Ignite Creation Date:
2024-05-06 @ 8:40 AM
Last Modification Date:
2024-10-26 @ 12:03 PM
Study NCT ID:
NCT02797964
Status:
COMPLETED
Last Update Posted:
2023-06-18
First Post:
2016-05-23
Brief Title:
A Phase 12 Trial of SRA737 in Subjects With Advanced Cancer
Sponsor:
Sierra Oncology LLC - a GSK company
Organization:
Sierra Oncology LLC - a GSK company
Study Overview
Official Title:
A Phase 12 Trial of SRA737 a Chk1 Inhibitor Administered Orally in Subjects With Advanced Cancer
Status:
COMPLETED
Status Verified Date:
2023-06
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
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
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 eg CCNE1 or MYC genetic mutations in DNA repair machinery eg BRCA1 or FANCA genetic mutations leading to a dysregulated cell cycle eg 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 SRA737s 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 subjects tumor must have a confirmed combination of mutations which are expected to confer sensitivity to Chk1 inhibition determined by the Sponsors 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 andor high microsatellite instability
Key tumor suppressor genes regulating G1 cell cycle progressionarrest 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 functionamplification of CHEK1 ATR or other related genes
Tumor genetics will be prospectively determined using Next-Generation Sequencing
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 SRA737s 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 subjects tumor must have a confirmed combination of mutations which are expected to confer sensitivity to Chk1 inhibition determined by the Sponsors 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 andor high microsatellite instability
Key tumor suppressor genes regulating G1 cell cycle progressionarrest 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 functionamplification of CHEK1 ATR or other related genes
Tumor genetics will be prospectively determined using Next-Generation Sequencing
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None