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Clinical Trial
. 2017 Mar 28;116(7):884-892.
doi: 10.1038/bjc.2017.36. Epub 2017 Feb 21.

A phase I study of intravenous and oral rucaparib in combination with chemotherapy in patients with advanced solid tumours

Richard H Wilson  1   2 , Tr Jeffry Evans  3 , Mark R Middleton  4 , L Rhoda Molife  5 , James Spicer  6 , Veronique Dieras  7 , Patricia Roxburgh  3 , Heidi Giordano  8 , Sarah Jaw-Tsai  8 , Sandra Goble  8 , Ruth Plummer  9   10
Affiliations
Clinical Trial

A phase I study of intravenous and oral rucaparib in combination with chemotherapy in patients with advanced solid tumours

Richard H Wilson et al. Br J Cancer. .

Abstract

Background: This study evaluated safety, pharmacokinetics, and clinical activity of intravenous and oral rucaparib, a poly(ADP-ribose) polymerase inhibitor, combined with chemotherapy in patients with advanced solid tumours.

Methods: Initially, patients received escalating doses of intravenous rucaparib combined with carboplatin, carboplatin/paclitaxel, cisplatin/pemetrexed, or epirubicin/cyclophosphamide. Subsequently, the study was amended to focus on oral rucaparib (once daily, days 1-14) combined with carboplatin (day 1) in 21-day cycles. Dose-limiting toxicities (DLTs) were assessed in cycle 1 and safety in all cycles.

Results: Eighty-five patients were enrolled (22 breast, 15 ovarian/peritoneal, and 48 other primary cancers), with a median of three prior therapies (range, 1-7). Neutropenia (27.1%) and thrombocytopenia (18.8%) were the most common grade ⩾3 toxicities across combinations and were DLTs with the oral rucaparib/carboplatin combination. Maximum tolerated dose for the combination was 240 mg per day oral rucaparib and carboplatin area under the curve 5 mg ml-1 min-1. Oral rucaparib demonstrated dose-proportional kinetics, a long half-life (≈17 h), and good bioavailability (36%). Pharmacokinetics were unchanged by carboplatin coadministration. The rucaparib/carboplatin combination had radiologic antitumour activity, primarily in BRCA1- or BRCA2-mutated breast and ovarian/peritoneal cancers.

Conclusions: Oral rucaparib can be safely combined with a clinically relevant dose of carboplatin in patients with advanced solid tumours (Trial registration ID: NCT01009190).

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Conflict of interest statement

RHW has received an honorarium from Clovis Oncology for attending an advisory board relating to rucaparib. The institution of TRJE has received reimbursement of study costs for this clinical trial and an honorarium from Clovis Oncology for his participation in an advisory board for another compound. MRM, LRM, JS, VD, and PR have no conflict of interest to declare. HG is an employee of Clovis Oncology. SJ-T was an employee of Clovis Oncology at the time of the study. SG is an employee of Clovis Oncology. RP has received honoraria for attending advisory boards relating to rucaparib, is named on a patent of use for rucaparib for which her institution will receive milestone payments, and has received research funding relating to this agent.

Figures

Figure 1
Figure 1
Study treatment arms.
Figure 2
Figure 2
Plasma rucaparib concentration–time profile following i.v. or oral administration. Graph shows the geometric mean plasma concentration of rucaparib in patients in arm A (oral rucaparib) (n=4) who received i.v. and oral doses on days −10 and −5, respectively.
See this image and copyright information in PMC

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