Phase I/Ib study of the PARP inhibitor olaparib (O) with carboplatin (C) in BRCA1/2 mutation carriers with breast or ovarian cancer (Br/OvCa) (NCT00647062).

Abstract

2514 Background: O capsules have single agent activity against Br/OvCa in BRCA1/2mut+carriers. Our goals were to define safety and explore predictive biomarkers for an OC regimen in these pts. Methods: 3x3 dose escalation optimized daily oral O (100 or 200mg q12h; DL1&2) with IV C/AUC3 on d8 and q21d, and on DL3-6, O d1-7 at 200 then 400mg q12h with C/AUC3-5 on d2. ≤ 8 OC cycles were given, followed by daily O until progression. Safety was assessed q cycle and response q2 cycles. PBMCs were collected for polymorphism analysis (PARP1; XRCC1), and serially for PAR incorporation by ELISA. Paired tumor biopsies (pre/postC1) were collected in phase Ib pts for protein microarray (RPPA) and TUNEL endpoints. Results: 45 women (37Ov/8Br) with BRCA1 (32), BRCA2 (11), 1 each BRCA1&2 and BRCApro 68% received OC. All OvCa pts previously received C (6-55mo prior, median 14). DLT was thrombocytopenia (O 200mg q12h, C/AUC3 2/5 pts). MTD was not reached on the intermittent schedule. RP2D is O 400mg q12hx14, C/AUC5 (1/6: g4 thrombocytopenia). Gr 3/4 AEs included neutropenia (42%), thrombocytopenia (20%), anemia (13%), C hypersensitivity (9%), and fatigue (7%). 7 pts discontinued C early for hypersensitivity reaction (4) or myelosuppression (3). Responses included 1 CR (BrCa, 17mo), PR in 15/34 OvCa (44%; 3-28+mo) and 6/8 BrCa (5-24+ mo), and stabilization in 14/34 OvCa (41%; 3-25+ mo) and a BrCa pt (11mo) for a clinical benefit rate of 85% OvCa, 100% BrCa. RPPA (N=10) showed high FOXO3 and NFκB1 preC1 correlated with time on study (r=0.822, p=0.0035; r=-0.832, p=0.0028, respectively). The change post-preC1 correlated with time on study for the combination of eIF4E/G, caspase 7, pPI3K, FOXO3a, p62, E-cadherin, PCNA, Bim, and Bcl2 (r=-0.855, p=0.0068). Post-preC1 TUNEL results trended to correlate with response (p=0.07). PBMC PAR concentrations and PARP1/XRCC1 polymorphisms did not correlate with response. Conclusions: O 400mg q12h x14 with C/AUC5 q21d is active and tolerable in Br/OvCa BRCAmut+ pts despite interactive marrow suppression. Exploratory translational studies indicate FOXO3 and NFkB1 may be predictive for response to therapy, requiring a prospective validation. Clinical trial information: NCT00647062.