See the published version of this preprint at Biomarker Research.
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Binghe Xu
National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College
Corresponding Author
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Background: SHR6390 is a novel inhibitor of cyclin-dependent kinase 4/6 which demonstrated promising anti-tumor potency in preclinical models. This first-in-human study was conducted to evaluate the tolerability, pharmacokinetics, safety, and preliminary antitumor activity of SHR6390 in patients with advanced breast cancer (ABC).
Methods: In this open-label, phase 1 study, patients who had failed standard therapy were enrolled to receive oral SHR6390 in 3 + 3 dose-escalation pattern at doses of 25−175 mg. Eligible patients were given a single-dose of SHR6390 in week 1, followed by once daily continuous doses for three weeks, and one week off in 28-day cycles. Based on the tolerability, pharmacokinetics, and activity data revealed from the dose-escalation phase, three dose cohorts were selected to expand to 8−10 patients. The primary endpoints were maximum tolerated dose (MTD) and pharmacokinetics.
Results: Between Apr 15, 2016 and Dec 21, 2018, 40 patients were enrolled; all were diagnosed of hormone receptor-positive and HER2-negative ABC. SHR6390 100 mg, 125 mg, and 150 mg cohorts were expanded to 10 patients. No dose limiting toxicity was observed and the MTD was not reached. Adverse events (AEs) of grade 3 or 4 were observed in 22 (55.0%) of 40 patients, being neutropenia (52.5%), leukopenia (35.0%), thrombocytopenia (5.0%), and hypertension (2.5%). No serious AEs were reported. At the doses of 50−175 mg, steady state areas under the concentration-time curve and peak concentration increased almost proportionally with dose. The disease control rate (DCR) was 62.5% (25/40, 95% CI: 45.8−77.3). Two patients (5%; 125 mg and 150 mg cohorts) achieved partial response, with responses lasting 169 and 356+ days, respectively. Among the three expansion cohorts, the 150 mg cohort had the numerically highest DCR of 80.0% (95% CI: 44.4‒97.5) and longest median progression-free survival of 8.4 months (95% CI: 2.1‒not reached).
Conclusions: SHR6390 showed acceptable safety profile and dose-dependent plasma exposure in patients with ABC. The recommended phase 2 dose was 150 mg. Preliminary evidence of clinical activity was observed, which warrants further validation.
Trial registration: ClinicalTrials.gov identifier: NCT02684266. Registered Feb 17, 2016. https://clinicaltrials.gov/ct2/show/NCT02684266.
Keywords
cyclin-dependent kinase 4/6 inhibitor, advanced breast cancer, first-in-human trial
This is a list of supplementary files associated with this preprint. Click to download.
- Supplementaryinformation.pdf
Additional file 1. Figure S1. Linear plot of concentration-time profile for SHR6390 by dose.
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View the published article at Biomarker Research.
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Reviewer #1 agreed
On 21 Dec, 2020
Reviewers invited
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Subject Areas
Cancer Biology
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See the published version of this preprint at Biomarker Research.
This is a preprint, a preliminary version of a manuscript that has not completed peer review at a journal. Research Square does not conduct peer review prior to posting preprints. The posting of a preprint on this server should not be interpreted as an endorsement of its validity or suitability for dissemination as established information or for guiding clinical practice.
Learn more about In Review
Research
Binghe Xu
National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College
Corresponding Author
Badges
Prescreen
This manuscript passed our Prescreen assessment
Complete author information
Appropriate declaration statements
Potential risks to human health
Prescreen
Peer Review Timeline
CURRENT STATUS: Published
View the published article at Biomarker Research.
Version 1
Posted 21 Dec, 2020
No community comments so far
Review #2 received
Received 09 Jan, 2021
Editorial decision: Major revision
On 09 Jan, 2021
Review #1 received
Received 01 Jan, 2021
Reviewer #2 agreed
On 22 Dec, 2020
Reviewer #1 agreed
On 21 Dec, 2020
Reviewers invited
Invitations sent on 20 Dec, 2020
Editor assigned
On 16 Dec, 2020
Submission checks complete
On 16 Dec, 2020
Editor invited
On 16 Dec, 2020
First submitted
On 13 Dec, 2020
Metrics
Comments: 0
PDF Downloads: ...
HTML Views: ...
Subject Areas
Cancer Biology
License:
This work is licensed under a CC BY 4.0 License. Read Full License
View the published article at Biomarker Research.
Background: SHR6390 is a novel inhibitor of cyclin-dependent kinase 4/6 which demonstrated promising anti-tumor potency in preclinical models. This first-in-human study was conducted to evaluate the tolerability, pharmacokinetics, safety, and preliminary antitumor activity of SHR6390 in patients with advanced breast cancer (ABC).
Methods: In this open-label, phase 1 study, patients who had failed standard therapy were enrolled to receive oral SHR6390 in 3 + 3 dose-escalation pattern at doses of 25−175 mg. Eligible patients were given a single-dose of SHR6390 in week 1, followed by once daily continuous doses for three weeks, and one week off in 28-day cycles. Based on the tolerability, pharmacokinetics, and activity data revealed from the dose-escalation phase, three dose cohorts were selected to expand to 8−10 patients. The primary endpoints were maximum tolerated dose (MTD) and pharmacokinetics.
Results: Between Apr 15, 2016 and Dec 21, 2018, 40 patients were enrolled; all were diagnosed of hormone receptor-positive and HER2-negative ABC. SHR6390 100 mg, 125 mg, and 150 mg cohorts were expanded to 10 patients. No dose limiting toxicity was observed and the MTD was not reached. Adverse events (AEs) of grade 3 or 4 were observed in 22 (55.0%) of 40 patients, being neutropenia (52.5%), leukopenia (35.0%), thrombocytopenia (5.0%), and hypertension (2.5%). No serious AEs were reported. At the doses of 50−175 mg, steady state areas under the concentration-time curve and peak concentration increased almost proportionally with dose. The disease control rate (DCR) was 62.5% (25/40, 95% CI: 45.8−77.3). Two patients (5%; 125 mg and 150 mg cohorts) achieved partial response, with responses lasting 169 and 356+ days, respectively. Among the three expansion cohorts, the 150 mg cohort had the numerically highest DCR of 80.0% (95% CI: 44.4‒97.5) and longest median progression-free survival of 8.4 months (95% CI: 2.1‒not reached).
Conclusions: SHR6390 showed acceptable safety profile and dose-dependent plasma exposure in patients with ABC. The recommended phase 2 dose was 150 mg. Preliminary evidence of clinical activity was observed, which warrants further validation.
Trial registration: ClinicalTrials.gov identifier: NCT02684266. Registered Feb 17, 2016. https://clinicaltrials.gov/ct2/show/NCT02684266.
This is a list of supplementary files associated with this preprint. Click to download.
- Supplementaryinformation.pdf
Additional file 1. Figure S1. Linear plot of concentration-time profile for SHR6390 by dose.
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