Targeting Triple Negative BREAst Cancer Metabolism With a Combination of Chemoimmunotherapy and a FASTing-like Approach in the Preoperative Setting: the BREAKFAST 2 Trial

NCT05763992 | Recruiting Phase 2

• 1 other identifier: INT214/22
• Study Type: interventional
• Target: 145
• Locations: 1 country
• Sites: 1

Brief Summary

Italian, multicenter, open-label, two-arm, comparative, randomized phase II study investigating if the addition of the experimental metabolic intervention consisting in cycles of Fasting-Like Approach, as administered every three weeks up to a maximum of 8 consecutive cycles, is able to increase the anticancer activity of standard preoperative chemo-immunotherapy in patients with localized invasive Triple Negative Breast Cancer.

Conditions

Breast Cancer; Triple Negative Breast Cancer; Dietary Exposure; Fasting

Keywords

Triple Negative Breast Cancer; Neoadjuvant chemoimmunotherapy; Fasting-Like Approach; Immunometabolism; Pathologic Complete Responses (pCRs); Randomized, phase II trial

Outcome Measures

Primary Outcomes (1)

• Rate of Pathologic complete response (pCR)

  Absence of residual tumor cells in both breast tissue and axillary lymph nodes (ypT0/ypTis ypN0)

  Surgical specimen (at the time of surgery)

Secondary Outcomes (12)

• Disease free survival (DFS)

  Time from surgery to tumor recurrence or patient death, assessed up to 36 months

• Event-free survival (EFS)

  From the date of randomization to the first documentation of progressive disease or patient death, assessed up to 36 months

• Distant metastasis free survival (DMFS)

  From surgery to the occurrence of distant metastases or patient death, assessed up to 36 months

• Overall Survival (OS)

  Time from randomization to the date of death, assessed up to 60 months

• Compliance (Dose-intensity)

  From the start to the end of the neoadjuvant treatment (about 6 months)

Other Outcomes (1)

• Translational (DNA repair, metabolic, autophagy and immunologic parameters effect on pCR)

  Surgical specimen (at the time of surgery)

Study Arms (2)

Arm A

PLACEBO COMPARATOR

12 consecutive cycles of weekly paclitaxel plus carboplatin (PCb) combined with 4 triweekly cycles of Pembrolizumab, followed by 4 consecutive cycles of triweekly anthracycline (doxorubicin or epirubicin)-cyclophosphamide (AC or EC) chemotherapy combined with 4 triweekly cycles of Pembrolizumab.

Dietary Supplement: Control diet (ARM A) or Fasting-Like Approach (FLA, ARM B)

Arm B

EXPERIMENTAL

Standard treatment (12 consecutive cycles of weekly paclitaxel plus carboplatin (PCb) combined with 4 triweekly cycles of Pembrolizumab, followed by 4 consecutive cycles of triweekly anthracycline (doxorubicin or epirubicin)-cyclophosphamide (AC or EC) chemotherapy combined with 4 triweekly cycles of Pembrolizumab) in combination with up to a maximum of 8 consecutive triweekly cycles of 5-day Fasting-Like Approach

Dietary Supplement: Control diet (ARM A) or Fasting-Like Approach (FLA, ARM B)

Interventions

Control diet (ARM A) or Fasting-Like Approach (FLA, ARM B) DIETARY_SUPPLEMENT

Each FLA cycle will consist of 5 consecutive days of a specific FLA scheme, which will be repeated with a three-week interval. The FLA will consist of a plant-based, low-calorie (about 600 Kcal on day 1; about 300 Kcal on day 2 to 5), low-protein, low-carbohydrate diet. The first FLA cycle will start two days prior to the day of first chemo-immunotherapy cycle administration and will continue for two more days after chemotherapy. In the absence of significant contraindications or severe adverse events, subsequent FLA cycles will recur with three-week intervals and will maintain the same timing with respect to chemo-immunotherapy administration.

Arm A; Arm B

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: female
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Female sex
• Age ≥ 18 and ≤ 75 years.
• Evidence of a personally signed and dated informed consent document (ICD), signed and dated from the patient of legal representative with or without an impartial witness, indicating that the patient has been informed of all pertinent aspects of the study before enrollment
• Willingness and ability to comply with the prescribed FLA regimen, the scheduled visits, treatment plans, laboratory tests and other procedures.
• Histologically confirmed diagnosis of invasive TNBC candidate to neoadjuvant chemo-immunotherapy and subsequent curative surgery. On the basis of International Guidelines, TNBC is defined by absent or minimal (\<1%) expression of oestrogen and progesterone receptors at IHC, and absence of HER2 protein over-expression and HER2 gene amplification, as defined as an IHC score of 0, 1+, or an IHC score of 2+ with in situ hybridization (ISH) analysis excluding HER2 gene amplification. The expression of hormone receptors (ER and PgR) and HER2 will be evaluated through immunohistochemistry (IHC), according to International Guidelines47,48
• Availability of a formalin-fixed, paraffin-embedded (FFPE) block containing tumor tissue, or at least 7 unstained tumor slides.
• Patients with tumor stage T1c AND nodal stage N1-2, or tumor stage T2-4 AND nodal stage N0-2 according to TNM.
• Presence of an Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1.
• Presence of adequate bone marrow and organ function as defined by the following laboratory values:
• ANC ≥ 1.5 x 103/l
• platelets ≥ 100 x 103/l
• hemoglobin ≥ 9.0 g/dl
• calcium (corrected for serum albumin) within normal limits or ≤ grade 1 according to NCI-CTCAE version 5.0 if not clinically significant
• potassium within the normal limits, or corrected with supplements
• creatinine \< 1.5 ULN

You may not qualify if:

• Prior systemic treatment for breast cancer or other malignancies within 5 years of treatment enrollment, except for adequately treated basal cell or squamous skin cancer or in situ cervical cancer. Other malignancies diagnosed more than 5 years before the diagnosis of breast cancer must have been radically treated without evidence of relapse at the moment of patient enrollment in the trial.
• Prior treatment with anthracyclines
• Prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or with an agent directed to another co-inhibitory T-cell receptor (e.g., CTLA-4, OX-40, CD137)
• Body mass index (BMI) \< 19 kg/m2.
• History of alcohol abuse.
• Non-intentional weight loss ≥ 5% in the previous 3 months, unless the patient has a BMI \> 22 kg/m2 and weight loss has been lower than 10% at the time of enrollment in the study; or non-intentional weight loss of ≥ 10% in the previous 3 months, unless the patient has a BMI \> 25 kg/m2 and weight loss has been lower than 15% at the time of the enrollment in the study. In both cases, weight must have been stable for at least one month before study enrollment.
• Active pregnancy or breast feeding.
• Known active B or C hepatitis or human immunodeficiency virus (HIV) infection, or occasional finding of active hepatitis B/C infection during screening tests before chemotherapy initiation, as defined as positive polymerase chain reaction (PCR) testing for HBV-DNA and HCV-RNA and qualitative PCR for HIV-RNA, or requiring active treatment at study enrollment.
• Serious infections in the previous 4 weeks before the FLA initiation, including, but not limited to, potential hospitalizations for complications of infections, bacteriemia or serious pneumonitis.
• Active autoimmune diseases requiring systemic treatments (e.g., systemic steroids or immune suppressants). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment.
• Active chronic therapy with systemic steroids at a dose ≥ 10 mg per day of prednisone or equivalent at study enrollment.
• Diagnosis of type 1 or 2 diabetes mellitus requiring pharmacologic therapy (including, but not limited to, insulin or insulin secretagogues), with the exception of metformin. A diagnosis of type 2 diabetes mellitus not requiring pharmacological treatments, or only requiring treatment with metformin, based on the judgment of a diabetologist, is compatible with patient enrollment in the trial.
• Anamnesis of clinically significant heart disease including:
• angina pectoris, coronary bypass, symptomatic pericarditis, myocardial infarction in the previous 12 months from the beginning of experimental therapy;
• congestive heart failure (NYHA III-IV).

Sponsors & Collaborators

• Fondazione IRCCS Istituto Nazionale dei Tumori, Milano: lead
• Istituto Oncologico Veneto IRCCS: collaborator
• Ospedale Policlinico San Martino: collaborator
• Federico II University: collaborator
• Azienda Policlinico Umberto I: collaborator
• European Institute of Oncology: collaborator
• Ospedale "Carlo Poma" - Mantova: collaborator
• Humanitas Clinical and Research Center: collaborator

Study Sites (1)

Fondazione IRCCS Istituto Nazionale dei Tumori

Milan, Italy

RECRUITING

Related Publications (15)

• 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.

  PMID: 19299237 RESULT

• 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.

  PMID: 24529560 RESULT

• 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.

  PMID: 25092775 RESULT

• Poggio F, Tagliamento M, Ceppi M, Bruzzone M, Conte B, Fregatti P, Punie K, de Azambuja E, Del Mastro L, Lambertini M. Adding a platinum agent to neoadjuvant chemotherapy for triple-negative breast cancer: the end of the debate. Ann Oncol. 2022 Mar;33(3):347-349. doi: 10.1016/j.annonc.2021.11.016. Epub 2021 Nov 30. No abstract available.

  PMID: 34861375 RESULT

• Cortes J, Cescon DW, Rugo HS, Nowecki Z, Im SA, Yusof MM, Gallardo C, Lipatov O, Barrios CH, Holgado E, Iwata H, Masuda N, Otero MT, Gokmen E, Loi S, Guo Z, Zhao J, Aktan G, Karantza V, Schmid P; KEYNOTE-355 Investigators. Pembrolizumab plus chemotherapy versus placebo plus chemotherapy for previously untreated locally recurrent inoperable or metastatic triple-negative breast cancer (KEYNOTE-355): a randomised, placebo-controlled, double-blind, phase 3 clinical trial. Lancet. 2020 Dec 5;396(10265):1817-1828. doi: 10.1016/S0140-6736(20)32531-9.

  PMID: 33278935 RESULT

• Mittendorf EA, Zhang H, Barrios CH, Saji S, Jung KH, Hegg R, Koehler A, Sohn J, Iwata H, Telli ML, Ferrario C, Punie K, Penault-Llorca F, Patel S, Duc AN, Liste-Hermoso M, Maiya V, Molinero L, Chui SY, Harbeck N. Neoadjuvant atezolizumab in combination with sequential nab-paclitaxel and anthracycline-based chemotherapy versus placebo and chemotherapy in patients with early-stage triple-negative breast cancer (IMpassion031): a randomised, double-blind, phase 3 trial. Lancet. 2020 Oct 10;396(10257):1090-1100. doi: 10.1016/S0140-6736(20)31953-X. Epub 2020 Sep 20.

  PMID: 32966830 RESULT

• Schmid P, Cortes J, Pusztai L, McArthur H, Kummel S, Bergh J, Denkert C, Park YH, Hui R, Harbeck N, Takahashi M, Foukakis T, Fasching PA, Cardoso F, Untch M, Jia L, Karantza V, Zhao J, Aktan G, Dent R, O'Shaughnessy J; KEYNOTE-522 Investigators. Pembrolizumab for Early Triple-Negative Breast Cancer. N Engl J Med. 2020 Feb 27;382(9):810-821. doi: 10.1056/NEJMoa1910549.

  PMID: 32101663 RESULT

• Gong Y, Ji P, Yang YS, Xie S, Yu TJ, Xiao Y, Jin ML, Ma D, Guo LW, Pei YC, Chai WJ, Li DQ, Bai F, Bertucci F, Hu X, Jiang YZ, Shao ZM. Metabolic-Pathway-Based Subtyping of Triple-Negative Breast Cancer Reveals Potential Therapeutic Targets. Cell Metab. 2021 Jan 5;33(1):51-64.e9. doi: 10.1016/j.cmet.2020.10.012. Epub 2020 Nov 11.

  PMID: 33181091 RESULT

• 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.

  PMID: 27872127 RESULT

• Salvadori G, Zanardi F, Iannelli F, Lobefaro R, Vernieri C, Longo VD. Fasting-mimicking diet blocks triple-negative breast cancer and cancer stem cell escape. Cell Metab. 2021 Nov 2;33(11):2247-2259.e6. doi: 10.1016/j.cmet.2021.10.008.

  PMID: 34731655 RESULT

• Caffa I, Spagnolo V, Vernieri C, Valdemarin F, Becherini P, Wei M, Brandhorst S, Zucal C, Driehuis E, Ferrando L, Piacente F, Tagliafico A, Cilli M, Mastracci L, Vellone VG, Piazza S, Cremonini AL, Gradaschi R, Mantero C, Passalacqua M, Ballestrero A, Zoppoli G, Cea M, Arrighi A, Odetti P, Monacelli F, Salvadori G, Cortellino S, Clevers H, De Braud F, Sukkar SG, Provenzani A, Longo VD, Nencioni A. Fasting-mimicking diet and hormone therapy induce breast cancer regression. Nature. 2020 Jul;583(7817):620-624. doi: 10.1038/s41586-020-2502-7. Epub 2020 Jul 15.

  PMID: 32669709 RESULT

• Di Tano M, Raucci F, Vernieri C, Caffa I, Buono R, Fanti M, Brandhorst S, Curigliano G, Nencioni A, de Braud F, Longo VD. Synergistic effect of fasting-mimicking diet and vitamin C against KRAS mutated cancers. Nat Commun. 2020 May 11;11(1):2332. doi: 10.1038/s41467-020-16243-3.

  PMID: 32393788 RESULT

• Vernieri C, Ligorio F, Zattarin E, Rivoltini L, de Braud F. Fasting-mimicking diet plus chemotherapy in breast cancer treatment. Nat Commun. 2020 Aug 26;11(1):4274. doi: 10.1038/s41467-020-18194-1.

  PMID: 32848145 RESULT

• Vernieri C, Fuca G, Ligorio F, Huber V, Vingiani A, Iannelli F, Raimondi A, Rinchai D, Frige G, Belfiore A, Lalli L, Chiodoni C, Cancila V, Zanardi F, Ajazi A, Cortellino S, Vallacchi V, Squarcina P, Cova A, Pesce S, Frati P, Mall R, Corsetto PA, Rizzo AM, Ferraris C, Folli S, Garassino MC, Capri G, Bianchi G, Colombo MP, Minucci S, Foiani M, Longo VD, Apolone G, Torri V, Pruneri G, Bedognetti D, Rivoltini L, de Braud F. Fasting-Mimicking Diet Is Safe and Reshapes Metabolism and Antitumor Immunity in Patients with Cancer. Cancer Discov. 2022 Jan;12(1):90-107. doi: 10.1158/2159-8290.CD-21-0030. Epub 2021 Nov 17.

  PMID: 34789537 RESULT

• Ligorio F, Fuca G, Provenzano L, Lobefaro R, Zanenga L, Vingiani A, Belfiore A, Lorenzoni A, Alessi A, Pruneri G, de Braud F, Vernieri C. Exceptional tumour responses to fasting-mimicking diet combined with standard anticancer therapies: A sub-analysis of the NCT03340935 trial. Eur J Cancer. 2022 Sep;172:300-310. doi: 10.1016/j.ejca.2022.05.046. Epub 2022 Jul 8.

  PMID: 35810555 RESULT

MeSH Terms

Conditions

Breast Neoplasms; Triple Negative Breast Neoplasms; Fasting; Pathologic Complete Response

Condition Hierarchy (Ancestors)

Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases; Feeding Behavior; Behavior; Disease Progression; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Study Officials

• Maria Vittoria Dieci, MD

  Istituto Oncologico Veneto, Via Gattamelata 64, 35128 Padova, Italy

  PRINCIPAL INVESTIGATOR

• Matteo Lambertini, MD

  IRCCS Ospedale Policlinico San Martino, Largo Rosanna Benzi 10, 16132 Genova

  PRINCIPAL INVESTIGATOR

• Sabino De Placido, MD

  University of Naples Federico II, Via Sergio Pansini 5, 80131 Naples

  PRINCIPAL INVESTIGATOR

• Monica Iorfida, MD

  Istituto Europeo di Oncologia

  PRINCIPAL INVESTIGATOR

• Alberto Zambelli, MD

  Humanitas Research Hospital, Via Alessandro Manzoni 56, 20089 Rozzano

  PRINCIPAL INVESTIGATOR

• Andrea Botticelli, MD

  "Sapienza" University of Rome, 00185, Rome

  PRINCIPAL INVESTIGATOR

• Carla Strina, MD

  A.O. "Istituti Ospitalieri", Viale Concordia 1, 26100 Cremona

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Claudio Vernieri, MD, PhD

CONTACT

0223903066; claudio.vernieri@istitutotumori.mi.it; claudio.vernieri@ifom.eu

Francesca Ligorio, MD

CONTACT

0223903066; francesca.ligorio@istitutotumori.mi.it

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Multicenter, open-label, two-arm, comparative, randomized phase II study

Study Record Dates

• First Submitted: January 18, 2023
• First Posted: March 10, 2023
• Study Start: May 15, 2023
• Primary Completion: May 15, 2025
• Study Completion (Estimated): May 15, 2026
• Last Updated: May 18, 2023

Record last verified: 2022-12

Data Sharing

• IPD Sharing: Will not share

Locations

IT (1)