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

Abstract

Background

Up to 17% of pancreatic cancer (PDAC) patients harbor pathogenic (germline or somatic) mutations in a homologous recombination, DNA damage response and repair (HR-DDR) gene, such as BRCA1/2, or PALB2. Platinum-based chemotherapy, or treatment with PARP inhibitors are of particular benefit in these patients. However, there may be even greater benefit when platinums and PARP inhibitors are combined.

Patients and Methods

We performed a single-arm, open-label, phase I/II study of the PARP inhibitor, veliparib, with 5-fluorouracil (no 5FU bolus) and oxaliplatin (FOLFOX) for patients with metastatic PDAC. Thirty-one patients were enrolled in a Phase I dose escalation of veliparib (40mg to 250mg BID, days 1–7 of each 14 day cycle), to identify the recommended phase II dose (RP2D) of veliparib for the combination. Another 33 patients were enrolled in two parallel Phase II trials to assess the objective response rate (ORR) in untreated or in previously treated patients. If available, germline or somatic testing was collected to identify pathogenic HR-DDR mutations.

Results

The combination of veliparib and FOLFOX was tolerable at a RP2D of veliparib of 200mg BID. The primary endpoint for both Phase II cohorts was met, and the ORR overall was 26%. There was greater activity in platinum-naïve patients, and those who harbored a pathogenic HR-DDR mutation. Specifically, the ORR of HR-DDR mutated, platinum-naive patients was 57%.

Conclusions

The combination of veliparib and FOLFOX was safe for patients with metastatic PDAC and showed promising activity particularly in patients with platinum-naive disease that harbors a pathogenic HR-DDR mutation.

ClinicalTrials.gov identifier: NCT01489865; ABT-888 with Modified FOLFOX6 in Patients with Metastatic Pancreatic Cancer

INTRODUCTION

Pancreatic cancer (PDAC) is a deadly disease which, with a 5 year survival of only 10%, is poised to become the second leading cause of cancer related death in the United States by 2030(1). Treatment for metastatic PDAC (mPDAC) has improved, but the median overall survival (OS) remains less than 1 year(2,3). However, for the subgroup of ~17% of patients with PDAC whose tumors harbor defects in the homologous recombination-DNA damage response and repair (HR-DDR) pathway(4–7), such as BRCA1/2 and PALB2 mutations, preliminary data suggest that treatment with platinum-based chemotherapy and/or poly(ADP-ribose) polymerase (PARP) inhibitors offers significant improvements in patient outcomes(8–14). In fact, based on the Phase III POLO trial, PARP inhibitors are now an FDA approved standard treatment option as maintenance therapy for mPDAC patients who harbor pathogenic germline BRCA1/2 mutations(15). PARP inhibitors have also been demonstrated to be active in PDAC patients whose tumors harbor pathogenic PALB2 mutations(16). There is also evidence in other cancer types of the 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 PARP inhibitor is combined with DNA damaging chemotherapy. PARP plays a critical role in facilitating the repair of both single- and double-stranded DNA breaks(18–20), and PARP inhibition results in less efficient DNA repair. Thus, PARP inhibitors act as sensitizing agents for DNA-damaging chemotherapies(21). Veliparib (ABT-888, Abbvie) is a PARP inhibitor that has proven in vivo activity(22), and increases tumor cell sensitivity to chemotherapy and radiation(23). In humans, veliparib is safe and demonstrates inhibition of PARP activity in tumor biopsies(22). In Phase III trials, veliparib has been used in combination with platinum-based chemotherapy at a dose of 150mg orally twice a day (BID); and at 400mg BID as maintenance therapy without chemotherapy(24).

We previously demonstrated in PDAC cells that genetically disrupting the DNA binding domain of PARP1, or treating with veliparib synergizes with oxaliplatin(21), particularly in HR-DDR deficient cell lines. Therefore, we designed a trial combining veliparib with oxaliplatin-based chemotherapy for patients with mPDAC. At the time of study design, FOLFIRINOX was not yet standard of care, and may present toxicity challenges in combination with a PARP inhibitor due to overlapping myelosuppression. Thus, herein, we present a Phase I/II clinical trial of veliparib plus 5-fluorouracil (5FU) and oxaliplatin (FOLFOX) for patients with mPDAC.

PATIENTS AND METHODS

Patients

Patients with mPDAC with measurable disease (as per RECIST 1.1(25)) were eligible. Patients were aged ≥18 years, had an Eastern Cooperative Oncology Group performance status score of ≤2, and had adequate organ and bone marrow function (hemoglobin ≥9.5 g/dL, absolute neutrophil count ≥1.5 × 10⁹/L, platelet count ≥75 × 10⁹/L, serum creatinine level <1.5 mg/dL, bilirubin level ≤2.5 × upper limit of normal (ULN), and ALT/AST levels ≤3 × ULN). For the Phase I portion of the study, patients were not selected based on prior therapy, family history (FH), nor germline or tumor HR-DDR mutational status.

For the Phase II portion, there were two cohorts. Patients in the untreated cohort had not had any prior systemic therapy for mPDAC, though adjuvant chemotherapy was allowed if completed >6 months prior; and prior palliative radiation to the primary mass was allowable. Patients in the previously treated cohort may have had any number of prior therapies, including platinum-based regimens such as FOLFIRINOX, FOLFOX, or gemcitabine and cisplatin, but they may not have received a prior PARP inhibitor. Also, for the Phase II portion (both cohorts), we preselected patients who either had a known pathogenic germline or somatic mutation (though testing was not required) in one of the HR-DDR genes (e.g. BRCA1/2, PALB2, ATM (expanded list in the supplemental materials)); and/or patients who had a FH suggestive of a breast or ovarian cancer syndrome, as detailed in the NCCN guidelines (summarized in the supplemental material)(26). For the post-hoc analyses detailed in the Results, outcomes for different patient subgroups were compared. Subgroups included: 1) Prior platinum exposure: Patients were placed into one of three categories as to whether their disease had:

1. Never been exposed to prior platinum

2. Been exposed, but not progressed on prior platinum (defined as no disease progression within 3 months of stopping platinum)

3. Progressed while on prior platinum

2) The presence or absence of a FH (as defined above); 3) The presence of a mutation in an HR-DDR gene; patients who were tested but did not harbor a pathogenic germline or somatic HR-DDR mutation were also identified and highlighted. The study protocol, amendments, and informed consent forms were approved by the Institutional Review Board at Georgetown University. Investigators obtained written informed consent from each participant or participant’s guardian prior to screening. The research was conducted in accordance with recognized ethical guidelines including the Declaration of Helsinki, CIOMS, Belmont Report, and U.S. Common Rule, as described during training in Good Clinical Practice guidelines (CITI Training).

Study Design and Treatment Schedule

This was a single center, Phase I/II, open label study. Initially, the dose and schedule for modified FOLFOX6(27) was used (5FU bolus 400mg/m² Day 1; leucovorin 400mg/m² Day 1; oxaliplatin 85mg/m² Day 1; and 5FU 2400mg/m² continuous infusion over 46 hours, Days 1–3). Each cycle was 14 days. However, the first 6 patients dosed at 40mg of veliparib demonstrated prolonged Grade 2 or 3 myelosuppression. Thus, the 5FU bolus was dropped for all subsequent patients. For the Phase I portion, the dose of veliparib was escalated in a standard 3+3 design from 40 to 60, 80, 100, 150, 200, and 250mg twice a day (BID), days 1–7 (Supplemental Table 1). As the primary endpoint of the Phase I portion was to determine the recommended Phase II dose (RP2D; as well as the maximally tolerated dose), Dose Limiting Toxicities (DLTs) were defined as any of the following that were definitely, possibly or probably related to therapy (veliparib + FOLFOX) that occurred during the first cycle of therapy:

1. Grade 4 neutropenia lasting greater than 5 days or complicated by fever or infection

2. Grade 4 anemia or thrombocytopenia

3. Grade 3 thrombocytopenia associated with bleeding for which a transfusion was required.

4. Grade 3 or 4 non-hematologic toxicity not manageable with routine supportive care (e.g. over the counter anti-diarrheals for diarrhea).

5. Any toxicity, regardless of grade, which resulted in withholding of therapy for greater than three weeks.

For the Phase II portion, the RP2D was 200mg of veliparib, though the protocol did allow for stepwise de-escalation to 150mg and then to 100mg for toxicity after the first cycle. Safety assessments were performed every 2 weeks for the first 4 cycles, then every 4 weeks thereafter. Tumor response was assessed radiographically every 8 – 12 weeks using RECIST 1.1(25). Study treatment was continued without interruption in the absence of unacceptable toxicity or progressive disease (PD). The protocol did allow for patients to stop the oxaliplatin for persistent neuropathy, at which time patients were maintained on the RP2D of veliparib plus the standard dose of continuous infusion 5FU.

Correlative Markers of Response to Therapy

For the Phase I portion, plasma samples were obtained according to the schedule in Supplemental Figure 1 for pharmacokinetic (PK) assessment of veliparib performed at Abbvie. Results were compared to historical controls to identify any effect on veliparib PKs by FOLFOX. In addition, when samples were available, next generation sequencing of cancer-related genes was performed commercially by Foundation Medicine, Caris Life Sciences, or Tempus laboratories on patient tumor samples. Several patients also had germline testing through Myriad or Ambry. Patients were defined as harboring HR-DDR mutations if a pathogenic mutation in an HR-DDR gene was identified in a blood sample (germline) or tumor sample (somatic). Pathogenic mutations for each patient are included in Supplemental Table 4. The study team centrally validated pathogenic mutations in the ClinVar and Cosmic databases.

Statistical Analysis

The primary objective of the Phase I portion was to determine the RP2D, with the primary endpoint being adverse events (AEs), as measured by NIH CTC version 4.03. The efficacy assessments included the objective response rate (ORR), disease control rate (DCR; stable disease through at least 4 cycles, partial response, or complete response), progression-free survival (PFS), and OS. For the Phase II portion, the primary endpoint was the ORR, and each Phase II cohort followed a Simon’s two-stage optimal design(28). For each cohort, 9 patients were accrued in the first Stage, and if ≥1 patient demonstrated a response, 15 additional patients were to be accrued in the second Stage for a total of 24 patients. If ≥3 patients among 24 patients demonstrated a response, then the treatment was considered sufficiently promising to warrant further testing. At the time this protocol was designed, the ORR for first-line standard of care gemcitabine was only 7%(29), and there was no standard second-line therapy. Each cohort was designed to differentiate a 5% ORR from a 25% ORR at a 1-sided 10% significance level with 90% power. Patient characteristics, medical features at study entry, and AEs at least possibly related to study therapy were tabulated. Differences in ORR and DCR among subgroups were compared using Fisher’s Exact tests. OS was defined as the number of months from enrollment until death or last contact. Patients who were alive at the time of analysis were censored at their last contact. PFS was defined as the number of months from enrollment to progression or death, whichever 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, 2019). The Kaplan-Meier methodology was used for analyzing OS and PFS. Analyses were performed in SAS software Version 9.4 [SAS Institute Inc., Cary, NC, USA.] and figures were created using STATA 12.1 [StatCorp LP, College Station, TX, USA].

The trial opened in January, 2011 and the Phase I portion accrued rapidly. However, when we restricted enrollment in the Phase II portion, as defined above, the accrual rate slowed considerably, and the trial was closed to enrollment in 2019 due to slow accrual, although, as discussed below, the primary endpoint had been met in the two Phase II cohorts.

RESULTS

Patient Characteristics and Treatment Cohorts

Between January, 2011 and December, 2018, 75 patients were consented, and 64 patients initiated treatment. Figure 1 depicts the screen failure and enrollment into the different cohorts. Thirty one patients initiated treatment in the Phase I portion; 15 patients initiated treatment in the untreated Phase II cohort; and 18 patients initiated treatment in the previously treated Phase II cohort. Patient characteristics are listed in Table 1. The median age for all 64 treated patients was 64 years (range 40 – 84); most patients had an ECOG score of 0 or 1 (95%); and 56% of patients were male. In the Phase I, and previously treated Phase II cohort, patients had a median of 1 and 2 lines of prior therapy, respectively (range, 1–7).

Figure 1: Cohort Flowchart.

Of the 75 patients consented, 64 initiated study treatment. Two of the 6 patients in the Phase I portion with the 5FU bolus come off due to toxicity before response evaluation. In the Phase I portion without the 5FU bolus, 2 patients withdrew consent early, 1 patient came off due to a perforated gall bladder, and one patient could not swallow the pills. In the Phase II cohorts, all patients were evaluable for toxicity and response.

Table 1.

Patient Characteristics

		All	Phase I	Phase II Untreated	Phase II Pre-Treated
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%)

Phase I Portion

For the Phase I portion, 27/31 patients were evaluable for dose limiting toxicities (DLTs), with four patients withdrawing consent after one cycle (not for toxicity). In the 40mg cohort, 3 of 6 patients required significant (>2 week) treatment delays for Grade 2 or 3 myelosuppression, but the only protocol-defined DLT was a treatment delay of >3 weeks. Therefore, the protocol was amended to drop the 5FU bolus. Only one other DLT occurred, which was at the 250mg cohort. Four of the 6 patients at 250mg experienced significant Grade 3 or 4 myelosuppression. Therefore, 200mg was selected as the RP2D, though the protocol allowed for stepwise de-escalation to 150mg and then to 100mg for toxicity after the first cycle.

PK samples were available for 14 patients in 5 dosing cohorts. The veliparib PK data suggested that co-administration of FOLFOX had no apparent impact on veliparib PKs (Supplemental Tables 2 and 3).

Suspected Drug Related Adverse Events (All Cohorts)

All 64 patients who received treatment were evaluable for AEs. Table 2 provides the number of patients experiencing AEs by category and cohort that are at least possibly related to treatment. No Grade 5 events occurred. Overall, the combination of veliparib and FOLFOX was well tolerated, although minor treatment adjustments were required over the course of therapy for most patients. The primary toxicity of concern was myelosuppression, and 16% of patients experienced Grade 3 or 4 neutropenia. One patient experienced Grade 3 thrombocytopenia, and 2 patients had Grade 3 or 4 anemia. Fifty-two and sixty-four percent, respectively of patients experienced mild fatigue and nausea, but only 2% and 6%, respectively were Grade 3 or 4. Other notable Grade 3 or 4 non-hematologic AEs included 1 patient each with a rash, diarrhea, and peripheral neuropathy. All patients required a reduction in the dose of veliparib, 5FU, and/or oxaliplatin at some point in the trial, either due to myelosuppression or nausea prior to the first restaging imaging, or beyond 4 cycles typically for neuropathy.

Table 2.

Numbers (Percentages) of Patients Experiencing Adverse Events at Least Possibly Related to Study Drug

AE Category	CTCAE Term	All (N=64) Grade, N (%)			Phase I N=31 Grade, N (%)			PhaseII treated N=18 Grade, N (%)			Phase II Untreated N=15 Grade, N (%)
		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 maculo-papular	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 neuropathy	2 (3)	1 (2)	2 (3)							2 (13)	1 (7)	2 (13)
	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 dysesthesia	1 (2)		1 (2)				1 (6)		1 (6)
	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)

Clinical Efficacy and Subgroup Assessment

Of the 64 patients who received study treatment, 6 patients in the Phase I portion came off study prior to response evaluation (for reasons other than progression of disease), and thus were not evaluable for response. Table 3 presents the responses and survival times for the 58 response evaluable patients. For the entire group, the ORR was 26%, which included 11 PRs and 4 CRs. The waterfall plot in Figure 2A demonstrates the responses for each patient. The DCR, PFS, and OS were 52%, 4.0 months, and 7.8 months, respectively. The swimmers plot in Figure 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 veliparib plus the standard dose of continuous infusion 5FU (n = 18, none of whom received more than 12 cycles of oxaliplatin). One patient (patient 44) was granted an exception and was allowed to discontinue the 5FU as well, after having remained in a complete response for nearly 4 years.

Table 3. Clinical Outcomes for Cohorts, Family History, and HR-DDR Status.

58 patients total were evaluable for response. Of those 58 patients, several subgroups, as detailed, were compared for the objective response rate (ORR), disease control rate (DCR, defined as partial response or complete response at any time, or stable disease at 2 months), median progression-free survival (PFS), and median overall survival (OS).

Subgroup (n)	ORR (%)	DCR (%)	PFS (mos)	OS (mos)
All Response Evaluable Patients (58)	26	52	4.4	7.8
Phase I Patients (25)	20	48	4.0	6.5
Phase II Untreated (15)	40	87	6.5	15.0
Phase II Previously Treated (18)	22	28	1.8	4.6
Prior Platinums
Exposure to Prior Platinum (14)	7	14	2.1	5.3
Non-Progression on Prior Platinum (4)	25	50	5.5	6.7
Progression on Prior Platinum (10)	0	0	1.5	4.0
No Prior Platinum (44)	32	64	5.5	8.8
Family History (FH)
(+) FH (43)	30	53	5.4	9.5
No FH (15)	13	47	3.8	5.5
HR-DDR Mutations
HR-DDR mutated (18)	44	61	6.0	10.4
Non-Mutated/Unknown (40)	18	48	3.6	6.9
HR-DDR Mutated, No progression on prior platinum (14)	57	79	8.4	11.2

Figure 2: Waterfall and Swimmers Plots.

2A) Waterfall Plot of Patient Responses. Best tumor response is graphed for the 58 evaluable patients. 2B) Swimmers Plot of Patient PFS and OS. For each of the 58 evaluable patients, progression free survival (blue) and overall survival (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). Additionally, notations are indication for patients who had a positive FH (as defined in the 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”.

For the Phase I portion (n=25), patients were not pre-selected based on FH and known HR-DDR mutational status, and the ORR was 20%. For the two Phase II cohorts combined (n=33), with patients selected based on FH or HR-DDR mutational status, the ORR was 31%. The ORR was 40% for patients who received no prior therapy (n=15), with a DCR, PFS, and OS of 87%, 6.5 months, and 13.0 months, respectively. The ORR was 22% for the previously treated patients (N=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 primary endpoint had been met in each of the two Phase II cohorts.

We examined efficacy in several patient subgroups (Table 3, and Figure 3). There is evidence to suggest that the mechanisms of resistance to platinums overlap the mechanisms of resistance to PARP inhibitors. Correspondingly, the ORR for patients who received prior platinum was only 7%, with a DCR of only 14% (N=14). This is compared to an ORR of 32% and a DCR of 64% for those who did not receive prior platinum (N=44) (Table 3, and Figures 3A and 3B). We further assessed outcomes for patients who had been previously exposed to platinums (Table 3 [Patient numbers were too small for corresponding Kalan-Meier curves]. Prior exposure to platinum was broken down into exposure, but non-progression on prior platinum (as defined in the Methods); and frank progression while on prior platinum. The ORR for patients who had been exposed to, but not progressed on prior platinum was 25%, with a DCR of 50% (N=4). However, none of the patients whose disease had progressed on prior platinum had a response, nor any reduction in tumor burden (Figure 2A), nor even disease control with the combination of veliparib and FOLFOX (N=10). Of note, patient 61 received neoadjuvant FOLFIRINOX for non-metastatic disease, and then was treated on study but did not meet the definition of prior platinum exposure in the metastatic setting. Unfortunately, her disease progressed on the combination of veliparib and FOLFOX.

Figure 3: Kaplan-Meier Curves.

Progression-free survival (PFS, A, C, E) and overall survival (OS, B, D, F) are graphed for patient subgroups. Figures 3A and 3B 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. Figures 3C and 3D compare the PFS and OS, respectively for all patients, patients who had a positive FH (as defined in the methods) and patients who did not have a FH. Figures 3E and 3F 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.

Forty-three patients had a positive FH and the ORR for these patients was 30%, with a DCR of 53% (N=43). This is compared to an ORR of 13% and a DCR of 47% for those with no FH (N=15) (Table 3, and Figures 3C and 3D).

Finally, 29 out of 58 evaluable patients had NGS testing for HR-DDR mutations. Of these, 14 patients had a BRCA1/2 mutation; 2 patients had an ATM mutation; 1 patient had a PALB2 mutation; and 1 patient had a FANCG mutation (Supplementary Table 4). The ORR of the HR-DDR mutated patients was 44%, with a DCR of 61% (N=18). The highest ORR overall was observed in HR-DDR mutated patients who had not previously received platinum at 57% with a DCR of 79% which was irrespective of the line of therapy (N=14) (Table 3, and Figures 3E and 3F). As visualized in Figure 2, all of the responses were observed in patients with germline or somatic BRCA1/2 or PALB2 mutations. The one patient with a FANCG mutation experienced stable disease (PFS of 4.7, and ongoing at the time of data cut-off); but neither of the patients with ATM mutations (both of whom were also platinum-naïve) achieved even stable disease.

DISCUSSION

Patients with mPDAC are in desperate need of additional therapies. The modern chemotherapy regimens of FOLFIRNOX and gemcitabine + nab-paclitaxel have improved outcomes, but response rates are only 31% and 23%, respectively(2,3). However, multiple sequencing efforts have revealed that a significant portion of PDACs harbor HR-DDR gene mutations, most commonly BRCA1/2 and ATM. Emerging data has revealed that patients with HR-DDR-mutated mPDAC, specifically those with BRCA1/2 or PALB2 mutations can respond to PARP inhibitors, and even CRs can be achieved(8–13,15). We and others have published that in pancreatic cancer patients whose tumors harbor HR-DDR mutations (ATM, ATRX, BAP1, BRIP1, FANCG, RAD50/51, etc) have an improved survival when treated with platinum-based therapy(14,30). Additionally, there exists pre-clinical published data suggesting a benefit to PARP inhibitors, or PARP inhibitor combinations in pancreatic cancer models, including cell lines, and patient-derived models, of that tumors with other HR-DDR mutations(31) . While we have had personal communication with colleagues who have shared anecdotal stories of patients with other HR-DDR mutations benefitting from off label PARP inhibitor therapy, there have not as yet been any published case reports of PARP inhibitor activity in such pancreatic cancer patients (PUBMED search, June 1^st, 2020).

In pancreatic cancer patients with germline or somatic BRCA1/2/PALB2 mutations, the activity of single agent PARP inhibitors has been limited, ranging from 16 – 21%(8,13). Shroff, et al, detailed that, similar to our findings, the majority of the responders were patients whose disease had not progressed on prior platinum(13). Yet, there may be enhanced benefit with the combination of a PARP inhibitor and a platinum, and preliminary results in a Phase Ib trial from O’Reilly, et al demonstrated a remarkable 78% ORR, and 23 month OS with the combination of gemcitabine, cisplatin, and veliparib in PDAC patients harboring germline BRCA1/2 mutations(11).

We present here the results of our Phase I/II trial of FOLFOX + veliparib, and we demonstrate that patients with mPDAC can respond to this combination (ORR = 26%). For the two Phase II cohorts, we chose to close the study early due to slow accrual, but we did meet our protocol-defined primary endpoint, with at least 3 responders in each cohort. In fact, with 40% of untreated, and 22% of previously treated patients achieving a PR or CR, this combination is worthy of further investigation. When patients were selected based on FH and/or the presence of HR-DDR mutations, the ORR increased to 45%, and the highest responses were observed in patients whose tumors harbored HR-DDR mutations, and who had not been exposed to prior platinum (ORR = 57%, N = 14). Our results also highlight the fact that patients whose disease has progressed on prior platinum are very unlikely to benefit from a PARP inhibitor combination. In our study, none of the 10 patients who had experienced disease progression on prior platinum had even a minor reduction in tumor burden (Figure 2), and the ORR and DCR for these patients was 0% (Table 3). Our results are in line with the detailed results provided in the rucaparib study by Shroff, et al (13), and emphasize the notion that future trials of PARP inhibitors for PDAC patients should exclude patients whose disease has progressed while on prior platinum. The combination was well tolerated, and, for the patients with long-term (>4–6 month) disease control, a strategy of “maintenance” therapy without the oxaliplatin was able to maintain disease control for a prolonged period, as demonstrated by the swimmer’s plot (Figure 2B).

What is uncertain is the contribution of the veliparib to FOLFOX. It is possible that patients with HR-DDR mutations would respond to FOLFOX alone. However, two patients whose disease was only stabilized with prior FOLFIRINOX (i.e., no reduction in tumor burden), did have a response to FOLFOX + veliparib. Similarly, Shroff, et al highlighted two patients who did not respond to platinum, but did respond to rucaparib(13). Yet, the results of the recently reported randomized Phase II trial of gemcitabine + cisplatin +/− veliparib in patients with BRCA1/2 or PALB2 mutations failed to demonstrate any benefit to the addition of veliparib(32). In this trial, patients treated with gemcitabine + cisplatin alone had an ORR of 65%, and a median overall survival of 16.4 months, which was not different in the group of patients who received veliparib as well. While veliparib was not of any benefit when added to gemcitabine and cisplatin, the PARP inhibitor may play a different role when combined with oxaliplatin-based chemotherapy, wherein patients can only remain on the platinum for ~4–6 months. In our study, 18 patients remained on therapy for >6 months, all of whom had gone off the oxaliplatin, due to neuropathy. Thus, there may be a role for transitioning patients off oxaliplatin while maintaining the PARP inhibitor as long term maintenance therapy, as was done in the POLO trial with olaparib(33). Such a strategy appeared effective in the Phase III trial of carboplatin and paclitaxel +/− veliparib in ovarian cancer (24). A similar trial of induction FOLFOX or even FOLFIRINOX, followed by maintenance veliparib versus, for example, maintenance 5FU (or oral capecitabine), would be an important study, and would address an important concern (the placebo control arm) of the POLO trial.

Furthermore, there is an ongoing debate on the functional role of PARP inhibition in the treatment of HR-DDR mutated cancers. Originally, PARP inhibitors were demonstrated to inhibit the catalytic activity of the PARP-1 enzyme, thus inhibiting single strand repair, particularly after co-treatment with a DNA-damaging chemotherapy(34). This mechanism was the foundation for exploring the combination of veliparib and chemotherapy(23). However, a second critical role of some PARP inhibitors involves the trapping of the PARP enzyme at the site of DNA damage(35). The trapped PARP enzyme complex results in replication fork arrest, leading to mitotic catastrophe and apoptotic cell death. Several PARP inhibitors such as olaparib, niraparib, rucaparib, and talazoparib can achieve PARP trapping, and thus are active as single agents(8,13). Veliparib at tolerable doses can only achieve catalytic inhibition of the PARP enzyme. While veliparib may not be effective as a single agent, the tradeoff may be that the limited spectrum of activity of veliparib may also allow for the safe combination with DNA damaging agents, such as radiation and chemotherapy. By contrast, many of the PARP trapping inhibitors have been too toxic to use in combination with DNA damaging chemotherapies (36–38). Ultimately, a trial that compares, for example FOLFOX + veliparib to a PARP trapping inhibitor would have to be done to compare outcomes of the two DNA damage targeting strategies.

Finally, our study emphasizes the need to identify patients whose disease harbors HR-DDR mutations. The NCCN has recently recommended that all patients with PDAC undergo germline testing for the presence of an inherited mutation. In addition, there has been more widespread testing for somatic mutations. Thus, we are optimistic that more patients will be identified, and a strategy to steer such patients towards PARP inhibitor-based clinical trials will be critical, and may lead to the proof that we can improve outcomes for this subgroup of patients.

STATEMENT OF TRANSLATIONAL RELEVANCE.

Platinum-based chemotherapies and PARP inhibitors have demonstrated promising activity in patients with metastatic pancreatic cancer who harbor pathogenic germline or somatic mutations in the homologous recombination, DNA damage response and repair (HR-DDR) genes, BRCA1/2, or PALB2. There is evidence of benefit of PARP inhibitors for patients whose tumors harbor other HR-DDR gene mutations as well. However, there may be even greater benefit when platinums and PARP inhibitors are combined. To assess the safety and efficacy of such a combination, we performed a Phase I/II clinical trial of 64 patients, with the combination of the PARP inhibitor, veliparib, with chemotherapy, FOLFOX. The combination was safe and effective for patients with metastatic pancreatic cancer. The greatest activity, with an ORR of 57%, was seen in patients whose disease had not progressed on prior platinum, and who harbored germline or somatic HR-DDR mutations.