E, Dean NM, Andreeff M (2006) Regulation and targeting of Eg5, a mitotic motor protein in blast crisis CML: overcoming imatinib resistance. Cell Cycle 5:2223–2229 7. Saijo T, Ishii G, Ochiai A, Yoh K, Goto K, Nagai K, Kato H, Nishiwaki Y, Saijo N (2006) Eg5 expression is closely correlated with the response of advanced non-small cell lung cancer to antimitotic agents combined with platinum chemotherapy. Lung Cancer 54:217–225 8. Ye XS, Fan L, Van Horn R, Yin T, Nakai R, Ohta Y, Credille K, Donoho G, Akinaga S, Murakata C, Perkins E, Ocheltree S, Yamashita Y, Blanchard K, Westin E (2009) A novel Eg5 inhibitor that causes mitotic arrest leading to rapid cancer cell death shows broad-spectrum antitumor activity in preclinical xenograft tumor models. In: Proceedings of the 2009 AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2009 Nov 15–19; Boston, MA: AACR; Mol Cancer Ther 8(12 Suppl 1): Abstract nr A62 9. Verschraegen C, Cohen RB, Olszanski AJ, Shaheen M, Nishida Y, Bauman J, Li L, Brandt JT, Nasir A, Hynes SM, Leohr JK, McGlothlin A, Westin EH (2011) A phase 1 study of LY2523355, an Eg5 inhibitor, administered on Days 1, 2, and 3 with or without pegfilgrastim in patients with advanced malignancy (NCT01214642). In: Proceedings of the 2011 AACR-NCIEORTC International Conference on Molecular Targets and Cancer Therapeutics; 2011 Nov 12–16; San Francisco, California. Philadelphia (PA): AACR; Mol Cancer Ther 10(11 Suppl): Abstract nr A86 10. Shih KC, Infante JR, Papadopoulos KP, Bendell JC, Tolcher AW, Burris HA, Beeram M, Jackson L, Arcos R, Westin EH,
Cancer Chemother Pharmacol Farrington D, McGlothlin A, Hynes S, Leohr J, Brandt JT, Nasir A, Patnaik A (2011) A phase I dose-escalation study of LY2523355, an Eg5 inhibitor, administered either on days 1, 5, and 9; days 1 and 8; or days 1 and 5 with pegfilgrastim (peg) every 21 days (NCT01214642). J Clin Oncol 29:(suppl; abstr 2600) 11. Infante JR, Kurzrock R, Spratlin J, Burris HA, Eckhardt SG, Li J, Wu K, Skolnik JM, Hylander-Gans L, Osmukhina A, Huszar D, Herbst RS (2012) A Phase I study to assess the safety, tolerability, and pharmacokinetics of AZD4877, an intravenous Eg5 inhibitor in patients with advanced solid tumors. Cancer Chemother Pharmacol 69:165–172 12. Kantarjian HM, Padmanabhan S, Stock W, Tallman MS, Curt GA, Li J, Osmukhina A, Wu K, Huszar D, Borthukar G, Faderl S, Garcia-Manero G, Kadia T, Sankhala K, Odenike O, Altman JK, Minden M (2012) Phase I/II multicenter study to assess the safety, tolerability, pharmacokinetics and pharmacodynamics of AZD4877 in patients with refractory acute myeloid leukemia. Invest New Drugs 30:1107–1115 13. Shah JJ, Zonder J, Cohen A, Orlowski RZ, Alexanian R, Thomas SK, Weber D, Kaufman JL, Harvey RD, Walker D, Litwiler K, Karan S, Hilder B, Ptaszynski AM, Lonial S (2011) ARRY-520 shows Durable responses in patients with relapsed/refractory multiple myeloma in a phase 1 dose-escalation study. Blood 118:2011 (ASH Annual Meeting; abstract 1860) 14. Khoury HJ, Garcia-Manero G, Borthakur G, Kadia T, Foudray MC, Arellano M, Langston A, Bethelmie-Bryan B, Rush S, Litwiler K, Karan S, Simmons H, Marcus AI, Ptaszynski M, Kantarjian H (2012) A phase 1 dose-escalation study of ARRY-520, a kinesin spindle protein inhibitor, in patients with advanced myeloid leukemias. Cancer 118:3556–3564 15. 4SC (2012) Press release: 4SC reports positive data from clinical Phase I trial with 4SC-205 in cancer patients and initiates study amendment. http://www.4sc.de/news-media/corporatenews/2012. Accessed 12 Feb 2014 16. Burris HA 3rd, Jones SF, Williams DD, Kathman SJ, Hodge JP, Pandite L, Ho PT, Boerner SA, Lorusso P (2011) A phase I study of ispinesib, a kinesin spindle protein inhibitor, administered weekly for three consecutive weeks of a 28-day cycle in patients with solid tumors. Invest New Drugs 29:467–472 17. Gomez HL, Philco M, Pimentel P, Kiyan M, Monsalvo ML, Conlan MG, Saikali KG, Chen MM, Seroogy JJ, Wolff AA, Escandon RD (2012) Phase I dose-escalation and pharmacokinetic study of ispinesib, a kinesin spindle protein inhibitor, administered on days 1 and 15 of a 28-day schedule in patients with no prior treatment for advanced breast cancer. Anticancer Drugs 23:335–341 18. Souid AK, Dubowy RL, Ingle AM, Conlan MG, Sun J, Blaney SM, Adamson PC (2010) A pediatric phase I trial and pharmacokinetic study of ispinesib: a Children’s Oncology Group phase I consortium study. Pediatr Blood Cancer 55:1323–1328 19. Blagden SP, Molife LR, Seebaran A, Payne M, Reid AH, Protheroe AS, Vasist LS, Williams DD, Bowen C, Kathman SJ, Hodge JP, Dar MM, de Bono JS, Middleton MR (2008) A phase I trial of ispinesib, a kinesin spindle protein inhibitor, with docetaxel in patients with advanced solid tumours. Br J Cancer 98:894–899 20. Calvo E, Chu Q, Til E, Rowinsky E, Patnaik A, Takimoto C, Kathman S, Williams D, Bowen C, Hodge J, Dar M, Tolcher A (2005) Phase I Study Of Ispinesib In Combination With Capecitabine in Patients With Advanced Solid Tumors. AACR-NCIEORTC, November 2005
21. Esaki T, Seto T, Ariyama H, Arita S, Fujimoto C, Tsukasa K, Kometani T, Nosaki K, Hirai F, Yagawa K (2011) Phase I study to assess the safety, tolerability and pharmacokinetics of AZD4877 in Japanese patients with solid tumors. Arch Drug Inf 4:23–31 22. Gerecitano JF, Stephenson JJ, Lewis NL, Osmukhina A, Li J, Wu K, You Z, Huszar D, Skolnik JM, Schwartz GK (2013) A Phase I trial of the kinesin spindle protein (Eg5) inhibitor AZD4877 in patients with solid and lymphoid malignancies. Invest New Drugs 31:355–362 23. Shah JJ, Feng L, Thomas SK, Weber DM, Wang M, Hilder B, Alexanian R, Orlowski RZ (2013) Phase 1 study of the novel kinesin spindle protein inhibitor ARRY-520 (Filanesib) + Carfilzomib (Car) in patients with relapsed and/or refractory multiple myeloma (RRMM). Annual Meeting of ASH: abstract 1982 24. Chari A, Htut M, Zonder J, Fay JW, Jakubowiak AJ, Harrison B, Lau K, Hilder B, Ptaszynski A, Rush SA, Kaufman JL, Burt SM (2013) A phase 1 study of ARRY-520 (Filanesib) with bortezomib (BTZ) and dexamethasone (dex) in relapsed or refractory multiple myeloma (RRMM). Annual Meeting of ASH: abstract 1938 25. Holen KD, Belani CP, Wilding G, Ramalingam S, Volkman JL, Ramanathan RK, Vasist LS, Bowen CJ, Hodge JP, Dar MM, Ho PT (2011) A first in human study of SB-743921, a kinesin spindle protein inhibitor, to determine pharmacokinetics, biologic effects and establish a recommended phase II dose. Cancer Chemother Pharmacol 67:447–454 26. Tabernero J, Shapiro GI, Lorusso PM, Cervantes A, Schwartz GK, Weiss GJ, Paz-Ares L, Cho DC, Infante JR, Alsina M, Gounder MM, Falzone R, Harrop J, White AC, Toudjarska I, Bumcrot D, Meyers RE, Hinkle G, Svrzikapa N, Hutabarat RM, Clausen VA, Cehelsky J, Nochur SV, Gamba-Vitalo C, Vaishnaw AK, Sah DW, Gollob JA, Burris HA 3rd (2013) First-in-humans trial of an RNA interference therapeutic targeting VEGF and KSP in cancer patients with liver involvement. Cancer Discov 3:406–417 27. Holen K, DiPaola R, Liu G, Tan AR, Wilding G, Hsu K, Agrawal N, Chen C, Xue L, Rosenberg E, Stein M (2012) A phase I trial of MK-0731, a kinesin spindle protein (KSP) inhibitor, in patients with solid tumors. Invest New Drugs 30:1088–1095 28. Rosen L, Chen L, Iyengar T, Goldman J, Lahr S, Savage R, Wang Y, Kazakin J, Chan TCK, Schwartz B, Abbadessa G, Von Hoff D (2011) First in human study with ARQ 621, a novel inhibitor of Eg5: final results. Annual Meeting of ASCO: abstract 3076 29. Hollebecque A, Deutsch E, Massard C, Gomez-Roca C, Bahleda R, Ribrag V, Bourgier C, Lazar V, Lacroix L, Gazzah A, Varga A, de Baere T, Beier F, Kroesser S, Trang K, Zenke FT, Klevesath M, Soria JC (2013) A phase I, dose-escalation study of the Eg5inhibitor EMD 534085 in patients with advanced solid tumors or lymphoma. Invest New Drugs. doi:10.1007/s10637-013-0026-9 30. Huang HC, Shi J, Orth JD, Mitchison TJ (2009) Evidence that mitotic exit is a better cancer therapeutic target than spindle assembly. Cancer Cell 16:347–358 31. Komlodi-Pasztor E, Sackett D, Wilkerson J, Fojo T (2011) Mitosis is not a key target of microtubule agents in patient tumors. Nat Rev Clin Oncol 8:244–250 32. Komlodi-Pasztor E, Sackett DL, Fojo AT (2012) Inhibitors targeting mitosis: tales of how great drugs against a promising target were brought down by a flawed rationale. Clin Cancer Res 18:51–63
13
