882PD - Phase 1/2 study of oral rucaparib: Updated phase 1 and preliminary phase 2 results

Date 28 September 2014
Event ESMO 2014
Session Gynaecological cancers
Topics Drug Development
Gynaecologic Malignancies
Presenter Rebecca Kristeleit
Citation Annals of Oncology (2014) 25 (suppl_4): iv305-iv326. 10.1093/annonc/mdu338
Authors R. Kristeleit1, R. Shapira-Frommer2, H. Burris3, M.R. Patel4, P. Lorusso5, A.M. Oza6, J. Balmana7, S.M. Domchek8, L. Chen9, A. Montes10, R. Plummer11, H. Arkenau12, L. Maloney13, E. Dominy14, G. Shapiro15
  • 1Uclh Dept. Of Oncology, UCL - University College London, WC1E 6BT - London/GB
  • 2., Chaim Sheba Medical Center, Tel Hashomer/IL
  • 3Dept. Drug Development, Sarah Cannon Research Institute, US-37203 - Nashville/US
  • 4Oncology, Florida Cancer Specialists, Sarasota/US
  • 5Research Administration, Karmanos Cancer Institute, 48201 - Detroit/US
  • 6Dept. Of Medicine, Princess Margaret Hospital, CA-M5G 2M9 - Toronto/CA
  • 7Oncologia Médica, Hospital Vall d'Hebron, 08035 - Barcelona/ES
  • 8Department Of Medicine, Abramson Cancer Center of the University of Pennsylvania, 19104 - Philadelphia/US
  • 9Department Of Obstetrics, Gynecology, And Reproductive Sciences, UCSF Helen Diller Family Comprehensive Cancer Center, 94158 - San Francisco/US
  • 10Guys Hospital - Department Of Oncology - Management Offices - Bermondsey Wing 4th Floor, Guy's and St. Thomas' Hospital NHS Trust, SE1 9RT - London/GB
  • 11Northern Centre For Cancer Care, Freeman Hospital, Newcastle upon Tyne/GB
  • 12Sarah Cannon Research Uk, Sarah Cannon Research UK, GB-W1G 6AD - London/GB
  • 13Clinical Science, Clovis Oncology, 80301 - Boulder/US
  • 14Clinical Operations, Clovis Oncology, 94158 - San Francisco/US
  • 15Oncology, Dana-Farber Cancer Institute, Boston/US

Abstract

Aim

Rucaparib is a potent, oral PARP inhibitor that induces synthetic lethality in homologous recombination deficient (HRD) tumors. Multiple mechanisms lead to HRD, which in turn leads to extensive genomic loss of heterozygosity (LOH). Patients (pts) with a BRCA mutation and/or high LOH may benefit from rucaparib treatment.

Methods

Phase 1 employed a 3 + 3 dose escalation design in patients with advanced solid tumors to identify the RP2D. Phase 2 is enrolling platinum-sensitive gBRCA OC pts (n = 41; 2-4 prior regimens required) with relapsed disease at the RP2D.

Results

Phase 1 enrolled 56 pts with advanced solid tumors (BRCA mutation and measurable disease not required) and established 600 mg BID as the RP2D. RECIST and/or CA-125 responses (2 CRs, 7 PRs, 3 CA-125) occurred in pts with ovarian, breast, or pancreatic cancer and a gBRCA mutation. At doses ≥360 mg BID, disease control (CR + PR + SD > 24 wks) in gBRCAmut OC pts was 82% (9/11), with 100% (3/3) of platinum-sensitive pts and 75% (6/8) of platinum-resistant pts deriving benefit. At the RP2D, 80% of gBRCAmut OC (3/4) and BC (1/1) pts had a RECIST or CA125 response. In addition, an OC pt, BRCAwt with high LOH in tumor, derived durable benefit (PFS = 36 wks). Overall, the most common AEs were mild to moderate GI effects and fatigue. At rucaparib doses ≥360 mg BID, treatment-related AEs in ≥20% of pts (n = 27) (%G1/G2/G3) included nausea (33/15/4), fatigue (19/22/0), vomiting (26/11/0). Grade 3 lab abnormalities included low Hgb (n = 5, 17%), low platelets (n = 2, 7%), low ANC (n = 1, 3%), and increased ALT (n = 1, 3%). No G4 AEs occurred and no pt discontinued rucaparib due to an AE. Phase 2 is ongoing, with early signs of clinical activity; updated efficacy and safety data will be presented at the meeting.

Conclusions

Overall, rucaparib is well tolerated with clinical benefit in pts with evidence of HRD in tumor. Durable benefit in a BRCAwt OC pt with high LOH highlights the treatment opportunity for rucaparib in this pt population. A pivotal program which prospectively tests an HRD molecular signature associated with rucaparib benefit in OC pts is ongoing.

Disclosure

R. Kristeleit: Membership on Clovis advisory boards;A.M. Oza: Clinical Trial Funding from sponsor to Princess Margaret Cancer Centre;J. Balmaña: Participated in a CLOVIS advisory board; L. Chen: Moderated a Genentech advisory board in 2014;R. Plummer: research funding from Clovis to run clinical trials and laboratory research, and honoraria for advisory boards;L. Maloney and E. Dominy: Employment and stock ownership; G. Shapiro: Research Funding is provided to Dana-Farber Cancer Institute for the conduct of the study. All other authors have declared no conflicts of interest.