ABT-888) in Combination with 5-Fluorouracil and Oxaliplatin in Patients with Metastatic Pancreatic Cancer Michael J

Published OnlineFirst July 15, 2020; DOI: 10.1158/1078-0432.CCR-20-1301

CLINICAL CANCER RESEARCH | CLINICAL TRIALS: TARGETED THERAPY

A Phase I/II Study of Veliparib (ABT-888) in Combination with 5-Fluorouracil and Oxaliplatin in Patients with Metastatic Pancreatic Cancer Michael J. Pishvaian1, Hongkun Wang2, Aiwu Ruth He2, Jimmy J. Hwang3, Brandon G. Smaglo4, Sunnie S. Kim5, Benjamin A. Weinberg2, Louis M. Weiner2, John L. Marshall2, and Jonathan R. Brody6

ABSTRACT ◥ Purpose: Up to 17% of patients with pancreatic ductal adenocar- two parallel phase II trials to assess the objective response rate cinoma (PDAC) harbor pathogenic (germline or somatic) mutations (ORR) in untreated or in previously treated patients. If available, in a homologous recombination, DNA damage response and repair germline or somatic testing was collected to identify pathogenic (HR-DDR) gene, such as BRCA1/2,orPALB2.Platinum-basedche- HR-DDR mutations. motherapy, or treatment with PARP inhibitors are of particular benefit Results: The combination of veliparib and FOLFOX was toler- in these patients. However, there may be even greater benefitwhen able at a RP2D of veliparib of 200 mg twice a day. The primary platinums and PARP inhibitors are combined. endpoint for both phase II cohorts was met, and the ORR overall was Patients and Methods: We performed a single-arm, open-label, 26%. There was greater activity in platinum-na€ve patients, and phase I/II study of the PARP inhibitor, veliparib, with 5-fluorouracil those who harbored a pathogenic HR-DDR mutation. Specifically, (no 5FU bolus) and oxaliplatin (FOLFOX) for patients with met- the ORR of HR-DDR mutated, platinum-na€ve patients was 57%. astatic PDAC. Thirty-one patients were enrolled in a phase I dose Conclusions: The combination of veliparib and FOLFOX was escalation of veliparib (40 mg to 250 mg twice a day, days 1–7 of each safe for patients with metastatic PDAC and showed promising 14-day cycle), to identify the recommended phase II dose (RP2D) of activity particularly in patients with platinum-na€ve disease that veliparib for the combination. Another 33 patients were enrolled in harbors a pathogenic HR-DDR mutation.

Introduction such as BRCA1/2 and PALB2 mutations, preliminary data suggest that treatment with platinum-based chemotherapy and/or PARP inhibi- Pancreatic ductal adenocarcinoma (PDAC) is a deadly disease tors offers significant improvements in patient outcomes (8–14). In which, with a 5-year survival of only 10%, is poised to become the fact, based on the phase III POLO trial, PARP inhibitors are now an second leading cause of cancer-related death in the United States by FDA-approved standard treatment option as maintenance therapy for 2030 (1). Treatment for metastatic PDAC (mPDAC) has improved, patients with mPDAC who harbor pathogenic germline BRCA1/2 but the median overall survival (OS) remains less than 1 year (2, 3). mutations (15). PARP inhibitors have also been demonstrated to be However, for the subgroup of approximately 17% of patients with active in patients with PDAC whose tumors harbor pathogenic PALB2 PDAC whose tumors harbor defects in the homologous recombina- mutations (16). There is also evidence in other cancer types of the tion-DNA damage response and repair (HR-DDR) pathway (4–7), efficacy of PARP inhibitors in tumors with other (non-BRCA1/2/ PALB2) HR-DDR mutations (17). Moreover, there exists the potential for enhanced benefit when a 1Department of Oncology, Johns Hopkins University School of Medicine, SKCC, PARP inhibitor is combined with DNA damaging chemotherapy. Washington, DC. 2Lombardi Comprehensive Cancer Center, Georgetown Uni- PARP plays a critical role in facilitating the repair of both single- and 3 versity, Washington, DC. Levine Cancer Center, Carolinas Medical Center, double-stranded DNA breaks (18–20), and PARP inhibition results in Charlotte, North Carolina. 4Department of Gastrointestinal Medical Oncology, less efficient DNA repair. Thus, PARP inhibitors act as sensitizing University of Texas, MD Anderson Cancer Center, Houston, Texas. 5The Uni- versity of Colorado Cancer Center, Aurora, Colorado. 6The Jefferson Pancreas, agents for DNA-damaging chemotherapies (21). Veliparib (ABT-888, Biliary and Related Cancer Center, Department of Surgery, and the Sidney Abbvie) is a PARP inhibitor that has proven in vivo activity (22), and Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania. increases tumor cell sensitivity to chemotherapy and radiation (23). In Note: Supplementary data for this article are available at Clinical Cancer humans, veliparib is safe and demonstrates inhibition of PARP activity Research Online (http://clincancerres.aacrjournals.org/). in tumor biopsies (22). In phase III trials, veliparib has been used in Prior presentation: Presented in part at the 2013 Gastrointestinal Cancers combination with platinum-based chemotherapy at a dose of 150 mg Symposium. orally twice a day; and at 400 mg twice a day as maintenance therapy without chemotherapy (24). ClinicalTrials.gov identifier: NCT01489865 (ABT-888 with Modified FOLFOX6 in Patients with Metastatic Pancreatic Cancer) We previously demonstrated in PDAC cells that genetically dis- rupting the DNA-binding domain of PARP1, or treating with veliparib Corresponding Author: Michael J. Pishvaian, Johns Hopkins University, – fi Washington, DC 20016. Phone: 202-660-6500; Fax: 202-660-6501; E-mail: synergizes with oxaliplatin (21), particularly in HR-DDR de cient cell [email protected] lines. Therefore, we designed a trial combining veliparib with FOL- FOX-based chemotherapy for patients with mPDAC. At the time of Clin Cancer Res 2020;XX:XX–XX study design, FOLFIRINOX was not yet standard-of-care, and may doi: 10.1158/1078-0432.CCR-20-1301 present toxicity challenges in combination with a PARP inhibitor due 2020 American Association for Cancer Research. to overlapping myelosuppression. Thus, herein, we present a phase I/

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(ii) the presence or absence of an FH (as defined previously); (iii) the Translational Relevance presence of a mutation in an HR-DDR gene; patients who were tested Platinum-based chemotherapies and PARP inhibitors have but did not harbor a pathogenic germline or somatic HR-DDR demonstrated promising activity in patients with metastatic pan- mutation were also identified and highlighted. The study protocol, creatic cancer who harbor pathogenic germline or somatic muta- amendments, and informed consent forms were approved by the tions in the homologous recombination, DNA damage response Institutional Review Board at Georgetown University (Washington, and repair (HR-DDR) genes, BRCA1/2,orPALB2. There is evi- DC). Investigators obtained written informed consent from each dence of benefit of PARP inhibitors for patients whose tumors participant or participant’s guardian prior to screening. The research harbor other HR-DDR gene mutations as well. However, there may was conducted in accordance with recognized ethical guidelines be even greater benefit when platinums and PARP inhibitors are including the Declaration of Helsinki, CIOMS, Belmont Report, and combined. To assess the safety and efficacy of such a combination, U.S. Common Rule, as described during training in Good Clinical we performed a phase I/II clinical trial of 64 patients, with the Practice guidelines (CITI Training). combination of the PARP inhibitor, veliparib, with chemotherapy, FOLFOX. The combination was safe and effective for patients with Study design and treatment schedule metastatic pancreatic cancer. The greatest activity, with an ORR of This was a single-center, phase I/II, open-label study. Initially, the 57%, was seen in patients whose disease had not progressed on dose and schedule for modified FOLFOX6 (27) were used (5FU bolus prior platinum, and who harbored germline or somatic HR-DDR 400 mg/m2, day 1; leucovorin 400 mg/m2, day 1; FOLFOX 85 mg/m2, mutations. day 1; and 5FU 2,400 mg/m2 continuous infusion over 46 hours, days 1–3). Each cycle was 14 days. However, the first 6 patients dosed at 40 mg of veliparib demonstrated prolonged grade 2 or 3 myelosuppression. Thus, the 5FU bolus was dropped for all subsequent patients. II clinical trial of veliparib plus 5-fluorouracil (5FU) and oxaliplatin For the phase I portion, the dose of veliparib was escalated in a (FOLFOX) for patients with mPDAC. standard 3þ3 design from 40 to 60, 80, 100, 150, 200, and 250 mg twice a day, days 1–7 (Supplementary Table S1). As the primary endpoint of the phase I portion was to determine the recommended Patients and Methods phase II dose (RP2D) as well as the maximally tolerated dose Patients (MTD), dose-limiting toxicities (DLTs) were defined as any of the Patients with mPDAC with measurable disease [as per RECIST 1.1 following that were definitely, possibly, or probably related to therapy (25)] were eligible. Patients were ages ≥18 years, had an Eastern (veliparib þ FOLFOX) that occurred during the first cycle of therapy: Cooperative Oncology Group performance status score of ≤2, and had adequate organ and bone marrow function [hemoglobin ≥9.5 g/dL, (i) Grade 4 neutropenia lasting greater than 5 days or complicated absolute neutrophil count ≥1.5 109/L, platelet count ≥75 109/L, by fever or infection. serum creatinine level <1.5 mg/dL, bilirubin level ≤2.5 upper limit of (ii) Grade 4 anemia or thrombocytopenia. normal (ULN), and ALT/AST levels ≤3 ULN]. For the phase I (iii) Grade 3 thrombocytopenia associated with bleeding for which a portion of the study, patients were not selected on the basis of prior transfusion was required. therapy, family history (FH), nor germline or tumor HR-DDR (iv) Grade 3 or 4 nonhematologic toxicity not manageable with mutational status. routine supportive care (e.g., over-the-counter antidiarrheals For the phase II portion, there were two cohorts. Patients in the for diarrhea). untreated cohort had not had any prior systemic therapy for (v) Any toxicity, regardless of grade, which resulted in withholding mPDAC, though adjuvant chemotherapy was allowed if completed of therapy for greater than 3 weeks. >6 months prior; and prior palliative radiation to the primary mass was allowable. Patients in the previously treated cohort may have For the phase II portion, the RP2D was 200 mg of veliparib, although had any number of prior therapies, including platinum-based the protocol did allow for stepwise deescalation to 150 mg and then to regimens such as FOLFIRINOX, FOLFOX, or gemcitabine and 100 mg for toxicity after the first cycle. Safety assessments were cisplatin, but they may not have received a prior PARP inhibitor. performed every 2 weeks for the first 4 cycles, then every 4 weeks Also, for the phase II portion (both cohorts), we preselected patients thereafter. Tumor response was assessed radiographically every 8 to who either had a known pathogenic germline or somatic mutation 12 weeks using RECIST 1.1 (25). Study treatment was continued without (though testing was not required) in one of the HR-DDR genes [e.g., interruption in the absence of unacceptable toxicity or progressive BRCA1/2, PALB2, ATM (expanded list in the Supplementary disease. The protocol did allow for patients to stop the oxaliplatin for Materials)]; and/or patients who had an FH suggestive of a breast persistent neuropathy, at which time they were maintained on the RP2D or ovarian cancer syndrome, as detailed in the NCCN guidelines of veliparib plus the standard dose of continuous infusion 5FU. (summarized in the Supplementary Materials; ref. 26). For the post hoc analyses detailed in the Results, outcomes for different patient Correlative markers of response to therapy subgroups were compared. Subgroups included: (i) prior platinum For the phase I portion, plasma samples were obtained according to exposure: patients were placed into one of three categories as to the schedule in Supplementary Fig. S1 for pharmacokinetic (PK) whether their disease had: assessment of veliparib performed at Abbvie. Results were compared with historical controls to identify any effect on veliparib PKs by * Never been exposed to prior platinum. FOLFOX. In addition, when samples were available, next-generation * Been exposed, but not progressed on prior platinum (defined as no sequencing of cancer-related genes was performed commercially by disease progression within 3 months of stopping platinum). Foundation Medicine, Caris Life Sciences, or Tempus laboratories on * Progressed while on prior platinum. patient tumor samples. Several patients also had germline testing

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through Myriad or Ambry. Patients were defined as harboring HR- toxicity). In the 40-mg cohort, three of six patients required significant DDR mutations if a pathogenic mutation in an HR-DDR gene was (>2 week) treatment delays for grade 2 or 3 myelosuppression, but the identified in a blood sample (germline) or tumor sample (somatic). only protocol-defined DLT was a treatment delay of >3 weeks. There- Pathogenic mutations for each patient are included in Supplementary fore, the protocol was amended to drop the 5FU bolus. Only one other Table S4. The study team centrally validated pathogenic mutations in DLT occurred, which was at the 250-mg cohort. Four of the six patients the ClinVar and Cosmic databases. at 250 mg experienced significant grade 3 or 4 myelosuppression. Therefore, 200 mg was selected as the RP2D, though the protocol Statistical analysis allowed for stepwise deescalation to 150 mg and then to 100 mg for The primary objective of the phase I portion was to determine the toxicity after the first cycle. RP2D, with the primary endpoint being adverse events (AEs), as PK samples were available for 14 patients in five dosing cohorts. The measured by NIH CTC version 4.03. The efficacy assessments included veliparib PK data suggested that coadministration of FOLFOX had no the objective response rate (ORR), disease control rate (DCR; stable apparent impact on veliparib PKs (Supplementary Tables S2 and S3). disease through at least four cycles, partial response, or complete response), progression-free survival (PFS), and OS. For the phase II Suspected drug-related AEs (all cohorts) portion, the primary endpoint was the ORR, and each phase II cohort All 64 patients who received treatment were evaluable for followed a Simon two-stage optimal design (28). For each cohort, nine AEs. Table 2 provides the number of patients experiencing AEs by patients were accrued in the first stage, and if ≥1 patient demonstrated a category and cohort that are at least possibly related to treatment. No response, 15 additional patients were to be accrued in the second stage grade 5 events occurred. Overall, the combination of veliparib and for a total of 24 patients. If ≥3 patients among 24 patients demonstrated a FOLFOX was well tolerated, although minor treatment adjustments response, then the treatment was considered sufficiently promising to were required over the course of therapy for most patients. The warrant further testing. At the time this protocol was designed, the ORR primary toxicity of concern was myelosuppression, and 16% of for first-line standard-of-care gemcitabine was only 7% (29), and there patients experienced grade 3 or 4 neutropenia. One patient experi- was no standard second-line therapy. Each cohort was designed to enced grade 3 thrombocytopenia, and two patients had grade 3 or 4 differentiate a 5% ORR from a 25% ORR at a one-sided 10% significance anemia. Fifty-two and 64%, respectively, of patients experienced mild level with 90% power. Patient characteristics, medical features at study fatigue and nausea, but only 2% and 6%, respectively, were grade 3 or 4. entry, and AEs at least possibly related to study therapy were tabulated. Other notable grade 3 or 4 nonhematologic AEs included one patient Differences in ORR and DCR among subgroups were compared using each with a rash, diarrhea, and peripheral neuropathy. All patients Fisher exact tests. OS was defined as the number of months from required a reduction in the dose of veliparib, 5FU, and/or FOLFOX at enrollment until death or last contact. Patients who were alive at the time some point in the trial, either due to myelosuppression or nausea prior of analysis were censored at their last contact. PFS was defined as the to the first restaging imaging, or beyond four cycles typically for number of months from enrollment to progression or death, whichever neuropathy. occurred first. Patients who were alive and progression-free at the time of analysis were censored at their last tumor assessment time (as of May 3, Clinical efficacy and subgroup assessment 2019). The Kaplan–Meier methodology was used for analyzing OS and Of the 64 patients who received study treatment, six patients in the PFS. Analyses were performed in SAS software Version 9.4 (SAS phase I portion came off study prior to response evaluation (for Institute Inc.) and figures were created using STATA 12.1 (StatCorp LP). reasons other than progression of disease), and thus were not evaluable The trial opened in January 2011 and the phase I portion accrued for response. Table 3 presents the responses and survival times for the rapidly. However, when we restricted enrollment in the phase II 58 response-evaluable patients. For the entire group, the ORR was portion, as defined above, the accrual rate slowed considerably, and 26%, which included 11 PRs and four CRs. The waterfall plot in Fig. 2A the trial was closed to enrollment in 2019 due to slow accrual, although, demonstrates the responses for each patient. The DCR, PFS, and OS as discussed below, the primary endpoint had been met in the two were 52%, 4.0 months, and 7.8 months, respectively. The swimmer’s phase II cohorts. plot in Fig. 2B demonstrates the treatment duration for each patient. The protocol did allow for patients to stop the oxaliplatin for persistent neuropathy, at which time patients were maintained on the RP2D of Results veliparib plus the standard dose of continuous infusion 5FU (n ¼ 18, Patient characteristics and treatment cohorts none of whom received more than 12 cycles of FOLFOX). One patient Between January 2011 and December 2018, 75 patients were con- (patient 44) was granted an exception and was allowed to discontinue sented and 64 patients initiated treatment. Figure 1 depicts the screen the 5FU as well, after having remained in a complete response for failure and enrollment into the different cohorts. Thirty-one patients nearly 4 years. initiated treatment in the phase I portion; 15 patients initiated For the phase I portion (n ¼ 25), patients were not preselected on the treatment in the untreated phase II cohort; and 18 patients initiated basis of FH and known HR-DDR mutational status, and the ORR was treatment in the previously treated phase II cohort. Patient character- 20%. For the two phase II cohorts combined (n ¼ 33), with patients istics are listed in Table 1. The median age for all 64 treated patients selected on the basis of FH or HR-DDR mutational status, the ORR was was 64 years (range, 40–84); most patients had an ECOG score of 0 or 1 31%. The ORR was 40% for patients who received no prior therapy (n ¼ (95%); and 56% of patients were male. In the phase I, and previously 15), with a DCR, PFS, and OS of 87%, 6.5 months, and 13.0 months, treated phase II cohort, patients had a median of 1 and 2 lines of prior respectively. The ORR was 22% for the previously treated patients (N ¼ therapy, respectively (range, 1–7). 18), with a DCR, PFS, and OS of 28%, 1.6 months, and 4.5 months, respectively. Although the study was closed early due to slow accrual, the Phase I portion primary endpoint had been met in each of the two phase II cohorts. For the phase I portion, 27/31 patients were evaluable for DLTs, We examined efficacy in several patient subgroups (Table 3; Fig. 3). with four patients withdrawing consent after one cycle (not for There is evidence to suggest that the mechanisms of resistance to

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Figure 1. Cohort ﬂowchart. Of the 75 patients consented, 64 initiated study treatment. Two of the six patients in the phase I portion with the 5FU bolus came off due to toxicity before response evaluation. In the phase I portion without the 5FU bolus, two patients with- drew consent early, one patient came off due to a perforated gallbladder and one patient could not swallow the pills. In the phase II cohorts, all patients were evaluable for toxicity and response.

platinums overlap the mechanisms of resistance to PARP inhibitors. prior platinum was 25%, with a DCR of 50% (N ¼ 4). However, none of Correspondingly, the ORR for patients who received prior platinum the patients whose disease had progressed on prior platinum had a was only 7%, with a DCR of only 14% (N ¼ 14). This is compared with response, nor any reduction in tumor burden (Fig. 2A), nor even an ORR of 32% and a DCR of 64% for those who did not receive prior disease control with the combination of veliparib and FOLFOX (N ¼ platinum (N ¼ 44; Table 3; Fig. 3A and B). We further assessed 10). Of note, patient 61 received neoadjuvant FOLFIRINOX for outcomes for patients who had been previously exposed to platinums nonmetastatic disease and then was treated on study but did not meet (Table 3; patient numbers were too small for corresponding Kaplan– the deﬁnition of prior platinum exposure in the metastatic setting. Meier curves). Prior exposure to platinum was broken down into Unfortunately, her disease progressed on the combination of veliparib exposure, but nonprogression on prior platinum (as deﬁned in the and FOLFOX. Patients and Methods); and frank progression while on prior platinum. Forty-three patients had a positive FH and the ORR for these The ORR for patients who had been exposed to, but not progressed on patients was 30%, with a DCR of 53% (N ¼ 43). This is compared

Table 1. Patient characteristics.

All Phase I Phase II untreated Phase II pretreated Category Subgroup 64 (100%) 31 (49%) 15 (23%) 18 (28%)

Age: median (min, max) 64 (40,84) 64 (46,84) 65 (40,73) 64 (52,80) Gender Female 28 (44%) 21 (68%) 10 (67%) 8 (44%) Male 36 (56%) 10 (32%) 5 (33%) 10 (56%) Race/ethnicity White/non-Hispanic 51 (80%) 26 (84%) 11 (73%) 14 (78%) Black/non-Hispanic 10 (16%) 4 (13%) 3 (20%) 3 (16%) Asian-PI/non-Hispanic 2 (3%) 0 (0%) 1 (7%) 1 (6%) Any/Hispanic 1 (1%) 1 (3%) 0 (0%) 0 (0%) ECOG 0 16 (25%) 7 (23%) 4 (27%) 5 (28%) 1 45 (70%) 23 (74%) 9 (60%) 13 (72%) 2 3 (5%) 1 (3%) 2 (13%) 0 (0%) Prior platinum Yes 17 (27%) 7 (23%) 0 (0%) 10 (56%) No 47 (73%) 24 (77%) 15 (100%) 8 (44%) Family history Yes 44 (69%) 12 (39%) 15 (100%) 17 (94%) No 20 (31%) 19 (61%) 0 (0%) 1 (6%) Known HR-DDR mutation Yes 19 (30%) 2 (6%) 5 (33%) 12 (67%) No 45 (70%) 29 (94%) 10 (67%) 6 (33%)

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Table 2. Numbers (percentages) of patients experiencing AEs at least possibly related to study drug.

All (N ¼ 64) grade, Phase I N ¼ 31 grade, Phase II treated Phase II untreated N (%) N (%) N ¼ 18 grade, N (%) N ¼ 15 grade, N (%) AE Category CTCAE Term All 3,4 1,2 All 3,4 1,2 All 3,4 1,2 All 3,4 1,2

Hematologic Neutropenia 21 (33) 10 (16) 17 (27) 13 (42) 5 (16) 12 (39) 2 (11) 1 (6) 2 (11) 6 (40) 4 (27) 3 (20) Thrombocytopenia 13 (20) 1 (2) 13 (20) 12 (39) 1 (3) 12 (39) 1 (7) 1 (7) Leukopenia 11 (17) 3 (5) 10 (16) 9 (29) 3 (10) 8 (26) 1 (6) 1 (6) 1 (7) 1 (7) Anemia 6 (9) 2 (3) 4 (6) 4 (13) 1 (3) 3 (10) 1 (6) 1 (6) 1 (7) 1 (7) Lymphopenia 5 (8) 1 (2) 4 (6) 4 (13) 1 (3) 3 (10) 1 (7) 1 (7) Cardiovascular Hot ﬂashes 1 (2) 1 (2) 1 (3) 1 (3) Hypertension 1 (2) 1 (2) 1 (6) 1 (6) Hypotension 1 (2) 1 (2) 1 (7) 1 (7) Sinus tachycardia 1 (2) 1 (2) 1 (3) 1 (3) Constitutional Fatigue 33 (52) 1 (2) 33 (52) 12 (39) 12 (39) 11 (61) 11 (61) 10 (67) 1 (7) 10 (67) Anorexia 14 (22) 14 (22) 4 (13) 4 (13) 6 (33) 6 (33) 4 (27) 4 (27) Pain 7 (11) 7 (11) 5 (16) 5 (16) 2 (11) 2 (11) Allergic reaction 5 (8) 5 (8) 2 (11) 2 (11) 3 (20) 3 (20) Weight loss 5 (8) 5 (8) 2 (6) 2 (6) 1 (6) 1 (6) 2 (13) 2 (13) Fever 2 (3) 2 (3) 1 (3) 1 (3) 1 (6) 1 (6) Chills 1 (2) 1 (2) 1 (3) 1 (3) Febrile neutropenia 1 (2) 1 (2) 1 (3) 1 (3) Infusion-related reaction 1 (2) 1 (2) 1 (6) 1 (6) Insomnia 1 (2) 1 (2) 1 (3) 1 (3) Malaise 1 (2) 1 (2) 1 (7) 1 (7) Dermatologic Rash maculopapular 2 (3) 1 (2) 2 (3) 1 (6) 1 (6) 1 (6) 1 (7) 1 (7) Alopecia 1 (2) 1 (2) 1 (7) 1 (7) Hand–foot syndrome 1 (2) 1 (2) 1 (6) 1 (6) Pruritus 1 (2) 1 (2) 1 (7) 1 (7) Gastrointestinal Nausea 41 (64) 4 (6) 40 (63) 17 (55) 17 (55) 13 (72) 2 (11) 13 (72) 11 (73) 2 (13) 10 (67) Vomiting 22 (34) 4 (6) 21 (33) 10 (32) 10 (32) 6 (33) 2 (11) 6 (33) 6 (40) 2 (13) 5 (33) Diarrhea 14 (22) 1 (2) 13 (20) 7 (23) 1 (3) 6 (19) 4 (22) 4 (22) 3 (20) 3 (20) Constipation 11 (17) 11 (17) 5 (16) 5 (16) 4 (22) 4 (22) 2 (13) 2 (13) Mucositis oral 7 (11) 7 (11) 2 (6) 2 (6) 3 (17) 3 (17) 2 (13) 2 (13) Dysgeusia 4 (6) 4 (6) 1 (3) 1 (3) 1 (6) 1 (6) 2 (13) 2 (13) ALT increased 3 (5) 1 (2) 2 (3) 1 (6) 1 (6) 2 (13) 2 (13) AST increased 3 (5) 1 (2) 2 (3) 1 (6) 1 (6) 2 (13) 2 (13) Gastroesophageal reﬂux 3 (5) 3 (5) 1 (3) 1 (3) 2 (13) 2 (13) Abdominal pain 2 (3) 2 (3) 1 (6) 1 (6) 1 (7) 1 (7) Bloating 2 (3) 2 (3) 2 (6) 2 (6) Dehydration 2 (3) 2 (3) 1 (3) 1 (3) 1 (7) 1 (7) Flatulence 2 (3) 2 (3) 1 (3) 1 (3) 1 (7) 1 (7) Gastroparesis 2 (3) 2 (3) 2 (6) 2 (6) Dry mouth 1 (2) 1 (2) 1 (3) 1 (3) Gastrointestinal pain 1 (2) 1 (2) 1 (3) 1 (3) Heartburn 1 (2) 1 (2) 1 (7) 1 (7) Hiccups 1 (2) 1 (2) 1 (7) 1 (7) Stomatitis 1 (2) 1 (2) 1 (7) 1 (7) Other 3 (5) 3 (5) 2 (6) 2 (6) 1 (6) 1 (6) Genitourinary Vaginal discharge 1 (2) 1 (2) 1 (7) 1 (7) Other 1 (2) 1 (2) 1 (3) 1 (3) Infection Infections 1 (2) 1 (2) 1 (3) 1 (3) Leukocytosis 1 (2) 1 (2) 1 (3) 1 (3) Musculoskeletal Pain in extremity 2 (3) 2 (3) 1 (6) 1 (6) 1 (7) 1 (7) Edema limbs 1 (2) 1 (2) 1 (3) 1 (3) Muscle weakness left-sided 1 (2) 1 (2) 1 (3) 1 (3) Decrease range of motion 1 (2) 1 (2) 1 (6) 1 (6) Other 1 (2) 1 (2) 1 (3) 1 (3) Neurologic Paresthesia 17 (27) 17 (27) 8 (26) 8 (26) 6 (33) 6 (33) 3 (20) 3 (20) Dysesthesia 14 (22) 14 (22) 8 (26) 8 (26) 3 (17) 3 (17) 3 (20) 3 (20) Headache 5 (8) 5 (8) 1 (3) 1 (3) 3 (17) 3 (17) 1 (7) 1 (7) Dizziness 4 (6) 4 (6) 1 (3) 1 (3) 1 (6) 1 (6) 2 (13) 2 (13) Cognitive disturbance 2 (3) 2 (3) 2 (6) 2 (6) Peripheral sensory 2 (3) 1 (2) 2 (3) 2 (13) 1 (7) 2 (13) neuropathy (Continued on the following page)

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Table 2. Numbers (percentages) of patients experiencing AEs at least possibly related to study drug. (Cont'd ) All (N ¼ 64) grade, Phase I N ¼ 31 grade, Phase II treated Phase II untreated N (%) N (%) N ¼ 18 grade, N (%) N ¼ 15 grade, N (%) AE Category CTCAE Term All 3,4 1,2 All 3,4 1,2 All 3,4 1,2 All 3,4 1,2

Vertigo 2 (3) 2 (3) 1 (3) 1 (3) 1 (7) 1 (7) Blurred vision 1 (2) 1 (2) 1 (6) 1 (6) Confusion 1 (2) 1 (2) 1 (3) 1 (3) Depression 1 (2) 1 (2) 1 (3) 1 (3) Eye disorders: other 1 (2) 1 (2) 1 (3) 1 (3) Jaw spasm 1 (2) 1 (2) 1 (7) 1 (7) Laryngopharyngeal 1 (2) 1 (2) 1 (6) 1 (6) dysesthesia Tinnitus 1 (2) 1 (2) 1 (6) 1 (6) Syncope 1 (2) 1 (2) 1 (7) 1 (7) Other 1 (2) 1 (2) 1 (7) 1 (7) Pulmonary Dyspnea 1 (2) 1 (2) 1 (3) 1 (3)

with an ORR of 13% and a DCR of 47% for those with no FH (N ¼ Discussion 15; Table 3; Fig. 3C and D). Patients with mPDAC are in desperate need of additional therapies. Finally, 29 of 58 evaluable patients had NGS testing for HR-DDR The modern chemotherapy regimens of FOLFIRNOX and gemcita- mutations. Of these, 14 patients had a BRCA1/2 mutation; two patients bine þ nab-paclitaxel have improved outcomes, but response rates are had an ATM mutation; one patient had a PALB2 mutation; and one only 31% and 23%, respectively (2, 3). However, multiple sequencing patient had a FANCG mutation (Supplementary Table S4). The ORR efforts have revealed that a significant portion of PDACs harbor of the HR-DDR–mutated patients was 44%, with a DCR of 61% (N ¼ HR-DDR gene mutations, most commonly BRCA1/2 and ATM. 18). The highest ORR overall was observed in HR-DDR–mutated Emerging data have revealed that patients with HR-DDR–mutated patients who had not previously received platinum at 57% with a DCR mPDAC, specifically those with BRCA1/2 or PALB2 mutations can of 79% which was irrespective of the line of therapy (N ¼ respond to PARP inhibitors, and even CRs can be achieved (8–13, 15). 14; Table 3; Fig. 3E and F). As visualized in Fig. 2, all of the responses We and others have published that in patients with pancreatic cancer were observed in patients with germline or somatic BRCA1/2 or PALB2 whose tumors harbor HR-DDR mutations (ATM, ATRX, BAP1, mutations. The one patient with a FANCG mutation experienced BRIP1, FANCG, RAD50/51, etc.) have an improved survival when stable disease (PFS of 4.7, and ongoing at the time of data cut-off); but treated with platinum-based therapy (14, 30). In addition, there exist neither of the patients with ATM mutations (both of whom were also preclinical published data suggesting a benefit to PARP inhibitors, or platinum-na€ve) achieved even stable disease. PARP inhibitor combinations in pancreatic cancer models, including cell lines and patient-derived models of tumors with other HR-DDR mutations (31). While we have had personal communication with Table 3. Clinical outcomes for cohorts, FH, and HR-DDR status. colleagues who have shared anecdotal stories of patients with other HR-DDR mutations benefitting from off-label PARP inhibitor ther- ORR DCR PFS OS apy, there have not as yet been any published case reports of PARP n ¼ number of patients Subgroup ( ) (%) (%) (mos) (mos) inhibitor activity in such patients with pancreatic cancer. All response-evaluable patients (58) 26 52 4.4 7.8 In patients with pancreatic cancer with germline or somatic BRCA1/ Phase I patients (25) 20 48 4.0 6.5 2/PALB2 mutations, the activity of single-agent PARP inhibitors has Phase II untreated (15) 40 87 6.5 15.0 been limited, ranging from 16% to 21% (8, 13). Shroff and colleagues Phase II previously treated (18) 22 28 1.8 4.6 detailed that, similar to our findings, the majority of the responders Prior platinums were patients whose disease had not progressed on prior platinum (13). 14 Exposure to prior platinum ( ) 7 14 2.1 5.3 Yet, there may be enhanced benefit with the combination of a PARP Nonprogression on prior platinum (4) 25 50 5.5 6.7 inhibitor and a platinum, and preliminary results in a phase Ib trial Progression on prior platinum (10) 0 0 1.5 4.0 ’ No prior platinum (44) 32 64 5.5 8.8 from O Reilly and colleagues demonstrated a remarkable 78% ORR, Family history (FH) and 23 months OS with the combination of gemcitabine, cisplatin, and (þ)FH(43) 30 53 5.4 9.5 veliparib in patients with PDAC harboring germline BRCA1/2 No FH (15) 13 47 3.8 5.5 mutations (11). HR-DDR mutations We present here the results of our phase I/II trial of FOLFOX þ HR-DDR–mutated (18) 44 61 6.0 10.4 veliparib, and we demonstrate that patients with mPDAC can respond Nonmutated/unknown (40) 18 48 3.6 6.9 to this combination (ORR ¼ 26%). For the two phase II cohorts, we HR-DDR mutated, chose to close the study early due to slow accrual, but we did meet our No progression on prior platinum (14) 57 79 8.4 11.2 protocol-defined primary endpoint, with at least 3 responders in each cohort. In fact, with 40% of untreated and 22% of previously treated Note: A total of 58 patients were evaluable for response. Of those 58 patients, several subgroups, as detailed, were compared for the ORR, DCR (defined as patients achieving a PR or CR, this combination is worthy of further partial response or complete response at any time, or stable disease at 2 investigation. When patients were selected on the basis of FH and/or months), median PFS, and median OS. the presence of HR-DDR mutations, the ORR increased to 45%, and

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Veliparib plus FOLFOX in Patients with Pancreatic Cancer

Figure 2. Waterfall and swimmer’s plots. A, Waterfall plot of patient responses. Best tumor response is graphed for the 58 evaluable patients. B, Swimmer’s plot of patient PFS and OS. For each of the 58 evaluable patients, PFS (blue) and OS (brown) are graphed. Notations for both figures are indicated are for patients who were never exposed to prior platinum (solid bar); patients who had been treated with, but never progressed on prior platinum (hatched bar); and patients whose disease had progressed on platinum therapy (open bar). In addition, notations are indication for patients who had a positive FH (as defined in the Patients and Methods); and patients who had germline or somatic NGS testing. Patients tested, but with no identified HR-DDR mutation are indicated by an open star. Patients found to have a pathogenic HR-DDR mutation are indicated with a solid star, the specific gene mutated is listed, and, in cases where the mutation was germline, the specific mutation is preceded by a “g.”

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Figure 3. Kaplan–Meier curves. PFS (A, C, E) and OS (B, D, F) are graphed for patient subgroups. Figure 3A and B compare the PFS and OS, respectively for all patients, patients who had no prior platinum therapy, and patients who had prior platinum therapy exposure, as indicated in the legend. Figure 3C and D compare the PFS and OS, respectively for all patients, patients who had a positive FH (as deﬁned in the Patients and Methods) and patients who did not have an FH. Figure 3E and F compare the PFS and OS, respectively for all patients who harbored a germline or somatic pathogenic homologous recombination, DNA damage repair (HR-DDR) mutation, the HR-DDR–mutated patients who had not received prior platinum therapy, and patients who did not (or were not known to) harbor an HR-DDR mutation.

the highest responses were observed in patients whose tumors har- unlikely to beneﬁt from a PARP inhibitor combination. In our study, bored HR-DDR mutations, and who had not been exposed to prior none of the 10 patients who had experienced disease progression on platinum (ORR ¼ 57%, N ¼ 14). Our results also highlight the fact that prior platinum had even a minor reduction in tumor burden (Fig. 2), patients whose disease has progressed on prior platinum are very and the ORR and DCR for these patients was 0% (Table 3). Our results

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Veliparib plus FOLFOX in Patients with Pancreatic Cancer

are in line with the detailed results provided in the rucaparib study Finally, our study emphasizes the need to identify patients whose by Shroff and colleagues (13), and emphasize the notion that future disease harbors HR-DDR mutations. The NCCN has recently recom- trials of PARP inhibitors for patients with PDAC should exclude mended that all patients with PDAC undergo germline testing for the patients whose disease has progressed while on prior platinum. The presence of an inherited mutation. In addition, there has been more combination was well tolerated, and, for the patients with long- widespread testing for somatic mutations. Thus, we are optimistic that term (>4–6 months) disease control, a strategy of “maintenance” more patients will be identified, and a strategy to steer such patients therapy without the FOLFOX was able to maintain disease control toward PARP inhibitor–based clinical trials will be critical, and may lead for a prolonged period, as demonstrated by the swimmer’splot to the proof that we can improve outcomes for this subgroup of patients. (Fig. 2B). What is uncertain is the contribution of the veliparib to FOLFOX. Disclosure of Potential Conflicts of Interest It is possible that patients with HR-DDR mutations would respond M.J. Pishvaian reports grants from AbbVie (institutional support only) during to FOLFOX alone. However, two patients whose disease was only the conduct of the study; grants, personal fees, and nonfinancial support from Merck (consultant/advisor, institution), AstraZeneca/Medimmune (consultant/advisor, stabilized with prior FOLFIRINOX (i.e., no reduction in tumor fi þ institution), Halozyme (consultant/advisor, institution); personal fees and non nan- burden), did have a response to FOLFOX veliparib. Similarly, cial support from Sirtex Medical (consultant/advisor, speaker), Caris Life Sciences Shroff and colleagues highlighted two patients who did not respond (consultant/advisor, speaker); personal fees from Rafael (consultant/advisor), to platinum, but did respond to rucaparib (13). Yet, the results of RenovoRx (consultant/advisor); personal fees, nonfinancial support, and other from the recently reported randomized phase II trial of gemcitabine þ Perthera (consultant/advisor/stock); grants from Bavarian Nordic (institutional cisplatin veliparib in patients with BRCA1/2 or PALB2 mutations support only), Celldex (institutional support only), Pfizer (institutional support failed to demonstrate any benefittotheadditionofveliparib(32).In only), Novartis (institutional support only), Boston Biomedical (institutional support þ only), Tesaro (institutional support only), Bristol-Myers Squibb (institutional support this trial, patients treated with gemcitabine cisplatin alone had an only), Genentech (institutional support only), ARMO Biosciences (institutional ORR of 65%, and a median OS of 16.4 months, which was not support only), Bayer (institutional support only), Calithera (institutional support different in the group of patients who received veliparib as well. only), Curegenix (institutional support only), Fibrogen (institutional support only), While veliparib was not of any benefit when added to gemcitabine Gilead (institutional support only), GlaxoSmithKline (institutional support only), and cisplatin, the PARP inhibitor may play a different role when Karyopharm (institutional support only), Regeneron (institutional support only), combined with FOLFOX -based chemotherapy, wherein patients Pharmacyclics (institutional support only); grants and personal fees from Celgene – (consultant/advisor, institution); and personal fees from Foundation Medicine canonlyremainontheplatinumforapproximately4 6months.In (consultant/advisor) outside the submitted work; and is listed as a coinventor on a > ourstudy,18patientsremainedontherapyfor 6months,allof pending patent regarding the use of FOLFOX þ veliparib in pancreatic cancer. whom had gone off the oxaliplatin, due to neuropathy. Thus, there J.J. Hwang reports personal fees from Genentech/Roche (speaker bureau/consultant), may be a role for transitioning patients off FOLFOX while main- Bristol-Myers Squibb (speaker bureau/consultant), Amgen (speaker bureau/consul- taining the PARP inhibitor as long-term maintenance therapy, as tant), Ipsen (speaker bureau/consultant), Celgene (consultant), Deciphera (consul- was done in the POLO trial with olaparib (33). Such a strategy tant), Eisai (consultant), Bayer (consultant), from Taiho (consultant), and Caris (consultant) outside the submitted work. B.A. Weinberg reports personal fees from appeared effective in the phase III trial of carboplatin and paclitaxel Lilly, Bayer, Sirtex, and Taiho outside the submitted work. L.M. Weiner reports veliparib in ovarian cancer (24). A similar trial of induction personal fees from Celldex Therapeutics, Cytomx Therapeutics, Jounce Therapeutics, FOLFOX or even FOLFIRINOX, followed by maintenance veliparib Immunome, Klus Pharmaceuticals, Tessa Therapeutics, and Samyang Biopharm versus, for example, maintenance 5FU (or oral capecitabine), would USA; other from Targeted Diagnostics & Therapeutics (shareholder), grants from be an important study, and would address an important concern Bioexcel Therapeutics outside the submitted work; and performs occasional con- (the placebo control arm) of the POLO trial. sulting on patent cases in areas unrelated to the subject of this paper. J.L. Marshall reports personal fees from Caris Life Sciences (interim CMO), Indivumed (interim Furthermore, there is an ongoing debate on the functional role of CMO), Amgen, Taiho, Merck, and Bayer outside the submitted work. J.R. Brody is – PARP inhibition in the treatment of HR-DDR mutated cancers. listed as a coinventor on a pending patent regarding methods of treating gastroin- Originally, PARP inhibitors were demonstrated to inhibit the catalytic testinal cancers and tumors thereof using combination therapy. No potential conflicts activity of the PARP-1 enzyme, thus inhibiting single-strand repair, of interest were disclosed by the other authors. particularly after cotreatment with a DNA-damaging chemothera- ’ py (34). This mechanism was the foundation for exploring the Authors Contributions combination of veliparib and chemotherapy (23). However, a second M.J. Pishvaian: Conceptualization, resources, data curation, formal analysis, supervision, funding acquisition, validation, investigation, visualization, critical role of some PARP inhibitors involves the trapping of the PARP methodology, writing-original draft, project administration, writing-review and enzyme at the site of DNA damage (35). The trapped PARP enzyme editing. H. Wang: Data curation, formal analysis, validation, methodology, complex results in replication fork arrest, leading to mitotic catastro- writing-review and editing. A.R. He: Resources, investigation, writing-review and phe and apoptotic cell death. Several PARP inhibitors such as olaparib, editing. J.J. Hwang: Resources, investigation, writing-review and editing. niraparib, rucaparib, and talazoparib can achieve PARP trapping, and B.G. Smaglo: Data curation, investigation, writing-review and editing. S.S. Kim: thus are active as single agents (8, 13). Veliparib at tolerable doses can Data curation, investigation, writing-review and editing. B.A. Weinberg: Data curation, investigation, writing-review and editing. L.M. Weiner: Data curation, only achieve catalytic inhibition of the PARP enzyme. While veliparib investigation, writing-review and editing. J.L. Marshall: Resources, data curation, may not be effective as a single agent, the tradeoff may be that the funding acquisition, investigation, writing-review and editing. J.R. Brody: limited spectrum of activity of veliparib may also allow for the safe Conceptualization, resources, data curation, formal analysis, supervision, funding combination with DNA-damaging agents, such as radiation and acquisition, validation, investigation, methodology, writing-original draft, writing- chemotherapy. In contrast, many of the PARP-trapping inhibitors review and editing. have been too toxic to use in combination with DNA-damaging chemotherapies (36–38). Ultimately, a trial that compares, for exam- Acknowledgments fi ple, FOLFOX þ veliparib with a PARP trapping inhibitor would have We would like to thank Meeta Jaiswal, PhD for scienti c guidance throughout protocol development and implementation. This work was funded by the Otto to be done to compare outcomes of the two DNA damage targeting J. Ruesch Center for the Cure of GI Cancers, Lombardi Comprehensive Cancer strategies. Center. Abbvie, Inc. has provided veliparib and partial research funding for the

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correlative science. M.J. Pishvaian and J.R. Brody are supported by 1R01CA212600-01 The costs of publication of this article were defrayed in part by the payment of page (NCI, NIH); a 2015 Pancreatic Cancer Action Network American Association for charges. This article must therefore be hereby marked advertisement in accordance Cancer Research Acceleration Network Grant (15-90-25-BROD); and M.J. Pishvaian with 18 U.S.C. Section 1734 solely to indicate this fact. and J.R. Brody are also supported in part by U01CA224012 (NCI, NIH). J.R. Brody was supported in part by the NCI of the NIH Award Number P30CA056036 SKCC Core Grant (Thomas Jefferson University). We also would like to acknowledge The Received April 7, 2020; revised June 8, 2020; accepted July 13, 2020; published ﬁrst Sarah Parvin Foundation for their generous support. July 15, 2020.

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A Phase I/II Study of Veliparib (ABT-888) in Combination with 5-Fluorouracil and Oxaliplatin in Patients with Metastatic Pancreatic Cancer

Michael J. Pishvaian, Hongkun Wang, Aiwu Ruth He, et al.

Clin Cancer Res Published OnlineFirst July 15, 2020.

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