Abstract 5586: Phase I study of PARP inhibitor ABT-888 and carboplatin with novel imaging in metastatic breast cancer (MBC) (NCI-8609)

Abstract

Purpose: ABT-888 is an oral inhibitor of PARP 1 and 2 and potentiates activity of platinums in preclinical models. We are conducting a phase I study of ABT-888 on 2 different schedules (7 and 14 day) plus q 3 week carboplatin (C) to identify the recommended phase II dose schedules (RPTD-7and 14 day) for this regimen in patients (pts) with MBC who are: (1) triple negative (TN); or (2) estrogen receptor positive (ER+) with defective Fanconi Anemia (FA) pathway (no FANCD2 foci in tumor). Study design: Eligible pts received C-AUC 5 Q 3weeks (except dose level 1-AUC 6) plus escalating doses of ABT-888 BID on a 7 or 14-day schedule using a 3+3 dose escalation design. Blood samples were collected during cycles 1 and 2 for PAR assay and CTCs isolated to measure gamma H2Ax. We performed 3′-[F-18] Fluoro-3′-deoxythymidine(FLT) PET scans to assess cellular tumor proliferation at baseline, cycle 1 day 7 and 14 and after cycle 3. FDG-PET-CT scans were used to assess response. Results: 22 pts (20-TN, 2-ER+ w/FA defect) with median age of 56.5 yrs (range 31-69) were enrolled on 5 dose levels. Dose level 1 with C at AUC 6 was too toxic with 3 DLTs (Table 1). Further dose escalations were performed with C at AUC-5. Dose reductions in C were made in subsequent cycles for thrombocytopenia, anemia and fatigue. Maximum reduction in thymidine uptake in tumors was seen on day 7 FLT scans. CTCs were isolated using an immunomagnetic negative depletion method on 8 pt samples to date (median-59, range 0-684 CTCs). Gamma H2Ax analysis on sequential samples is ongoing. Four pts have had an unconfirmed partial response (PR) with > 50% tumor shrinkage; 2 of the 4 pts had a defective FA pathway. Conclusions: Thrombocytopenia is the major DLT when ABT-888 is given in combination with C, where lower AUC of C is better tolerated and shows promising activity of this combination. FA deficiency (5/14=27%) seen in this group is consistent with our previous reports. The study is supported U01 CA076576. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5586. doi:1538-7445.AM2012-5586