For more information, visit ClinicalTrials.gov, identifier: NCT02797964
This first-in-human, multicenter, Phase 1 Monotherapy study consists of two phases, a Dose Escalation Phase and a Cohort Expansion Phase, being run concurrently.
The Dose Escalation Phase of the SRA737 Phase 1 monotherapy trial is investigating the safety and tolerability of SRA737 and seeking to identify its optimal dose, schedule, and maximum tolerated dose (MTD). Single patient cohorts will receive escalating doses of SRA737, starting at 20 mg, administered orally on a continuous daily dosing schedule in 28-day cycles until SRA737-related Grade 2 toxicity is observed in a dose escalation subject during Cycle 1. At that point, that dose level and all subsequent dose level cohorts will be expanded to three to six subjects, following a rolling six design. Intensive PK and pharmacodynamic assessments will be obtained on all subjects.
In the Cohort Expansion Phase, enrollment into five indication-specific cohort expansions was initiated once the minimum efficacious dose level was reached. These indications include:
- colorectal cancer;
- ovarian cancer;
- castration-resistant prostate cancer;
- non-small cell lung cancer; and
- head and neck squamous cell carcinoma.
To qualify for enrolment in the Cohort Expansion Phase, the subject’s tumor must have a confirmed minimum of two different types of genetic alterations, determined using Next-Generation Sequencing. These include 1) a deleterious mutation in a key tumor suppressor gene, such as TP53, and 2) at least one of the following:
- a deleterious mutation in the DNA damage repair machinery such as ATM, BRCA1, BRCA2, or other gene in the DNA damage response pathway implicated in Chk1 pathway sensitivity;
- a genetic indicator of replicative stress, defined as a deleterious mutation in CHEK1 or ATR or other related gene; or
- a deleterious mutation in an oncogenic driver such as MYC, RAS, or other gene implicated in Chk1 pathway sensitivity.
Colorectal cancer patients with high microsatellite instability are eligible if they also have evidence of a deleterious mutation in a key tumor suppressor gene. A deleterious mutation in a key tumor suppressor gene is not required for head and neck squamous cell carcinoma patients with HPV-positive disease.
The Dose Escalation Phase will continue concurrently until the MTD and Recommended Phase 2 Dose are identified.
Phase 1 study of SRA737 in combination with DNA-targeting chemotherapies (gemcitabine plus cisplatin or gemcitabine alone)
For more information, visit ClinicalTrials.gov, identifier: NCT02797977
This first-in-human Phase 1, multicenter study consists of two stages:
In Stage 1, a triplet combination (SRA737 with gemcitabine and cisplatin) is being evaluated in subjects with solid tumors. Cohorts consisting of three to six subjects will receive escalating doses of SRA737. Intensive PK and pharmacodynamic assessments will be obtained on all subjects. Enrolment for this stage has concluded and the study has transitioned to Stage 2.
In the Dose Escalation Phase of Stage 2, cohorts of three to six subjects will be given escalating doses of SRA737 on an intermittent schedule in addition to low-dose gemcitabine until the combination MTD is reached. The starting dose of SRA737 for the first cohort was 40 mg. SRA737 will be administered orally on days 2, 3, 9, 10, 16 & 17 of a 28-day cycle; 300 mg/m2 of gemcitabine will be administered intravenously on days 1, 8, & 15.
Once the MTD of SRA737 in combination with gemcitabine has been identified, the Cohort Expansion Phase of Stage 2 will begin. Qualifying patients will be enrolled into two indication-specific cohort expansions, bladder cancer and pancreatic cancer. To qualify for enrolment into these cohorts, the subject’s tumor must have a confirmed minimum of two genomic alterations hypothesized to confer sensitivity to Chk1 inhibition, determined using Next Generation Sequencing.