Ignite Creation Date:
2024-05-06 @ 8:41 AM
Last Modification Date:
2024-10-26 @ 12:03 PM
Study NCT ID:
NCT02797977
Status:
COMPLETED
Last Update Posted:
2023-06-22
First Post:
2016-05-23
Brief Title:
A Phase 12 Trial SRA737 in Combination With Gemcitabine and Cisplatin or Gemcitabine Alone in Advanced Cancer Subjects
Sponsor:
Sierra Oncology LLC - a GSK company
Organization:
Sierra Oncology LLC - a GSK company
Study Overview
Official Title:
A Phase 12 Trial of Oral SRA737 a Chk1 Inhibitor Given in Combination With Gemcitabine Plus Cisplatin or Gemcitabine Alone in Subjects With Advanced Cancer
Status:
COMPLETED
Status Verified Date:
2022-06
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 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 have predicted sensitivity to Chk1 inhibition based on factors including genetic profiling of tumor tissue or ctDNA HPV status and germline BRCA1 and BRCA2 gene status Specific cancer indications that frequently feature these factors 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
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
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 FA 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
The critical role of Chk1 in mediating cellular responses to RS affords the opportunity to combine SRA737 with sub-therapeutic concentrations of the RS-inducing agent gemcitabine Low concentrations of gemcitabine cause a prolonged cell cycle S-phase and induce hallmarks of RS without inducing overt cytotoxicity Gemcitabine profoundly depletes DNA replication building blocks and targets proliferating cells by inducing RS through induction of stalled replication forks In response Chk1 has an important role in stabilizing and preserving replication fork complexes in the context of RS preventing catastrophic replication fork collapse and double strand breaks Extensive preclinical data as well as clinical data support the synergistic interaction between Chk1 inhibition and gemcitabine
The purpose of this clinical study is to establish the safety profile determine the MTD and propose a RP2D and schedule for SRA737 in combination with low dose gemcitabine In addition the study aims to evaluate the preliminary efficacy of SRA737 in combination with low dose gemcitabine in prospectively-selected subjects with tumors that have predicted sensitivity to Chk1 inhibition
This clinical study consists of three phases
1 A Standard-Dose Triplet Combo Dose Escalation Phase 1 This phase which has concluded evaluated a triplet combination of SRA737 with standard-dose gemcitabine and cisplatin in subjects with solid tumors
2 A Low-Dose Gemcitabine Combo Dose Escalation Phase 1 Cohorts of 3 to 6 subjects are being given escalating doses of SRA737 on an intermittent schedule in addition to low dose gemcitabine until the combination MTD is reached The dose or frequency of gemcitabine may also be reduced during this process and alternative dosing schedules for SRA737 may be considered When the MTD or a minimum efficacious dose range has been achieved for SRA737 or when evidence of anti-tumor activity is observed the gemcitabine dose may be escalated with corresponding decreases in the SRA737 dose as necessary for safety
3 A Low-Dose Gemcitabine Combo Cohort Expansion Phase 2 After the MTD andor RP2D has been identified the trial will explore the preliminary efficacy of SRA737 plus low dose gemcitabine 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 Enrollment for expansion cohorts may alternatively begin prior to the completion of dose escalation and determination of MTD or RP2D if there is evidence of anti-tumor activity or if the minimal plasma concentration of SRA737 is maintained above a threshold at which sustained Chk1 inhibition is anticipated at 24 hours after dosing
This phase is targeting enrollment of genetically-selected patients into four expansion cohorts from specific indications that are predicted to have a high prevalence of such alterations including locally advanced or metastatic
high-grade serous ovarian cancer HGSOC
small cell lung cancer SCLC
soft tissue sarcoma STS and
cervicalanogenital cancer
To qualify for enrolment into these cohorts the subjects tumor must have evidence of predicted sensitivity to Chk1 inhibition based on factors including
For subjects with HGSOC documented somatic or germline BRCA1 and BRCA2 wild-type status will confer eligibility without requirement for prospective genetic profiling If documented BRCA status is not available genetic profiling may be performed prospectively to determine eligibility
Subjects with SCLC are eligible without requirement for prospective genetic profiling on the basis of very high prevalence of cancer related alterations in the tumor suppressor genes eg TP53 and RB1 in this population
For subjects with STS and any others for whom genetic profiling is performed prospectively eligibility will be determined by the sponsors review of genetic abnormalities detected in genes in the following categories
Key tumor suppressor genes regulating G1 cell cycle progressionarrest such as RB1 TP53 etc
The DNA damage response pathway including ATM BRCA1 BRCA2 mismatch repair genetic alterations andor high microsatellite instability
Genetic indicators of replicative stress such as gain of functionamplification of Chk1 or ATR or other related gene
Oncogenic drivers such as MYC CCNE1 etc
For subjects with anogenital cancer known HPV positive status will confer eligibility without requirement for prospective genetic profiling If HPV status is not known or not positive genetic profiling or HPV testing where appropriate may be performed prospectively to determine eligibility Subjects with cervical cancer or squamous cell carcinoma of the anus are eligible without requirement for prospective genetic profiling based on the very high prevalence of HPV positivity in these populations
Tumor genetics will be determine using Next-Generation Sequencing
The critical role of Chk1 in mediating cellular responses to RS affords the opportunity to combine SRA737 with sub-therapeutic concentrations of the RS-inducing agent gemcitabine Low concentrations of gemcitabine cause a prolonged cell cycle S-phase and induce hallmarks of RS without inducing overt cytotoxicity Gemcitabine profoundly depletes DNA replication building blocks and targets proliferating cells by inducing RS through induction of stalled replication forks In response Chk1 has an important role in stabilizing and preserving replication fork complexes in the context of RS preventing catastrophic replication fork collapse and double strand breaks Extensive preclinical data as well as clinical data support the synergistic interaction between Chk1 inhibition and gemcitabine
The purpose of this clinical study is to establish the safety profile determine the MTD and propose a RP2D and schedule for SRA737 in combination with low dose gemcitabine In addition the study aims to evaluate the preliminary efficacy of SRA737 in combination with low dose gemcitabine in prospectively-selected subjects with tumors that have predicted sensitivity to Chk1 inhibition
This clinical study consists of three phases
1 A Standard-Dose Triplet Combo Dose Escalation Phase 1 This phase which has concluded evaluated a triplet combination of SRA737 with standard-dose gemcitabine and cisplatin in subjects with solid tumors
2 A Low-Dose Gemcitabine Combo Dose Escalation Phase 1 Cohorts of 3 to 6 subjects are being given escalating doses of SRA737 on an intermittent schedule in addition to low dose gemcitabine until the combination MTD is reached The dose or frequency of gemcitabine may also be reduced during this process and alternative dosing schedules for SRA737 may be considered When the MTD or a minimum efficacious dose range has been achieved for SRA737 or when evidence of anti-tumor activity is observed the gemcitabine dose may be escalated with corresponding decreases in the SRA737 dose as necessary for safety
3 A Low-Dose Gemcitabine Combo Cohort Expansion Phase 2 After the MTD andor RP2D has been identified the trial will explore the preliminary efficacy of SRA737 plus low dose gemcitabine 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 Enrollment for expansion cohorts may alternatively begin prior to the completion of dose escalation and determination of MTD or RP2D if there is evidence of anti-tumor activity or if the minimal plasma concentration of SRA737 is maintained above a threshold at which sustained Chk1 inhibition is anticipated at 24 hours after dosing
This phase is targeting enrollment of genetically-selected patients into four expansion cohorts from specific indications that are predicted to have a high prevalence of such alterations including locally advanced or metastatic
high-grade serous ovarian cancer HGSOC
small cell lung cancer SCLC
soft tissue sarcoma STS and
cervicalanogenital cancer
To qualify for enrolment into these cohorts the subjects tumor must have evidence of predicted sensitivity to Chk1 inhibition based on factors including
For subjects with HGSOC documented somatic or germline BRCA1 and BRCA2 wild-type status will confer eligibility without requirement for prospective genetic profiling If documented BRCA status is not available genetic profiling may be performed prospectively to determine eligibility
Subjects with SCLC are eligible without requirement for prospective genetic profiling on the basis of very high prevalence of cancer related alterations in the tumor suppressor genes eg TP53 and RB1 in this population
For subjects with STS and any others for whom genetic profiling is performed prospectively eligibility will be determined by the sponsors review of genetic abnormalities detected in genes in the following categories
Key tumor suppressor genes regulating G1 cell cycle progressionarrest such as RB1 TP53 etc
The DNA damage response pathway including ATM BRCA1 BRCA2 mismatch repair genetic alterations andor high microsatellite instability
Genetic indicators of replicative stress such as gain of functionamplification of Chk1 or ATR or other related gene
Oncogenic drivers such as MYC CCNE1 etc
For subjects with anogenital cancer known HPV positive status will confer eligibility without requirement for prospective genetic profiling If HPV status is not known or not positive genetic profiling or HPV testing where appropriate may be performed prospectively to determine eligibility Subjects with cervical cancer or squamous cell carcinoma of the anus are eligible without requirement for prospective genetic profiling based on the very high prevalence of HPV positivity in these populations
Tumor genetics will be determine 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