A Study of Tetrathiomolybdate (TM) Plus Capecitabine

NCT06134375 | Recruiting Phase 1 DMC FDA Drug

• 5 other identifiers: STUDY02001837R01CA290013CDMRP-eBRAP BC24034522VAH837NCI-2025-05879
• Study Type: interventional
• Target: 204
• Locations: 1 country
• Sites: 3

Brief Summary

There are two parts to this study. It is a phase 1b followed by a randomized phase 2 study to assess whether adding 3 years of adjuvant tetrathiomolybdate (TM) to standard 6 months treatment of adjuvant capecitabine and pembrolizumab in high risk for relapse triple negative breast cancer. In the phase 1b part of the study, TM is added to adjuvant capecitabine and pembrolizumab in high risk for relapse triple negative breast cancer (RCB 2, 3, risk for relapse \>60% at 5 years) after completion of neoadjuvant chemo-immunotherapy and surgery to establish the safety of the combination. This will be followed by a randomized phase 2 clinical trial of adjuvant TM and capecitabine vs capecitabine alone. If pembrolizumab was administered in the neoadjuvant setting, it may be continued in the adjuvant setting per investigator discretion.

Conditions

Triple Negative Breast Cancer; Residual Disease

Keywords

Triple Negative Breast cancer; Residual Disease

Outcome Measures

Primary Outcomes (2)

• Phase 1b: To establish the safety of the combination of adjuvant tetrathiomolybdate with capecitabine and pembrolizumab by the number of dose limiting toxicities

  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-pCR (RCB 2, 3) after standard surgery. The safe dose is defined as the dose level at which no more than 1 out of 6 patients has a DLT on Cycle 1. A dose limiting toxicity (DLT) is defined as a grade 3 hematologic toxicity or non-hematologic toxicity excluding hand foot syndrome, mucositis, or diarrhea. The DLT window is 4 weeks. All toxicities will be summarized.

  3 years

• Phase 2: Distant relapse-free survival (DRFS) between TM and capecitabine versus capecitabine as measured with the STEEP system

  The primary endpoint of this study is distant relapse-free survival (DRFS) between TM and capecitabine versus capecitabine. The continued use of adjuvant immunotherapy with pembrolizumab is left to investigator choice. DRFS is defined in accordance with the STEEP system. This definition of DRFS, includes the following as events: distant recurrence, death from breast cancer, death from non-breast cancer or unknown causes, or any second primary invasive cancer. DRFS will be compared by arm in each of the two RCB groups separately using time-to-event analytic methods such as the log-rank test and Cox regression.

  10 years

Secondary Outcomes (9)

• Phase 1b: Distant Relapse free survival (DRFS) between TM, capecitabine and pembrolizumab versus capecitabine and pembrolizumab as measured with the STEEP system

  3 years

• Phase 1b: Plasma concentrations of capecitabine, pembrolizumab and TM will be performed in a sub cohort of at least nine patients enrolled in the phase 1b part of this study

  3 years

• Phase 2: Overall Survival compared by arm in each of the two RCB groups separately

  10 years

• Phase 2: invasive disease-free survival compared by arm in each of the two RCB groups separately

  10 years

• Phase 2: Number of participants with treatment-related adverse events as assessed by CTCAE v5.0 comparing capecitabine and tetrathiomolybdate +/- pembrolizumab versus capecitabine alone +/- pembrolizumab

  5 years

Study Arms (2)

TM and Capecitabine with or without Pembrolizumab

EXPERIMENTAL

Tetrathiomolybdate (TM) and Capecitabine +/- Pembrolizumab will be administered concurrently for 6 months, TM will continue for 2.5 more years (total duration of TM treatment is 3 years)

Drug: Tetrathiomolybdate; Drug: Capecitabine; Drug: Pembrolizumab

Capecitabine with or without Pembrolizumab

ACTIVE COMPARATOR

Capecitabine +/- Pembrolizumab will be administered for 6 months (participants will remain on study for 2.5 more years).

Drug: Capecitabine; Drug: Pembrolizumab

Interventions

Tetrathiomolybdate DRUG

Tetrathiomolybdate (TM): Ammonium tetrathiomolybdate (TM), an oral copper lowering agent, has been established as safe in patients with Wilson's disease and advanced cancer. TM forms stable copper-molybdenum clusters sequestering copper and thereby limiting its availability, for the proper functioning of angiogenic factors, including secreted metalloenzymes. TM inhibits several copper containing enzymes including ceruloplasmin, cytochrome oxidase, tyrosinase and downregulates cytokines such as MMP9 and VEGF as well as transcription factors such as NF-kB. Both pre-clinical and clinical data suggest that TM may effectively reduce both overt and sub-clinical tumor load by both targeting the metastases initiating stem cell component of primary tumors inactivating Complex IV, shifting oxphos to glycolysis and through stromal remodeling.

Also known as: TM

TM and Capecitabine with or without Pembrolizumab

Capecitabine DRUG

1000mg/m2 twice daily, Days 1-14 Q21days for 6 months

Also known as: Xeloda

Capecitabine with or without Pembrolizumab; TM and Capecitabine with or without Pembrolizumab

Pembrolizumab DRUG

If pembrolizumab was administered in the neoadjuvant setting and the oncology team chooses to continue in the adjuvant setting, standard doses will be used (200 mg IV Q3weeks or 400 mg IV Q6 weeks for one year total as per package insert)

Also known as: Keytruda

Capecitabine with or without Pembrolizumab; TM and Capecitabine with or without Pembrolizumab

Eligibility Criteria

• Age: 18 Years - 80 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients must have histologically confirmed breast malignancy that is Triple negative tumors as defined as ER and PR \<1% and HER2 negative as per ASCO/CAP guidelines
• The patient must have completed standard neoadjuvant chemotherapy which constitutes at least 6 cycles of chemotherapy.
• Phase Ib: Patients must have residual invasive carcinoma, at minimum in one of the following capacities: (1) node positive disease after treatment without residual invasive carcinoma in the breast; (2) RCB 2 or RCB 3 MDAH Calculator; Standard therapy consists of the following: (1) Local therapy: (a) Lumpectomy or mastectomy to negative margins. (b) Sentinel lymph node biopsy or axillary node dissection; (c) Radiation therapy to breast if patient received a lumpectomy and per investigator choice if considering chest wall/extended field RT. (2) 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). Patients 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: Patients must have residual invasive carcinoma, at minimum in one of the following capacities: (1) node positive disease after treatment without residual invasive carcinoma in the breast; (2) RCB 2 or RCB 3 MDAH Calculator; Standard therapy consists of the following: (1) Local therapy: (a) Lumpectomy or mastectomy to negative margins. (b) Sentinel lymph node biopsy or axillary node dissection; (c) Radiation therapy to breast if patient received a lumpectomy and per investigator choice if considering chest wall/extended field RT. (2) 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. Patients will be stratified by: (1) Treatment (chemotherapy vs chemotherapy + immunotherapy); (2) Age (Age ≤ 40 yrs vs \> 40 yrs); and (3) RCB 2 vs RCB 3. These important stratification factors represent variables that are known to affect outcome for patients with 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.
• No 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).
• Previous treatment with capecitabine is not allowed.
• 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.
• KPS 90 or 100.
• Life expectancy of greater than 3 months.
• Patients must have normal organ and marrow function as defined below:
• hemoglobin \>10mg/dL
• absolute neutrophil count \>1,500/ µL
• platelets \>100,000/µL
• total bilirubin \<1.5 x normal institutional limits

You may not qualify if:

• Patients who have had chemotherapy or radiotherapy within 2 weeks prior to entering the study. Patients who have had surgery within 4 weeks.
• Patients who have received capecitabine or who are on warfarin
• Patients who had their final breast surgery more than 12 weeks prior to study start.
• Phase Ib: patients who have not received neoadjuvant immunotherapy and/or do not plan to continue treatment with immunotherapy for at least the first cycle of study treatment.
• Objective evidence of breast cancer.
• Metastatic disease
• Carcinomatous meningitis or active parenchymal brain metastases.
• Estimated creatinine clearance \< 60 ml/min
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to TM or capecitabine.
• Pregnant women 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 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 with TM.

Sponsors & Collaborators

• Dartmouth-Hitchcock Medical Center: lead
• National Cancer Institute (NCI): collaborator
• Congressionally Directed Medical Research Programs: collaborator

Study Sites (3)

Indiana University Simon Cancer Center

Indianapolis, Indiana, 46202, United States

NOT YET RECRUITING

Dartmouth Hitchcock Medical Center

Lebanon, New Hampshire, 03756, United States

RECRUITING

NYU Langone perimutter Cancer Center

New York, New York, 10016, United States

RECRUITING

MeSH Terms

Conditions

Triple Negative Breast Neoplasms; Neoplasm, Residual

Interventions

tetrathiomolybdate; Capecitabine; pembrolizumab

Condition Hierarchy (Ancestors)

Breast Neoplasms; Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases; Neoplastic Processes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Deoxycytidine; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Fluorouracil; Uracil; Pyrimidinones; Deoxyribonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides

Study Officials

• Linda Vahdat, MD

  Study Principal Investigator

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Raven J Lavoie, RN

CONTACT

(603) 653-3661; Raven.M.Lavoie@hitchcock.org

Naomi Kornhauser, MPH

CONTACT

naomi.t.kornhauser@hitchcock.org

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Model Details: Phase 1 portion is single group. Phase 2 portion is parallel.

Study Record Dates

• First Submitted: October 3, 2023
• First Posted: November 18, 2023
• Study Start: November 26, 2024
• Primary Completion (Estimated): June 26, 2031
• Study Completion (Estimated): June 26, 2036
• Last Updated: April 20, 2026

Record last verified: 2026-01

Data Sharing

• IPD Sharing: Will not share

Locations

US (3)