A phase I study of oral SRA737 (formerly CCT245737) given in combination with gemcitabine plus cisplatin or gemcitabine alone in patients with advanced cancer.

Abstract

TPS2613 Background: SRA737 is a highly selective, orally bioavailable small molecule inhibitor of Checkpoint kinase 1 (Chk1), a key cell cycle checkpoint and central regulator of the DNA Damage Response (DDR) network. In cancer cells, replication stress induced by genomic alterations in oncogenes (eg, MYC and RAS) combined with loss of function in tumor suppressors (eg, TP53 and ATM) results in persistent DNA damage and genomic instability. Targeted inhibition of components of the DDR network such as Chk1 by SRA737 may be synthetically lethal to cancer cells. Chk1 is also believed to facilitate tumor cell resistance to chemotherapy or radiation-induced DNA damage and the combination of SRA737 with these standards-of-care may provide synergistic antitumor activity. SRA737 is being investigated in two Phase 1 trials in patients with advanced cancer. We now describe the Phase 1 multicenter, dose-escalation study of SRA737 in combination with gemcitabine/cisplatin (GC) or gemcitabine (G) alone (NCT02797977). Methods: Up to 70 patients will receive escalating doses of SRA737+GC in Stage 1 or SRA737+G in Stage 2 until a recommended Phase 2 dose (RP2D) is established, followed by expansion cohorts. Patients will receive a single SRA737 PK run-in dose followed by Gem on D1 and 8, Cis on D1, SRA737 on D2, 3, 9 and 10 of each 21-d cycle or Gem on D1, 8 and 15, SRA737 on D2, 3, 9, 10, 16, 17 of each 28-d cycle. Eligibility criteria include WHO performance status of 0-1 and ≤ 3 prior lines of cytotoxic chemotherapy for metastatic disease. Primary objectives are to assess the safety profile of SRA737 combination therapy and to establish a RP2D. The PK profile and PD biomarkers (eg, phosphorylation of Chk1 at Ser296, Ser345 and γH2AX foci in PBMCs and tumor tissue) will be explored. The study was opened to enrollment in mid-2016. An amendment, which includes the addition of an indication specific expansion cohort of subjects with genetically-defined tumors known to have Chk1-sensitizing aberrations (eg, gene mutations and amplifications/deletions), has been submitted and is pending regulatory review while enrollment continues. At the Annual Meeting, the amended design will be described. Clinical trial information: NCT02797977.