A Phase 1/2 Trial of SRA737 (a Chk1 Inhibitor) Administered Orally in Subjects With Advanced Cancer
The purpose of this clinical study is to establish the safety profile, determine the maximum tolerated dose (MTD) and recommend a Phase 2 dose and schedule of SRA737; and to evaluate the efficacy of SRA737 in prospectively-selected subjects with genetically-defined tumors that harbor genomic alterations linked to increased replication stress and that are hypothesized to be more sensitive to checkpoint kinase 1 (Chk1) inhibition via synthetic lethality. Specific cancer indications that frequently harbor these genetic mutations will be studied.
• For Dose Escalation Only: any locally advanced or metastatic, histologically or cytologically proven solid tumor or NHL, relapsed after or progressing despite conventional treatment
• Life expectancy of at least 12 weeks
• World Health Organization (WHO) performance status of 0-1
• Must meet select hematological and biochemical laboratory indices
• Archival tumor tissue or accessible tumor and willingness to consent to a biopsy
∙ Expansion Only:
• Any locally advanced or metastatic malignancy of the following types for which no other conventional therapy is considered appropriate:
‣ Metastatic Colorectal Cancer (CRC)
⁃ Platinum-resistant or intolerant High Grade Serious Ovarian Cancer (HGSOC)
⁃ Advanced Non-Small Cell Lung Cancer (NSCLC)
⁃ Metastatic Castration-Resistant Prostate Cancer (mCRPC)
⁃ Head and Neck Squamous Cell Carcinoma (HNSCC) or squamous cell carcinoma of the anus (SCCA).
⁃ Eligibility may be further restricted by the select number of prior regimens specific to each indication
• Measurable disease per RECIST v1.1, or for mCRPC, evaluable disease per any of the following:
‣ Measurable disease per RECIST v1.1
⁃ Increasing PSA
⁃ Circulating tumor cell (CTC) count of 5 or more cells per 7.5 ml of blood
• Tumor tissue or ctDNA evidence that subject's tumor harbors a combination of mutations which are expected to confer sensitivity to Chk1 inhibition. Eligibility will be determined by the Sponsor's review of genetic abnormalities detected in genes in the following categories:
‣ Oncogenic drivers such as MYC, CCNE1, etc.
⁃ Key tumor suppressor genes regulating G1 cell cycle progression/arrest such as RAD50, TP53, etc. For patients with NHSCC or SCCA, positive HPV status is also considered for eligibility.
⁃ The DDR pathway including BRCA1, BRCA2 and FANC. For patients with CRC, MMR genetic alterations and/or high microsatellite instability are also considered for eligibility.
⁃ Genetic indicators of replicative stress such as gain of function/amplification of Chk1 or ATR or other related gene.