Phase I combination study of the PARP inhibitor veliparib plus carboplatin and gemcitabine in patients with advanced ovarian cancer and other solid malignancies

Our plain-English summary of Phase I combination study of the PARP inhibitor veliparib plus carboplatin and gemcitabine in patients with advanced ovarian cancer and other solid malignancies, by H.J. Gray, K. Bell-McGuinn, G.F. Fleming, et al (Gynecologic Oncology, 2018).

The study

• Authors: H.J. Gray, K. Bell-McGuinn, G.F. Fleming, M. Cristea, H. Xiong, D. Sullivan, Y. Luo, M.D. McKee, W. Munasinghe, L.P. Martin
• Journal: Gynecologic Oncology
• Published: 2018;148(3):507-514
• Cited by: 63 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Objective: Determine the maximum tolerated dose (MTD) and recommended phase II dose (RP2D) of veliparib combined with carboplatin and gemcitabine in patients with advanced ovarian cancer and other nonhematologic malignancies.

Methods: In this phase I study, patients with metastatic or unresectable solid tumors and ≤2 prior chemotherapy regimens received veliparib combined with carboplatin area under the curve (AUC) 4 on day 1 and gemcitabine 800mg/m2 on days 1 and 8 of a 21-day cycle for maximum 10cycles, followed by optional veliparib maintenance therapy. Veliparib dosing commenced twice-daily (BID) continuously on day 1 of cycle 2; granulocyte colony-stimulating factor was permitted. Dose escalation used a Bayesian continual reassessment method. Safety, tolerability, and efficacy were evaluated.

Results: Seventy-five patients were enrolled (ovarian cancer, n=54; breast cancer, n=12). Thirty-six patients with ovarian cancer (67%) had known germline BRCA mutations. Most common treatment-related adverse events (TRAEs; ≥60%) were thrombocytopenia, neutropenia, nausea, and anemia. Most common grade 3/4 TRAEs (≥40%) were neutropenia and thrombocytopenia. Dose-limiting toxicities were thrombocytopenia and neutropenia. The MTD/RP2D was established at veliparib 250mg with carboplatin AUC 4 plus gemcitabine 800mg/m2. Responses were observed in 69% of patients with BRCA-deficient ovarian cancer (45% partial, 24% complete responses). Five patients remained on veliparib (80-310mg BID) for >34cycles.

Conclusions: Veliparib plus carboplatin/gemcitabine is tolerated, with a safety profile similar to carboplatin and gemcitabine alone. Combination therapy demonstrated promising preliminary antitumor activity in platinum-sensitive ovarian cancer patients with germline BRCA mutations. Trial registration ID: NCT01063816.

Copyright © 2018 Elsevier Inc. All rights reserved.

In plain English

This article is a cancer drug trial, not a study of asbestos exposure. One of its 75 patients had epithelioid mesothelioma. It reports a phase I study at 6 US centers that added veliparib, a pill taken twice daily, to the chemotherapy drugs carboplatin and gemcitabine. From February 2010 to March 2013, 75 patients with advanced solid tumors enrolled: 54 with ovarian cancer and 12 with breast cancer. The highest tolerable dose was veliparib 250 mg twice daily with carboplatin AUC 4 and gemcitabine 800 mg/m2. Side effects were mostly in the blood. 67 of 75 patients (89%) had grade 3 or 4 side effects, including low white-cell counts (neutropenia, 56%) and low platelet counts (thrombocytopenia, 53%). Of 59 patients with measurable tumors, 9 had complete and 20 had partial responses. Among these, 68.9% of ovarian cancer patients with germline BRCA mutations (29 patients) responded, versus 42.8% with wildtype or unknown BRCA status (14 patients). The authors called all efficacy results exploratory. They concluded the combination was tolerable except for blood-related toxicity.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Phase I open-label, multicenter, dose-escalation drug trial with a dose-escalation phase and a safety expansion phase
• Who was studied: 75 adults with advanced (metastatic or unresectable) solid tumors, enrolled February 2010 to March 2013 at 6 US hospital centers: 54 ovarian cancer, 12 breast cancer, 9 other cancers (including 1 epithelioid mesothelioma)
• Exposure: No asbestos exposure was studied. The treatment studied was the drug veliparib (doses 30 to 310 mg twice daily during combination therapy). It was added from cycle 2 to carboplatin (AUC 4) and gemcitabine (1000 mg/m2 in the first cohort, then 800 mg/m2), in 21-day cycles for up to 10 cycles, with optional veliparib alone afterwards
• Main results:
  • The maximum tolerated dose and recommended phase II dose of veliparib was 250 mg twice daily with carboplatin AUC 4 plus gemcitabine 800 mg/m2
  • Dose-limiting toxicities occurred in 6 patients: grade 4 thrombocytopenia in 5 and grade 4 neutropenia in 1
  • All 75 patients had at least 1 side effect. Grade 3 or 4 side effects occurred in 67 patients (89%), including neutropenia in 42 (56%) and thrombocytopenia in 40 (53%)
  • Dose reduction was required for veliparib in 20 patients (27%) and for gemcitabine in 27 patients (36%)
  • Of 59 patients with objective response data (measurable disease at baseline), 9 (15.3%) had a complete response, 20 (33.9%) a partial response, and 30 (50.8%) were nonresponders
  • Among evaluable ovarian cancer patients, the radiographic response rate was 68.9% in those with germline BRCA mutations (n = 29). This was numerically higher than the 42.8% in those with wildtype or unknown BRCA status (n = 14)
  • Median progression-free survival was 7.0 months (95% CI 5.3 to 8.4) overall. It was 8.6 months (95% CI 7.1 to 11.7) in BRCA-mutated ovarian cancer and 5.9 months (95% CI 4.1 to 9.9) in BRCA-wildtype or unknown ovarian cancer
  • In the expanded safety group, carboplatin and gemcitabine had no effect on how veliparib was handled by the body (pharmacokinetics)
• The authors' conclusion: The authors concluded that continuous veliparib was tolerable except for blood-related toxicity at 250 mg twice daily with carboplatin and gemcitabine. They described the response and survival results as promising, particularly in ovarian cancer patients with a germline BRCA mutation
• Limitations the authors state:
  • BRCA status was unknown in a subset of patients, including 11 with ovarian cancer
  • All efficacy endpoints were exploratory

Topics

The National Library of Medicine indexes this study under subjects our site covers: Ovarian cancer.

Medical terms in this study, explained in our Lexicon: Carboplatin, Gemcitabine, Ovarian Cancer, Unresectable, Chemotherapy, Neutropenia.

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