J Neurooncol DOI 10.1007/s11060-015-1733-1
CLINICAL STUDY
Veliparib in combination with whole brain radiation therapy in patients with brain metastases: results of a phase 1 study Minesh P. Mehta • Ding Wang • Fen Wang • Lawrence Kleinberg • Anthony Brade • H. Ian Robins • Aruna Turaka • Terri Leahy • Diane Medina Hao Xiong • Nael M. Mostafa • Martin Dunbar • Ming Zhu • Jane Qian • Kyle Holen • Vincent Giranda • Walter J. Curran
•
Received: 10 November 2014 / Accepted: 1 February 2015 Ó Springer Science+Business Media New York 2015
Abstract Veliparib, a potent, oral PARP inhibitor, potentiates the antitumor activity of radiation therapy and crosses the blood–brain barrier. This was a phase 1 doseescalation study evaluating the safety, and secondarily the antitumor activity of veliparib in combination with whole brain radiation therapy (WBRT) in patients with brain metastases, in order to power future trials. Patients with brain metastases from primary solid tumors were treated with WBRT (30.0 or 37.5 Gy in 10 or 15 fractions) and veliparib (escalating doses of 10–300 mg, orally BID). Safety and tumor response were assessed. Observed survival was compared to predicted survival based on a published nomogram. Eighty-one patients (median age 58 years) were treated. The most common primary tumor types were nonsmall cell lung (NSCLC; n = 34) and breast cancer (n = 25). The most common AEs deemed possibly related to veliparib (AEs, C15 %) were fatigue (30 %), nausea (22 %), and decreased appetite (15 %). Fatigue (5 %), hypokalemia and hyponatremia (3 % each) were the only
Grade 3/4 AEs deemed possibly related to veliparib observed in C2 patients. Although this was an uncontrolled study, preliminary efficacy results were better than predicted: the median survival time (MST, 95 % CI) for the NSCLC subgroup was 10.0 mo (3.9–13.5) and for the breast cancer subgroup was 7.7 mo (2.8–15.0) compared to a nomogram-model-predicted MST of 3.5 mo (3.3–3.8) and 4.9 mo (4.2–5.5). The addition of veliparib to WBRT did not identify new toxicities when compared to WBRT alone. Based on encouraging safety and preliminary efficacy results, a randomized, controlled phase 2b study is ongoing. Keywords Phase 1 clinical trial Veliparib PARP inhibitor Whole brain radiation therapy Brain metastases
Introduction Brain metastases develop in approximately 10–30 % of all cancers, affecting an estimated 170,000 Americans
M. P. Mehta (&) Department of Radiation Oncology, University of Maryland School of Medicine, 22 S. Greene Street, GGK19, Baltimore, MD 21201, USA e-mail: [email protected]
H. I. Robins University of Wisconsin, Madison, WI, USA
D. Wang Henry Ford Hospital, Detroit, MI, USA
T. Leahy D. Medina H. Xiong N. M. Mostafa M. Dunbar M. Zhu J. Qian K. Holen V. Giranda AbbVie, Inc., North Chicago, IL, USA
F. Wang The University of Kansas Medical Center, Kansas City, KS, USA
A. Turaka Fox Chase Cancer Center, Philadelphia, PA, USA
W. J. Curran Winship Cancer Institute of Emory University, Atlanta, GA, USA
L. Kleinberg Johns Hopkins University, Baltimore, MD, USA A. Brade Princess Margaret Hospital, Toronto, ON, Canada
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annually [1]. In one regional incidence evaluation, brain metastatic lesions developed in approximately 10 % of all cancers, with the highest incidence ascribed to lung cancer (20 %), followed by melanoma (7 %), renal (6.5 %), and breast cancer (5 %) [2]. Prognosis is poor, with median survival times often measured in weeks or months, for the vast majority [3]. Multiple metastases also occur frequently, complicating local treatment options [4]. Whole brain radiation therapy (WBRT) is the standard of care for brain metastases for patients with surgically unresectable lesions or multiple lesions [4]. In cases where surgery is an option (either solitary lesion or symptomatic lesions), patients often receive WBRT as an adjuvant to treatment [5]. Patients receiving WBRT have reduced intracranial relapse rates, and overall survival is extended to three to 6 months [6, 7]. Stereotactic radiosurgery (SRS) is an alternative approach, using focused radiation delivered directly to the brain lesion [8]. Patients undergoing SRS alone have higher intracranial relapse rates than with standard WBRT, but might experience less neurotoxicity [9, 10]. A randomized trial evaluating the addition of SRS to WBRT prolonged survival for patients with a single lesion, but showed no improvement in survival for patients with multiple metastases [11]. Chemotherapy is also a possible alternative approach to WBRT, although determination of a safe dose at which an agent can cross the blood–brain barrier has been an obstacle to widespread use, and its role has mostly been limited to highly chemosensitive cancers such as small cell lung cancer, germ cell tumors, etc. [12]. DNA-damaging agents, such as chemotherapy or radiation therapy, which are often employed in the treatment of primary or metastatic cancers, capitalize on the proliferative capacity of cancer cells, causing DNA damage that overwhelms repair mechanisms and triggers cell death [13]. Inducing DNA damage with chemotherapy or radiation therapy can prove effective if the tumor has decreased repair capacity, such as in homologous recombination (breast cancer associated gene-1 or -2) deficient breast cancer [14]. In some cancer types, however, alternate DNA repair mechanisms are upregulated to accommodate defects in other pathways [15]. This is a common mechanism of resistance to conventional DNA damaging agents [16, 17]. Poly(ADP-ribose) Polymerase (PARP) is a DNA repair protein involved in both the single and double strand break repair pathways. Overexpression or increased activity of PARP has been observed in a number of cancer types and is thought to be one possible mechanism by which cancer cells resist death by DNA-damaging therapeutics [18–20]. Inhibition of PARP-mediated repair, therefore, may be efficacious as an adjuvant to traditional DNA damage-
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inducing therapy by prolonging strand breaks and causing cells to default to a cell-death signaling pathway. Veliparib (ABT-888) is a novel, potent PARP inhibitor that has been shown to efficiently cross the blood–brain barrier [21]. A phase 0 biopsy trial demonstrated that veliparib significantly inhibited poly (ADP-ribose) levels in tumors [22]. Veliparib has also been shown to enhance cell death in combination with radiation therapy in preclinical models [21, 23]. Consequently, a study evaluating veliparib in combination with WBRT for patients with brain metastases was conducted.
Methods This was a phase 1, open-label, dose escalation study evaluating veliparib in combination with WBRT in patients with brain metastases. The primary objectives of this study were to assess the safety and tolerability of veliparib in combination with WBRT, as well as to determine the maximum tolerated dose (MTD) and/or recommended phase 2 dose (RPTD). Secondary objectives were assessment of the pharmacokinetics (PK) of veliparib with WBRT and evaluation of tumor response and overall survival. This study was approved by an Independent Ethics Committee (IEC)/Independent Review Board (IRB) prior to initiation and was performed in accordance with the 1964 Helsinki Declaration and its later amendments. All patients provided informed consent prior to their participation. Eligible patients were over the age of 18, had Karnofsky performance status (KPS) scores C70, histologically or cytologically confirmed non-CNS primary solid malignancies, and pathologically or radiographically confirmed brain metastases for which WBRT was clinically indicated. Patients with non-measurable lesions, including leptomeningeal carcinomatosis were eligible. Patients could not have received prior WBRT. Prior SRS was permissible if performed more than 14 days prior to the start of WBRT. WBRT was delivered in 2.5 Gy daily fractions 5 days per week for 3 weeks (15 fractions, 37.5 Gy total), or, starting at 150 mg BID, 3.0 Gy fractions daily (10 fractions, 30 Gy total) over 2 weeks. Schedule choice was at the discretion of the investigator. Veliparib dose was escalated in consecutive cohorts starting at 10 mg and escalated to 20, 30, 50, 80, 100, 150, 200, and 300 mg BID for assessment of the MTD/RPTD. Veliparib was administered orally throughout the course of WBRT, twice daily (BID) (Fig. 1). Safety evaluations included adverse event monitoring and reporting using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE, version 3.0).
J Neurooncol Table 1 Baseline characteristics and treatment-emergent adverse events Baseline characteristics (N = 81) Median age, years (range)
58 (31–84)
Gender, n (%) Men/women
26 (32)/55 (68)
KPS, n (%) Fig. 1 Study design
Blood samples were taken for assessment of PK of veliparib on WBRT Day 1, 6, and 15. Values for pharmacokinetic parameters, including the maximum observed plasma concentration (Cmax), the time to Cmax (Tmax), and the area under the plasma concentration–time curve (AUC) from time 0 to the time of last measurable concentration, were determined using non-compartmental methods. Preliminary efficacy endpoints included assessment of objective response rate (ORR) in patients with measurable disease at baseline and overall survival (OS). Radiographic assessments of brain lesions were conducted at baseline and at the final visit and changes were evaluated using the response evaluation criteria in solid tumors (RECIST 1.1). Exploratory survival analyses compared overall observed survival to predicted survival based on a previously published nomogram [24]. Predicted survival time was calculated using established prognostic indicators such as site and histology of tumor, status of primary disease, metastatic spread status, age, KPS, and number of brain lesions. Results Baseline characteristics Eighty one patients were enrolled and dosed, 55/26 male/ female with a median age of 58 years (range 31–84) (Table 1). Fifty six percent of patients had between 1 and 5 prior anti-cancer therapies and 51 % had prior radiation therapy. The most common primary tumor types were nonsmall cell lung cancer (NSCLC, n = 34) and breast cancer (n = 25). Fourteen (17.3 %) patients discontinued treatment, and the most common reason was an adverse event (n = 11, 13.6 %). Safety All patients experienced at least one adverse event (AE, n = 81), of them 48 (59 %) were deemed at least possibly
70
9 (11)
80
29 (36)
90
28 (35)
100
15 (19)
Prior anti-cancer therapy agents, n (%) 0 1–5
26 (32) 45 (56)
6–10
8 (10)
[10
2 (3)
Prior radiation therapy, n (%) Yes
41 (51)
No
40 (49)
Primary tumor type, n (%) Breast Colorectal
25 (31) 2 (3)
Melanoma
11 (14)
NSCLC
34 (42)
Renal
1 (1)
Other
8 (10)
Treatment-emergent adverse events AEs in [10 % patients, n (%) Fatigue Nausea
45 (56) 32 (40)
Headache
29 (36)
Alopecia
22 (27)
Decreased appetite
19 (24)
Vomiting
18 (22)
Radiation skin injury
15 (19)
Constipation
12 (15)
Insomnia
11 (14)
Dizziness
11 (14)
Diarrhea
9 (11)
Weight decrease
9 (11)
Erythema
9 (11)
Grade 3/4 AEs in [2 patients, n (%) Fatigue
6 (7)
Hyponatraemia Lymphopenia
5 (6) 4 (5)
Dehydration
4 (5)
Anemia
3 (4)
Hyperglycemia
3 (4)
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J Neurooncol Fig. 2 Time on study, best responses, and dose cohort by primary cancer for a NSCLC, b breast cancer and c melanoma and other subgroups. CR Complete response, PR partial response, SD stable disease, PD progressive disease, UN unknown, NR no response recorded
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related to veliparib. The most common (C10 % of patients) treatment-emergent AEs and Grade 3 or 4 AEs occurring in two or more patients are listed in Table 1. AEs deemed possibly related to veliparib occurring in C10 % of patients were fatigue (30 %), nausea (22 %), decreased appetite (15 %), and vomiting (14 %). Grade 3 or 4 AEs deemed possibly related to veliparib observed in C2 (2 %) patients were fatigue (5 %), hypokalemia (3 %), and hyponatremia (3 %). Twenty-four patients experienced serious AEs, 4 (5 %) were possibly related to veliparib. Eleven deaths resulted from a reported treatment emergent AE, however none were considered to be related to study drug. Three dose limiting toxicities (DLTs) occurred, 2 at 150 mg veliparib, one grade 3 hypokalemia and one grade 3 hyponatraemia. Per protocol, dose escalation was continued based on sponsor and investigator review. One DLT of grade 4 posterior reversible encephalopathy syndrome occurred at 200 mg BID. At the 300 mg BID veliparib dose, five of eight subjects experienced AEs of nausea and/ or vomiting with two events leading to discontinuation of study drug. These events did not meet the criteria of DLT. Because the 300 mg BID dose was not well-tolerated, the RPTD of veliparib was determined to be 200 mg BID in combination with 30 Gy WBRT (3 Gy/fraction/10 fractions), the most common radiation combination at higher doses.
subtype patients (Fig. 3). A dose–response analysis of all 21 NSCLC patients demonstrated that subjects who received lower veliparib doses appeared to have similar changes in brain tumor burden to those who received higher veliparib doses in combination with WBRT. This was an uncontrolled study, and as such, any timeto-endpoint efficacy conclusions can be misinterpreted due to selection bias. To better control for selection, a standard nomogram was used to predict subject survival times. Exploratory survival analyses were performed using predicted survival times based on a nomogram [24]. Median survival time (MST; 95 % CI) for patients in the NSCLC subgroup was 10.0 (95 %CI 3.9–13.5) months. A nomogram based model using a similar NSCLC patient population treated with WBRT predicted an MST of 3.5 (3.3–3.8) months, representing an increase of more than 6 months (Fig. 4a). In addition, the MST for the breast cancer subgroup was 7.7 months (2.8–15.0) compared to a nomogram predicted MST of 4.9 months (4.2–5.5), representing an increase of 2.8 months (Fig. 4b). Further examination of dose–response relationships in terms of overall survival in the NSCLC subgroup showed comparable survival curves among subjects who received
Pharmacokinetics Veliparib was absorbed rapidly following oral administration, with an average Tmax of 0.8 to 1.9 h under fasting condition and 1.8–2.9 h under non-fasting condition in the dose cohorts studied. Exposure of veliparib increased approximately dose-proportionally from 10 to 300 mg BID. Food had no significant impact on veliparib Cmax or AUC. Comparison of exposures on Day 1, 6, and 15 demonstrated that accumulation is minimal. The non-fasting steady-state Cmax at 200 mg BID was 2.07 ± 1.00 lg/mL and the AUC was 14.4 ± 5.5 lg h/mL. Preliminary efficacy Patient time on study is represented along with best responses in Fig. 2. 6 month survival rates were 54 % (42–64 %) for all patients, 61 % (43–75 %) for NSCLC patients and 61 % (39–78 %) for breast cancer patients. In patients with measureable disease at baseline, 30 % of patients achieved a partial or complete best response in the NSCLC subgroup and 41 % in the breast cancer subgroup. The best percent change in target lesion was determined for patients with measurable disease at baseline. Tumors were assessed at baseline and at the final study visit in 21 NSCLC, 19 breast cancer, and 9 other primary tumor
Fig. 3 Best percent change from baseline in tumor size for a NSCLC, b breast cancer and c melanoma and other subgroups. The legend represents the final dose cohort of each patient
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J Neurooncol Fig. 4 NSCLC and breast cancer nomogram analysis and NSCLC nomogram dose response analysis. Nomogram analysis is represented for the a NSCLC and b breast cancer subgroups and survival is represented by dose in the c observed and d predicted population
(a) 20 mg to 80 mg veliparib (n = 10), (b) 100 mg to 150 mg veliparib (n = 12), or (c) 200 mg to 300 mg veliparib (n = 13) in combination with WBRT (Fig. 4c). The predicted overall survival based on the graded prognostic factors in the published nomogram was similar among the three groups of patients, indicating the patients in these three dose groups were relatively balanced (Fig. 4d).
Discussion The current study sought to establish dosing parameters and a preliminary toxicity profile for veliparib in
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combination with WBRT for patients with brain metastases. The dose escalation portion of this study did not reach pre-defined criteria for the MTD, although amplification of adverse events such as nausea and vomiting were reported in the highest dose cohort, 300 mg BID. Assessment of the 200 mg BID veliparib cohort with WBRT demonstrated an adverse event profile similar to that of WBRT alone, with a limited number of grade 3 or 4 treatment emergent adverse events deemed at least possibly related to veliparib. In addition, the PK of veliparib was linear in relation to dosing parameters, and there was minimal accumulation at the 200 mg BID dose. These results support the selection of 200 mg BID as the RPTD.
J Neurooncol Fig. 4 continued
Although results of uncontrolled, historical comparisons must be treated with caution, assessment of the observed survival times of patients in the NSCLC and breast cancer subgroups prompted further analyses in light of historical survival data using WBRT alone. Statistical prediction models accounting for established prognostic factors have been developed to help physicians and patients more accurately make decisions about care. Nomograms compare favorably to traditional predictive tools and have gained widespread use [25, 26]. The nomogram model employed in this study was internally validated using data from 2,367
patients in 7 brain metastasis randomized trials [24]. However, even with careful selection of potential covariates, historical controls will not have had the all of the same study interventions or previous therapies; therefore care must be taken in interpretation of the results. The extent to which observed MST was increased compared to nomogram predicted MST is suggestive of a potential survival benefit in the NSCLC subgroup. The predicted MST for the NSCLC subgroup is more than 6 months greater than the nomogram predicted median survival time, with confidence intervals that do not overlap.
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These results have prompted the initiation of a phase 2, randomized, placebo-controlled, double-blinded trial in patients with NSCLC brain metastases. Although veliparib doses from 20–200 mg BID demonstrated similar antitumor activity in this study, it is not yet known whether doses of veliparib lower than the RPTD, 200 mg, would improve the safety profile while remaining equally efficacious. In addition to efficiently crossing the blood brain barrier in preclinical models, veliparib at 50 mg daily demonstrated significant reduction in Poly(ADP-ribose) in peripheral blood mononuclear cells and tumor tissue in a phase 0 study [21, 22]. The phase 2 study, therefore, will evaluate the differences between low dose (50 mg) veliparib, high dose (200 mg) veliparib, and placebo in combination with WBRT. Tumor metastasis is one of the primary drivers of lethal cancer [1]. Even with treatment options such as WBRT and SRS, the prognosis for patients with brain metastases remains poor. New therapies are needed to enhance or replace current practices in order to achieve better clinical benefit for patients. Veliparib’s established mechanism of action suggests that it could serve as an effective sensitizer to WBRT in this patient population. Acknowledgements Medical writing support was provided by Jacqueline Nielsen and Jaimee Glasgow, employees of AbbVie. Conflict of interest MMehta has served as a consultant for AbbVie, Elekta, Merck, BMS, Novelos, Novocure, and Roche. He serves on the Board of Directors for Pharmacyclics; owns stocks with Pharmacyclics, and Accuray. W Curran is a consultant for BMS and receives research funding from AbbVie. L Kleinberg receives research funding from AbbVie. HI Robins has been a consultant for AbbVie. A Turaka, D Wang, F Wang and A Brade have no conflicts of interest to declare. J Qian, M Zhu, TL Leahy, D Median, H Xiong, N Mostafa, M Dunbar, K Holen, and VL Giranda are AbbVie employees and may own stock; V. L. Giranda has a pending patent application related to the subject matter in the manuscript. Funding AbbVie provided financial support for this study and participated in the design, study conduct, analysis and interpretation of the data as well as the writing, review, and approval of this manuscript. Human rights All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
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CLINICAL STUDY
Veliparib in combination with whole brain radiation therapy in patients with brain metastases: results of a phase 1 study Minesh P. Mehta • Ding Wang • Fen Wang • Lawrence Kleinberg • Anthony Brade • H. Ian Robins • Aruna Turaka • Terri Leahy • Diane Medina Hao Xiong • Nael M. Mostafa • Martin Dunbar • Ming Zhu • Jane Qian • Kyle Holen • Vincent Giranda • Walter J. Curran
•
Received: 10 November 2014 / Accepted: 1 February 2015 Ó Springer Science+Business Media New York 2015
Abstract Veliparib, a potent, oral PARP inhibitor, potentiates the antitumor activity of radiation therapy and crosses the blood–brain barrier. This was a phase 1 doseescalation study evaluating the safety, and secondarily the antitumor activity of veliparib in combination with whole brain radiation therapy (WBRT) in patients with brain metastases, in order to power future trials. Patients with brain metastases from primary solid tumors were treated with WBRT (30.0 or 37.5 Gy in 10 or 15 fractions) and veliparib (escalating doses of 10–300 mg, orally BID). Safety and tumor response were assessed. Observed survival was compared to predicted survival based on a published nomogram. Eighty-one patients (median age 58 years) were treated. The most common primary tumor types were nonsmall cell lung (NSCLC; n = 34) and breast cancer (n = 25). The most common AEs deemed possibly related to veliparib (AEs, C15 %) were fatigue (30 %), nausea (22 %), and decreased appetite (15 %). Fatigue (5 %), hypokalemia and hyponatremia (3 % each) were the only
Grade 3/4 AEs deemed possibly related to veliparib observed in C2 patients. Although this was an uncontrolled study, preliminary efficacy results were better than predicted: the median survival time (MST, 95 % CI) for the NSCLC subgroup was 10.0 mo (3.9–13.5) and for the breast cancer subgroup was 7.7 mo (2.8–15.0) compared to a nomogram-model-predicted MST of 3.5 mo (3.3–3.8) and 4.9 mo (4.2–5.5). The addition of veliparib to WBRT did not identify new toxicities when compared to WBRT alone. Based on encouraging safety and preliminary efficacy results, a randomized, controlled phase 2b study is ongoing. Keywords Phase 1 clinical trial Veliparib PARP inhibitor Whole brain radiation therapy Brain metastases
Introduction Brain metastases develop in approximately 10–30 % of all cancers, affecting an estimated 170,000 Americans
M. P. Mehta (&) Department of Radiation Oncology, University of Maryland School of Medicine, 22 S. Greene Street, GGK19, Baltimore, MD 21201, USA e-mail: [email protected]
H. I. Robins University of Wisconsin, Madison, WI, USA
D. Wang Henry Ford Hospital, Detroit, MI, USA
T. Leahy D. Medina H. Xiong N. M. Mostafa M. Dunbar M. Zhu J. Qian K. Holen V. Giranda AbbVie, Inc., North Chicago, IL, USA
F. Wang The University of Kansas Medical Center, Kansas City, KS, USA
A. Turaka Fox Chase Cancer Center, Philadelphia, PA, USA
W. J. Curran Winship Cancer Institute of Emory University, Atlanta, GA, USA
L. Kleinberg Johns Hopkins University, Baltimore, MD, USA A. Brade Princess Margaret Hospital, Toronto, ON, Canada
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annually [1]. In one regional incidence evaluation, brain metastatic lesions developed in approximately 10 % of all cancers, with the highest incidence ascribed to lung cancer (20 %), followed by melanoma (7 %), renal (6.5 %), and breast cancer (5 %) [2]. Prognosis is poor, with median survival times often measured in weeks or months, for the vast majority [3]. Multiple metastases also occur frequently, complicating local treatment options [4]. Whole brain radiation therapy (WBRT) is the standard of care for brain metastases for patients with surgically unresectable lesions or multiple lesions [4]. In cases where surgery is an option (either solitary lesion or symptomatic lesions), patients often receive WBRT as an adjuvant to treatment [5]. Patients receiving WBRT have reduced intracranial relapse rates, and overall survival is extended to three to 6 months [6, 7]. Stereotactic radiosurgery (SRS) is an alternative approach, using focused radiation delivered directly to the brain lesion [8]. Patients undergoing SRS alone have higher intracranial relapse rates than with standard WBRT, but might experience less neurotoxicity [9, 10]. A randomized trial evaluating the addition of SRS to WBRT prolonged survival for patients with a single lesion, but showed no improvement in survival for patients with multiple metastases [11]. Chemotherapy is also a possible alternative approach to WBRT, although determination of a safe dose at which an agent can cross the blood–brain barrier has been an obstacle to widespread use, and its role has mostly been limited to highly chemosensitive cancers such as small cell lung cancer, germ cell tumors, etc. [12]. DNA-damaging agents, such as chemotherapy or radiation therapy, which are often employed in the treatment of primary or metastatic cancers, capitalize on the proliferative capacity of cancer cells, causing DNA damage that overwhelms repair mechanisms and triggers cell death [13]. Inducing DNA damage with chemotherapy or radiation therapy can prove effective if the tumor has decreased repair capacity, such as in homologous recombination (breast cancer associated gene-1 or -2) deficient breast cancer [14]. In some cancer types, however, alternate DNA repair mechanisms are upregulated to accommodate defects in other pathways [15]. This is a common mechanism of resistance to conventional DNA damaging agents [16, 17]. Poly(ADP-ribose) Polymerase (PARP) is a DNA repair protein involved in both the single and double strand break repair pathways. Overexpression or increased activity of PARP has been observed in a number of cancer types and is thought to be one possible mechanism by which cancer cells resist death by DNA-damaging therapeutics [18–20]. Inhibition of PARP-mediated repair, therefore, may be efficacious as an adjuvant to traditional DNA damage-
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inducing therapy by prolonging strand breaks and causing cells to default to a cell-death signaling pathway. Veliparib (ABT-888) is a novel, potent PARP inhibitor that has been shown to efficiently cross the blood–brain barrier [21]. A phase 0 biopsy trial demonstrated that veliparib significantly inhibited poly (ADP-ribose) levels in tumors [22]. Veliparib has also been shown to enhance cell death in combination with radiation therapy in preclinical models [21, 23]. Consequently, a study evaluating veliparib in combination with WBRT for patients with brain metastases was conducted.
Methods This was a phase 1, open-label, dose escalation study evaluating veliparib in combination with WBRT in patients with brain metastases. The primary objectives of this study were to assess the safety and tolerability of veliparib in combination with WBRT, as well as to determine the maximum tolerated dose (MTD) and/or recommended phase 2 dose (RPTD). Secondary objectives were assessment of the pharmacokinetics (PK) of veliparib with WBRT and evaluation of tumor response and overall survival. This study was approved by an Independent Ethics Committee (IEC)/Independent Review Board (IRB) prior to initiation and was performed in accordance with the 1964 Helsinki Declaration and its later amendments. All patients provided informed consent prior to their participation. Eligible patients were over the age of 18, had Karnofsky performance status (KPS) scores C70, histologically or cytologically confirmed non-CNS primary solid malignancies, and pathologically or radiographically confirmed brain metastases for which WBRT was clinically indicated. Patients with non-measurable lesions, including leptomeningeal carcinomatosis were eligible. Patients could not have received prior WBRT. Prior SRS was permissible if performed more than 14 days prior to the start of WBRT. WBRT was delivered in 2.5 Gy daily fractions 5 days per week for 3 weeks (15 fractions, 37.5 Gy total), or, starting at 150 mg BID, 3.0 Gy fractions daily (10 fractions, 30 Gy total) over 2 weeks. Schedule choice was at the discretion of the investigator. Veliparib dose was escalated in consecutive cohorts starting at 10 mg and escalated to 20, 30, 50, 80, 100, 150, 200, and 300 mg BID for assessment of the MTD/RPTD. Veliparib was administered orally throughout the course of WBRT, twice daily (BID) (Fig. 1). Safety evaluations included adverse event monitoring and reporting using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE, version 3.0).
J Neurooncol Table 1 Baseline characteristics and treatment-emergent adverse events Baseline characteristics (N = 81) Median age, years (range)
58 (31–84)
Gender, n (%) Men/women
26 (32)/55 (68)
KPS, n (%) Fig. 1 Study design
Blood samples were taken for assessment of PK of veliparib on WBRT Day 1, 6, and 15. Values for pharmacokinetic parameters, including the maximum observed plasma concentration (Cmax), the time to Cmax (Tmax), and the area under the plasma concentration–time curve (AUC) from time 0 to the time of last measurable concentration, were determined using non-compartmental methods. Preliminary efficacy endpoints included assessment of objective response rate (ORR) in patients with measurable disease at baseline and overall survival (OS). Radiographic assessments of brain lesions were conducted at baseline and at the final visit and changes were evaluated using the response evaluation criteria in solid tumors (RECIST 1.1). Exploratory survival analyses compared overall observed survival to predicted survival based on a previously published nomogram [24]. Predicted survival time was calculated using established prognostic indicators such as site and histology of tumor, status of primary disease, metastatic spread status, age, KPS, and number of brain lesions. Results Baseline characteristics Eighty one patients were enrolled and dosed, 55/26 male/ female with a median age of 58 years (range 31–84) (Table 1). Fifty six percent of patients had between 1 and 5 prior anti-cancer therapies and 51 % had prior radiation therapy. The most common primary tumor types were nonsmall cell lung cancer (NSCLC, n = 34) and breast cancer (n = 25). Fourteen (17.3 %) patients discontinued treatment, and the most common reason was an adverse event (n = 11, 13.6 %). Safety All patients experienced at least one adverse event (AE, n = 81), of them 48 (59 %) were deemed at least possibly
70
9 (11)
80
29 (36)
90
28 (35)
100
15 (19)
Prior anti-cancer therapy agents, n (%) 0 1–5
26 (32) 45 (56)
6–10
8 (10)
[10
2 (3)
Prior radiation therapy, n (%) Yes
41 (51)
No
40 (49)
Primary tumor type, n (%) Breast Colorectal
25 (31) 2 (3)
Melanoma
11 (14)
NSCLC
34 (42)
Renal
1 (1)
Other
8 (10)
Treatment-emergent adverse events AEs in [10 % patients, n (%) Fatigue Nausea
45 (56) 32 (40)
Headache
29 (36)
Alopecia
22 (27)
Decreased appetite
19 (24)
Vomiting
18 (22)
Radiation skin injury
15 (19)
Constipation
12 (15)
Insomnia
11 (14)
Dizziness
11 (14)
Diarrhea
9 (11)
Weight decrease
9 (11)
Erythema
9 (11)
Grade 3/4 AEs in [2 patients, n (%) Fatigue
6 (7)
Hyponatraemia Lymphopenia
5 (6) 4 (5)
Dehydration
4 (5)
Anemia
3 (4)
Hyperglycemia
3 (4)
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J Neurooncol Fig. 2 Time on study, best responses, and dose cohort by primary cancer for a NSCLC, b breast cancer and c melanoma and other subgroups. CR Complete response, PR partial response, SD stable disease, PD progressive disease, UN unknown, NR no response recorded
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related to veliparib. The most common (C10 % of patients) treatment-emergent AEs and Grade 3 or 4 AEs occurring in two or more patients are listed in Table 1. AEs deemed possibly related to veliparib occurring in C10 % of patients were fatigue (30 %), nausea (22 %), decreased appetite (15 %), and vomiting (14 %). Grade 3 or 4 AEs deemed possibly related to veliparib observed in C2 (2 %) patients were fatigue (5 %), hypokalemia (3 %), and hyponatremia (3 %). Twenty-four patients experienced serious AEs, 4 (5 %) were possibly related to veliparib. Eleven deaths resulted from a reported treatment emergent AE, however none were considered to be related to study drug. Three dose limiting toxicities (DLTs) occurred, 2 at 150 mg veliparib, one grade 3 hypokalemia and one grade 3 hyponatraemia. Per protocol, dose escalation was continued based on sponsor and investigator review. One DLT of grade 4 posterior reversible encephalopathy syndrome occurred at 200 mg BID. At the 300 mg BID veliparib dose, five of eight subjects experienced AEs of nausea and/ or vomiting with two events leading to discontinuation of study drug. These events did not meet the criteria of DLT. Because the 300 mg BID dose was not well-tolerated, the RPTD of veliparib was determined to be 200 mg BID in combination with 30 Gy WBRT (3 Gy/fraction/10 fractions), the most common radiation combination at higher doses.
subtype patients (Fig. 3). A dose–response analysis of all 21 NSCLC patients demonstrated that subjects who received lower veliparib doses appeared to have similar changes in brain tumor burden to those who received higher veliparib doses in combination with WBRT. This was an uncontrolled study, and as such, any timeto-endpoint efficacy conclusions can be misinterpreted due to selection bias. To better control for selection, a standard nomogram was used to predict subject survival times. Exploratory survival analyses were performed using predicted survival times based on a nomogram [24]. Median survival time (MST; 95 % CI) for patients in the NSCLC subgroup was 10.0 (95 %CI 3.9–13.5) months. A nomogram based model using a similar NSCLC patient population treated with WBRT predicted an MST of 3.5 (3.3–3.8) months, representing an increase of more than 6 months (Fig. 4a). In addition, the MST for the breast cancer subgroup was 7.7 months (2.8–15.0) compared to a nomogram predicted MST of 4.9 months (4.2–5.5), representing an increase of 2.8 months (Fig. 4b). Further examination of dose–response relationships in terms of overall survival in the NSCLC subgroup showed comparable survival curves among subjects who received
Pharmacokinetics Veliparib was absorbed rapidly following oral administration, with an average Tmax of 0.8 to 1.9 h under fasting condition and 1.8–2.9 h under non-fasting condition in the dose cohorts studied. Exposure of veliparib increased approximately dose-proportionally from 10 to 300 mg BID. Food had no significant impact on veliparib Cmax or AUC. Comparison of exposures on Day 1, 6, and 15 demonstrated that accumulation is minimal. The non-fasting steady-state Cmax at 200 mg BID was 2.07 ± 1.00 lg/mL and the AUC was 14.4 ± 5.5 lg h/mL. Preliminary efficacy Patient time on study is represented along with best responses in Fig. 2. 6 month survival rates were 54 % (42–64 %) for all patients, 61 % (43–75 %) for NSCLC patients and 61 % (39–78 %) for breast cancer patients. In patients with measureable disease at baseline, 30 % of patients achieved a partial or complete best response in the NSCLC subgroup and 41 % in the breast cancer subgroup. The best percent change in target lesion was determined for patients with measurable disease at baseline. Tumors were assessed at baseline and at the final study visit in 21 NSCLC, 19 breast cancer, and 9 other primary tumor
Fig. 3 Best percent change from baseline in tumor size for a NSCLC, b breast cancer and c melanoma and other subgroups. The legend represents the final dose cohort of each patient
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J Neurooncol Fig. 4 NSCLC and breast cancer nomogram analysis and NSCLC nomogram dose response analysis. Nomogram analysis is represented for the a NSCLC and b breast cancer subgroups and survival is represented by dose in the c observed and d predicted population
(a) 20 mg to 80 mg veliparib (n = 10), (b) 100 mg to 150 mg veliparib (n = 12), or (c) 200 mg to 300 mg veliparib (n = 13) in combination with WBRT (Fig. 4c). The predicted overall survival based on the graded prognostic factors in the published nomogram was similar among the three groups of patients, indicating the patients in these three dose groups were relatively balanced (Fig. 4d).
Discussion The current study sought to establish dosing parameters and a preliminary toxicity profile for veliparib in
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combination with WBRT for patients with brain metastases. The dose escalation portion of this study did not reach pre-defined criteria for the MTD, although amplification of adverse events such as nausea and vomiting were reported in the highest dose cohort, 300 mg BID. Assessment of the 200 mg BID veliparib cohort with WBRT demonstrated an adverse event profile similar to that of WBRT alone, with a limited number of grade 3 or 4 treatment emergent adverse events deemed at least possibly related to veliparib. In addition, the PK of veliparib was linear in relation to dosing parameters, and there was minimal accumulation at the 200 mg BID dose. These results support the selection of 200 mg BID as the RPTD.
J Neurooncol Fig. 4 continued
Although results of uncontrolled, historical comparisons must be treated with caution, assessment of the observed survival times of patients in the NSCLC and breast cancer subgroups prompted further analyses in light of historical survival data using WBRT alone. Statistical prediction models accounting for established prognostic factors have been developed to help physicians and patients more accurately make decisions about care. Nomograms compare favorably to traditional predictive tools and have gained widespread use [25, 26]. The nomogram model employed in this study was internally validated using data from 2,367
patients in 7 brain metastasis randomized trials [24]. However, even with careful selection of potential covariates, historical controls will not have had the all of the same study interventions or previous therapies; therefore care must be taken in interpretation of the results. The extent to which observed MST was increased compared to nomogram predicted MST is suggestive of a potential survival benefit in the NSCLC subgroup. The predicted MST for the NSCLC subgroup is more than 6 months greater than the nomogram predicted median survival time, with confidence intervals that do not overlap.
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These results have prompted the initiation of a phase 2, randomized, placebo-controlled, double-blinded trial in patients with NSCLC brain metastases. Although veliparib doses from 20–200 mg BID demonstrated similar antitumor activity in this study, it is not yet known whether doses of veliparib lower than the RPTD, 200 mg, would improve the safety profile while remaining equally efficacious. In addition to efficiently crossing the blood brain barrier in preclinical models, veliparib at 50 mg daily demonstrated significant reduction in Poly(ADP-ribose) in peripheral blood mononuclear cells and tumor tissue in a phase 0 study [21, 22]. The phase 2 study, therefore, will evaluate the differences between low dose (50 mg) veliparib, high dose (200 mg) veliparib, and placebo in combination with WBRT. Tumor metastasis is one of the primary drivers of lethal cancer [1]. Even with treatment options such as WBRT and SRS, the prognosis for patients with brain metastases remains poor. New therapies are needed to enhance or replace current practices in order to achieve better clinical benefit for patients. Veliparib’s established mechanism of action suggests that it could serve as an effective sensitizer to WBRT in this patient population. Acknowledgements Medical writing support was provided by Jacqueline Nielsen and Jaimee Glasgow, employees of AbbVie. Conflict of interest MMehta has served as a consultant for AbbVie, Elekta, Merck, BMS, Novelos, Novocure, and Roche. He serves on the Board of Directors for Pharmacyclics; owns stocks with Pharmacyclics, and Accuray. W Curran is a consultant for BMS and receives research funding from AbbVie. L Kleinberg receives research funding from AbbVie. HI Robins has been a consultant for AbbVie. A Turaka, D Wang, F Wang and A Brade have no conflicts of interest to declare. J Qian, M Zhu, TL Leahy, D Median, H Xiong, N Mostafa, M Dunbar, K Holen, and VL Giranda are AbbVie employees and may own stock; V. L. Giranda has a pending patent application related to the subject matter in the manuscript. Funding AbbVie provided financial support for this study and participated in the design, study conduct, analysis and interpretation of the data as well as the writing, review, and approval of this manuscript. Human rights All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
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