drugset / Trial / NCT04248998
Calorie Restriction With or Without Metformin in Triple Negative Breast Cancer
Phase 2
Unknown
30 enrolled
Fondazione IRCCS Istituto Nazionale dei Tumori, Milano
European Institute of Oncology · collabIFOM ETS - The AIRC Institute of Molecular Oncology · collabUniversity of Milan · collab
RandomizedParallel-groupOpen-labelTreatment
Summary
Glucose starvation and metformin have synergistic antitumor effects that are mediated through the concomitant inhibition of glycolysis and mitochondrial oxidative phosphorylation. The BREAKFAST trial will evaluate the antitumor activity of combining cyclic fasting-mimicking diet (FMD), which reproduces the in vitro effects of glucose starvation, plus/minus metformin with standard preperative anthracycline-taxane chemotherapy in patients with stage I-III TNBC
Timeline
- Start
- 2020-05-05
- Primary completion
- 2024-05-01
- Completion
- 2024-05-01
Publications
- Results Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018 Nov;68(6):394-424. doi: 10.3322/caac.21492. Epub 2018 Sep 12.
- Results Ferlay J, Colombet M, Soerjomataram I, Dyba T, Randi G, Bettio M, Gavin A, Visser O, Bray F. Cancer incidence and mortality patterns in Europe: Estimates for 40 countries and 25 major cancers in 2018. Eur J Cancer. 2018 Nov;103:356-387. doi: 10.1016/j.ejca.2018.07.005. Epub 2018 Aug 9.
- Results Iqbal J, Ginsburg O, Rochon PA, Sun P, Narod SA. Differences in breast cancer stage at diagnosis and cancer-specific survival by race and ethnicity in the United States. JAMA. 2015 Jan 13;313(2):165-73. doi: 10.1001/jama.2014.17322.
- Results Kassam F, Enright K, Dent R, Dranitsaris G, Myers J, Flynn C, Fralick M, Kumar R, Clemons M. Survival outcomes for patients with metastatic triple-negative breast cancer: implications for clinical practice and trial design. Clin Breast Cancer. 2009 Feb;9(1):29-33. doi: 10.3816/CBC.2009.n.005.
- Results Gobbini E, Ezzalfani M, Dieras V, Bachelot T, Brain E, Debled M, Jacot W, Mouret-Reynier MA, Goncalves A, Dalenc F, Patsouris A, Ferrero JM, Levy C, Lorgis V, Vanlemmens L, Lefeuvre-Plesse C, Mathoulin-Pelissier S, Petit T, Uwer L, Jouannaud C, Leheurteur M, Lacroix-Triki M, Cleaud AL, Robain M, Courtinard C, Cailliot C, Perol D, Delaloge S. Time trends of overall survival among metastatic breast cancer patients in the real-life ESME cohort. Eur J Cancer. 2018 Jun;96:17-24. doi: 10.1016/j.ejca.2018.03.015. Epub 2018 Apr 13.
- Results Park S, Koo JS, Kim MS, Park HS, Lee JS, Lee JS, Kim SI, Park BW. Characteristics and outcomes according to molecular subtypes of breast cancer as classified by a panel of four biomarkers using immunohistochemistry. Breast. 2012 Feb;21(1):50-7. doi: 10.1016/j.breast.2011.07.008. Epub 2011 Aug 23.
- Results Lehmann BD, Bauer JA, Chen X, Sanders ME, Chakravarthy AB, Shyr Y, Pietenpol JA. Identification of human triple-negative breast cancer subtypes and preclinical models for selection of targeted therapies. J Clin Invest. 2011 Jul;121(7):2750-67. doi: 10.1172/JCI45014.
- Results Schmid P, Adams S, Rugo HS, Schneeweiss A, Barrios CH, Iwata H, Dieras V, Hegg R, Im SA, Shaw Wright G, Henschel V, Molinero L, Chui SY, Funke R, Husain A, Winer EP, Loi S, Emens LA; IMpassion130 Trial Investigators. Atezolizumab and Nab-Paclitaxel in Advanced Triple-Negative Breast Cancer. N Engl J Med. 2018 Nov 29;379(22):2108-2121. doi: 10.1056/NEJMoa1809615. Epub 2018 Oct 20.
- Results Sharma P, Lopez-Tarruella S, Garcia-Saenz JA, Khan QJ, Gomez HL, Prat A, Moreno F, Jerez-Gilarranz Y, Barnadas A, Picornell AC, Monte-Millan MD, Gonzalez-Rivera M, Massarrah T, Pelaez-Lorenzo B, Palomero MI, Gonzalez Del Val R, Cortes J, Fuentes-Rivera H, Morales DB, Marquez-Rodas I, Perou CM, Lehn C, Wang YY, Klemp JR, Mammen JV, Wagner JL, Amin AL, O'Dea AP, Heldstab J, Jensen RA, Kimler BF, Godwin AK, Martin M. Pathological Response and Survival in Triple-Negative Breast Cancer Following Neoadjuvant Carboplatin plus Docetaxel. Clin Cancer Res. 2018 Dec 1;24(23):5820-5829. doi: 10.1158/1078-0432.CCR-18-0585. Epub 2018 Jul 30.
- Results Tutt A, Tovey H, Cheang MCU, Kernaghan S, Kilburn L, Gazinska P, Owen J, Abraham J, Barrett S, Barrett-Lee P, Brown R, Chan S, Dowsett M, Flanagan JM, Fox L, Grigoriadis A, Gutin A, Harper-Wynne C, Hatton MQ, Hoadley KA, Parikh J, Parker P, Perou CM, Roylance R, Shah V, Shaw A, Smith IE, Timms KM, Wardley AM, Wilson G, Gillett C, Lanchbury JS, Ashworth A, Rahman N, Harries M, Ellis P, Pinder SE, Bliss JM. Carboplatin in BRCA1/2-mutated and triple-negative breast cancer BRCAness subgroups: the TNT Trial. Nat Med. 2018 May;24(5):628-637. doi: 10.1038/s41591-018-0009-7. Epub 2018 Apr 30.
- Results O'Shaughnessy J, Schwartzberg L, Danso MA, Miller KD, Rugo HS, Neubauer M, Robert N, Hellerstedt B, Saleh M, Richards P, Specht JM, Yardley DA, Carlson RW, Finn RS, Charpentier E, Garcia-Ribas I, Winer EP. Phase III study of iniparib plus gemcitabine and carboplatin versus gemcitabine and carboplatin in patients with metastatic triple-negative breast cancer. J Clin Oncol. 2014 Dec 1;32(34):3840-7. doi: 10.1200/JCO.2014.55.2984. Epub 2014 Oct 27.
- Results Rugo HS, Barry WT, Moreno-Aspitia A, Lyss AP, Cirrincione C, Leung E, Mayer EL, Naughton M, Toppmeyer D, Carey LA, Perez EA, Hudis C, Winer EP. Randomized Phase III Trial of Paclitaxel Once Per Week Compared With Nanoparticle Albumin-Bound Nab-Paclitaxel Once Per Week or Ixabepilone With Bevacizumab As First-Line Chemotherapy for Locally Recurrent or Metastatic Breast Cancer: CALGB 40502/NCCTG N063H (Alliance). J Clin Oncol. 2015 Jul 20;33(21):2361-9. doi: 10.1200/JCO.2014.59.5298. Epub 2015 Jun 8.
- Results Yardley DA, Coleman R, Conte P, Cortes J, Brufsky A, Shtivelband M, Young R, Bengala C, Ali H, Eakel J, Schneeweiss A, de la Cruz-Merino L, Wilks S, O'Shaughnessy J, Gluck S, Li H, Miller J, Barton D, Harbeck N; tnAcity investigators. nab-Paclitaxel plus carboplatin or gemcitabine versus gemcitabine plus carboplatin as first-line treatment of patients with triple-negative metastatic breast cancer: results from the tnAcity trial. Ann Oncol. 2018 Aug 1;29(8):1763-1770. doi: 10.1093/annonc/mdy201.
- Results Carey LA, Dees EC, Sawyer L, Gatti L, Moore DT, Collichio F, Ollila DW, Sartor CI, Graham ML, Perou CM. The triple negative paradox: primary tumor chemosensitivity of breast cancer subtypes. Clin Cancer Res. 2007 Apr 15;13(8):2329-34. doi: 10.1158/1078-0432.CCR-06-1109.
- Results Rastogi P, Anderson SJ, Bear HD, Geyer CE, Kahlenberg MS, Robidoux A, Margolese RG, Hoehn JL, Vogel VG, Dakhil SR, Tamkus D, King KM, Pajon ER, Wright MJ, Robert J, Paik S, Mamounas EP, Wolmark N. Preoperative chemotherapy: updates of National Surgical Adjuvant Breast and Bowel Project Protocols B-18 and B-27. J Clin Oncol. 2008 Feb 10;26(5):778-85. doi: 10.1200/JCO.2007.15.0235.
- Results Cortazar P, Zhang L, Untch M, Mehta K, Costantino JP, Wolmark N, Bonnefoi H, Cameron D, Gianni L, Valagussa P, Swain SM, Prowell T, Loibl S, Wickerham DL, Bogaerts J, Baselga J, Perou C, Blumenthal G, Blohmer J, Mamounas EP, Bergh J, Semiglazov V, Justice R, Eidtmann H, Paik S, Piccart M, Sridhara R, Fasching PA, Slaets L, Tang S, Gerber B, Geyer CE Jr, Pazdur R, Ditsch N, Rastogi P, Eiermann W, von Minckwitz G. Pathological complete response and long-term clinical benefit in breast cancer: the CTNeoBC pooled analysis. Lancet. 2014 Jul 12;384(9938):164-72. doi: 10.1016/S0140-6736(13)62422-8. Epub 2014 Feb 14.
- Results Poggio F, Bruzzone M, Ceppi M, Ponde NF, La Valle G, Del Mastro L, de Azambuja E, Lambertini M. Platinum-based neoadjuvant chemotherapy in triple-negative breast cancer: a systematic review and meta-analysis. Ann Oncol. 2018 Jul 1;29(7):1497-1508. doi: 10.1093/annonc/mdy127.
- Results Loibl S, O'Shaughnessy J, Untch M, Sikov WM, Rugo HS, McKee MD, Huober J, Golshan M, von Minckwitz G, Maag D, Sullivan D, Wolmark N, McIntyre K, Ponce Lorenzo JJ, Metzger Filho O, Rastogi P, Symmans WF, Liu X, Geyer CE Jr. Addition of the PARP inhibitor veliparib plus carboplatin or carboplatin alone to standard neoadjuvant chemotherapy in triple-negative breast cancer (BrighTNess): a randomised, phase 3 trial. Lancet Oncol. 2018 Apr;19(4):497-509. doi: 10.1016/S1470-2045(18)30111-6. Epub 2018 Feb 28.
- Results Sikov WM, Berry DA, Perou CM, Singh B, Cirrincione CT, Tolaney SM, Kuzma CS, Pluard TJ, Somlo G, Port ER, Golshan M, Bellon JR, Collyar D, Hahn OM, Carey LA, Hudis CA, Winer EP. Impact of the addition of carboplatin and/or bevacizumab to neoadjuvant once-per-week paclitaxel followed by dose-dense doxorubicin and cyclophosphamide on pathologic complete response rates in stage II to III triple-negative breast cancer: CALGB 40603 (Alliance). J Clin Oncol. 2015 Jan 1;33(1):13-21. doi: 10.1200/JCO.2014.57.0572. Epub 2014 Aug 4.
- Results McAndrew N, DeMichele A. Neoadjuvant Chemotherapy Considerations in Triple-Negative Breast Cancer. J Target Ther Cancer. 2018 Feb;7(1):52-69. Epub 2018 Feb 14.
- Results Houvenaeghel G, Goncalves A, Classe JM, Garbay JR, Giard S, Charytensky H, Cohen M, Belichard C, Faure C, Uzan S, Hudry D, Azuar P, Villet R, Gimbergues P, Tunon de Lara C, Martino M, Lambaudie E, Coutant C, Dravet F, Chauvet MP, Chereau Ewald E, Penault-Llorca F, Esterni B. Characteristics and clinical outcome of T1 breast cancer: a multicenter retrospective cohort study. Ann Oncol. 2014 Mar;25(3):623-628. doi: 10.1093/annonc/mdt532. Epub 2014 Jan 7.
- Results Vernieri C, Casola S, Foiani M, Pietrantonio F, de Braud F, Longo V. Targeting Cancer Metabolism: Dietary and Pharmacologic Interventions. Cancer Discov. 2016 Dec;6(12):1315-1333. doi: 10.1158/2159-8290.CD-16-0615. Epub 2016 Nov 21.
- Results Lee C, Raffaghello L, Brandhorst S, Safdie FM, Bianchi G, Martin-Montalvo A, Pistoia V, Wei M, Hwang S, Merlino A, Emionite L, de Cabo R, Longo VD. Fasting cycles retard growth of tumors and sensitize a range of cancer cell types to chemotherapy. Sci Transl Med. 2012 Mar 7;4(124):124ra27. doi: 10.1126/scitranslmed.3003293. Epub 2012 Feb 8.
- Results Safdie FM, Dorff T, Quinn D, Fontana L, Wei M, Lee C, Cohen P, Longo VD. Fasting and cancer treatment in humans: A case series report. Aging (Albany NY). 2009 Dec 31;1(12):988-1007. doi: 10.18632/aging.100114.
- Results de Groot S, Vreeswijk MP, Welters MJ, Gravesteijn G, Boei JJ, Jochems A, Houtsma D, Putter H, van der Hoeven JJ, Nortier JW, Pijl H, Kroep JR. The effects of short-term fasting on tolerance to (neo) adjuvant chemotherapy in HER2-negative breast cancer patients: a randomized pilot study. BMC Cancer. 2015 Oct 5;15:652. doi: 10.1186/s12885-015-1663-5.
- Results Dorff TB, Groshen S, Garcia A, Shah M, Tsao-Wei D, Pham H, Cheng CW, Brandhorst S, Cohen P, Wei M, Longo V, Quinn DI. Safety and feasibility of fasting in combination with platinum-based chemotherapy. BMC Cancer. 2016 Jun 10;16:360. doi: 10.1186/s12885-016-2370-6.
- Results Braghiroli MI, de Celis Ferrari AC, Pfiffer TE, Alex AK, Nebuloni D, Carneiro AS, Caparelli F, Senna L, Lobo J, Hoff PM, Riechelmann RP. Phase II trial of metformin and paclitaxel for patients with gemcitabine-refractory advanced adenocarcinoma of the pancreas. Ecancermedicalscience. 2015 Aug 11;9:563. doi: 10.3332/ecancer.2015.563. eCollection 2015.
- Results Martin-Castillo B, Pernas S, Dorca J, Alvarez I, Martinez S, Perez-Garcia JM, Batista-Lopez N, Rodriguez-Sanchez CA, Amillano K, Dominguez S, Luque M, Stradella A, Morilla I, Vinas G, Cortes J, Cuyas E, Verdura S, Fernandez-Ochoa A, Fernandez-Arroyo S, Segura-Carretero A, Joven J, Perez E, Bosch N, Garcia M, Lopez-Bonet E, Saidani S, Buxo M, Menendez JA. A phase 2 trial of neoadjuvant metformin in combination with trastuzumab and chemotherapy in women with early HER2-positive breast cancer: the METTEN study. Oncotarget. 2018 Nov 2;9(86):35687-35704. doi: 10.18632/oncotarget.26286. eCollection 2018 Nov 2.
- Results Tsakiridis T, Hu C, Skinner HD, et al. Initial reporting of NRG-LU001 (NCT02186847), randomized phase II trial of concurrent chemoradiotherapy (CRT) +/- metformin in locally advanced Non-Small Cell Lung Cancer (NSCLC). Journal of Clinical Oncology. 2019;37(15_suppl):8502-8502.
- Results Jiralerspong S, Palla SL, Giordano SH, Meric-Bernstam F, Liedtke C, Barnett CM, Hsu L, Hung MC, Hortobagyi GN, Gonzalez-Angulo AM. Metformin and pathologic complete responses to neoadjuvant chemotherapy in diabetic patients with breast cancer. J Clin Oncol. 2009 Jul 10;27(20):3297-302. doi: 10.1200/JCO.2009.19.6410. Epub 2009 Jun 1.
- Results Masuda N, Lee SJ, Ohtani S, Im YH, Lee ES, Yokota I, Kuroi K, Im SA, Park BW, Kim SB, Yanagita Y, Ohno S, Takao S, Aogi K, Iwata H, Jeong J, Kim A, Park KH, Sasano H, Ohashi Y, Toi M. Adjuvant Capecitabine for Breast Cancer after Preoperative Chemotherapy. N Engl J Med. 2017 Jun 1;376(22):2147-2159. doi: 10.1056/NEJMoa1612645.
- Results Hammond ME, Hayes DF, Dowsett M, Allred DC, Hagerty KL, Badve S, Fitzgibbons PL, Francis G, Goldstein NS, Hayes M, Hicks DG, Lester S, Love R, Mangu PB, McShane L, Miller K, Osborne CK, Paik S, Perlmutter J, Rhodes A, Sasano H, Schwartz JN, Sweep FC, Taube S, Torlakovic EE, Valenstein P, Viale G, Visscher D, Wheeler T, Williams RB, Wittliff JL, Wolff AC; American Society of Clinical Oncology; College of American Pathologists. American Society of Clinical Oncology/College of American Pathologists guideline recommendations for immunohistochemical testing of estrogen and progesterone receptors in breast cancer (unabridged version). Arch Pathol Lab Med. 2010 Jul;134(7):e48-72. doi: 10.5858/134.7.e48.
- Results Wolff AC, Hammond MEH, Allison KH, Harvey BE, Mangu PB, Bartlett JMS, Bilous M, Ellis IO, Fitzgibbons P, Hanna W, Jenkins RB, Press MF, Spears PA, Vance GH, Viale G, McShane LM, Dowsett M. Human Epidermal Growth Factor Receptor 2 Testing in Breast Cancer: American Society of Clinical Oncology/College of American Pathologists Clinical Practice Guideline Focused Update. Arch Pathol Lab Med. 2018 Nov;142(11):1364-1382. doi: 10.5858/arpa.2018-0902-SA. Epub 2018 May 30.
- Results Sardanelli F, Boetes C, Borisch B, Decker T, Federico M, Gilbert FJ, Helbich T, Heywang-Kobrunner SH, Kaiser WA, Kerin MJ, Mansel RE, Marotti L, Martincich L, Mauriac L, Meijers-Heijboer H, Orecchia R, Panizza P, Ponti A, Purushotham AD, Regitnig P, Del Turco MR, Thibault F, Wilson R. Magnetic resonance imaging of the breast: recommendations from the EUSOMA working group. Eur J Cancer. 2010 May;46(8):1296-316. doi: 10.1016/j.ejca.2010.02.015. Epub 2010 Mar 19.
- Results Kuhl C. The current status of breast MR imaging. Part I. Choice of technique, image interpretation, diagnostic accuracy, and transfer to clinical practice. Radiology. 2007 Aug;244(2):356-78. doi: 10.1148/radiol.2442051620.
- Results Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, Gwyther S, Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, Lacombe D, Verweij J. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009 Jan;45(2):228-47. doi: 10.1016/j.ejca.2008.10.026.
- Results Oktay K, Harvey BE, Partridge AH, Quinn GP, Reinecke J, Taylor HS, Wallace WH, Wang ET, Loren AW. Fertility Preservation in Patients With Cancer: ASCO Clinical Practice Guideline Update. J Clin Oncol. 2018 Jul 1;36(19):1994-2001. doi: 10.1200/JCO.2018.78.1914. Epub 2018 Apr 5.
- Results Hammond ME, Hayes DF, Dowsett M, Allred DC, Hagerty KL, Badve S, Fitzgibbons PL, Francis G, Goldstein NS, Hayes M, Hicks DG, Lester S, Love R, Mangu PB, McShane L, Miller K, Osborne CK, Paik S, Perlmutter J, Rhodes A, Sasano H, Schwartz JN, Sweep FC, Taube S, Torlakovic EE, Valenstein P, Viale G, Visscher D, Wheeler T, Williams RB, Wittliff JL, Wolff AC. American Society of Clinical Oncology/College Of American Pathologists guideline recommendations for immunohistochemical testing of estrogen and progesterone receptors in breast cancer. J Clin Oncol. 2010 Jun 1;28(16):2784-95. doi: 10.1200/JCO.2009.25.6529. Epub 2010 Apr 19.
- Results Wolff AC, Hammond MEH, Allison KH, Harvey BE, Mangu PB, Bartlett JMS, Bilous M, Ellis IO, Fitzgibbons P, Hanna W, Jenkins RB, Press MF, Spears PA, Vance GH, Viale G, McShane LM, Dowsett M. Human Epidermal Growth Factor Receptor 2 Testing in Breast Cancer: American Society of Clinical Oncology/College of American Pathologists Clinical Practice Guideline Focused Update. J Clin Oncol. 2018 Jul 10;36(20):2105-2122. doi: 10.1200/JCO.2018.77.8738. Epub 2018 May 30.
- Results Carey LA, Metzger R, Dees EC, Collichio F, Sartor CI, Ollila DW, Klauber-DeMore N, Halle J, Sawyer L, Moore DT, Graham ML. American Joint Committee on Cancer tumor-node-metastasis stage after neoadjuvant chemotherapy and breast cancer outcome. J Natl Cancer Inst. 2005 Aug 3;97(15):1137-42. doi: 10.1093/jnci/dji206.
- Results Ivanova A, Qaqish BF, Schell MJ. Continuous toxicity monitoring in phase II trials in oncology. Biometrics. 2005 Jun;61(2):540-5. doi: 10.1111/j.1541-0420.2005.00311.x.
- Ligorio F, Vingiani A, Torelli T, Sposetti C, Drufuca L, Iannelli F, Zanenga L, Depretto C, Folli S, Scaperrotta G, Capri G, Bianchi GV, Ferraris C, Martelli G, Maugeri I, Provenzano L, Nichetti F, Agnelli L, Lobefaro R, Fuca G, Fotia G, Mariani L, Morelli D, Ladisa V, De Santis MC, Lozza L, Trecate G, Belfiore A, Brich S, Bertolotti A, Lorenzini D, Ficchi A, Martinetti A, Sottotetti E, Arata A, Corsetto P, Sorrentino L, Rediti M, Salvadori G, Minucci S, Foiani M, Apolone G, Pagani M, Pruneri G, de Braud F, Vernieri C. Early downmodulation of tumor glycolysis predicts response to fasting-mimicking diet in triple-negative breast cancer patients. Cell Metab. 2025 Feb 4;37(2):330-344.e7. doi: 10.1016/j.cmet.2024.11.004. Epub 2024 Dec 17.
Drugs
| Evaluation | Drug | Modality | Dose | Route |
|---|---|---|---|---|
| Subject | Metformin | Small molecule | 850 mg | — |
| Background | Cyclophosphamide | Other / unclassified | 600 mg/m2 | — |
| Background | Doxorubicin | Other / unclassified | 60 mg/m2 | — |
| Background | Paclitaxel | Small molecule | 80 mg/m2 | — |