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Clinical Studies

A Phase 1B open-label study of gedatolisib (PF-05212384) in combination with other anti-tumour agents for patients with advanced solid tumours and triple-negative breast cancer

A Correction to this article was published on 25 January 2023

This article has been updated

Abstract

Background

This Phase 1b study (B2151002) evaluated the PI3K/mTOR inhibitor gedatolisib (PF-05212384) in combination with other anti-tumour agents in advanced solid tumours.

Methods

Patients with various malignancies were administered gedatolisib (90‒310 mg intravenously every week [QW]) plus docetaxel (arm A) or cisplatin (arm B) (each 75 mg/m2 intravenously Q3W) or dacomitinib (30 or 45 mg/day orally). The safety and tolerability of combination therapies were assessed during dose escalation; objective response (OR) and safety were assessed during dose expansion.

Results

Of 110 patients enrolled, 107 received gedatolisib combination treatment. Seven of 70 (10.0%) evaluable patients had dose-limiting toxicities; the most common was grade 3 oral mucositis (n = 3). Based upon reprioritisation of the sponsor’s portfolio, dose expansion focused on arm B, gedatolisib (180 mg QW) plus cisplatin in patients (N = 22) with triple-negative breast cancer (TNBC). OR (95% CI) was achieved in four of ten patients in first-line (overall response rate 40.0% [12.2–73.8%]) and four of 12 in second/third-line (33.3% [9.9–65.1%]) settings. One patient in each TNBC arm (10%, first-line; 8.3%, second/third-line) achieved a complete response.

Conclusions

Gedatolisib combination therapy showed an acceptable tolerability profile, with clinical activity at the recommended Phase 2 dose in patients with TNBC.

Clinical trial

ClinicalTrial.gov: NCT01920061.

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Fig. 1: Waterfall plots of best changes (%) in target lesions in patients with measurable disease in response-evaluable set during Part 1 of the study.
Fig. 2: Response to treatment in patients with triple-negative breast cancer participating in Part 2 of the study.

Data availability

On request, and subject to certain criteria, conditions and exceptions, Celcuity, Inc. will provide access to individual de-identified participant data from Celcuity sponsored interventional clinical studies conducted for medicines (1) for indications that have been approved or (2) where development has been terminated. A brief research proposal will be assessed and form the basis of a data-sharing agreement. Data requests may be submitted by using the form provided at https://www.celcuity.com/contact/. https://www.nature.com/documents/aj-research-data-policy-type-3.pdf.

Change history

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Acknowledgements

The authors thank the patients, their families, and/or caregivers, investigators, and site personnel who have supported and contributed to this study. Eva Ciruelos at the University Hospital, Madrid, Spain, is acknowledged for her early contributions to this study. Medical writing support was provided by Sue Reinwald, PhD, of Engage Scientific Solutions (funded by Pfizer) and Michael G Baker, PhD, of Haselwood Biosciences (funded by Celcuity).

Funding

This study was sponsored by Pfizer.

Author information

Authors and Affiliations

Authors

Contributions

GC, GIS, EC, KK, KJP and HSR contributed to the conception and design of the study. All authors contributed to the acquisition, analysis, or interpretation of data, and to drafting or revising the submitted manuscript. All authors approved the final version of the manuscript and agree to be accountable for all aspects of the work. Dr. Curigliano (corresponding and co-first author) and Dr. Shapiro (co-first author) confirm they had full access to the data in the study and final responsibility for the decision to submit for publication.

Corresponding author

Correspondence to Giuseppe Curigliano.

Ethics declarations

Competing interests

GC: research funding: Merck; personal consultation fees: Pfizer, Roche, AstraZeneca, BMS, Daichii Sankyo, Seagen, Gilead, Novartis, Eli Lilly; Ellipsis, and Merck. GIS: research funding: Eli Lilly, Merck KGaA/EMD-Serono, Merck, and Sierra Oncology; Advisory boards: Pfizer, Eli Lilly, G1 Therapeutics, Roche, Merck KGaA/EMD-Serono, Sierra Oncology, Bicycle Therapeutics, Fusion Pharmaceuticals, Cybrexa Therapeutics, Astex, Almac, Ipsen, Bayer, Angiex, Daiichi Sankyo, Seattle Genetics, Boehringer Ingelheim, ImmunoMet, Asana, Artios, Atrin, Concarlo Holdings, Syros, Zentalis, CytomX Therapeutics and Blueprint Medicines; holds a patent titled “Dosage regimen for sapacitabine and seliciclib” also issued to Cyclacel Pharmaceuticals, and a pending patent titled “Compositions and Methods for Predicting Response and Resistance to CDK4/6 Inhibition” together with Liam Cornell. RSK has received grants from MSD and Clovis; Consultancy: Basilea, Pharmamar; Advisor: AstraZeneca, GSK, iTEOS, Eisai, and InCyte. ARAR: research funding: Pfizer. SL: research funding: institution funding as principal investigator on trials for Pfizer, BMS, Deciphera, and Karyopharma; employment: on faculty at University of Colorado at the time of this research, since June 2020 an employee of Merck. MA: consultancy: BMS, MSD, Lilly, and Servier. AG: author declared no conflict of interest. KAG: research funding: Pfizer, AstraZeneca, and BMS; advisory board member: Pfizer, Novartis, Eli Lilly, Roche, Merck, Mylan, AstraZeneca, Gilead, and Ayala. ES-R: research funding: Susan G. Komen, V Foundation and NIH; employment: principal or sub-investigator of Pfizer sponsor clinical trials, fees paid to the institution; consultancy fees: Eli Lilly, Merck, Macrogenics, and AstraZeneca. UNV: research support: Merck, BMS and Astellas Inc. Consulting and Honoraria: Merck, Exelixis, BMS, Pfizer, AAA, Alkermes, Bayer, and EMD-Serono. MM: Grants: Roche, AstraZeneca, GRAIL; grants and personal fees: GSK; personal fees and other: BiolineRx, BMS, Novartis; grants, personal fees and other: Immunocore; other: Pfizer, Regeneron; personal fees, non-financial support and other: Merck/MSD; personal fees and non-financial support: Replimune, personal fees: Kineta and Silicon Therapeutics. AJO: research funding: Pfizer, Merck, and BMS – compensation for ad board. HSR: research support: Pfizer, Merck, Novartis, Lilly, Roche, Daiichi, Seattle Genetics, Macrogenics, Sermonix, Boehringer Ingelheim, Polyphor, AstraZeneca, Ayala and Gilead; honoraria: Puma, Samsung and NAPO. KAK: an employee of and holds stock options in Pfizer. NP: research funding: Pfizer; an employee of and holds stock options in Pfizer. RP: Was an employee and held stock options in Pfizer at the time the work was done. KJP: an employee of and holds stock options in Pfizer. SCM: an employee of and holds stock options in Celcuity; holds stock in Alpine Immune Sciences. ZAW: research funding: Plexxikon, Novartis and BMS; advisory boards: AstraZeneca, Eli Lilly, Genentech, Merck KGaA/EMD-Serono, Ipsen, Bayer, Daiichi Sankyo, Seagen, Merck, BMS, Amgen, Five Prime and Macrogenics Molecular Templates.

Ethics approval and consent to participate

The protocol, its amendments, and informed consent documentation were reviewed and approved by the institutional review board(s) or independent ethics committee(s) at each site. Study procedures followed the Declaration of Helsinki and the International Council for Harmonisation Good Clinical Practice guidelines and all local regulatory requirements. All patients provided informed consent before participating in any study-related procedure.

Consent to publish

Not applicable.

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The original online version of this article was revised: As per Italian regulation, the two affiliations for Dr. Curigliano (Instituto Europeo di Oncologia, IRCCS and University of Milan, Milano, Italy) must be separated out for proper accreditation within their systems.

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Curigliano, G., Shapiro, G.I., Kristeleit, R.S. et al. A Phase 1B open-label study of gedatolisib (PF-05212384) in combination with other anti-tumour agents for patients with advanced solid tumours and triple-negative breast cancer. Br J Cancer 128, 30–41 (2023). https://doi.org/10.1038/s41416-022-02025-9

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