Capecitabine with or without Tetrathiomolybdate and Pembrolizumab for the Treatment of Triple Negative Breast Cancer at High Risk for Relapse
This phase I/II trial tests the safety, side effects, best dose and how well giving capecitabine with or without tetrathiomolybdate and pembrolizumab works to treat patients with triple negative breast cancer that is at high risk for coming back after a period of improvement (relapse). Capecitabine is in a class of medications called antimetabolites. It is taken up by cancer cells and breaks down into fluorouracil, a substance that kills cancer cells. Tetrathiomolybdate works by lowering the amount of copper in the blood to a level where normal cell functioning can take place, but does not help the cancer to spread. Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving capecitabine with or without tetrathiomolybdate and pembrolizumab may be safe and effective in treating patients with triple negative breast cancer that is at high risk of relapse.
Inclusion Criteria
- Participants must have histologically confirmed breast malignancy that is a triple negative tumor defined as estrogen receptor (ER) and progesterone receptor (PR) < 1% and HER2 negative as per American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guidelines
- The patient must have completed standard neoadjuvant chemotherapy which constitutes at least 6 cycles of chemotherapy
- PHASE IB: Participants must have residual invasive carcinoma, at minimum in one of the following capacities: * Node positive disease after treatment without residual invasive carcinoma in the breast * RCB 2 or RCB 3 MD Anderson Health (MDAH) Calculator Standard therapy consists of the following: * Local therapy: ** Lumpectomy or mastectomy to negative margins ** Sentinel lymph node biopsy or axillary node dissection ** Radiation therapy to breast if patient received a lumpectomy and per investigator choice if considering chest wall/extended field radiation therapy (RT) * Systemic therapy: ** Prior chemotherapy is required for patients entered on the trial. Neoadjuvant treatment should consist of the following standard therapy: Anthracycline and taxane based therapy (i.e. adriamycin, cytoxan (AC)->taxol (T), AC->T carboplatin (carbo), Keynote 522 regimen) or a non-anthracycline based chemo and immunotherapy regimen (NeoPACT). Participants must have received neoadjuvant pembrolizumab for the phase Ib only and plan to continue it in the adjuvant setting for at least the first cycle of treatment
- RANDOMIZED PHASE 2: Participants must have residual invasive carcinoma, at minimum in one of the following capacities: * Node positive disease after treatment without residual invasive carcinoma in the breast * RCB 2 or RCB 3 MDAH Calculator * Standard therapy consists of the following: ** Local therapy: *** Lumpectomy or mastectomy to negative margins *** Sentinel lymph node biopsy or axillary node dissection *** Radiation therapy to breast if patient received a lumpectomy and per investigator choice if considering chest wall/extended field RT. ** Systemic therapy: Prior chemotherapy is required for patients entered on the trial. Neoadjuvant treatment should consist of the following standard therapy: Anthracycline and taxane-based therapy (i.e. AC->T, AC->Tcarbo, Keynote 522 regimen) or a non-anthracycline based chemo and immunotherapy regimen (NeoPACT). Pembrolizumab is allowed. Participants will be stratified by: * Treatment (chemotherapy vs chemotherapy + immunotherapy) * Age (Age ≤ 40 yrs vs > 40 yrs); and * RCB 2 vs RCB 3 These important stratification factors represent variables that are known to affect outcome for patients with triple negative breast cancer (TNBC).
- At least two weeks must have elapsed from last chemotherapy or radiation therapy. At least 4 weeks must have elapsed from most recent surgery
- Karnofsky performance status (KPS) 90 or 100
- Life expectancy of greater than 3 months
- Hemoglobin ≥ 10mg/dL
- Absolute neutrophil count ≥ 1,500/ µL
- Platelets ≥ 100,000/µL
- Total bilirubin ≤ 1.5 x normal institutional limits
- Aspartate aminotransferase (AST)(serum glutamic oxaloacetic transaminase [SGOT])/ alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT]) ≤ 1.5 X institutional upper limit of normal
- Estimated creatinine clearance ≥ 60 ml/min
- Antiresorptive therapy and denosumab may be administered
- Participants must be on stable medical therapy for at least 2 weeks if they are being treated medically for their chemotherapy induced peripheral neuropathy
- The effects of TM on the developing human fetus are unknown. For this reason, females of childbearing potential and males must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence of vaginal intercourse if the participant or their partner is of childbearing potential) prior to study entry, for the duration of study treatment and one month after the end of study treatment. Participants must also agree to not donate sperm or ova prior to study entry and for the duration of study treatment and one month after the end of study treatment. Should a female become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately
- Ability to understand and the willingness to sign a written informed consent document
- Normal B12 levels
Exclusion Criteria
- Participants who have received capecitabine or who are on warfarin, copper containing vitamins or supplements, or prophylactic colony-stimulating factors (i.e., granulocyte colony-stimulating factor [GCSF], etc.)
- Participants with clinical or radiologic evidence of disease after surgery and/or systemic treatment (by CT scan of chest, abdomen and pelvis and bone scan or PET scan prior to enrollment),including metastatic disease, carcinomatous meningitis or active parenchymal brain metastases
- Participants who had their final breast surgery more than 18 weeks prior to study start
- Participants with known BRCA mutations in whom treatment with adjuvant Olaparib is planned
- If a participant has already had dihydropyrimidine dehydrogenase (DYPD) testing and has a known mutation (however DYPD testing is not required for the trial)
- History of allergic reactions attributed to compounds of similar chemical or biologic composition to TM or capecitabine
- Pregnant females are excluded from this study because TM has the potential to have teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with TM, breastfeeding should be discontinued if the mother is treated with TM
- Because no dosing or adverse event data are currently available on the use of TM in patients <18 years of age, children are excluded from this study
- Participants who are receiving protease inhibitors. Because patients with immune deficiency are at increased risk of lethal infections when treated with marrow suppressive therapy, HIV-positive patients receiving combination anti- retroviral therapy are excluded from the study because of possible pharmacokinetic interactions of protease inhibitors with TM. Similarly, participants who are receiving protease inhibitors to treat hepatitis C are excluded from the study
Additional locations may be listed on ClinicalTrials.gov for NCT06134375.
Locations matching your search criteria
United States
New Hampshire
Lebanon
PRIMARY OBJECTIVES:
I. To establish the safety of the combination of adjuvant tetrathiomolybdate with capecitabine and pembrolizumab administered to patients with triple negative breast cancer after completion of neoadjuvant chemotherapy and with a non-pathologic complete response (pCR) (residual cancer burden [RCB] 2, 3 or node positive) after standard surgery. (Phase Ib)
II. To assess the efficacy and safety of adjuvant capecitabine and tetrathiomolybdate plus (+)/minus (-) pembrolizumab versus adjuvant capecitabine +/- pembrolizumab in patients with triple negative breast cancer after completion of neoadjuvant chemotherapy and with a non-pCR (RCB 2, 3 or node positive) after standard surgery. (Phase II)
SECONDARY OBJECTIVES:
I. To investigate distant relapse-free survival (DRFS). (Phase Ib)
II. To evaluate the pharmacokinetics of capecitabine, pembrolizumab and tetrathiomolybdate (TM). (Phase Ib)
III. To compare overall survival (OS) and invasive disease-free survival (iDFS) between the two arms. (Phase II)
IV. To assess the toxicity of capecitabine and tetrathiomolybdate +/- pembrolizumab versus capecitabine alone+/- pembrolizumab. (Phase II)
V. To compare OS and iDFS in patients that complete at least 6 months of TM and capecitabine therapy versus capecitabine alone (+/- pembrolizumab for each arm). (Phase II)
VI. To measure the effect of copper depletion on serial blood-based biomarkers including:
VIa. Vascular endothelial growth factor 2 plus endothelial progenitor cells (VEGFR2+ EPCs);
VIb. Lysyl oxidaseL-2 (LOXL-2);
VIc. Circulating tumor deoxyribonucleic acid (ctDNA);
VId. Other biomarkers in process of validation. (Phase II)
VII. To evaluate patient-reported quality of life (PROs) including oral, gastrointestinal, cutaneous, neurological, and treatment-related symptoms. (Phase II)
VIII. To evaluate the pharmacokinetics in a sub-study cohort of patients modeled on data from the phase 1b. (Phase II)
EXPLORATORY OBJECTIVES:
I. To assess single nucleotide polymorphisms of the ceruloplasmin gene and CTR1 and correlate it to the ability to be copper depleted with tetrathiomolybdate.
II. To assess the presence of ATOX 1 in primary breast tumor samples and its association with outcome (DRFS and OS).
III. To investigate the ability of copper depletion to affect markers of collagen remodeling including C1M, ProC3 and C6M and outcome (DRFS, OS).
IV. To investigate the effect of copper depletion on the metabolic profile of patients enrolled in the trial.
V. To evaluate adherence to oral therapy in patients receiving capecitabine and TM and patient reported outcomes, including the relationship between adherence and invasive disease-free survival, and to explore associations between adherence and demographic variables, clinical variables, and patient reported outcome (PRO) quality of life measures.
OUTLINE: This is a phase I, dose-escalation study of tetrathiomolybdate in combination with capecitabine and pembrolizumab followed by a phase II study.
PHASE IB: Patients receive tetrathiomolybdate orally (PO) twice daily (BID) on days 1-21 and capecitabine PO BID on days 1-14 of each cycle. Patients also receive pembrolizumab intravenously (IV) every 3 or 6 weeks per physician's discretion. Cycles repeat every 21 days for 6 months for capecitabine, 3 years for tetrathiomolybdate, and at least 1 cycle and subsequently per physician's discretion in the absence of disease progression or unacceptable toxicity. Patients undergo computed tomography (CT) scan, and blood sample collection and may undergo positron emission tomography (PET) and/or bone scan throughout the study.
PHASE II: Patients are randomized to 1 of 2 arms.
ARM I: Patients receive tetrathiomolybdate PO BID on days 1-21 and capecitabine PO BID on days 1-14 of each cycle. Cycles repeat every 21 days for 6 months for capecitabine and 3 years for tetrathiomolybdate in the absence of disease progression or unacceptable toxicity. If patients received pembrolizumab as part of neoadjuvant therapy, they may continue to receive pembrolizumab IV every 3 or 6 weeks per physician's discretion for 1 year in the absence of disease progression or unacceptable toxicity. Patients undergo CT scan, and blood sample collection and may undergo PET and/or bone scan throughout the study.
ARM II: Patients receive capecitabine PO BID on days 1-14 of each cycle. Cycles repeat every 21 days for 6 months in the absence of disease progression or unacceptable toxicity. If patients received pembrolizumab as part of neoadjuvant therapy, they may continue to receive pembrolizumab IV every 3 or 6 weeks per physicians discretion for 1 year in the absence of disease progression or unacceptable toxicity. Patients undergo CT scan, and blood sample collection and may undergo PET and/or bone scan throughout the study.
After completion of study treatment, patients are followed up every 6 months for 5 years.
Trial PhasePhase I/II
Trial Typetreatment
Lead OrganizationDartmouth Hitchcock Medical Center/Dartmouth Cancer Center
Principal InvestigatorLinda T Vahdat
- Primary IDStudy02001837
- Secondary IDsNCI-2025-05879, 22VAH837
- ClinicalTrials.gov IDNCT06134375