Sierra Oncology Receives Clearance to Enhance Ongoing Clinical Trials for SRA737

- Phase 1 monotherapy and combination clinical trials amended to focus on novel genetically-driven, prospective patient selection strategy designed to demonstrate synthetic lethality -

VANCOUVER, May 10, 2017 /CNW/ - 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, today reported that it has received clearance from regulators in the UK to amend the two ongoing Phase 1 trials for its Chk1 inhibitor, SRA737. 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.

"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.

About Sierra Oncology
Sierra Oncology is a clinical stage drug development company advancing next generation DNA Damage Response (DDR) therapeutics for the treatment of patients with cancer. Our lead drug candidate, SRA737, is a potent, highly selective, orally bioavailable small molecule inhibitor of Checkpoint kinase 1 (Chk1), a key regulator of important cell cycle checkpoints and central mediator of the DDR network. In cancer cells, replication stress induced by oncogenes (e.g., MYC or RAS) or genetic mutations in DNA repair machinery (e.g., BRCA1 or FA) combined with loss of function in tumor suppressors (e.g., TP53 or ATM) results in persistent DNA damage and genomic instability leading to an increased dependency on Chk1 for survival. Targeted inhibition by SRA737 may therefore be synthetically lethal to these cancer cells and have utility as a monotherapy in a range of tumor indications. 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 anti-tumor activity. SRA737 is currently being investigated in two Phase 1 clinical trials in patients with advanced cancer.

Sierra Oncology is also advancing SRA141, a potent, selective, orally bioavailable small molecule inhibitor of Cell division cycle 7 kinase (Cdc7) undergoing preclinical development. Cdc7 is a key regulator of DNA replication and is involved in the DDR network, making it a compelling emerging target for the potential treatment of a broad range of tumor types. For more information, please visit www.sierraoncology.com.

Cautionary Note on Forward-Looking Statements
This press release contains forward-looking statements within the meaning of the "safe harbor" provisions of the Private Securities Litigation Reform Act of 1995, including, but not limited to, statements regarding Sierra Oncology's anticipated clinical development, protocol amendments, target indications, trial designs and potential benefits of Sierra Oncology's product candidates. All statements other than statements of historical fact are statements that could be deemed forward-looking statements. These statements are based on management's current expectations and beliefs and are subject to a number of risks, uncertainties and assumptions that could cause actual results to differ materially from those described in the forward-looking statements. Such forward-looking statements are subject to risks and uncertainties, including, among others, the risk that Sierra Oncology may be unable to successfully develop and commercialize product candidates, SRA737 and SRA141 are at early stages of development and may not demonstrate safety and efficacy or otherwise produce positive results, Sierra Oncology may experience delays in the preclinical and anticipated clinical development of SRA737 or SRA141, Sierra Oncology may be unable to acquire additional assets to build a pipeline of additional product candidates, Sierra Oncology's third-party manufacturers may cause its supply of materials to become limited or interrupted or fail to be of satisfactory quantity or quality, Sierra Oncology's cash resources may be insufficient to fund its current operating plans and it may be unable to raise additional capital when needed, Sierra Oncology may be unable to obtain and enforce intellectual property protection for its technologies and product candidates and the other factors described under the heading "Risk Factors" set forth in Sierra Oncology's filings with the Securities and Exchange Commission from time to time. Sierra Oncology undertakes no obligation to update the forward-looking statements contained herein or to reflect events or circumstances occurring after the date hereof, other than as may be required by applicable law.

SOURCE Sierra Oncology

James Smith, Vice President of Corporate Affairs, Sierra Oncology, 604.558.6536, [email protected]