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
|Condition or disease||Intervention/treatment||Phase|
|Advanced Solid Tumors or Non-Hodgkin's Lymphoma (NHL)||Drug: SRA737||Phase 1 Phase 2|
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)|
|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|
|Experimental: Open label||
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.
- 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 ]
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
|Contact: Ines Verdon, MDfirstname.lastname@example.org|
|Contact: Penny Nadolnyemail@example.com|
|Royal Marsden Hospital||Recruiting|
|Sutton, London, United Kingdom, SM2 5PT|
|Contact: Udai Banerji, MD Udai.Banerji@icr.ac.uk|
|Principal Investigator: Udai Banerji, MD|
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|Headington, Oxford, United Kingdom, OX3 7LE|
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|Velindre Cancer Centre - Cardiff||Recruiting|
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|The Beatson West of Scotland Cancer Centre||Recruiting|
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|University Hospitals of Leicester||Recruiting|
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|Guy's and St. Thomas||Recruiting|
|London, United Kingdom, SE1 9RT|
|Contact: Debashis Sarker|
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|Sarah Cannon Research Institute||Recruiting|
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|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|
|Manchester, United Kingdom, M20 4BX|
|Contact: Louise Carter|
|Principal Investigator: Louise Carter|
|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|