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A Phase 1/2 Trial of SRA737 in Subjects With Advanced Cancer

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ClinicalTrials.gov Identifier: NCT02797964
Recruitment Status : Recruiting
First Posted : June 14, 2016
Last Update Posted : June 8, 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 and schedule of SRA737; and to evaluate the efficacy of SRA737 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.

Condition or disease Intervention/treatment Phase
Advanced Solid Tumors or Non-Hodgkin's Lymphoma (NHL) Drug: SRA737 Phase 1 Phase 2

Detailed Description:

SRA737 is a potent, highly selective, orally bioavailable small molecule inhibitor of Chk1, a key regulator of cell cycle progression and the DNA Damage Response (DDR) replication stress response. In cancer cells, intrinsic replication stress (RS) is induced by factors such as oncogenes (e.g., CCNE1 or MYC), genetic mutations in DNA repair machinery (e.g. BRCA1 or FANCA), genetic mutations leading to a dysregulated cell cycle (e.g., TP53 or RAD50) or other genomic alterations. This replication stress 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 cancer cells with elevated intrinsic RS.

This study has been designed to: establish the safety profile; determine the pharmacokinetic profile; identify the optimal dose, schedule, and MTD; obtain preliminary evidence of activity; and evaluate SRA737's efficacy in prospectively-selected subjects with tumors that harbor genomic alterations linked to increased replication stress and that are hypothesized to be more sensitive to Chk1 inhibition via synthetic lethality.

This clinical study consists of two phases, a Dose Escalation Phase 1 portion and a Cohort Expansion Phase 2 portion.

In the Dose Escalation Phase 1 portion, 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 Cohort Expansion Phase 2 portion, subjects with genetically-defined tumors that harbor genomic alterations linked to increased replication stress and that are hypothesized to be more sensitive to Chk1 inhibition will be prospectively enrolled into six indication-specific cohorts to explore the preliminary efficacy of SRA737. Subjects must have advanced or metastatic disease of one of the following types:

  • castration-resistant prostate cancer (mCRPC);
  • high grade serous ovarian cancer (HGSOC) without CCNE1 gene amplification;
  • HGSOC with CCNE1 gene amplification (or alternative genetic alteration with similar functional effect);
  • non-small cell lung cancer (NSCLC);
  • head and neck squamous cell carcinoma (HNSCC) or squamous cell carcinoma of the anus (SCCA); and
  • colorectal cancer (mCRC).

To qualify for enrolment in the Cohort Expansion Phase 2 portion, the subject's tumor must have a confirmed combination of mutations which are expected to confer sensitivity to Chk1 inhibition, determined by the Sponsor's review of genetic abnormalities detected in the following categories:

  • Oncogenic drivers such as CCNE1 or MYC, etc.
  • Genes involved in the DNA repair process including BRCA1, BRCA2, FANC genes, mismatch repair (MMR) genetic alterations and/or high microsatellite instability.
  • Key tumor suppressor genes regulating G1 cell cycle progression/arrest such as TP53, RAD50, etc. For patients with HNSCC or SCCA, positive human papilloma virus (HPV) status is also considered for eligibility.
  • Genetic indicators of replicative stress such as gain of function/amplification of CHEK1, ATR or other related genes.

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


Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 170 participants
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 1/2 Trial of SRA737 (a Chk1 Inhibitor) Administered Orally in Subjects With Advanced Cancer
Actual Study Start Date : July 2016
Estimated Primary Completion Date : September 2019
Estimated Study Completion Date : April 2020


Arm Intervention/treatment
Experimental: Open label Drug: SRA737
SRA737 will be administered orally on each day of a 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

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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 Only: 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 (CRC)
    • Platinum-resistant or intolerant High Grade Serious Ovarian Cancer (HGSOC)
    • Advanced Non-Small Cell Lung Cancer (NSCLC)
    • Metastatic Castration-Resistant Prostate Cancer (mCRPC)
    • Head and Neck Squamous Cell Carcinoma (HNSCC) or squamous cell carcinoma of the anus (SCCA).
    • 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 any 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 harbors a combination of mutations which 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:

    • Oncogenic drivers such as MYC, CCNE1, etc.
    • Key tumor suppressor genes regulating G1 cell cycle progression/arrest such as RAD50, TP53, etc. For patients with NHSCC or SCCA, positive HPV status is also considered for eligibility.
    • The DDR pathway including BRCA1, BRCA2 and FANC. For patients with CRC, MMR genetic alterations and/or high microsatellite instability are also considered for eligibility.
    • Genetic indicators of replicative stress such as gain of function/amplification of Chk1 or ATR or other related 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
    • Any prior treatment with a Chk1 inhibitor or prior treatment with an ATR inhibitor within 6 months prior to receiving SRA737
  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 Cohort 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 gastrointestinal (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 ClinicalTrials.gov identifier (NCT number): 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         
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       Robert.Hugh.Jones@wales.nhs.uk   
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       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: NCT02797964     History of Changes
Other Study ID Numbers: SRA737-01
First Posted: June 14, 2016    Key Record Dates
Last Update Posted: June 8, 2018
Last Verified: June 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
Metastatic Colorectal Cancer
Platinum-Resistant or Intolerant High Grade Serious Ovarian Cancer
Advanced Non-Small Cell Lung Cancer
Metastatic Castration-Resistant Prostate Cancer
Head and Neck Squamous Cell Carcinoma
Squamous Cell Carcinoma of the Anus
Phase 1
Phase 2
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