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A Phase 1 Trial of SRA737 in Subjects With Advanced Cancer

This study is currently recruiting participants.
See Contacts and Locations
Verified May 2017 by Sierra Oncology, Inc.
Sponsor:
Information provided by (Responsible Party):
Sierra Oncology, Inc.
ClinicalTrials.gov Identifier:
NCT02797964
First received: May 23, 2016
Last updated: May 25, 2017
Last verified: May 2017
  Purpose

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

Study Type: Interventional
Study Design: Intervention Model: Single Group Assignment
Masking: No masking
Primary Purpose: Treatment
Official Title: A Phase 1 Trial of SRA737 (a Chk1 Inhibitor) Administered Orally in Subjects With Advanced Cancer

Resource links provided by NLM:


Further study details as provided by Sierra Oncology, Inc.:

Primary Outcome Measures:
  • Number of subjects with adverse events as assessed by CTCAE 4.03 [ Time Frame: Up to 30 days after last dose of SRA737 ]
  • Maximum tolerated dose of SRA737 [ Time Frame: Cycle 1 (28 days) in the Dose Escalation Phase ]
  • Recommended Phase 2 dose of SRA737 [ Time Frame: Up to 30 days after last dose of SRA737 ]
  • 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 ]

Estimated Enrollment: 90
Actual Study Start Date: July 2016
Estimated Primary Completion Date: February 2019 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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.

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.

  Eligibility

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

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
  Contacts and Locations
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, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT02797964

Contacts
Contact: Ines Verdon, MD 001-415-309-4051 iverdon@sierraoncology.com
Contact: Penny Nadolny 001-919-307-4039 pnadolny@sierraoncology.com

Locations
United Kingdom
Royal Marsden Hospital Recruiting
Sutton, London, United Kingdom, SM2 5PT
Contact: Udai Banerji, MD       Udai.Banerji@icr.ac.uk   
Principal Investigator: Udai Banerji, MD         
Velindre Cancer Centre - Cardiff Recruiting
Cardiff, Whitchurch, United Kingdom, CF14 2TL
Contact: Rob Jones, MD       Robert.Hugh.Jones@wales.nhs.uk   
Principal Investigator: Rob Jones, MD         
Freeman Hospital Recruiting
Newcastle upon Tyne, United Kingdom, NE7 7DN
Contact: Elizabeth R Plummer       Ruth.Plummer@newcastle.ac.uk   
Principal Investigator: Elizabeth R Plummer, MD         
Sponsors and Collaborators
Sierra Oncology, Inc.
  More Information

Responsible Party: Sierra Oncology, Inc.
ClinicalTrials.gov Identifier: NCT02797964     History of Changes
Other Study ID Numbers: SRA737-01
Study First Received: May 23, 2016
Last Updated: May 25, 2017
Individual Participant Data  
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
Lymphoma
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases

ClinicalTrials.gov processed this record on June 26, 2017