Trial Title:
Targeting Triple Negative BREAst Cancer Metabolism With a Combination of Chemoimmunotherapy and a FASTing-like Approach in the Preoperative Setting: the BREAKFAST 2 Trial
NCT ID:
NCT05763992
Condition:
Breast Cancer
Triple Negative Breast Cancer
Dietary Exposure
Fasting
Conditions: Official terms:
Breast Neoplasms
Triple Negative Breast Neoplasms
Conditions: Keywords:
Triple Negative Breast Cancer
Neoadjuvant chemoimmunotherapy
Fasting-Like Approach
Immunometabolism
Pathologic Complete Responses (pCRs)
Randomized, phase II trial
Study type:
Interventional
Study phase:
Phase 2
Overall status:
Recruiting
Study design:
Allocation:
Randomized
Intervention model:
Parallel Assignment
Intervention model description:
Multicenter, open-label, two-arm, comparative, randomized phase II study
Primary purpose:
Treatment
Masking:
None (Open Label)
Intervention:
Intervention type:
Dietary Supplement
Intervention name:
Control diet (ARM A) or Fasting-Like Approach (FLA, ARM B)
Description:
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 group label:
Arm A
Arm group label:
Arm B
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.
Detailed description:
TNBC is the most aggressive subtype of breast cancer. TNBC patients who achieve pCR
during neoadjuvant chemo-immunotherapy have significantly lower rates of disease
recurrence or death. Preclinical studies indicate that combining nutrient starvation, in
the form of cycles of FLA, with anthracycline- or platinum-based chemotherapy remarkably
increases the therapeutic index of chemotherapy against murine and human models of breast
cancer, including models of TNBC. In particular, the chemotherapy-fasting/FLA combination
increases the anticancer activity of chemotherapy, while reducing treatment-related
adverse events (AEs). Moreover, the FLA has demonstrated potent and desirable
immunomodulatory effects both in in vivo studies and in patients with cancer, and the
activation of antitumor immunity is a crucial mediator of the anticancer effects of the
FLA, either alone or in combination with chemotherapy. Therefore, there is a strong
biological rationale to combine cyclic FLA with ICIs in cancer therapy.
Based on these data, we hypothesize that combining the FLA with standard-of-care,
preoperative, anthracycline-taxane-carboplatin chemotherapy plus Pembrolizumab can
increase the rate of pCR in a population of patients with stage II-III TNBC.
This is an Italian, multicenter, open-label, two-arm, comparative, randomized phase II
study. This study is designed to investigate if the addition if the experimental
metabolic intervention consisting in cycles of FLA, 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 consisting of
antracycline-taxane-carboplatin-based chemotherapy plus pembrolizumab in patients with
treatment naïve, localized (tumor stage T1c AND nodal stage N1-2, or tumor stage T2-4 AND
nodal stage N0-2) invasive Triple Negative Breast Cancer (HER2 negative, ER <1%, PgR
<1%). Bilateral and/or multifocal primary tumor is allowed, as well as inflammatory
breast cancer, and the tumor with the most advanced T stage should be used to assess the
eligibility. If multi-focal/multi-centric disease, TNBC needs to be confirmed for each
focus. The primary study endpoint is pathologic complete response (pCR).
Patients will be randomly allocated to one of the following treatment arms:
- Arm A (control arm): 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. This
combination treatment will be further referred to as "standard treatment".
- Arm B (experimental arm): standard treatment in combination with up to a maximum of
8 consecutive triweekly cycles of 5-day FLA.
Enrolled patients will be randomized in a 1:1 ratio and stratified according to a)
disease stage: stage II (T1N1, T2N0, T2N1, T3N0) vs. stage III (T3N1; any T4; any N2); b)
patient body mass index (BMI ≥25 kg/m2 vs <25 kg/m2).
After completion of the experimental preoperative protocol, patients will undergo surgery
between 14 and 28 days after the last chemotherapy administration.
After surgery, patients will receive 9 additional triweekly pembrolizumab administration
at the same dosage, and regardless of the pathologic tumor response (pCR yes vs. no).
After surgery, patients may receive local radiotherapy, depending on the pathological
stage and according to local and international guidelines.
Criteria for eligibility:
Criteria:
Inclusion Criteria:
1. Female sex
2. Age ≥ 18 and ≤ 75 years.
3. 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
4. Willingness and ability to comply with the prescribed FLA regimen, the scheduled
visits, treatment plans, laboratory tests and other procedures.
5. 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
6. Availability of a formalin-fixed, paraffin-embedded (FFPE) block containing tumor
tissue, or at least 7 unstained tumor slides.
7. Patients with tumor stage T1c AND nodal stage N1-2, or tumor stage T2-4 AND nodal
stage N0-2 according to TNM.
8. Presence of an Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1.
9. Presence of adequate bone marrow and organ function as defined by the following
laboratory values:
1. ANC ≥ 1.5 x 103/l
2. platelets ≥ 100 x 103/l
3. hemoglobin ≥ 9.0 g/dl
4. calcium (corrected for serum albumin) within normal limits or ≤ grade 1
according to NCI-CTCAE version 5.0 if not clinically significant
5. potassium within the normal limits, or corrected with supplements
6. creatinine < 1.5 ULN
7. blood uric acid < 10 mg/dl
8. ALT and AST ≤ 2 x ULN
9. total bilirubin < 1.5 ULN except for patients with Gilbert syndrome who may
only be included if the total bilirubin is < 3.0 x ULN or direct bilirubin <
1.5 x ULN
10. Fasting glucose ≤ 250 mg/dl.
10. Female patients of childbearing potential must agree to sexual abstinence or to use
two highly effective methods of contraception throughout the study and for at least
six months after the end of the FLA. Abstinence is only acceptable if it is in line
with the preferred and usual lifestyle of the patient. Examples of contraceptive
methods with a failure rate of < 1% per year include tubal ligation, male
sterilization, hormonal implants, established, proper use of combined oral or
injected hormonal contraceptives, and certain intrauterine devices. Alternatively,
two methods (e.g., two barrier methods such as a condom and a cervical cap) may be
combined to achieve a failure rate of < 1% per year. Barrier methods must always be
supplemented with the use of a spermicide. A patient is of childbearing potential
if, in the opinion of the Investigator, she is biologically capable of having
children and is sexually active.
11. Female patients are not of childbearing potential if they meet at least one of the
following criteria:
1. Have undergone a documented hysterectomy and/or bilateral oophorectomy
2. Have medically confirmed ovarian failure
3. Achieved post-menopausal status, defined as: ≥ 12 months of non-therapy-induced
amenorrhea or surgically sterile (absence of ovaries); in women <45 years of
age FSH level in the postmenopausal range may be used to confirm a
post-menopausal state in women not using hormonal contraception or hormonal
replacement therapy.
Exclusion Criteria:
1. 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.
2. Prior treatment with anthracyclines
3. 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)
4. Body mass index (BMI) < 19 kg/m2.
5. History of alcohol abuse.
6. 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.
7. Active pregnancy or breast feeding.
8. 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.
9. 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.
10. 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.
11. Active chronic therapy with systemic steroids at a dose ≥ 10 mg per day of
prednisone or equivalent at study enrollment.
12. 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.
13. Anamnesis of clinically significant heart disease including:
1. angina pectoris, coronary bypass, symptomatic pericarditis, myocardial
infarction in the previous 12 months from the beginning of experimental
therapy;
2. congestive heart failure (NYHA III-IV).
14. Anamnesis of clinically meaningful cardiac arrhythmias, such as ventricular
tachycardia, chronic atrial fibrillation, complete bundle branch block, high grade
atrio-ventricular block like bi-fascicular block, type II Mobitz and third grade
atrio-ventricular block, nodal arrhythmias, supra-ventricular arrhythmia.
15. Left ventricular ejection fraction lower than 50% at the cardiac scan with
radionuclides or at echocardiography.
16. Previous episodes of symptomatic hypotension leading to loss of consciousness.
17. History of eating disorders (anorexia, bulimia).
18. Baseline plasma fasting glucose ≤ 60 mg/dL.
19. Medical or psychiatric comorbidities rendering the patient not candidate to the
clinical trial, according to the investigator's judgement.
20. Other cardiac, liver, lung or renal comorbidities, not specified in the previous
inclusion or exclusion criteria, but potentially exposing the patient to a high risk
of lactic acidosis.
21. Known history of active TB (Bacillus Tuberculosis).
Gender:
Female
Minimum age:
18 Years
Maximum age:
75 Years
Healthy volunteers:
No
Locations:
Facility:
Name:
Fondazione IRCCS Istituto Nazionale dei Tumori
Address:
City:
Milan
Country:
Italy
Status:
Recruiting
Contact:
Last name:
Claudio Vernieri
Email:
claudio.vernieri@istitutotumori.mi.it
Contact backup:
Last name:
Francesca Ligorio
Email:
francesca.ligorio@istitutotumori.mi.it
Start date:
May 15, 2023
Completion date:
May 15, 2026
Lead sponsor:
Agency:
Fondazione IRCCS Istituto Nazionale dei Tumori, Milano
Agency class:
Other
Collaborator:
Agency:
Istituto Oncologico Veneto IRCCS
Agency class:
Other
Collaborator:
Agency:
Ospedale Policlinico San Martino
Agency class:
Other
Collaborator:
Agency:
Federico II University
Agency class:
Other
Collaborator:
Agency:
Azienda Policlinico Umberto I
Agency class:
Other
Collaborator:
Agency:
European Institute of Oncology
Agency class:
Other
Collaborator:
Agency:
Ospedale "Carlo Poma" - Mantova
Agency class:
Other
Collaborator:
Agency:
Humanitas Clinical and Research Center
Agency class:
Other
Source:
Fondazione IRCCS Istituto Nazionale dei Tumori, Milano
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT05763992
