TY - JOUR
T1 - A Phase 1/2 trial of SRA737 (a Chk1 inhibitor) administered orally in patients with advanced cancer
AU - Kristeleit, Rebecca
AU - Plummer, Ruth
AU - Jones, Robert
AU - Carter, Louise
AU - Blagden, Sarah
AU - Sarker, Debashis
AU - Arkenau, Tobias
AU - Evans, Thomas R.Jeffry
AU - Danson, Sarah
AU - Symeonides, Stefan N.
AU - Veal, Gareth J.
AU - Klencke, Barbara J.
AU - Kowalski, Mark M.
AU - Banerji, Udai
N1 - Funding Information:
Medical writing support was provided by Tina Ippolito, an independent consultant funded by Sierra Oncology. Andrew Dye, an employee of Sierra Oncology also provided medical writing support and data curation. Bryan Strouse, an employee of Sierra Oncology also contributed to data curation for this report. UK clinical trial sites acknowledge infrastructural funding from Experimental Cancer Medical Centres and National Institute of Health and Care Research Biomedical Research Centres. The Institute of Cancer Research, London, UK (ICR)/Royal Marsden Hospital (RMH) in addition acknowledge Cancer Research UK funding to Cancer Centre Funding and funding to the Cancer Therapeutics Unit. U. Banerji is a recipient of the NIHR RP-2016-07-028. Preliminary data presented at annual meeting of the American Society of Clinical Oncology (31-May to 04-June 2019, Chicago, Illinois, USA) in abstract 3094 entitled: A first-in-human Phase I/II trial of SRA737 (a Chk1 inhibitor) in subjects with advanced cancer [17].
Funding Information:
The trial was sponsored by Sierra Oncology, Inc.
Funding Information:
SRA737 was discovered in collaboration with The Institute of Cancer Research, London, UK (ICR). UB is an employee of ICR but does not receive royalties for discovery of SRA737. UB has spoken at Sierra Oncology and AVACTA advisory boards (non-remunerated) and has received honoraria from Pegasys, Boehringer Ingelheim, Idea Pharma, Novartis, and Karus Therapeutics unrelated to the presented work. He has received research funding from Avacta, Verastem Oncology, Chugai, Carrick Therapeutics, BTG, and Onyx all unrelated to this work. Evans is Clinical Subjects Editor, British Journal of Cancer. SB has received research funding from Nucana PLC, Astex, Incyte, Tesaro, Redx, MSD, Roche, UCB and consulting fees from Ellipses and Theolytics, unrelated to this work.
Funding Information:
Medical writing support was provided by Tina Ippolito, an independent consultant funded by Sierra Oncology. Andrew Dye, an employee of Sierra Oncology also provided medical writing support and data curation. Bryan Strouse, an employee of Sierra Oncology also contributed to data curation for this report. UK clinical trial sites acknowledge infrastructural funding from Experimental Cancer Medical Centres and National Institute of Health and Care Research Biomedical Research Centres. The Institute of Cancer Research, London, UK (ICR)/Royal Marsden Hospital (RMH) in addition acknowledge Cancer Research UK funding to Cancer Centre Funding and funding to the Cancer Therapeutics Unit. U. Banerji is a recipient of the NIHR RP-2016-07-028. Preliminary data presented at annual meeting of the American Society of Clinical Oncology (31-May to 04-June 2019, Chicago, Illinois, USA) in abstract 3094 entitled: A first-in-human Phase I/II trial of SRA737 (a Chk1 inhibitor) in subjects with advanced cancer [].
Publisher Copyright:
© 2023, The Author(s).
PY - 2023/7/27
Y1 - 2023/7/27
N2 - Background: This was a first-in-human Phase 1/2 open-label dose-escalation study of the novel checkpoint kinase 1 (Chk1) inhibitor SRA737. Methods: Patients with advanced solid tumours enrolled in dose-escalation cohorts and received SRA737 monotherapy orally on a continuous daily (QD) dosing schedule in 28-day cycles. Expansion cohorts included up to 20 patients with prospectively selected, pre-specified response predictive biomarkers. Results: In total, 107 patients were treated at dose levels from 20–1300 mg. The maximum tolerated dose (MTD) of SRA737 was 1000 mg QD, the recommended Phase 2 dose (RP2D) was 800 mg QD. Common toxicities of diarrhoea, nausea and vomiting were generally mild to moderate. Dose-limiting toxicity at daily doses of 1000 and 1300 mg QD SRA737 included gastrointestinal events, neutropenia and thrombocytopenia. Pharmacokinetic analysis at the 800 mg QD dose showed a mean C min of 312 ng/mL (546 nM), exceeding levels required to cause growth delay in xenograft models. No partial or complete responses were seen. Conclusions: SRA737 was well tolerated at doses that achieved preclinically relevant drug concentrations but single agent activity did not warrant further development as monotherapy. Given its mechanism of action resulting in abrogating DNA damage repair, further clinical development of SRA737 should be as combination therapy. Clinical trial registration: Clinicaltrials.gov NCT02797964.
AB - Background: This was a first-in-human Phase 1/2 open-label dose-escalation study of the novel checkpoint kinase 1 (Chk1) inhibitor SRA737. Methods: Patients with advanced solid tumours enrolled in dose-escalation cohorts and received SRA737 monotherapy orally on a continuous daily (QD) dosing schedule in 28-day cycles. Expansion cohorts included up to 20 patients with prospectively selected, pre-specified response predictive biomarkers. Results: In total, 107 patients were treated at dose levels from 20–1300 mg. The maximum tolerated dose (MTD) of SRA737 was 1000 mg QD, the recommended Phase 2 dose (RP2D) was 800 mg QD. Common toxicities of diarrhoea, nausea and vomiting were generally mild to moderate. Dose-limiting toxicity at daily doses of 1000 and 1300 mg QD SRA737 included gastrointestinal events, neutropenia and thrombocytopenia. Pharmacokinetic analysis at the 800 mg QD dose showed a mean C min of 312 ng/mL (546 nM), exceeding levels required to cause growth delay in xenograft models. No partial or complete responses were seen. Conclusions: SRA737 was well tolerated at doses that achieved preclinically relevant drug concentrations but single agent activity did not warrant further development as monotherapy. Given its mechanism of action resulting in abrogating DNA damage repair, further clinical development of SRA737 should be as combination therapy. Clinical trial registration: Clinicaltrials.gov NCT02797964.
UR - http://www.scopus.com/inward/record.url?scp=85153728002&partnerID=8YFLogxK
U2 - 10.1038/s41416-023-02279-x
DO - 10.1038/s41416-023-02279-x
M3 - Article
C2 - 37120671
AN - SCOPUS:85153728002
SN - 0007-0920
VL - 129
SP - 38
EP - 45
JO - British journal of cancer
JF - British journal of cancer
IS - 1
ER -