DNA damage caused by TMZ can sensitize tumors to PARP inhibitors. Pamiparib is an investigational PARP1/2 inhibitor that has shown PARP trapping activity, brain penetration, and synergistic cytotoxicity with ld TMZ in nonclinical studies.
This ongoing study consists of a dose-escalation phase (3 + 3 design) and a dose-expansion phase enrolling pts with gastric or small cell lung cancer (GC and SCLC). During dose escalation, pamiparib was administered at 60 mg PO BID on days 1–28 and ld TMZ was given at escalating doses PO QD on days 1–7, 1–14, or 1–28 of 28-day cycles. During dose expansion, pts are being treated at the recommended phase 2 dose (RP2D); eligibility criteria include metastatic GC and extensive stage SCLC pts treated with ≤2 prior lines of chemotherapy. Tumor assessments are performed every 8 weeks. Primary and secondary endpoints include safety/tolerability and antitumor activity (RECIST v1.1)/PK, respectively; biomarker assessment (eg, BRCA) is exploratory. We present updated results that include the RP2D and data from expansion cohort pts.
As of 1 March 2019, 66 pts were enrolled in 8 dose escalation cohorts and 24 pts were enrolled at the RP2D pamiparib 60 mg PO BID days 1–28 and TMZ 60 mg PO QD days 1–7 (N = 90). Median age was 65 years (range, 30–85) and median prior lines of therapy was 3 (range, 1–10). The most common adverse events (AEs) related to study drugs across all doses were nausea (46%; 0% grade (G)3/4), anemia (43%; 24% G3/4), fatigue (41%; 1% G3/4), neutropenia (26%; 21% G3/4), and thrombocytopenia (27%; 14% G3/4). There were no fatal AEs. Pamiparib + TMZ plasma exposure was similar to that of each single agent. Among 63 dose escalation pts with measurable disease evaluated for efficacy, 9 achieved partial response (PR; 14%; 95% CI, 7–25) across ld TMZ doses and indications (6 confirmed PR). Responses were seen in pts regardless of known BRCA status. Disease control rate was 53% and median duration of response was 5.5 months (range, 1.9–7.3).
Pamiparib combined with ld TMZ continues to demonstrate promising antitumor activity and remains generally well tolerated in pts with advanced solid tumors.
NCT03150810.
Ira Mills, PhD, and Shannon Davis at Ashfield Healthcare Communications, Middletown, CT.
BeiGene USA, Inc.
BeiGene USA, Inc.
A. Stradella: Honoraria (self): Roche; Honoraria (self): Celgene; Honoraria (self): Pfizer. M.L. Johnson: Research grant / Funding (institution): BerGenBio; Research grant / Funding (institution): Lilly; Research grant / Funding (institution): EMD Serono; Research grant / Funding (institution): Janssen; Advisory / Consultancy, Research grant / Funding (institution): Mirati Therapeutics; Research grant / Funding (institution): Genmab; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Stemcentrix; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Checkpoint Therapeutics; Research grant / Funding (institution): Array BioPharma; Research grant / Funding (institution): Regeneron; Research grant / Funding (institution): Apexigen; Research grant / Funding (institution): AbbVie; Research grant / Funding (institution): Tarveda; Research grant / Funding (institution): Adaptimmune; Research grant / Funding (institution): Syndax; Research grant / Funding (institution): Neovia; Advisory / Consultancy, Research grant / Funding (institution): Boehringer Ingelheim; Advisory / Consultancy, Research grant / Funding (institution): Sanofi; Research grant / Funding (institution): Hengrui Therapeutics, INC; Research grant / Funding (institution): Merck; Research grant / Funding (institution): Daiichi - Sankyo; Research grant / Funding (institution): Lycera; Research grant / Funding (institution): GI Therapeutics; Research grant / Funding (institution): Dynavax; Advisory / Consultancy: Celgene; Advisory / Consultancy: LOXO. S. Goel: Research grant / Funding (self), Support for clinical trial: BeiGene. S.R. Chandana: Research grant / Funding (institution): START MIDWEST; Advisory / Consultancy, Speaker Bureau / Expert testimony: Ipsen; Speaker Bureau / Expert testimony: Eisai; Advisory / Consultancy: Astrazaneca; Advisory / Consultancy: Novartis; Advisory / Consultancy: Bayer; Advisory / Consultancy: AMGEN. M.D. Galsky: Advisory / Consultancy: Merck; Advisory / Consultancy: Genentech; Advisory / Consultancy: Pfizer; Advisory / Consultancy: BMS; Advisory / Consultancy: Dracen; Advisory / Consultancy: Dragonfly Therapeutics; Advisory / Consultancy: AstraZeneca. E. Calvo: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Astellas; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Novartis; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Nanobiotix; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Pfizer; Honoraria (self), Advisory / Consultancy: Janssen-Cilag; Honoraria (self), Advisory / Consultancy: GLG; Honoraria (self), Advisory / Consultancy: PsiOxus Therapeutics; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Merck; Honoraria (self), Advisory / Consultancy: Medscape; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): BMS; Honoraria (self), Advisory / Consultancy: Gilead; Honoraria (self), Advisory / Consultancy: Seattle Genetics; Honoraria (self), Advisory / Consultancy: Pierre Fabre; Honoraria (self), Advisory / Consultancy: Boehringer Ingelheim; Honoraria (self), Advisory / Consultancy: Cerulean Pharma; Honoraria (self), Advisory / Consultancy: EUSA; Honoraria (self), Advisory / Consultancy: Gehrmann Consulting; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Honoraria (self), Advisory / Consultancy: Roche; Honoraria (self), Advisory / Consultancy: Guidepoint; Honoraria (self), Advisory / Consultancy: Servier; Honoraria (self), Advisory / Consultancy: Celgene; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Abbvie; Honoraria (self), Advisory / Consultancy: Amcure; Honoraria (self), Advisory / Consultancy: OncoDNA; Honoraria (self), Advisory / Consultancy: Alkermes; Leadership role, Shareholder / Stockholder / Stock options, Officer / Board of Directors: START Madrid; Leadership role, Full / Part-time employment, Officer / Board of Directors: HM Hospitals Group; Shareholder / Stockholder / Stock options: Oncoart Associated; Shareholder / Stockholder / Stock options: International Cancer Consultants; Research grant / Funding (institution): BeiGene; Research grant / Funding (institution): ACEO; Research grant / Funding (institution): Amcure; Research grant / Funding (institution): AMGEN; Research grant / Funding (institution): Cytomx; Research grant / Funding (institution): GSK; Research grant / Funding (institution): Genentech/Roche; Research grant / Funding (institution): H3; Research grant / Funding (institution): Incyte; Research grant / Funding (institution): Janssen; Research grant / Funding (institution): Kura; Research grant / Funding (institution): Lilly; Research grant / Funding (institution): Loxo; Research grant / Funding (institution): Nektar; Research grant / Funding (institution): Macrogenics; Research grant / Funding (institution): Menarini; Research grant / Funding (institution): Merus; Research grant / Funding (institution): PharmaMar; Research grant / Funding (institution): Principia; Research grant / Funding (institution): PUMA; Research grant / Funding (institution): Sanofi; Research grant / Funding (institution): Taiho; Research grant / Funding (institution): Tesaro; Research grant / Funding (institution): Transgene; Research grant / Funding (institution): Takeda; Research grant / Funding (institution): Innovio; Research grant / Funding (institution): MSD; Research grant / Funding (institution), Officer / Board of Directors: PsiOxus; Research grant / Funding (institution): Seattle Genetics; Research grant / Funding (institution): Mersana; Research grant / Funding (institution): Daiichi; Research grant / Funding (institution): ORCA; Research grant / Funding (institution): Boston Therapeutics; Research grant / Funding (institution): Dynavax; Research grant / Funding (institution): DebioPharm; Research grant / Funding (institution): Boehringen Ingelheim; Research grant / Funding (institution): Regeneron; Research grant / Funding (institution): Millenium; Research grant / Funding (institution): Synthon; Research grant / Funding (institution): Spectrum; Research grant / Funding (institution): Rigontec; Leadership role, Founder and president: non-for-profit Foundation INTHEOS; Officer / Board of Directors: Zeist. V. Moreno: Advisory / Consultancy: BMS. H. Park: Research grant / Funding (institution), And non-financial support: BeiGene; Research grant / Funding (institution): Ambrx; Research grant / Funding (institution): Amgen; Research grant / Funding (institution): Array BioPharma; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Bayer; Research grant / Funding (institution): Bristol-Myers Squibb; Research grant / Funding (institution): Daiichi Pharmaceutical; Research grant / Funding (institution): Eli Lilly; Research grant / Funding (institution): EMD Serono; Research grant / Funding (institution): Genentech; Research grant / Funding (institution): Gilead Sciences; Research grant / Funding (institution): GlaxoSmithKline; Research grant / Funding (institution): Hoffman-LaRoche; Research grant / Funding (institution): Immunomedics; Research grant / Funding (institution): Incyte; Research grant / Funding (institution): MacroGenics; Research grant / Funding (institution): Medimmune; Research grant / Funding (institution): Medivation; Research grant / Funding (institution): MERCK; Research grant / Funding (institution): Millennium; Research grant / Funding (institution): Novartis Pharmaceuticals; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Puma Biotechnology; Research grant / Funding (institution): Regeneron Pharmaceuticals; Research grant / Funding (institution): Taiho Pharmaceutical; Research grant / Funding (institution): Vertex Pharmaceuticals; Research grant / Funding (institution): Xencor Inc. A. Cervantes: Research grant / Funding (institution): BeiGene; Research grant / Funding (institution): Merck Serono; Speaker Bureau / Expert testimony, Research grant / Funding (institution): Roche; Officer / Board of Directors: Biomedical Research Institute INCLIVA; Advisory / Consultancy: Bayer; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Servier; Advisory / Consultancy, Research grant / Funding (institution): Lilly; Advisory / Consultancy, Research grant / Funding (institution): Novartis; Advisory / Consultancy: Takeda; Research grant / Funding (institution): Astelas; Advisory / Consultancy: Amgen; Advisory / Consultancy: Foundation Medicine; Research grant / Funding (institution): Fibrogen; Research grant / Funding (institution): Amcure; Research grant / Funding (institution): Sierra Oncology; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Medimmune; Research grant / Funding (institution): BMS; Research grant / Funding (institution): MSD; Research grant / Funding (institution): Genentech.L. Fariñas Madrid: Research grant / Funding (institution), Support for clinical trial: BeiGene. L. Mileshkin: Travel / Accommodation / Expenses: BeiGene. R. Plummer: Honoraria (self), Travel / Accommodation / Expenses: Bristol-Myers Squibb; Honoraria (institution): Pfizer; Honoraria (self), Advisory / Consultancy: Roche/Genentech; Advisory / Consultancy: Astex Pharmaceuticals; Advisory / Consultancy: Bayer; Advisory / Consultancy: Clovis Oncology; Advisory / Consultancy: Modulatex; Advisory / Consultancy, Travel / Accommodation / Expenses: MSD Oncology; Advisory / Consultancy, Speaker Bureau / Expert testimony: Novartis; Advisory / Consultancy: Octimet; Advisory / Consultancy: Pierre Fabre; Advisory / Consultancy: Vertex; Research grant / Funding (institution): AstraZeneca/MedImmune; Licensing / Royalties, Named on patent of use of PARP inhibitor rucaparib (Inst): PARP inhibitor rucaparib (Inst). J. Evans: Research grant / Funding (institution), Support for clinical trials: BeiGene; Advisory / Consultancy: Karus Therapeutics; Advisory / Consultancy: Baxalta. A. Prawira: Research grant / Funding (institution): BeiGene; Research grant / Funding (institution): MSD; Research grant / Funding (institution): BMS; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Genentech/Roche; Research grant / Funding (institution): Akesobio; Research grant / Funding (institution): CStone; Research grant / Funding (institution): Bayer; Research grant / Funding (institution): Macrogenics; Research grant / Funding (institution): Eli Lilly; Research grant / Funding (institution): Arcusbio; Research grant / Funding (institution): Apollomics; Research grant / Funding (institution): Henlius; Research grant / Funding (institution): Five Prime; Research grant / Funding (institution): Viamet. R.J. Pelham: Full / Part-time employment: BeiGene. S. Mu: Full / Part-time employment: BeiGene. C. Andreu-Vieyra: Full / Part-time employment: BeiGene. All other authors have declared no conflicts of interest.