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A Phase 1 Trial of SRA737 in Combination With Gemcitabine Plus Cisplatin or Gemcitabine Alone in Subjects With Advanced Cancer

This study is currently recruiting participants.
Verified May 2017 by Sierra Oncology, Inc.
Sponsor:
ClinicalTrials.gov Identifier:
NCT02797977
First Posted: June 14, 2016
Last Update Posted: May 9, 2017
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.
Information provided by (Responsible Party):
Sierra Oncology, Inc.
  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 is a complex series of pathways which detect DNA damage, pause the cell cycle, and repair damaged DNA. Chk1 regulates multiple cell-cycle 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.

In addition, Chk1 is believed to facilitate tumor cell resistance to chemotherapy-induced DNA damage and, as such, the combination of SRA737 with DNA-damaging chemotherapies may provide synergistic anti-tumor activity, consistent with findings in preclinical oncology models.

The purpose of this clinical study is to establish the safety profile, determine the maximum tolerated dose (MTD) and to propose a recommended Phase 2 dose of SRA737 in combination with gemcitabine. To determine potential patient selection strategies for further clinical development, following MTD determination the study will also evaluate the preliminary efficacy of SRA737 in combination with gemcitabine 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 Drug: SRA737, gemcitabine, cisplatin Drug: SRA737, gemcitabine Phase 1

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 1 Trial of Oral SRA737 (a Chk1 Inhibitor) Given in Combination With Gemcitabine Plus Cisplatin or Gemcitabine Alone 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 administered in combination with gemcitabine [ Time Frame: Cycle 1 (28 days) in the Dose Escalation Phase ]
  • Recommended Phase 2 dose of SRA737 in combination with gemcitabine [ Time Frame: Up to 30 days after last dose of SRA737 ]

Estimated Enrollment: 65
Actual Study Start Date: July 2016
Estimated Primary Completion Date: April 2019 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Stage 1
SRA737 will be administered orally on Days 2, 3, 9, and 10 of each 21-day cycle. Subjects will receive a single dose of SRA737 between 4 to 7 days prior to starting the first cycle for PK profiling. Gemcitabine will be administered intravenously on Days 1 and 8 of each 21-day cycle. Cisplatin will be administered on Day 1 of each 21-day cycle. Subjects can continue taking the study treatment if they are safely receiving clinical benefit and able to follow the requirements of the study.
Drug: SRA737, gemcitabine, cisplatin
Experimental: Stage 2
SRA737 will be administered orally on Days 2, 3, 9, 10, 16, and 17 of each 28-day cycle. Subjects will receive a single dose of SRA737 between 4 to 7 days prior to starting the first cycle. Gemcitabine will be administered intravenously on Days 1, 8, and 15 of each 28-day cycle. Subjects can continue taking the study treatment if they are safely receiving clinical benefit and able to follow the requirements of the study.
Drug: SRA737, gemcitabine

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. In addition, Chk1 is believed to facilitate tumor cell resistance to chemotherapy-induced DNA damage and, as such, the combination of SRA737 with DNA-damaging chemotherapies may provide synergistic anti-tumor activity, consistent with findings in preclinical oncology models.

The study has been designed to investigate the safety and tolerability of SRA737 in combination with gemcitabine; to determine the pharmacokinetics of SRA737 in combination with gemcitabine; to identify the optimal dose, schedule, and maximum tolerated dose (MTD) for the combination; to propose a recommended Phase 2 dose of SRA737 in combination with gemcitabine; to obtain preliminary evidence of activity in combination with gemcitabine; and to evaluate the preliminary efficacy of the combination in prospectively-screened, genetically-selected subjects.

This clinical study consists 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, a Dose Escalation Phase and a Dose Expansion Phase, where subjects are given SRA737 in addition to gemcitabine. In the Dose Escalation Phase, cohorts of 3 to 6 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 trial 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, 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 pathway 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.

Tumor genetics will be determine using Next-Generation Sequencing.

  Eligibility

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
Criteria

Key Inclusion Criteria:

  1. For Dose Escalation: subjects with locally advanced or metastatic, histologically or cytologically proven solid tumor, 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. Histologically or cytolgically proven advanced malignancy of the following types, for which no other conventional therapy is considered appropriate:

    • Bladder Cancer
    • Unresectable Locally Advanced or Metastatic Pancreatic Cancer
  2. Measurable disease per RECIST v1.1
  3. Tumor tissue or ctDNA evidence that their tumor has a mutation in a key tumor suppressor gene regulating G1 cell cycle progression/arrest AND at least one of the following:

    • 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
    • Amplification of an oncogenic driver gene

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. No more than 3 previous lines of cytotoxic chemotherapy for metastatic disease
  3. Other malignancy within the past 2 years, except for adequately treated tumors
  4. If, in the opinion of the Investigator, the subject is highly likely to experience clinically significant myelosuppression
  5. Ongoing toxic manifestations of previous treatments greater than NCI-CTCAE Grade 1
  6. History of allergy to gemcitabine
  7. For Dose Escalation: new or progressing brain metastases. For Dose Expansion: present or prior brain metastases
  8. High medical risk because of nonmalignant systemic disease
  9. Serologically positive for hepatitis B, hepatitis C or HIV
  10. 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
  11. Prior bone marrow transplant or extensive radiotherapy to greater than 25% of bone marrow within 8 weeks
  12. Peanut allergy
  13. QTcF > 450 msec in adult makes and > 470 msec in adult females
  14. Impairment of GI function or GI disease that may significantly alter the absorption of SRA737
  15. Inability to swallow capsules without chewing or crushing
  16. Is a participant or plans to participate in another interventional clinical trial
  17. Any other condition which in the Investigator's opinion would not make the subject a good candidate
  Contacts and Locations
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 ClinicalTrials.gov identifier (NCT number): NCT02797977


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 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: NCT02797977     History of Changes
Other Study ID Numbers: SRA737-02
First Submitted: May 23, 2016
First Posted: June 14, 2016
Last Update Posted: May 9, 2017
Last Verified: May 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Keywords provided by Sierra Oncology, Inc.:
Advanced solid tumors
Bladder cancer
Pancreatic cancer
Phase 1
Dose escalation
Chk1 inhibitor
Checkpoint Kinase 1
Synthetic lethality
Next-Generation Sequencing
Genetic biomarkers

Additional relevant MeSH terms:
Gemcitabine
Cisplatin
Antineoplastic Agents
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antiviral Agents
Anti-Infective Agents
Enzyme Inhibitors
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs