Abstract OT1-03-10: A phase I followed by a

r

andomiz

e

d phase II trial of two cycles carboplatin-olaparib followed by olaparib monotherapy

v

ersus capec

i

tabine in BRCA-1 or -2 mutated Her2 negative ad

v

anced breast c

a

ncer as first

l

ine treatment (REVIVAL study)
Authors: Dackus GMHE , Schouten PC , Geenen JJ , Marchetti S , Sonke GS , Linn SC , Schellens JHM 
Published: May 2016

Abstract
Background
Preclinical studies revealed that the combination of platinum compounds and olaparib is additive and possibly even synergistic in cell models with BRCA1 or -2 mutations. Early clinical trials suggested high benefit of olaparib with induction carboplatin in BRCA1 and -2 mutation carrier enriched populations. However, there is no evidence yet that carboplatin-olaparib has a superior benefit-risk compared to current standard therapy in advanced breast cancer in BRCA1 and -2 mutation carriers.
Trial design
We initiated a phase-I/II study due to an olaparib formulation change from capsule to tablet. During phase-I a traditional 3+3 dose escalation study is performed. Carboplatin will be dose escalated in 1 step from AUC 3 to AUC 4 with a constant olaparib dose of 25 mg BID. Olaparib is then dose escalated in 3 steps to 50, 75 and 100 mg BID until &gt; 1/6 patients develop a DLT, the previous safe dose-level will be determined the MTD. After the MTD is established a randomised phase-II trial will be initiated where patients are randomised between standard capecitabine 1250 mg/m2 BID day 1-14, q day 22 or 2 cycles carboplatin-olaparib followed by olaparib monotherapy 300mg BID. After progression, patients in the experimental arm receive capecitabine, all other patients receive physicians choice of paclitaxel, vinorelbine or eribulin at standard dose. A compassionate use program with olaparib is available for patients in the standard arm after progression on second line treatment.
Eligibility criteria
In phase-II patients with histological or cytological proof of advanced BRCA1 or -2 mutated HER2 negative breast cancer are eligible if they are ≥18 years, have measureable disease according to RECIST 1.1 criteria, a WHO performance status of 0–2, a life expectancy ≥ 3 months and a negative pregnancy test. Pretreatment should contain an anthracycline and/or taxane in the (neo)adjuvant setting, unless not indicated. In the advanced setting only hormonal pre-treatment is allowed. Minimal laboratory values ANC ≥ 1.5 x 109 /L, Hb ≥ 6.2 mM (no transfusions in the last 28 days), platelet count ≥ 100 x 109 /L, serum bilirubin &lt; 1.5 x ULN, ASAT and ALAT &lt; 2.5 x ULN and a serum creatinine &lt; 1.5 x ULN or creatinine clearance ≥ 50 mL/min.
Aims
In phase-1 we establish the MTD for treatment in phase-II where we study progression free survival on first line treatment(PFS1) compared with standard of care capecitabine.
Statistical methods
Toxicity analysis in phase-I can take place after all patients completed their 28 day DLT period.
A total of 104 events in 110 patients on first line treatment need to be observed in phase-II to detect a clinical meaningful improvement in median PFS1 in the experimental arm from 4 to 7 months, assuming an accrual of 2 years and a follow-up of ≥6 months, providing a power of 80% (two-sided significance level of 5%). An interim analysis for futility and efficacy will be performed when 52 events have been observed.
Accrual
It is expected that 15-20 patients are needed in phase-I, inclusion is due around November 2015. Phase-II will be multicentre and is expected to start accrual December 2015.
Citation Format: Dackus GMHE, Schouten PC, Geenen JJ, Marchetti S, Sonke GS, Linn SC, Schellens JHM. A phase I followed by a randomized phase II trial of two cycles carboplatin-olaparib followed by olaparib monotherapy versus capecitabine in BRCA-1 or -2 mutated Her2 negative advanced breast cancer as first line treatment (REVIVAL study). [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr OT1-03-10.