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Clinical Trial
. 2025 Apr:195:66-74.
doi: 10.1016/j.ygyno.2025.03.003. Epub 2025 Mar 8.

A randomized phase II/III study of paclitaxel/carboplatin/metformin versus paclitaxel/carboplatin/placebo as initial therapy for measurable stage III or IVA, stage IVB, or recurrent endometrial cancer: An NRG oncology/GOG study

Victoria L Bae-Jump  1 , Michael W Sill  2 , Paola A Gehrig  3 , Jason D Merker  4 , David L Corcoran  5 , Adam D Pfefferle  6 , Michele C Hayward  7 , Joan L Walker  8 , Andrea R Hagemann  9 , Steven E Waggoner  10 , Roisin E O'Cearbhaill  11 , Megan E McDonald  12 , Mitchell I Edelson  13 , Paul A DiSilvestro  14 , Amy L McNally  15 , Aimee Fleury  16 , Ramey D Littell  17 , Frederick R Ueland  18 , Heather A Lankes  19 , Carol Aghajanian  20
Affiliations
Clinical Trial

A randomized phase II/III study of paclitaxel/carboplatin/metformin versus paclitaxel/carboplatin/placebo as initial therapy for measurable stage III or IVA, stage IVB, or recurrent endometrial cancer: An NRG oncology/GOG study

Victoria L Bae-Jump et al. Gynecol Oncol. 2025 Apr.

Abstract

Introduction: We evaluated the efficacy of the addition of the anti-diabetic drug metformin to standard-of-care paclitaxel and carboplatin (PC) in patients with advanced and recurrent endometrial cancer (EC).

Methods: In this phase II/III trial, EC patients with chemotherapy-naïve stage III/IVA (with measurable disease) and stage IVB or recurrent (with or without measurable disease) disease were randomly assigned to PC/metformin (850 mg BID) versus PC/placebo. Metformin or placebo was continued as maintenance therapy after completion of PC until disease progression. The primary endpoint of phase II was progression-free survival (PFS). The primary endpoint of phase III was overall survival (OS). Secondary endpoints were objective response, duration of response, and toxicity.

Results: From 3/17/2014 to 12/22/2017, 448 patients were randomized to phase II/III studies, and the data were frozen for interim analysis. The phase II study deemed metformin worthy of further investigation in the phase III study. The interim phase III analysis stopped accrual for futility on 2/1/2018. The addition of metformin to PC had a slightly higher hazard of death compared to the PC regimen (HR = 1.088; 90% CI 0.803 to 1.475), which was sufficient to close the study early. The PFS had (HR = 0.814; 90% CI 0.635 to 1.043). At a median follow-up of 10 months and 121 deaths, median OS was not determined and 28 months, on PC/placebo and PC/metformin, respectively.

Conclusion: The hazard ratios for PFS and OS endpoints was not sufficiently decreased with the addition of metformin to PC to justify continuing the trial.

Keywords: Carboplatin; Clinical trial; Endometrial Cancer; Metformin; Paclitaxel.

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Conflict of interest statement

CONFLICTS OF INTEREST

Drs. Bae-Jump, Sill, Corcoran, Pfefferle, Hayward, Walker, McDonald, DiSilvestro, Fleury, Littell, Ueland and Lankes.

Dr. Paolo Gehrig reports uncompensated role as Treasurer for the American Gynecologic and Obstetrical Society as well as receiving payment for serving as Associate Editor for Gynecologic Oncology.

Dr. Jason Merker reports receiving grant funding from Illumina for: 1) the study of circulating rumor RNA and 2) development of reference materials by the National Institute of Standards and Technology for tumor sequencing. Dr. Merker reports receiving consulting fees from PierianDx. Dr. Merker currently serves as an Executive Committee Member for the Alliance for Clinical Trials in Oncology Translational Research Program (TRP). Dr. Merker previously served on the Molecular Pathology Board of Directors, which ended in 2022.

Dr. Andrea Hagemann receiving NIH Specialized Program of Research Excellence P50 CA265793-01A1 Route 66 Endometrial Cancer SPORE Project 3: Primary Prevention and Uterine Preservation in Premenopausal Women with Obesity and Endometrial Hyperplasia/Cancer.

Dr. Steven Waggoner serves as Principal Investigator for GOG and NRG Oncology with payments for accrual made to his Institution.

Dr. O’Cearbhaill reports funding from NCI/NIH (P30 CA008748). She also reports grants paid to her Institution from Bayer/Celgene/Juno, Arsenalbio, Tesaro/GSK, Merck, Ludwig Cancer Institute, AbbVie/Stem Centrx, Regeneron, TCR 2 Therapeutics, Atara Biotherapeutics/Marker Therapeutics, Syndax Pharmaceuticals, Genmab/Seagen Therapeutics, Genentech, Alkermes/Mural Oncology, Kite Pharma, Acrivon, OnCusp Therapeutics, and Gynecologic Oncology Foundation, Lyell Immunopharma. Dr. O’Cearbhaill reports receiving payments from GSK, SITC, Gynecology Oncology of Canada for once off lectures as well as payment from Curio/Onclive/PER/MJH/Aptitude Health for Once off lectures. Dr. O’Cearbhaill received funding for travel from Hitech Health, Gathering Around Cancer, Ireland and GOG Foundation (SGO). Dr. O’Cearbhaill reports serving in an uncompensated capacity on Steering Committees for the following: AstraZeneca (DUO-O), GSK (Moonstone, Primar) and Acrivon. Additionally, Dr. O’Cearbhaill has served as an Advisor for Carina Biotech and Link Therapeutics (uncompensated). She also served as an Advisor for OnCusp Therapeutics. She served on Advisory Boards for the following: Tesaro/GSK, Regeneron Advisory, Seattle Genetics/SeaGen, Immunogen Board Bayer, R-Pharm, Fresenius Kabi, Miltenyi, 2seventybio, Bayer and Loxo. In addition, she served as Vice-Chair CPC, SGO as well as the Chair of the DT Committee for NRG Oncology.

Dr. Edelson reports receiving payments for advisory board participation 6/2021 for GSK as well as receiving support for travel from Intuitive Surgical (12/2022). Dr. Edelson reports that his spouse receives stock options as an employee from Merck and was a salaried employee until 8/2022. He also reports that his spouse is a salaried employee since 3/2023 for Pfizer.

Dr. Aghajanian reports receiving clinical trial funding to institution (MSK) from AbbVie – MSK PI, GOG3005, Artios Pharma-International Coordinating Investigator, ARTIST, AstraZeneca – MSK PI, SOLO1/GOG3004; National Coordinating Investigator & MSK PI, D081RC00001; ENGOT-ov4; AGO-OVAR 23; GOG-3025; Clovis – MSK PI, ARIEL 2 & 3. Dr. Aghajanian reports serving on an Advisory Board for Blueprint Medicine-Virtual Advisory Board 6/30/21 (uncompensated), Merck – Global Cervical and Ovarian Cancer Virtual Advisory Board 7/10/23; AstraZeneca – AZ eVOLVE DMC 4/26/23 – ongoing; AstraZeneca – Future Clinical Strategies for Endometrial Cancer Virtual Advisory Board 3/13/24 and Verastem, RAMP 3001 Steering Committee, 3/6/24 – ongoing. She also reports serving on the Board of Directors for the GOG Foundation (uncompensated) and the NRG Oncology Board of Directors (uncompensated).

References

    1. Giaquinto AN, Broaddus RR, Jemal A, Siegel RL. The Changing Landscape of Gynecologic Cancer Mortality in the United States. Obstetrics and gynecology. 2022;139(3):440–2. Epub 2022/02/05. doi: 10.1097/AOG.0000000000004676. - DOI - PMC - PubMed
    1. Clarke MA, Devesa SS, Hammer A, Wentzensen N. Racial and Ethnic Differences in Hysterectomy-Corrected Uterine Corpus Cancer Mortality by Stage and Histologic Subtype. JAMA Oncol. 2022. Epub 2022/05/06. doi: 10.1001/jamaoncol.2022.0009. - DOI - PMC - PubMed
    1. Kim S, Scheffler K, Halpern AL, Bekritsky MA, Noh E, Kallberg M, Chen X, Kim Y, Beyter D, Krusche P, Saunders CT. Strelka2: fast and accurate calling of germline and somatic variants. Nat Methods. 2018;15(8):591–4. Epub 2018/07/18. doi: 10.1038/s41592-018-0051-x. - DOI - PubMed
    1. Ko EM, Walter P, Clark L, Jackson A, Franasiak J, Bolac C, Havrilesky L, Secord AA, Moore DT, Gehrig PA, Bae-Jump VL. The complex triad of obesity, diabetes and race in Type I and II endometrial cancers: Prevalence and prognostic significance. Gynecol Oncol. 2014;133(1):28–32. Epub 2014/04/01. doi: 10.1016/j.ygyno.2014.01.032. - DOI - PubMed
    1. Schmandt RE, Iglesias DA, Co NN, Lu KH. Understanding obesity and endometrial cancer risk: opportunities for prevention. Am J Obstet Gynecol. 2011;205(6):518–25. Epub 2011/08/02. doi: 10.1016/j.ajog.2011.05.042. - DOI - PMC - PubMed

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