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A Phase 1/2 Trial of SRA737 in Combination With Gemcitabine Plus Cisplatin or Gemcitabine Alone in Subjects With Advanced Cancer

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ClinicalTrials.gov Identifier: NCT02797977
Recruitment Status : Recruiting
First Posted : June 14, 2016
Last Update Posted : November 15, 2018
Sponsor:
Information provided by (Responsible Party):
Sierra Oncology, Inc.

Brief Summary:

The purpose of this clinical study is to establish the safety profile, determine the maximum tolerated dose (MTD) and recommend a Phase 2 dose (RP2D) and schedule of SRA737 in combination with low dose gemcitabine; and to evaluate the efficacy of SRA737 in combination with low dose gemcitabine in prospectively-selected subjects with genetically-defined tumors that harbor genomic alterations linked to increased replication stress and that are hypothesized to be more sensitive to checkpoint kinase 1 (Chk1) inhibition via synthetic lethality. Specific cancer indications that frequently harbor these genetic mutations will be studied.

Preclinical and clinical data support the hypothesis that active doses of SRA737 may be strongly potentiated by sub-therapeutic doses of gemcitabine, which should lead to clinical efficacy. To test this hypothesis, SRA737 in combination with low dose gemcitabine is being explored in this study.


Condition or disease Intervention/treatment Phase
Advanced Solid Tumors Drug: SRA737, gemcitabine, cisplatin Drug: SRA737, gemcitabine Phase 1 Phase 2

  Show Detailed Description

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 140 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 1/2 Trial of Oral SRA737 (a Chk1 Inhibitor) Given in Combination With Gemcitabine Plus Cisplatin or Gemcitabine Alone in Subjects With Advanced Cancer
Actual Study Start Date : July 2016
Estimated Primary Completion Date : October 2019
Estimated Study Completion Date : June 2020


Arm Intervention/treatment
Experimental: Standard-Dose Triplet Combination
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: Low-Dose Gemcitabine Combination
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



Primary Outcome Measures :
  1. Number of subjects with adverse events as assessed by CTCAE4.03 [ Time Frame: Up to 30 days after last dose of SRA737 ]
  2. Maximum tolerated dose of SRA737 administered in combination with gemcitabine [ Time Frame: Cycle 1 (28 days) in the Dose Escalation Phase ]
  3. Recommended Phase 2 dose of SRA737 in combination with gemcitabine. [ Time Frame: Up to 30 days after last dose of SRA737 ]


Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
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 cytologically proven advanced malignancy of the following types, for which no other conventional therapy is considered appropriate:

    • Urothelial carcinoma
    • Small cell lung cancer
    • Soft tissue sarcoma
    • Cervical/anogenital cancer.
  2. Measurable disease per RECIST v1.1
  3. Tumor tissue or ctDNA evidence that their tumor has tumor tissue or ctDNA evidence that their tumor harbors one or more mutations that are expected to confer sensitivity to Chk1 inhibition. Eligibility will be determined by the sponsor's review of genetic abnormalities detected in genes in the following categories:

    • Key tumor suppressor genes regulating G1 cell cycle progression/arrest such as RB1, TP53, etc. For relevant cancers, positive human papilloma virus (HPV) status is also considered for eligibility.
    • The DNA damage response pathway including ATM, BRCA1, BRCA2, mismatch repair genetic alterations and/or high microsatellite instability.
    • Genetic indicators of replicative stress such as gain of function/amplification of Chk1 or ATR or other related genes.
    • Oncogenic drivers such as MYC, KRAS, etc.

Key Exclusion Criteria:

  1. Received the following prior or current anticancer therapy in the timeframes noted prior to receiving SRA737:

    • Radiotherapy during the previous 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 previous 4 weeks
    • Prior treatment with a Chk1 inhibitor at any point or ATR inhibitor within 6 months
  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. New or progressing brain metastases. Subjects with brain metastases that have been asymptomatic and radiologically stable over an 8-week period and have not been treated with steroids during that time may be included with approval from the sponsor.
  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 the previous 8 weeks
  12. Peanut allergy
  13. QTcF > 450 msec in adult makes and > 470 msec in adult females
  14. Impairment of gastrointestinal (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

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: Sylvie Arbour 001-514-558-2581 sarbour@sierraoncology.com

Locations
Spain
Hospital Universitario Vall d'Hebron Recruiting
Barcelona, Spain, 08035
Contact: Elena Garralda       egarralda@vhio.net   
Principal Investigator: Elena Garralda         
Hospital Clinic de Barcelona Recruiting
Barcelona, Spain, 08036
Contact: Javier Garcia Corbacho         
Principal Investigator: Javier Garcia Corbacho         
START Madrid Recruiting
Madrid, Spain, 28040
Contact: Victor Moreno       victor.moreno@start.stoh.com   
Principal Investigator: Victor Moreno         
Hospital Universitario 12 de Octobre Recruiting
Madrid, Spain, 28041
Contact: Daniel Castellano         
Principal Investigator: Daniel Castellano         
Hospital Universitario Virgen de la Victoria Recruiting
Málaga, Spain, 29010
Contact: Begona Jimenez Rodrigues         
Principal Investigator: Begona Jimenez Rodrigues         
Biomedical Research Institute INCLIVA Recruiting
Valencia, Spain, 46010
Contact: Desamparados Roda Perez         
Principal Investigator: Desamparados Roda Perez         
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         
Belfast City Hospital Recruiting
Belfast, Northern Ireland, United Kingdom, BT9 7AB
Contact: Melanie Morris    02890638468    melanie.morris@belfasttrust.hscni.net   
Principal Investigator: Vicky Coyle         
Oxford University Hospitals Recruiting
Headington, Oxford, United Kingdom, OX3 7LE
Contact: Sarah Blagden         
Principal Investigator: Sarah Blagden         
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         
The Clatterbridge Cancer Centre Recruiting
Bebington, Wirral, United Kingdom, CH63 4JY
Contact: Daniel Palmer         
Principal Investigator: Daniel Palmer         
The Beatson West of Scotland Cancer Centre Recruiting
Glasgow, United Kingdom, G12 0YN
Contact: Patricia Roxburgh, MD       p.roxburgh@beatson.gla.ac.uk   
Principal Investigator: Patricia Roxburgh, MD         
Leeds Teaching Hospital of St James University Hospital Recruiting
Leeds, United Kingdom, LS9 7TF
Contact: David A Anthoney         
Principal Investigator: David A Anthoney         
University Hospital of Leceister NHS TRUST Recruiting
Leicester, United Kingdom, LE1 5WW
Contact: Harriet Walter       hw191@le.ac.uk   
Principal Investigator: Harriet Walter         
Guy's and St Thomas' Recruiting
London, United Kingdom, SE1 9RT
Contact: Debashis Sarker       debashis.sarker@kcl.ac.uk   
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 Recruiting
London, United Kingdom, WC1E 6BT
Contact: Rebecca Kristeleit       r.kristeleit@ucl.ac.uk   
Principal Investigator: Rebecca Kristeleit         
The Christie NHS Foundation Trust Recruiting
Manchester, United Kingdom, M20 4BX
Contact: Louise Carter       louise.carter@christie.nhs.uk   
Principal Investigator: Louise Carter         
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         
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.
ClinicalTrials.gov Identifier: NCT02797977     History of Changes
Other Study ID Numbers: SRA737-02
First Posted: June 14, 2016    Key Record Dates
Last Update Posted: November 15, 2018
Last Verified: November 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Keywords provided by Sierra Oncology, Inc.:
Replication Stress
Advanced solid tumors
CCNE1
TP53
BRCA1
BRCA2
MYC
RAD50
Fanconi anemia
Cell Cycle
Urothelial carcinoma
Small cell lung cancer
Soft tissue sarcoma
Cervical/anogenital cancer
Phase 1
Phase 2
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