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A Phase 1 Trial of SRA737 in Subjects With Advanced Cancer

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. Identifier: NCT02797964
Recruitment Status : Recruiting
First Posted : June 14, 2016
Last Update Posted : February 5, 2018
Information provided by (Responsible Party):
Sierra Oncology, Inc.

Brief Summary:

The study drug, SRA737, is a highly selective, orally bioavailable small molecule inhibitor of checkpoint kinase 1 (Chk1). Chk1 is a serine-threonine kinase which acts as a central regulator of the DNA Damage Response (DDR) network. The DDR network is a complex series of pathways which detect DNA damage, pause the cell cycle, and repair damaged DNA. Chk1 regulates multiple cell-cycles phases, temporarily pausing the progression of cell replication and division allowing DNA repair processes to be undertaken. In addition, Chk1 directly activates several important downstream DDR proteins involved in the repair of damaged DNA.

The purpose of this clinical study is to determine the maximum tolerated dose (MTD) of SRA737, to assess its preliminary safety and activity, and to propose a recommended dose for subsequent clinical studies.

To determine potential selection strategies for further clinical development, the study will also evaluate the preliminary efficacy of SRA737 in prospectively-selected subjects with tumors identified to have genetic aberrations hypothesized to confer sensitivity to Chk1 inhibition. Specific cancer indications that frequently harbor these genetic mutations will be studied.

Condition or disease Intervention/treatment Phase
Advanced Solid Tumors or Non-Hodgkin's Lymphoma (NHL) Drug: SRA737 Phase 1

Detailed Description:

SRA737 is a 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 DNA Damage Response network. In cancer cells, replication stress induced by oncogenes (e.g., MYC and RAS) or genetic mutations in DNA repair machinery (e.g. BRCA1 and FA) combined with loss of function in tumor suppressors (e.g., TP53 and ATM) results in persistent DNA damage and genomic instability leading to an increased dependency on Chk1 for survival. Targeted inhibition of Chk1 by SRA737 may therefore be synthetically lethal to these cancer cells.

The study has been designed to investigate the safety and tolerability of SRA737; to determine the pharmacokinetics of SRA737; to identify the optimal dose, schedule, and maximum tolerated dose (MTD); to obtain preliminary evidence of activity; and to evaluate preliminary efficacy in prospectively-screened, genetically-selected subjects.

This clinical study consists of two phases, a Dose Escalation Phase and a Dose 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 3 to 6 subjects, and subsequent dose level cohorts will follow a rolling 6 design until the MTD has been identified.

In the parallel 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:

  • previously treated metastatic colorectal cancer;
  • platinum-resistant ovarian cancer;
  • metastatic castration-resistant prostate cancer;
  • advanced non-small cell lung cancer; and
  • head and neck squamous cell carcinoma.

To qualify for enrolment in the Expansion Phase, the subject's tumor must have a confirmed minimum of two different types of genetic abnormalities, including 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 response network 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.

Tumor genetics will be prospectively determined using Next-Generation Sequencing.

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 90 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 1 Trial of SRA737 (a Chk1 Inhibitor) Administered Orally in Subjects With Advanced Cancer
Actual Study Start Date : July 2016
Estimated Primary Completion Date : February 2019

Resource links provided by the National Library of Medicine

U.S. FDA Resources

Arm Intervention/treatment
Experimental: Open label Drug: SRA737
SRA737 will be administered orally once daily for each 28-day cycle. Subjects will receive a single dose of SRA737 between 4 to 7 days prior to starting the first cycle for PK profiling. Subjects can continue taking SRA737 if they are receiving clinical benefit and able to safely take the drug and follow the requirements of the study.

Primary Outcome Measures :
  1. Number of subjects with adverse events as assessed by CTCAE 4.03 [ Time Frame: Up to 30 days after last dose of SRA737 ]
  2. Maximum tolerated dose of SRA737 [ Time Frame: Cycle 1 (28 days) in the Dose Escalation Phase ]
  3. Recommended Phase 2 dose of SRA737 [ Time Frame: Up to 30 days after last dose of SRA737 ]
  4. Objective response rate of SRA737 [ Time Frame: From date of first dose until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 32 months ]

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Key Inclusion Criteria:

  1. Any locally advanced or metastatic, histologically or cytologically proven solid tumor or NHL, relapsed after or progressing despite conventional treatment
  2. Life expectancy of at least 12 weeks
  3. World Health Organization (WHO) performance status of 0-1
  4. Must meet select hematological and biochemical laboratory indices
  5. Archival tumor tissue or accessible tumor and willingness to consent to a biopsy

Expansion Only:

  1. Any locally advanced or metastatic malignancy of the following types for which no other conventional therapy is considered appropriate:

    • Metastatic Colorectal Cancer
    • Platinum-Resistant Ovarian Cancer
    • Advanced Non-Small Cell Lung Cancer
    • Metastatic Castration-Resistant Prostate Cancer (mCRPC)
    • Head and Neck Squamous Cell Carcinoma (HNSCC)
    • Eligibility may be further restricted by the select number of prior regimens specific to each indication
  2. Measurable disease per RECIST v1.1, or for mCRPC, evaluable disease per one 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
  3. Tumor tissue or ctDNA evidence that subject's tumor has:

    • a deleterious mutation in a key tumor suppressor gene regulating G1 cell cycle progression/arrest (Note: Not required for HNSCC subjects who are HPV positive.) AND at least one of the following (Note: Not required for CRC subjects with high microsatellite instability who also have evidence of a deleterious mutation in a key tumor suppressor gene):
    • Deleterious mutation in the DNA damage response pathway
    • Genetic indicator of replicative stress defined as gain of function/amplification of Chk1 or ATR or other related gene
    • Gain of function mutation/amplification of an oncogenic driver

Key Exclusion Criteria:

  1. Received the following prior or current anticancer therapy:

    • Radiotherapy within the last 6 weeks
    • Endocrine therapy during the previous 4 weeks
    • Chemotherapy during the previous 4 weeks
    • Immunotherapy during the previous 6 weeks
    • Nitrosoureas or Mitomycin C during the previous 6 weeks
    • Other Investigational Medicinal Product during the 4 weeks before treatment
    • Prior treatment with a Chk1 or ATR inhibitor
  2. Other malignancy within the past 2 years, except for adequately treated tumors
  3. Ongoing toxic manifestations of previous treatments greater than NCI-CTCAE Grade 1
  4. For Dose Escalation: new or progressing brain metastases. For Dose Expansion: present or prior brain metastases
  5. High medical risk because of nonmalignant systemic disease
  6. Serologically positive for hepatitis B, hepatitis C or HIV
  7. Serious cardiac condition, left ventricular ejection fraction < 45% at baseline, history of cardiac ischemia within the past 6 months, or prior history of cardiac arrhythmia requiring treatment
  8. Prior bone marrow transplant or extensive radiotherapy to greater than 25% of bone marrow within 8 weeks
  9. Peanut allergy
  10. QTcF> 450 msec in adult males and > 470 msec in adult females
  11. Impairment of GI function or GI disease that may significantly alter the absorption of SRA737
  12. Inability to swallow capsules without chewing or crushing
  13. Is a participant or plans to participate in another interventional clinical trial
  14. Any other condition which in the Investigator's opinion would not make the subject a good candidate

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT02797964

Contact: Ines Verdon, MD 001-415-309-4051
Contact: Penny Nadolny 001-919-307-4039

United Kingdom
Royal Marsden Hospital Recruiting
Sutton, London, United Kingdom, SM2 5PT
Contact: Udai Banerji, MD   
Principal Investigator: Udai Banerji, MD         
Oxford University Hospitals Recruiting
Headington, Oxford, United Kingdom, OX3 7LE
Contact: Sarah Blagden         
Principal Investigator: Sarah Blagden         
Velindre Cancer Centre - Cardiff Recruiting
Cardiff, Whitchurch, United Kingdom, CF14 2TL
Contact: Rob Jones, MD   
Principal Investigator: Rob Jones, MD         
Western General Hospital Recruiting
Edinburgh, United Kingdom, EH4 2XU
Contact: Stefan Symeonides         
Principal Investigator: Stefan Symeonides         
The Beatson West of Scotland Cancer Centre Recruiting
Glasgow, United Kingdom, G12 0YN
Contact: Jeff Evans         
Principal Investigator: Jeff Evans         
University Hospitals of Leicester Recruiting
Leicester, United Kingdom, LE1 5WW
Contact: Harriet Walter         
Principal Investigator: Harriet Walter         
Guy's and St. Thomas Recruiting
London, United Kingdom, SE1 9RT
Contact: Debashis Sarker         
Principal Investigator: Debashis Sarker         
Sarah Cannon Research Institute Recruiting
London, United Kingdom, W1G 6AD
Contact: Hendrik-Tobias Arkenau         
Principal Investigator: Hendrik-Tobias Arkenau         
University College London Hospitals Recruiting
London, United Kingdom, W1T 7HA
Contact: Rebecca Kristeleit         
Principal Investigator: Rebecca Kristeleit         
The Christie Recruiting
Manchester, United Kingdom, M20 4BX
Contact: Louise Carter         
Principal Investigator: Louise Carter         
Freeman Hospital Recruiting
Newcastle upon Tyne, United Kingdom, NE7 7DN
Contact: Elizabeth R Plummer   
Principal Investigator: Elizabeth R Plummer, MD         
Sheffield Teaching Hospitals Recruiting
Sheffield, United Kingdom, S10 2SJ
Contact: Sarah Danson         
Principal Investigator: Sarah Danson         
Sponsors and Collaborators
Sierra Oncology, Inc.

Responsible Party: Sierra Oncology, Inc. Identifier: NCT02797964     History of Changes
Other Study ID Numbers: SRA737-01
First Posted: June 14, 2016    Key Record Dates
Last Update Posted: February 5, 2018
Last Verified: February 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Keywords provided by Sierra Oncology, Inc.:
Advanced solid tumors
Non-Hodgkin Lymphoma
Metastatic Colorectal Cancer
Platinum-Resistant Ovarian Cancer
Advanced Non-Small Cell Lung Cancer
Metastatic Castration-Resistant Prostate Cancer
Head and Neck Squamous Cell Carcinoma
Phase 1
Dose escalation
Chk1 Inhibitor
Checkpoint kinase 1
Synthetic lethality
Next-Generation Sequencing
Genetic biomarkers

Additional relevant MeSH terms:
Lymphoma, Non-Hodgkin
Neoplasms by Histologic Type
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases