First-in-human trial of novel oral PARP inhibitor BMN 673 in patients with solid tumors.

Abstract

2580 Background: BMN 673 is the most potent and specific inhibitor of PARP1/2 in clinical development (IC50<1nM). In tumors genetically dependent on DNA repair by homologous recombination PARP inhibition induces synthetic lethality. Methods: Pharmacokinetics (PK), pharmacodynamics (PD), safety and anti-tumor activity of BMN 673 were evaluated in a 2-stage dose-escalation study with 3-6 patients (pts)/dose level. In dose escalation (Stage 1) cycle 1 was 6 wks, with drug taken on days 1 and 8-35, for PK and PD assays, followed by daily continuous dosing in 4-wk cycles. Stage 2 (expansion at MTD) recruits pts with tumors defective in DNA repair: Ewing sarcoma, small cell lung cancer or tumors associated with BRCA mutation (mut). Results: 39 pts (33F/6M) were enrolled in 9 cohorts from 25 to 1100 µg/d that defined a MTD of 1000 µg/d. Median (range) age was 58 (19-81), PS 0 (0-1) and # of prior therapies 4 (1-13). Tumors (# with deleterious BRCA 1/2 mut) included 23 ovarian/primary peritoneal (17); 8 breast (6); 3 pancreas; 2 colon; 1 prostate (1), and 1 mullerian carcinosarcoma. 17 and 8 pts had BRCA 1 and 2 mut, respectively. Dose-limiting thrombocytopenia occurred in 1/6 and 2/5 pts at 900 and 1100 µg/d, respectively. Potentially-related adverse events in >10% of pts (# grade 1 and 2/grade 3 and 4) included fatigue (10/0); nausea (10/0); flatulence (4/0); anemia (5/2); neutropenia (4/3); thrombocytopenia (1/3); and grade 1 alopecia (10). Inhibition of PARP activity in PBMCs was observed at doses ≥ 100 µg/d. BMN 673 plasma concentrations peaked 1-2 hrs post-dose; exposure increased dose proportionally. Steady state plasma concentrations were reached by the end of the 2nd week of daily dosing; mean Cmax: 0.30 - 25.4 ng/mL and AUC0-24: 3.96 - 203 ng-hr/mL across the 25 to 1100 µg/d dose range after 28d of daily dosing. RECIST and/or CA-125 responses occurred at doses ≥ 100 µg/d in 11/17 BRCA carrier ovarian/peritoneal cancer pts. Objective responses occurred in 2/6 BRCA-carrier breast cancer pts. Conclusions: BMN 673 is well tolerated with impressive anti-tumor activity in pts with BRCA mut with a single agent recommended Phase II trial dose of 1000 µg/d due to dose-limiting thrombocytopenia. Clinical trial information: NCT01286987.

Safety and pharmacokinetics of veliparib extended‐release in patients with advanced solid tumors: a phase I study

“…From a tolerability perspective, treatment with PARP inhibitors is commonly associated with dose interruptions, and a smaller proportion of patients require dose reduction and treatment discontinuation. The most common AEs leading to treatment discontinuation include nausea, vomiting, anemia, and thrombocytopenia [5,6,[12][13][14][15][16].…”

DNA Repair in Prostate Cancer: Biology and Clinical Implications

“…In the TOPARP-A trial, anemia (20%) and fatigue (12%) were the most common grade !3 adverse events; gastrointestinal toxicities were less relevant than reported for ovarian cancer [67]. Hematologic toxicities and fatigue were also the dose-limiting events determining the recommended dose for other PARP inhibitors such as BMN673 and niraparib [54,63].…”

“…Other PARP inhibitors are in clinical development; data for PC patients are primarily from [ 1 1 _ T D $ D I F F ] gBRCA1/2 mutation carriers with PC who participated in early clinical trials of these compounds. Preclinical studies of BMN673 (Biomarin/ Medivation) demonstrated high potency in inhibiting PARP [62], and tumor responses were seen in BRCA1/2 mutation carriers across tumor types in a phase 1 clinical trial [63]. Rucaparib (AG-014699/CO-338, Pfizer/Clovis Oncology) and veliparib (ABT-888, Abbott Laboratories) have mainly been developed so far in combination with chemotherapies or other targeted agents [64,65].…”

A Review on DNA Repair Inhibition by PARP Inhibitors in Cancer Therapy

“…The structures of various PARP inhibitors are shown developed to expand application of PARP inhibitors which show more selectivity towards PARP with more potency and lower toxicity. [41][42][43] GI symptoms, fatigue, anemia 44,45 Veliparib Dizziness, nausea, dysgeusia 35 Nausea, fatigue, lymphopenia 46 Talazoparib Fatigue, nausea, alopecia, anemia, neutropenia, thrombocytopenia 47 Fatigue, alopecia, GI symptoms, anemia, neutropenia, thrombocytopenia 48 Niraparib Anemia, nausea, thrombocytopenia, vomiting, insomnia, constipation, fatigue, anorexia 49 Anemia, thrombocytopenia, neutropenia, GI symptoms, fatigue 49 Rucaparib Fatigue, nausea, diarrhea, vomiting, dizziness, anorexia 50 GI symptoms, fatigue, anaemia 50 azole derivatives as potential dual inhibitors…”