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Clinical Trial
. 2022 Mar;126(4):576-585.
doi: 10.1038/s41416-021-01632-2. Epub 2021 Nov 18.

Phase 1A/1B dose-escalation and -expansion study to evaluate the safety, pharmacokinetics, food effects and antitumor activity of pamiparib in advanced solid tumours

Jason D Lickliter  1 , Mark Voskoboynik  1   2 , Linda Mileshkin  3 , Hui K Gan  4   5   6 , Ganessan Kichenadasse  7 , Kathy Zhang  8 , Maggie Zhang  8 , Zhiyu Tang  8 , Michael Millward  9
Affiliations
Clinical Trial

Phase 1A/1B dose-escalation and -expansion study to evaluate the safety, pharmacokinetics, food effects and antitumor activity of pamiparib in advanced solid tumours

Jason D Lickliter et al. Br J Cancer. 2022 Mar.

Erratum in

Abstract

Background: Pamiparib, a PARP1/2 inhibitor, demonstrated antitumor activity in preclinical models.

Methods: This Phase 1A/1B dose-escalation/dose-expansion study enrolled adults (≥18 years) with advanced/metastatic cancer. The dose-escalation phase evaluated the recommended Phase 2 dose (RP2D), maximum tolerated dose (MTD), and pharmacokinetics; the dose-expansion phase evaluated the antitumor activity and food effects.

Results: Patients (N = 101) were enrolled in dose-escalation (n = 64) and dose-expansion (n = 37). During BID dose-escalation, dose-limiting toxicities were Grade 2 nausea (n = 1, 40 mg; n = 1, 80 mg); Grade 2 nausea and Grade 2 anorexia (n = 1, 120 mg), Grade 2 nausea, Grade 3 fatigue and Grade 3 paraesthesia (n = 1, 120 mg); MTD was 80 mg BID and RP2D was 60 mg BID. Common adverse events (AEs) were nausea (69.3%), fatigue (48.5%) and anaemia (35.6%); the most common Grade ≥3 AE was anaemia (24.8%). There was a dose-proportional increase in pamiparib exposure; no food effects on pharmacokinetics were observed. In the efficacy-evaluable population (n = 77), objective response rate (ORR) was 27.3% (95% CI, 17.7-38.6%). Median duration of response was 14.9 months (95% CI, 8.7-26.3). In the epithelial ovarian cancer (EOC)-evaluable population (n = 51), ORR was 41.2% (95% CI, 27.6-55.8%).

Conclusions: Pamiparib was tolerated with manageable AEs, and antitumor activity was observed in patients with EOC. CLINICALTRIALS.

Gov identifier: NCT02361723.

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Conflict of interest statement

Dr. JDL has no competing interests to declare. Dr. MV reports personal fees from Merck Sharp & Dohme and personal fees from AstraZeneca outside the submitted work. Dr. LM reports other support from BeiGene outside the submitted work. Dr. HG reports personal fees from Merck Serono, Eisai, and Bristol-Myers Squibb outside the submitted work. Dr. GK has nothing to disclose. Dr. KZ, Dr. MZ and Dr. ZT are employees with stock grant or options in BeiGene, Ltd. Dr. MM reports personal fees and non-financial support from AstraZeneca, Bristol-Myers Squibb, and Roche; and personal fees from Merck Sharp & Dohme, Pfizer and Novartis outside the submitted work.

Figures

Fig. 1
Fig. 1. Study design.
BID twice daily, mCRPC metastatic castration-resistant prostate cancer, MTD maximum tolerated dose, QD once daily, RP2D recommended Phase 2 dose, SCLC small-cell lung cancer, TNBC triple-negative breast cancer.
Fig. 2
Fig. 2. Mean concentration-time profiles with BID dosing.
a With single dose on Cycle 1 day 1. b At steady state on Cycle 1 day 17. c Food effects with single dose. BID twice a day.
Fig. 3
Fig. 3. Duration of treatment and best percentage change from baseline in target lesions in patients with EOC.
a Duration of treatment. b Best percentage change from baseline in target lesions. Symbols > in (a) and + in (b) denote the seven patients who continued pamiparib after closure of the study. BID twice a day, BRCA breast cancer susceptibility gene, CR complete response, EOC epithelial ovarian cancer, HRD homologous recombination deficiency, MU mutated, NA not applicable, NE not estimable, PD progressive disease, PR partial response, QD once a day, SD stable disease, UN unknown, WT wild-type.
See this image and copyright information in PMC

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