Sierra Oncology Reports Encouraging Initial Progress from Ongoing Phase 1 Clinical Trials of Chk1 Inhibitor SRA737

- Presenting two posters describing innovative trial designs leveraging Chk1 synthetic lethality at the ASCO 2017 Annual Meeting -

VANCOUVER, June 5, 2017 /PRNewswire/ - 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 reports on the initial progress of the two ongoing Phase 1 trials of its Chk1 inhibitor, SRA737. In addition, today Sierra is presenting two posters describing the innovative clinical designs of these trials at the 2017 American Society of Clinical Oncology (ASCO) Annual Meeting, being held in Chicago.

"The Dose Escalation Phase of our monotherapy study for SRA737 employs an accelerated titration design which has allowed us to rapidly and efficiently advance through several 100% dose escalations with single patient cohorts," said Dr. Barbara Klencke, Chief Development Officer of Sierra Oncology. "We have not yet observed any dose limiting toxicity and are achieving excellent exposure with several cohorts having surpassed the proposed minimum efficacious plasma concentration for SRA737 based on preclinical modelling. This has enabled the commencement of the parallel Cohort Expansion Phase of the study, described in detail in one of our posters presented at ASCO today. This innovative clinical trial design will enroll prospectively-selected genetically-defined patients into five indication-specific cohort expansions at potentially active dose levels."

The SRA737 Phase 1 monotherapy trial has advanced through six single patient dose cohorts of 20, 40, 80, 160, 300 and 600 mg/day, administered under a continuous daily oral dosing regimen in 28-day cycles. Dose escalation will continue until a maximum tolerated dose (MTD) is reached, in parallel with ongoing Cohort Expansion enrollment.

Preliminary observations from the ongoing monotherapy study are as follows:

• SRA737 has been well-tolerated to date: No Grade 2 or higher SRA737-related Adverse Events have been reported. No dose-limiting toxicities have been observed and an MTD has not been reached.
• Dose-proportional exposure: Pharmacokinetic (PK) parameters for SRA737 have been generally linear across the dose range tested to date.
• Plasma concentrations of SRA737 exceeding the proposed minimum efficacious threshold (Cmin) of 100 nM were maintained for 24 hours post-dose at the 160 mg/day dose level and above.

Having successfully surpassed the proposed minimum efficacious exposure threshold, the Cohort Expansion Phase of the trial has commenced and is enrolling patients with tumors identified to have genetic aberrations hypothesized to confer sensitivity to Chk1 inhibition via synthetic lethality into five indication-specific cohorts: colorectal, head and neck, non-small cell lung, ovarian, and prostate cancers.

For the Phase 1 Chemotherapy Combination study, Stage 1, which is evaluating SRA737 in combination with gemcitabine and cisplatin, has concluded enrolment and the study has transitioned to Stage 2. This stage is seeking to establish the safety profile, determine the MTD and to propose a recommended dose for further development of SRA737 in combination with low-dose gemcitabine. Once an MTD and dosing schedule have been determined, the study will also evaluate the preliminary efficacy of SRA737 in combination with low-dose gemcitabine in indication-specific cohorts of prospectively-selected, genetically-defined subjects with bladder or pancreatic cancer. 

"In addition to advancing our novel synthetic lethality-oriented monotherapy study, we are also excited by the potential for SRA737 to combine synergistically with other agents. Gemcitabine is a potent inducer of replication stress and DNA damage via multiple mechanisms, and represents a rational drug combination for SRA737, given Chk1's fundamental biological role in responding to such stressors. Our preclinical modeling demonstrates robust synergistic anti-tumor activity of SRA737 in combination with low-dose gemcitabine," added Dr. Nick Glover, President and CEO of Sierra Oncology. "We expect to accrue a solid understanding of dose, schedule, pharmacodynamic and pharmacokinetic parameters for SRA737 from these two studies, and the data observed to date are encouraging and consistent with our preclinical research. Our SRA737 development program remains on track and we expect to provide an update from these studies, including potential preliminary activity data, in early 2018."

About SRA737
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 a 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.

Profound mechanistic potentiation has also been reported when Chk1 inhibition is combined with DNA damaging cytotoxic agents or radiation. The widely-used chemotherapy gemcitabine is a strong exogenous inducer of replication stress and preclinical modeling demonstrates robust synergistic anti-tumor activity for SRA737 potentiated by gemcitabine.

SRA737 was discovered and initially developed at the Cancer Research UK (CRUK) Cancer Therapeutics Unit at the Institute of Cancer Research (ICR).

About the SRA737 Monotherapy Trial Design
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. Subjects with colorectal, head and neck, non-small cell lung, ovarian, and prostate cancer will be selected based on prospective, tumor tissue genetic profiling using Next Generation Screening (NGS) and must have tumors that harbor a minimum of two genomic alterations hypothesized to confer sensitivity to Chk1 inhibition. The Dose Escalation Phase will continue concurrently until the MTD and Recommended Phase 2 Dose are identified.

About the SRA737 Chemotherapy Combination Trial Design 
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 NGS.

About the SRA737 ASCO 2017 Poster Presentations
Two "Trials in Progress" posters describing the innovative Phase 1 clinical designs for SRA737 are being presented today at the 2017 ASCO Annual Meeting. The posters are available on the company's website at www.sierraoncology.com

SRA737 Monotherapy Poster
Title: A phase I study of SRA737 (formerly known as CCT245737) administered orally in patients with advanced cancer.
Trials in Progress Abstract: #TPS2607
Poster: #93b
Poster Session: Developmental Therapeutics - Clinical Pharmacology and Experimental Therapeutics
Date and Time: Monday, June 5, 2017, 8:00 – 11:30am CT
Location: McCormick Place, Event room: Hall A, 2301 S King Dr., Chicago, Illinois

SRA737 Chemotherapy Combination Poster
Title: A phase I study of oral SRA737 (formerly CCT245737) given in combination with gemcitabine plus cisplatin or gemcitabine alone in patients with advanced cancer.
Trials in Progress Abstract: #TPS2613
Poster: #96b
Poster Session: Developmental Therapeutics - Clinical Pharmacology and Experimental Therapeutics
Date and Time: Monday, June 5, 2017, 8:00 – 11:30am CT
Location: McCormick Place, Event room: Hall A, 2301 S King Dr., Chicago, Illinois

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. 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, trial designs, target indications, timing of updated data, expectations from current data 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