Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Clinical Trial
. 2023 Jul;129(1):38-45.
doi: 10.1038/s41416-023-02279-x. Epub 2023 Apr 29.

A Phase 1/2 trial of SRA737 (a Chk1 inhibitor) administered orally in patients with advanced cancer

Rebecca Kristeleit  1 , Ruth Plummer  2 , Robert Jones  3 , Louise Carter  4 , Sarah Blagden  5 , Debashis Sarker  6 , Tobias Arkenau  7 , Thomas R Jeffry Evans  8 , Sarah Danson  9 , Stefan N Symeonides  10 , Gareth J Veal  11 , Barbara J Klencke  12 , Mark M Kowalski  12 , Udai Banerji  13
Affiliations
Clinical Trial

A Phase 1/2 trial of SRA737 (a Chk1 inhibitor) administered orally in patients with advanced cancer

Rebecca Kristeleit et al. Br J Cancer. 2023 Jul.

Abstract

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 Cmin 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.

PubMed Disclaimer

Conflict of interest statement

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.

Figures

Fig. 1
Fig. 1. SRA737 monotherapy study enrolment by dose level.
Patient numbers and tumour types enrolled in different cohorts in dose escalation and expansion phases of the study.
Fig. 2
Fig. 2. Single dose pharmacokinetic profile of SRA737.
Mean plasma concentrations of SRA737 across different dose levels over a 48 hour sampling window. Note: Error bars indicate ±1 standard deviation.
Fig. 3
Fig. 3. Clinical efficacy of SRA737.
A waterfall plot of change in size of tumours represented as percentage at baseline in patients treated on the expansion cohorts. The genomic profile of individual patients are shown on the chart below the waterfall plot.
See this image and copyright information in PMC

References

    1. Sanchez Y, Wong C, Thoma RS, Richman R, Wu Z, Piwnica-Worms H, et al. Conservation of the Chk1 checkpoint pathway in mammals: linkage of DNA damage to Cdk regulation through Cdc25. Science. 1997;277:1497–501. doi: 10.1126/science.277.5331.1497. - DOI - PubMed
    1. Pilie PG, Tang C, Mills GB, Yap TA. State-of-the-art strategies for targeting the DNA damage response in cancer. Nat Rev Clin Oncol. 2019;16:81–104. doi: 10.1038/s41571-018-0114-z. - DOI - PMC - PubMed
    1. Liu Q, Guntuku S, Cui XS, Matsuoka S, Cortez D, Tamai K, et al. Chk1 is an essential kinase that is regulated by Atr and required for the G(2)/M DNA damage checkpoint. Genes Dev. 2000;14:1448–59. doi: 10.1101/gad.14.12.1448. - DOI - PMC - PubMed
    1. Smith HL, Southgate H, Tweddle DA, Curtin NJ. DNA damage checkpoint kinases in cancer. Expert Rev Mol Med. 2020;22:e2. doi: 10.1017/erm.2020.3. - DOI - PubMed
    1. Osborne JD, Matthews TP, McHardy T, Proisy N, Cheung KM, Lainchbury M, et al. Multiparameter lead optimization to give an oral checkpoint kinase 1 (CHK1) inhibitor clinical candidate: (R)-5-((4-((morpholin-2-ylmethyl)amino)-5-(trifluoromethyl)pyridin-2-yl)amino)pyr azine-2-carbonitrile (CCT245737) J Med Chem. 2016;59:5221–37. doi: 10.1021/acs.jmedchem.5b01938. - DOI - PubMed

Publication types

MeSH terms

Substances

Associated data