A Phase 1 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 : May 9, 2017
The study drug, SRA737, is a highly selective, orally bioavailable small molecule inhibitor of checkpoint kinase 1 (Chk1). Chk1 is a serine-threonine kinase which acts as a central regulator of the DNA Damage Response (DDR) network. The DDR is a complex series of pathways which detect DNA damage, pause the cell cycle, and repair damaged DNA. Chk1 regulates multiple cell-cycle phases, temporarily pausing the progression of cell replication and division allowing DNA repair processes to be undertaken. In addition, Chk1 directly activates several important downstream DDR proteins involved in the repair of damaged DNA.
In addition, Chk1 is believed to facilitate tumor cell resistance to chemotherapy-induced DNA damage and, as such, the combination of SRA737 with DNA-damaging chemotherapies may provide synergistic anti-tumor activity, consistent with findings in preclinical oncology models.
The purpose of this clinical study is to establish the safety profile, determine the maximum tolerated dose (MTD) and to propose a recommended Phase 2 dose of SRA737 in combination with gemcitabine. To determine potential patient selection strategies for further clinical development, following MTD determination the study will also evaluate the preliminary efficacy of SRA737 in combination with gemcitabine in prospectively-selected subjects with tumors identified to have genetic aberrations hypothesized to confer sensitivity to Chk1 inhibition. Specific cancer indications that frequently harbor these genetic mutations will be studied.
|Condition or disease||Intervention/treatment||Phase|
|Advanced Solid Tumors||Drug: SRA737, gemcitabine, cisplatin Drug: SRA737, gemcitabine||Phase 1|
SRA737 is a highly selective, orally bioavailable small molecule inhibitor of Checkpoint kinase 1 (Chk1), a key regulator of important cell cycle checkpoints and central mediator of the DNA Damage Response network. In cancer cells, replication stress induced by oncogenes (e.g., MYC and RAS) or genetic mutations in DNA repair machinery (e.g. BRCA1 and FA) combined with loss of function in tumor suppressors (e.g., TP53 and ATM) results in persistent DNA damage and genomic instability leading to an increased dependency on Chk1 for survival. In addition, Chk1 is believed to facilitate tumor cell resistance to chemotherapy-induced DNA damage and, as such, the combination of SRA737 with DNA-damaging chemotherapies may provide synergistic anti-tumor activity, consistent with findings in preclinical oncology models.
The study has been designed to investigate the safety and tolerability of SRA737 in combination with gemcitabine; to determine the pharmacokinetics of SRA737 in combination with gemcitabine; to identify the optimal dose, schedule, and maximum tolerated dose (MTD) for the combination; to propose a recommended Phase 2 dose of SRA737 in combination with gemcitabine; to obtain preliminary evidence of activity in combination with gemcitabine; and to evaluate the preliminary efficacy of the combination in prospectively-screened, genetically-selected subjects.
This clinical study consists of two stages:
Stage 1, which has concluded enrollment, consists of a Dose Escalation Phase where subjects are given SRA737 in addition to gemcitabine and cisplatin.
Stage 2 consists of two phases, a Dose Escalation Phase and a Dose Expansion Phase, where subjects are given SRA737 in addition to gemcitabine. In the Dose Escalation Phase, cohorts of 3 to 6 subjects will be given escalating doses of SRA737 on an intermittent schedule in addition to gemcitabine until the combination MTD is reached. After the MTD has been identified, the trial will explore the preliminary efficacy of SRA737 plus gemcitabine in prospectively enrolled subjects with tumors that harbor genomic alterations hypothesized to confer sensitivity to Chk1 inhibition.
Qualifying patients will be enrolled into two indication-specific cohort expansions, bladder cancer and pancreatic cancer, as these indications are predicted to have a high prevalence of genetic aberrations hypothesized to confer sensitivity to Chk1 inhibition, and because gemcitabine is often an important component of the standard-of-care treatment for these indications.
To qualify for enrolment into these cohorts, the subject's tumor must have a confirmed minimum of two different types of genetic abnormalities, including 1) a deleterious mutation in a key tumor suppressor gene, such as TP53, and 2) at least one of the following:
- a loss of function or deleterious mutation in the DNA damage response pathway such as ATM, BRCA1, BRCA2, or other gene in the DNA damage response pathway implicated in Chk1 pathway sensitivity;
- a genetic indicator of replicative stress, defined as gain of function or amplification of CHEK1 or ATR or other related gene; or
- a gain of function mutation or amplification of an oncogenic driver such as MYC, RAS, or other gene implicated in Chk1 pathway sensitivity.
Tumor genetics will be determine using Next-Generation Sequencing.
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||65 participants|
|Intervention Model:||Parallel Assignment|
|Masking:||None (Open Label)|
|Official Title:||A Phase 1 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 :||April 2019|
Experimental: Stage 1
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: Stage 2
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|
- 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 administered in combination with gemcitabine [ Time Frame: Cycle 1 (28 days) in the Dose Escalation Phase ]
- Recommended Phase 2 dose of SRA737 in combination with gemcitabine [ Time Frame: Up to 30 days after last dose of SRA737 ]
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
|Contact: Ines Verdon, MDemail@example.com|
|Contact: Penny Nadolnyfirstname.lastname@example.org|
|Royal Marsden Hospital||Recruiting|
|Sutton, London, United Kingdom, SM2 5PT|
|Contact: Udai Banerji, MD Udai.Banerji@icr.ac.uk|
|Principal Investigator: Udai Banerji, MD|
|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|
|Newcastle upon Tyne, United Kingdom, NE7 7DN|
|Contact: Elizabeth R Plummer Ruth.Plummer@newcastle.ac.uk|
|Principal Investigator: Elizabeth R Plummer, MD|