Abstract LB-202: Responses to sequential sapacitabine and seliciclib in patients with BRCA-deficient solid tumors.
Authors: Shapiro Geoffrey I. , Hilton John , Cleary James M. , Tolaney Sara M. , Ghandi Leena , Kwak Eunice L. , Clark Jeffrey W. , Wolanski Andrew , Bell Tracy , Schulz John , Frame Sheelagh , Saladino Chiara , Hogben Morag , Rodig Scott J. , Chiao Judy H. , Blake David 
Published: August 2014

Abstract
Background: Sapacitabine is an orally administered nucleoside analogue; the active metabolite, CNDAC (2′-C-cyano-2′-deoxy-1-β-D-arabino-pentofuranosylcytosine), generates single-strand DNA breaks that are converted to double-strand DNA breaks (DSBs) during subsequent replication, resulting in cell death if unrepaired. Repair of CNDAC-induced DSBs is dependent on the homologous recombination (HR) repair pathway. Depletion or inhibition of components of the HR pathway (including ATM, BRCA1/2, Rad 51, and XRCC3) greatly sensitizes tumor cell lines to CNDAC-induced cell death in vitro. Seliciclib is an orally bioavailable inhibitor of cyclin-dependent kinases (CDKs) 2, 7 and 9. CDK2 has been shown to participate in DNA repair and to be a therapeutic target in BRCA-deficient cancers. Seliciclib inhibits DSB repair, and also reduces BRCA1 and BRCA2 mRNA levels in cancer cell lines, sensitizing tumor cells to CNDAC. This phase I study evaluates sequential sapacitabine and seliciclib. Methods: Dose escalation was conducted in patients with incurable solid tumors and adequate organ function with sapacitabine bid x 7 consecutive days (d1-7), seliciclib bid x 3 consecutive days (d8-10) followed by 11 days of rest. At least 3 patients were evaluated per dose level. MTD was the highest dose level at which less than one-third of at least 6 patients experienced cycle 1 DLT. Skin biopsies were obtained to assess DNA damage following sapacitabine (d8 vs pre-treatment) and further augmentation of DNA damage after seliciclib (d11 vs d8). Results: 38 patients were treated. The MTD is sapacitabine 50 mg bid/seliciclib 1200 mg bid. DLTs were reversible transaminase elevations and neutropenia. The most frequent adverse events (all cycles, regardless of causality) included, fatigue, abdominal pain, diarrhea, constipation, decreased appetite, nausea, vomiting, anemia, neutropenia, pyrexia, AST elevation, alkaline phosphatase elevation, creatinine elevation, hyperglycemia, hypophosphatemia, cough, and alopecia, the majority mild to moderate in intensity. Skin biopsies showed a 2.3-fold increase in γ-H2AX staining post-sapacitabine (n=16; p=0.007) and a further 0.58-fold increase post-seliciclib (n=12; p=0.069). Four confirmed PRs occurred in patients with pancreatic, breast (2 pts) and ovarian cancer, all BRCA mutation carriers, lasting 21, 78+, 36+ and 42+ weeks, respectively. SD as best response ≥= 12 weeks was observed in 8 additional patients, including two BRCA mutation carriers with ovarian and breast cancer, lasting 64 and 21 weeks, respectively. Conclusions: Sequential sapacitabine and seliciclib is safe with preliminary antitumor activity. BRCA mutation carrier status may be a potential biomarker for response across multiple tumor types. An alternative schedule with concomitant administration of sapacitabine and seliciclib is currently under evaluation.
Citation Format: Geoffrey I. Shapiro, John Hilton, James M. Cleary, Sara M. Tolaney, Leena Ghandi, Eunice L. Kwak, Jeffrey W. Clark, Andrew Wolanski, Tracy Bell, John Schulz, Sheelagh Frame, Chiara Saladino, Morag Hogben, Scott J. Rodig, Judy H. Chiao, David Blake. Responses to sequential sapacitabine and seliciclib in patients with BRCA-deficient solid tumors. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-202. doi:10.1158/1538-7445.AM2013-LB-202