Clinical Trial

. 2023 Jan;128(1):30-41.

doi: 10.1038/s41416-022-02025-9. Epub 2022 Nov 5.

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

Giuseppe Curigliano^#^{1

2}, Geoffrey I Shapiro^#³, Rebecca S Kristeleit⁴, Albiruni R Abdul Razak⁵, Stephen Leong⁶, Maria Alsina⁷, Antonio Giordano⁸, Karen A Gelmon⁹, Erica Stringer-Reasor¹⁰, Ulka N Vaishampayan¹¹, Mark Middleton¹², Anthony J Olszanski¹³, Hope S Rugo¹⁴, Kenneth A Kern¹⁵, Nuzhat Pathan¹⁵, Rachelle Perea¹⁵, Kristen J Pierce¹⁶, Sarah C Mutka¹⁷, Zev A Wainberg¹⁸

Affiliations

¹ Istituto Europeo di Oncologia, IRCCS, Milano, Italy. giuseppe.curigliano@ieo.it.
² University of Milan, Milano, Italy. giuseppe.curigliano@ieo.it.
³ Dana-Farber Cancer Institute, Boston, MA, USA.
⁴ University College London, Cancer Institute, London, UK.
⁵ Phase 1 Program, Princess Margaret Cancer Centre, Toronto, ON, Canada.
⁶ University of Colorado Cancer Center, Aurora, CO, USA.
⁷ Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain.
⁸ Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, USA.
⁹ BC Cancer, Vancouver, BC, Canada.
¹⁰ University of Alabama at Birmingham O'Neal Comprehensive Cancer Center, Birmingham, AL, USA.
¹¹ University of Michigan/Karmanos Cancer Institute, Wayne State University, Detroit, MI, USA.
¹² University of Oxford, Oxford, UK.
¹³ Fox Chase Cancer Center, Philadelphia, PA, USA.
¹⁴ University of California San Francisco Helen Diller Family Comprehensive Cancer Center, San Francisco, CA, USA.
¹⁵ Pfizer, San Diego, CA, USA.
¹⁶ Pfizer, Groton, CT, USA.
¹⁷ Celcuity, Minneapolis, MD, USA.
¹⁸ David Geffen School of Medicine at University of California, Los Angeles, CA, USA.

^# Contributed equally.

PMID: 36335217
PMCID: PMC9814742
DOI: 10.1038/s41416-022-02025-9

Clinical Trial

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

Giuseppe Curigliano et al. Br J Cancer. 2023 Jan.

. 2023 Jan;128(1):30-41.

doi: 10.1038/s41416-022-02025-9. Epub 2022 Nov 5.

Authors

Affiliations

¹ Istituto Europeo di Oncologia, IRCCS, Milano, Italy. giuseppe.curigliano@ieo.it.
² University of Milan, Milano, Italy. giuseppe.curigliano@ieo.it.
³ Dana-Farber Cancer Institute, Boston, MA, USA.
⁴ University College London, Cancer Institute, London, UK.
⁵ Phase 1 Program, Princess Margaret Cancer Centre, Toronto, ON, Canada.
⁶ University of Colorado Cancer Center, Aurora, CO, USA.
⁷ Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain.
⁸ Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, USA.
⁹ BC Cancer, Vancouver, BC, Canada.
¹⁰ University of Alabama at Birmingham O'Neal Comprehensive Cancer Center, Birmingham, AL, USA.
¹¹ University of Michigan/Karmanos Cancer Institute, Wayne State University, Detroit, MI, USA.
¹² University of Oxford, Oxford, UK.
¹³ Fox Chase Cancer Center, Philadelphia, PA, USA.
¹⁴ University of California San Francisco Helen Diller Family Comprehensive Cancer Center, San Francisco, CA, USA.
¹⁵ Pfizer, San Diego, CA, USA.
¹⁶ Pfizer, Groton, CT, USA.
¹⁷ Celcuity, Minneapolis, MD, USA.
¹⁸ David Geffen School of Medicine at University of California, Los Angeles, CA, USA.

^# Contributed equally.

PMID: 36335217
PMCID: PMC9814742
DOI: 10.1038/s41416-022-02025-9

Erratum in

Correction to: 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.
Curigliano G, Shapiro GI, Kristeleit RS, Abdul Razak AR, Leong S, Alsina M, Giordano A, Gelmon KA, Stringer-Reasor E, Vaishampayan UN, Middleton M, Olszanski AJ, Rugo HS, Kern KA, Pathan N, Perea R, Pierce KJ, Mutka SC, Wainberg ZA. Curigliano G, et al. Br J Cancer. 2023 Jan;128(2):400. doi: 10.1038/s41416-023-02161-w. Br J Cancer. 2023. PMID: 36697966 Free PMC article. No abstract available.

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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Conflict of interest statement

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.

Figures

**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.**
Results for (a) arm A, n = 16; (b) arm B, n = 27; and (c) arm C, n = 25 depicted by tumour type.

**Fig. 2. Response to treatment in patients with triple-negative breast cancer participating in Part 2 of the study.**
a Swimmer plot with solid bars representing the duration of treatment and symbols showing the timing of best overall response.^a b Waterfall plot illustrating best change (%) in target lesions for patients with measurable disease and a corresponding baseline tumour genomic profile (molecular profiling tumour analysis set^b). ^aOf note, a 66-year-old White woman in the 2L/3L arm received gedatolisib 180 mg + cisplatin over 104 weeks (728 days) in this study. Prior to her enrolment in December 2017, she had received a primary diagnosis of Stage III (TNM) ductal carcinoma in December 2015 and a diagnosis of metastatic disease in February 2016. In January 2020 she discontinued from the study when it ended and continued on compassionate use gedatolisib alone for the treatment of Stage IV disease. ^bTumour analysis set was defined as all enrolled patients who start treatment and have a baseline archived tumour biopsy FFPE (or fresh FFPE if archived sample is not available) and were analysed for at least one of the selected biomarkers. 1L first-line treatment, 2L/3L second/third-line treatment, CR complete response, ctDNA circulating DNA, FFPE formalin-fixed paraffin-embedded, PR partial response, SD stable disease, TNM tumour, node, metastasis.

See this image and copyright information in PMC

References

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1. Shapiro GI, Bell-McGuinn KM, Molina JR, Bendell J, Spicer J, Kwak EL, et al. First-in-human study of PF-05212384 (PKI-587), a small-molecule, intravenous, dual inhibitor of PI3K and mTOR in patients with advanced cancer. Clin Cancer Res. 2015;21:1888–95. doi: 10.1158/1078-0432.CCR-14-1306. - DOI - PMC - PubMed

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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

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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

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