A first-in-human phase I/II trial of SRA737 (a Chk1 Inhibitor) in subjects with advanced cancer.

Abstract

3094 Background: SRA737 is a potent, highly selective and orally-bioavailable inhibitor of checkpoint kinase 1 (Chk1). SRA737-01 was designed to investigate the safety and tolerability of continuous, daily dosing with SRA737 and to evaluate preliminary efficacy in expansion cohorts of prospectively-selected genetically-defined subjects with advanced tumors. Methods: The escalation phase employed an accelerated titration design starting at 20 mg administered orally in 28-day cycles. Incremental 100% dose escalations in single-subject cohorts were followed by a rolling-6 design once SRA737-related ≥ Grade 2 toxicity was observed during Cycle 1. The expansion phase enrolled subjects prospectively selected by next-generation sequencing with: high grade serous ovarian, colorectal, metastatic castration-resistant prostate, non-small cell lung, and head and neck cancers. Results: In escalation, 18 subjects received SRA737 in 9 dose level cohorts, from 20 to 1300 mg QD; median treatment duration 62.5 days (range 1 to 226). Of these subjects, 3 experienced dose limiting toxicity (DLT; inability to receive 75% of the planned dose); 2 at 1300 mg QD due to gastrointestinal intolerability and 1 at 500 mg BID due to thrombocytopenia. The maximum tolerated dose (MTD) was established at 1000 mg QD or 500 mg BID. The Cmax and AUC0-24 at 1000 mg QD were 2391 ng/mL and 26795 ng∙h/mL respectively and the Cmin (411 ng/mL) exceeded that determined in preclinical models to be effective. Doses ≥ 300 mg QD also exceeded this level. Of 462 subjects prospectively screened for genetic alterations associated with Chk1 sensitivity, 93 were enrolled in expansion across all tumor types. Overall, the most commonly reported treatment-emergent adverse events were diarrhea (70%), nausea (64%), vomiting (51%), and fatigue (47%); the majority were of mild to moderate severity. Conclusions: In this first-in-human trial of SRA737 monotherapy, the MTD was 1000 mg/day and based on overall tolerability and PK, the recommended Phase 2 dose is 800 mg/day. The successful enrollment of prospectively-selected genetically-defined subjects will allow response data to be correlated with genomic profiles hypothesized to confer sensitivity to Chk1 inhibition. Clinical trial information: NCT02797964.

Systems Biology Approach Identifies Prognostic Signatures of Poor Overall Survival and Guides the Prioritization of Novel BET-CHK1 Combination Therapy for Osteosarcoma

“…Therefore, we hypothesized that by inhibiting key regulators of RS that control its severity, RS would increase to intolerable levels and lead to OS cell death. Targeting RS in OS has not been studied in great detail and a number of promising small molecule inhibitors to RS regulators are in clinical trials [51,54,58,60,63]. In these studies, we utilized in-vitro and in-vivo models of pediatric and AYA OS that harbor the MYC-RAD21 CNV+ risk signature to explore the efficacy of inhibiting two RS regulators: BETs and CHK1.…”

“…The levels of BETi/OTX-015 clinically achievable in human plasma are dose regimen-dependent, with plasma exposure of up to 1-2 µM OTX-015 [58]. The C max of CHK1i/SRA737 that can be safely obtained in the human plasma was approximately 6 µM CHK1i/SRA737 [63]. In a phase I study (NCT02203513), an average plasma concentration of 0.1-0.2 µM CHK1i/LY2606368 could be obtained over a 24 h time interval [74].…”

“…Our rationale for selecting MYC-RAD21+ as the molecular signature to target was further supported by the fact that a network link between MYC and RAD21 exists, for RAD21 gene expression can be regulated by MYC [61]. RAD21 is often overexpressed in highly replicative cancers [61] and it has been reported that RAD21 is amplified in OS and other cancers [62,63]. RAD21 functions as a chromatid cohesion subunit that plays an essential role in DNA replication and repair.…”

“…Preclinical and clinical (NCT03205176) evaluation of BETi/OTX-015 is under evaluation in refractory solid tumors such as OS [66]. In addition, CHK1i/SRA737 is also being employed in a clinical trial for advanced cancers (NCT02797964, [63]), and CHK1i/LY2606368 is under evaluation by Cincinnati Children's Hospital Medical Center in a Phase 1 Study in mutant TP53 refractory solid and liquid tumors [8,62,67]. To the best of our knowledge, our study is the first to integrate the analysis of CNVs, gene expression, and OS patient survival data to prioritize actionable therapeutic targets and functionally validate drug responses in preclinical models of OS with the MYC-RAD21+ signature.…”

“…* Within the range of clinically achievable concentrations. Clinically achievable doses include BETi/OTX-015 (1-2 µM)[58], CHK1i/SRA737 (6 µM)[63], and CHK1i/LY2606368 (0.1-0.2 µM)[74]. Data are compiled from three independent experiments.…”