A Phase 1 Trial of SRA737 in Subjects With Advanced Cancer
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 network is a complex series of pathways which detect DNA damage, pause the cell cycle, and repair damaged DNA. Chk1 regulates multiple cell-cycles 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.
The purpose of this clinical study is to determine the maximum tolerated dose (MTD) of SRA737, to assess its preliminary safety and activity, and to propose a recommended dose for subsequent clinical studies.
To determine potential selection strategies for further clinical development, the study will also evaluate the preliminary efficacy of SRA737 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.
|Advanced Solid Tumors or Non-Hodgkin's Lymphoma (NHL)||Drug: SRA737||Phase 1|
|Study Design:||Intervention Model: Single Group Assignment
Masking: No masking
Primary Purpose: Treatment
|Official Title:||A Phase 1 Trial of SRA737 (a Chk1 Inhibitor) Administered Orally in Subjects With Advanced Cancer|
- 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 ]
|Actual Study Start Date:||July 2016|
|Estimated Primary Completion Date:||February 2019 (Final data collection date for primary outcome measure)|
|Experimental: Open label||
SRA737 will be administered orally once daily for each 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.
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. Targeted inhibition of Chk1 by SRA737 may therefore be synthetically lethal to these cancer cells.
The study has been designed to investigate the safety and tolerability of SRA737; to determine the pharmacokinetics of SRA737; to identify the optimal dose, schedule, and maximum tolerated dose (MTD); to obtain preliminary evidence of activity; and to evaluate preliminary efficacy in prospectively-screened, genetically-selected subjects.
This clinical study consists of two phases, a Dose Escalation Phase and a Dose Expansion Phase, being run concurrently.
In the Dose Escalation Phase, 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 parallel Expansion Phase, subjects with genetically-defined tumors that harbor genomic alterations hypothesized to confer sensitivity to checkpoint kinase 1 (Chk1) inhibition will be prospectively enrolled into several indication-specific cohorts to explore the preliminary efficacy of SRA737. These indications include:
- previously treated metastatic colorectal cancer;
- platinum-resistant ovarian cancer;
- metastatic castration-resistant prostate cancer;
- advanced non-small cell lung cancer; and
- head and neck squamous cell carcinoma.
To qualify for enrolment in the Expansion Phase, 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 network 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.
Colorectal cancer patients with high microsatellite instability are eligible if they also have evidence of a deleterious mutation in a key tumor suppressor gene. A deleterious mutation in a key tumor suppressor gene is not required for head and neck squamous cell carcinoma patients with HPV-positive disease.
Tumor genetics will be prospectively determined using Next-Generation Sequencing.
Please refer to this study by its ClinicalTrials.gov identifier: 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|
|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|
|Newcastle upon Tyne, United Kingdom, NE7 7DN|
|Contact: Elizabeth R Plummer Ruth.Plummer@newcastle.ac.uk|
|Principal Investigator: Elizabeth R Plummer, MD|