Pamiparib dose escalation in Chinese patients with non‐mucinous high‐grade ovarian cancer or advanced triple‐negative breast cancer

Abstract Background The recommended phase 2 dose (RP2D) of pamiparib, an investigational PARP1/2 inhibitor, was established as 60 mg twice daily (BID) in a first‐in‐human (FIH) study (NCT02361723). Methods Chinese patients with advanced non‐mucinous high‐grade ovarian cancer (HGOC) or triple‐negative breast cancer (TNBC) whose disease either progressed despite standard therapy, or for which there is no standard therapy were enrolled in the dose‐escalation (DE) portion of a phase 1/2 study (NCT03333915). The primary endpoint was safety/tolerability; secondary objectives were pharmacokinetics and antitumor activity. BRCA1/2 mutation status was retrospectively evaluated. Results Nine HGOC and six TNBC patients (N = 15; n = 4, 20 mg; n = 4, 40 mg; n = 7, 60 mg) were enrolled; as of 30 September 2019, one HGOC patient remained on treatment. Seven patients (n = 5, HGOC; n = 2, TNBC) had germline BRCA1/2 mutation (gBRCA mut); all HGOC patients were resistant/refractory to platinum. Asthenia and nausea (n = 12 each) were the most common treatment‐related adverse events (TRAEs). Decreased hemoglobin was the most common grade 3 TRAE (n = 3); no grade ≥4 AEs were observed. No dose‐limiting toxicities (DLTs) were reported. Pamiparib plasma exposure was similar to exposure observed in the FIH study after a single‐dose administration, albeit slightly higher at steady state. Among 13 RECIST‐evaluable patients, two with HGOC (gBRCA mut, n = 1) achieved a confirmed partial response and six with HGOC (gBRCA mut, n = 4) achieved stable disease; all TNBC RECIST‐evaluable patients (n = 5) reported progressive disease. Conclusions Pamiparib was generally well tolerated in Chinese patients, with durable responses observed in patients with HGOC. Based on these results, pamiparib 60 mg BID was confirmed as the RP2D.


| INTRODUCTION
Poly (ADP-ribose) polymerase 1 and 2 (PARP1/2) enzymes are associated with nuclear process regulations, including the repair of DNA, genomic stability, and programmed cell death. 1 The primary function of PARP1/2 enzymes is to detect DNA breaks (single-strand) and target them for repair. 2 Inhibiting PARP enzymes ultimately leads to the conversion of single-strand breaks to double-strand breaks, resulting in genomic instability and apoptosis. 2 Repair of double-strand DNA breaks normally occurs through homologous recombination in the presence of tumor suppressor proteins BRCA1 and BRCA2. 2 Within BRCA-deficient cells, homologous recombination is impaired, leading to genomic instability, which may favor tumorigenesis.
Small molecule inhibitors of PARP (PARPi) represent a new class of therapeutic agents being used to treat patients with different types of cancers with genomic instability, including tumors associated with BRCA1/2 mutations. 3,4 The mechanism of PARP inhibition is currently under investigation. Inhibitors of PARP have been found to bind directly to and inhibit the activity of PARP enzymes, thus preventing DNA repair and trapping PARP-DNA complexes at the site of DNA damage. 5,6 Agents that inhibit PARP are particularly effective treatments for tumors with homologous recombination deficiency (HRD) because they cannot accurately repair the DNA damage.
Pamiparib (BGB-290) is an investigational selective inhibitor of PARP1/2 that has been shown to have PARP-DNA complex trapping capabilities and brain penetration. 7 Pamiparib suppressed PARP activity in patient-acquired xenografts of glioblastoma multiforme and small cell lung cancer. [7][8][9] Additionally, pamiparib was found to be 10-fold more potent than olaparib 8 and was able to potentiate the effects of temozolomide. 7,9 Preliminary results of the firstin-human (FIH) study (NCT02361723) demonstrated that pamiparib was generally well tolerated and showed antitumor activity, notably in patients with non-mucinous high-grade ovarian cancer (HGOC). [10][11][12] The FIH study also established the recommended phase 2 dose (RP2D) of pamiparib as 60 mg orally (PO) twice daily (BID) and demonstrated that pamiparib exposure is linear up to 80 mg BID, which has been determined as the maximum tolerated dose (MTD). 10,12 Here, we present results from the phase 1 component of an ongoing phase 1/2 study in Chinese patients with advanced HGOC or advanced triple-negative breast cancer (TNBC) (NCT03333915); results of the ongoing phase 2 component of the study are forthcoming.

| Study design
This phase 1/2, open-label, multicenter study assessed the safety and antitumor activity of pamiparib in Chinese patients ≥18 years with advanced solid tumors whose disease progressed despite standard therapy or for which there is no standard therapy. Phase 1 was a dose-escalation study, with a 3 + 3 design, that evaluated the single-agent safety/tolerability, pharmacokinetic (PK) profile, and preliminary antitumor activity of pamiparib and confirmed the RP2D in Chinese patients ( Figure 1). The phase 2 dose-expansion component of this study is investigating the single-agent antitumor activity and safety/tolerability of pamiparib.
In phase 1, patients received pamiparib at 20, 40, and 60 mg BID dose levels. The starting dose for pamiparib (20 mg BID) was selected as one-third of the RP2D (60 mg BID) and one-fourth of the MTD (80 mg BID), which Conclusions: Pamiparib was generally well tolerated in Chinese patients, with durable responses observed in patients with HGOC. Based on these results, pamiparib 60 mg BID was confirmed as the RP2D. were determined in the FIH study. Results of the FIH study showed a favorable risk-benefit profile for each dosage. 10,12 A 23-day initial treatment cycle (dose-limiting assessment window) of each dose level consisted of a single administration of pamiparib on Day 1 followed by a treatment-free period on Day 2 and a 21-day period of BID administration from Day 3 to Day 23. Safety evaluations, including dose-limiting toxicities (DLTs), of ≥3 patients completing one cycle of treatment at a specific dose level were required before proceeding to the next cohort with a higher dose level. Patients could continue the study treatment in 21-day cycles and subsequent cycles at the discretion of the investigator.

K E Y W O R D S
Phase 2 enrolled platinum-sensitive HGOC patients (disease progression occurring ≥6 months after last platinum treatment [Cohort 1]) or platinum-resistant HGOC patients (Cohort 2). Patients with either known deleterious or suspected deleterious germline BRCA mutation (gBRCA mut ) who previously received at least two lines of standard chemotherapy were eligible for enrollment.

| Phase 1 study population
Phase 1 enrolled patients with histologically or cytologically confirmed locally advanced or metastatic HGOC, including fallopian and primary peritoneal cancer, or TNBC for which no effective standard therapy was available. BRCA1/2 mutations were not required, but enrichment of this patient population was preferred. Patients with gBRCA mut were retrospectively identified by central testing. When available, archival tumor tissues were collected to assess tumor BRCA (tBRCA) status. Patients were defined as platinum refractory if disease progression occurred during their last platinum treatment and as platinum resistant if disease progression occurred less than 6 months after their last platinum treatment. Patients were required to have measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1, 13 an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1, and adequate organ function. Patients were not permitted to have received chemotherapy, biologic therapy, immunotherapy, investigational agent, anticancer Chinese medicine or anticancer herbal remedies, or to have undergone radiotherapy for any cause within 14 days of the first dose of study drug. Patients who had untreated and/ or active brain metastases, or had previously received therapies targeting PARP, were excluded from the study.

| Phase 1 endpoints and assessments
The primary objective in phase 1 was to evaluate the safety and tolerability of pamiparib. Safety and tolerability endpoint assessments were based on monitoring of treatment-emergent adverse events (AEs), in addition to vital signs, electrocardiograms, physical examinations, and clinical laboratory results. The incidence and severity of all AEs and incidence of serious AEs were assessed according to the National Cancer Institute-Common Terminology Criteria for Adverse Events v4.03. Secondary objectives were assessment of PK parameters and antitumor activity. Blood samples for the PK analysis were collected at Cycle 1 on Days 1, 2, and 3. Pharmacokinetic sampling was performed at Cycle 1 on Day 1 (predose and at 0.5, 1, 2, 4, 6, 9, and 12 hours postdose), Day 2, Day 3, and Day 10 (predose and at 0.5, 1, 2, 4, 6, 9, and 12 hours postdose); then at Cycles 2 and 3 on Day 1 (predose and at 2 hours postdose). Across all patients, assessments of antitumor activity included objective response rate (ORR), duration of response (DoR), durable clinical benefit rate (CBR, defined as the percent of patients achieving complete response [CR], partial response [PR], or stable disease [SD] of ≥24 weeks), and progression-free survival (PFS) per investigator assessment based on RECIST v1.1. Tumor assessments were performed by the investigators at screening, every 6 weeks after the first dose of pamiparib in the 1st year, and every 12 weeks thereafter until progression, per RECIST v1.1. Patients completed the study at the time of their safety follow-up visit; therefore, radiological assessment of disease progression was not performed after the safety follow-up visit.
Among eligible patients with HGOC, carcinoma antigen 125 (CA-125) response rate per Gynecologic Cancer Intergroup was also assessed. Patients with HGOC had CA-125 tested in a local laboratory at baseline, every 6 weeks in the 1st year, and then, every 12 weeks thereafter. CA-125 responses must have been confirmed and maintained for at least 28 days. Germline and tBRCA1/2 mutations were analyzed as predictive biomarkers of antitumor activity and resistance to pamiparib. BRCA mutations were assessed using next-generation sequencing, performed by BGI Genomics Co., Ltd, using the germline (gBRCA) or somatic (tBRCA) Hereditary Breast and Ovarian Cancer Test.

| Analysis populations
Approximately 14 to 18 evaluable patients were expected to enroll in the phase 1 part of the study. The safety population included all patients who received ≥1 dose of pamiparib. The PK population included all patients for whom valid pamiparib PK parameters could be estimated. Antitumor activity per RECIST v1.1 was assessed in all evaluable patients. Patients were considered response evaluable if they had measurable disease at baseline per RECIST v1.1 and had ≥1 post-baseline tumor assessment, unless treatment had been discontinued due to clinical progression or death prior to tumor assessment. The population evaluable for CA-125 response included patients in the safety population with baseline CA-125 ≥2 x upper limit of normal.

| Disposition, demographic, and baseline disease characteristics
Here, we present the results from the 15 Chinese female patients (HGOC, n = 9; TNBC, n = 6) who were enrolled in the phase 1 portion of this study (Table 1). Overall median age was 49 years (range: 32-70), and 73% of patients had previously received at least three lines of therapy. A total of seven patients were confirmed as having a gBRCA mut (HGOC, n = 5; TNBC, n = 2); eight patients had gBRCA wild type (gBRCA WT ; HGOC, n = 4; TNBC, n = 4). A total of eight patients had qualified tumor samples available and had tBRCA status assessed (HGOC, n = 6; TNBC, n = 2). Five of these eight patients were confirmed to be carrying tBRCA mutations, all of whom also had gBRCA mut (HGOC, n = 3; TNBC, n = 2); the other three patients had wild-type germline and tBRCA.
Overall, three patients experienced a serious AE (abdominal infection, n = 1; pleural effusion, n = 1; intestinal obstruction, n = 1), none of which were considered related  to study treatment. Two patients discontinued treatment as a result of serious AEs (abdominal infection, n = 1; pleural effusion, n = 1).

| Pharmacokinetic profile of pamiparib
Mean pamiparib plasma concentration-time profiles after a single dose (Cycle 1 Day 1) and at steady state (Cycle 1 Day 10) are presented in Figure 2. A summary of the PK parameters of pamiparib are presented in Table 3. Pamiparib plasma exposure (AUC and C max ) increased near proportionally with increasing doses between 20 mg and 60 mg BID after a single dose (Table S2). At the RP2D of 60 mg BID, pamiparib is rapidly absorbed and eliminated after oral administration with median T max of approximately 1 hour and t 1/2 of approximately 14 hours; steady-state geometric mean (%CV) AUC 0-12 and C max were 47099.9 (30.4) ng/mL*h and 5861.3 (29.2) ng/mL, respectively. The AUC and C max accumulation ratios at 60 mg BID were 3.4 and 2.6, respectively (Table 4).
Best overall response for all five patients with RECISTevaluable TNBC was progressive disease (Table 5; Figure  3). Four of these patients were gBRCA WT and one harbored both germline and tBRCA mutations. All patients with TNBC experienced disease progression during or after their previous platinum-based chemotherapy and all patients had distant metastases to the lung, liver, or bone at study entry.

| Progression-free survival
The median follow-up of PFS for patients with HGOC was 5.6 months (95% CI: 0.03-23.6) (  be incomplete for HGOC patients because more than half of the patients reached end of treatment for reasons other than disease progression; however, radiological assessment of disease progression was not performed after the safety follow-up visit, per phase 1 study design. Among patients with TNBC (n = 6), median PFS was 1.5 months (95% CI: 1.5-1.6), and at the time of data cut-off, all TNBC patients with ≥1 post-baseline tumor assessment (n = 5) had disease progression.

| DISCUSSION
Development of PARPi therapy over the past decade has resulted in novel therapeutic choices for patients with ovarian and breast cancer. The phase 1 DE component of this phase 1/2 study aimed to examine the safety and tolerability, PK profile, and antitumor activity of single-agent pamiparib as well as confirm 60 mg BID to be the RP2D in Chinese patients with advanced HGOC or TNBC.  At doses of 20 to 60 mg BID, pamiparib was generally well tolerated by patients in this study. The resulting safety and tolerability profile of pamiparib is similar to the profiles of other PARPi. The majority of AEs observed with pamiparib were generally mild-to-moderate in severity with asthenia and nausea being the most commonly reported AEs considered related to treatment. While most reported TRAEs were grade ≤2, decreased hemoglobin was the only grade 3 TRAE reported in more than two patients; no grade 4 or 5 TRAEs were reported.
Pamiparib was rapidly absorbed (T max = ~1 hr) and plasma exposure increased in a near dose-proportional manner. Plasma exposure after administration of a single dose of pamiparib was similar to plasma exposure observed in the FIH study, 10,12 while the steady-state exposure was slightly higher.
Confirmed and durable clinical responses were observed with pamiparib in patients with HGOC as assessed by both RECIST v1.1 and CA-125 criteria. All RECIST-evaluable patients with HGOC (n = 8) achieved either a PR or SD (DCR = 100%; durable CBR = 62.5%); all patients were considered refractory (n = 1) or resistant (n = 7) to platinum chemotherapy. Clinical responses were observed among patients with gBRCA WT as well as in patients with disease resistant/refractory to platinum-based chemotherapy. As of 30 September 2019, one patient with HGOC refractory to platinum-based chemotherapy and gBRCA WT from the 20 mg DE cohort still remains on treatment with a best response of PR.
The phase 1 portion of this study confirmed pamiparib 60 mg BID as the RP2D in Chinese patients. This confirmation was based on the observation that the safety/tolerability and PK profiles observed in the 15 Chinese patients were generally consistent with that from the FIH study, [10][11][12] and that no DLTs or serious AEs considered related to pamiparib were observed across the dose range. Additionally, confirmed clinical responses were observed in patients with HGOC at the 60 mg BID dose.
As these data are from a small, non-randomized, DE portion of a phase 1/2 study in Chinese female patients, the generalization of these results is limited. However, as these data confirmed the RP2D of pamiparib, they may serve as a foundation for future studies in this patient population. Once the results from the phase 2 dose-expansion portion of this study as well as the results from the other studies of pamiparib monotherapy (NCT03712930, NCT03519230, and NCT03427814) and combination therapy (NCT03150810, NCT03150862, and NCT02660034) become available, more definitive conclusions can be drawn regarding the efficacy, safety, and tolerability of pamiparib across different solid tumors.