On May 10, 2017 Sierra Oncology, Inc. (NASDAQ: SRRA), a clinical stage drug development company focused on advancing next generation DNA Damage Response (DDR) therapeutics for the treatment of patients with cancer, reported that it has received clearance from regulators in the UK to amend the two ongoing Phase 1 trials for its Chk1 inhibitor, SRA737 (Press release, Sierra Oncology, MAY 10, 2017, View Source [SID1234518991]). The amended trials will include cohort expansions of prospectively selected patients with tumors identified to have genetic aberrations hypothesized to confer sensitivity to Chk1 inhibition.

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"Collaborating closely with our investigators and The Institute of Cancer Research, London, and The Royal Marsden in the UK, we have designed significant enhancements to our ongoing clinical trials for SRA737, which can now be implemented immediately and that are intended to enrich these studies with patients we believe are promising candidates for treatment with our drug," said Dr. Nick Glover, President and CEO of Sierra Oncology. "Furthermore, between these two studies, we will have the opportunity to evaluate preliminary efficacy across seven distinct cancer indications exploring the possibility of inducing synthetic lethality with SRA737-driven inhibition of Chk1 in tumors with defined genetic alterations. An initial update from these trials is anticipated in early 2018."

"Sierra is pursuing a leading-edge strategy for the development of SRA737 that thoughtfully leverages Chk1’s fundamental biological role in cancer and the DDR network with the objective of enhancing patient selection and maximizing potential responses. With the advancement of sophisticated genetic analysis tools, a novel genetically-driven clinical development approach such as this becomes feasible, furthering our progress towards personalized oncology therapy," added the studies’ Chief Investigator Dr. Udai Banerji, Deputy Director of the Drug Development Unit at The Institute of Cancer Research and The Royal Marsden.

Amended Phase 1 SRA737 monotherapy study (ClinicalTrials.gov identifier: NCT02797964)
This study, as originally designed, is investigating the safety and tolerability of SRA737 and seeking to identify its optimal dose, schedule, and maximum tolerated dose (MTD) as a monotherapy. The amended design will now also concurrently evaluate preliminary efficacy in prospectively-selected, genetically-defined subjects.

The study will now consist of two phases, a Dose Escalation Phase and a Cohort Expansion Phase, being run concurrently.

In the Dose Escalation Phase, cohorts consisting initially of a single subject will receive escalating doses of SRA737, administered orally on a continuous daily dosing schedule in 28-day cycles. Once an SRA737-related Grade 2 toxicity is observed in a dose escalation cohort during Cycle 1, that cohort will be expanded to three to six subjects, and subsequent dose level cohorts will follow a rolling six design until the MTD has been identified.
In the parallel Cohort Expansion Phase, subjects with genetically-defined tumors that harbor genomic alterations hypothesized to confer sensitivity to checkpoint kinase 1 (Chk1) inhibition will be prospectively enrolled into several indication-specific cohorts to explore the preliminary efficacy of SRA737. 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 loss of function or 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 gain of function or amplification of CHEK1 or ATR or other related gene; or

· a gain of function mutation or amplification of 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.

Amended Phase 1 study of SRA737 in combination with DNA-targeting chemotherapy (gemcitabine) (ClinicalTrials.gov identifier: NCT02797977)

This study, as originally designed, is seeking to establish the safety profile, determine the MTD and to propose a recommended dose of SRA737 in combination with gemcitabine for further development. The amended study will now also evaluate the preliminary efficacy of SRA737 in combination with gemcitabine in prospectively-selected, genetically-defined subjects once an MTD and dosing schedule have been determined.

The study will now consist of two stages:

Stage 1, which has concluded enrollment, consists of a Dose Escalation Phase where subjects are given SRA737 in addition to gemcitabine and cisplatin.

Stage 2 consists of two phases where subjects will be given SRA737 in addition to gemcitabine.
Initially, 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 gemcitabine until the combination MTD is reached.

After the MTD has been identified, the Cohort Expansion Phase of Stage 2 will explore the preliminary efficacy of SRA737 plus gemcitabine in prospectively enrolled subjects with tumors that harbor genomic alterations hypothesized to confer sensitivity to Chk1 inhibition. Qualifying patients will be enrolled into two indication-specific cohort expansions, bladder cancer and pancreatic cancer, as these indications are predicted to have a high prevalence of genetic aberrations hypothesized to confer sensitivity to Chk1 inhibition, and because gemcitabine is often an important component of the standard-of-care treatment for these indications. To qualify for enrolment into these cohorts, the subject’s tumor must have a confirmed minimum of two different types of genetic abnormalities, similar to those defined for the monotherapy trial, determined using Next Generation Sequencing.