Triple Negative Breast CancerPhase 1/2NCT06134375
A Study of Tetrathiomolybdate (TM) Plus Capecitabine
A Phase 1/2 study testing Tetrathiomolybdate, Capecitabine and Pembrolizumab in people with Triple Negative Breast Cancer and Residual Disease, run by Dartmouth-Hitchcock Medical Center at 3 sites in United States.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 to 80 years
- Conditions the study is for
- Triple Negative Breast Cancer, Residual Disease
- What is being tested?
- Tetrathiomolybdate, Capecitabine and Pembrolizumab
- Type of treatment
- Pill or oral medicine, Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 204 participants
- Where
- 3 sitesUnited States
- Study dates
- 26 Nov 2024to 26 Jun 2036
- Phase
- Phase 1/2
- Are there results?
- Not yet: the study is under way
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 80 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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).
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- 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
- AST (SGOT)/ALT (SGPT) <1.5 X institutional upper limit of normal
- Antiresorptive therapy and denosumab may be administered.
- Patients 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, women of childbearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. Should a woman 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.
Who cannot join
- 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
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- 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.
Trial locations and contacts
3 sites in 1 country. Contact the study team or a site near you to ask about taking part.
Naomi Kornhauser, MPH contact
United States3 sites, 3 recruiting
- Not yet recruiting
Indiana University Simon Cancer Center
Indianapolis, Indiana, 46202
Bryan Schneider, MD
- Recruiting
Dartmouth Hitchcock Medical Center
Lebanon, New Hampshire, 03756
Raven Lavoie, (603) 653-3661, Raven.M.Lavoie@hitchcock.org
Naomi Kornhauser, Naomi.T.Kornhauser@hitchcock.org
- Recruiting
NYU Langone perimutter Cancer Center
New York, New York, 10016
Nancy Chan, MD, 212-731-5349, Nancy.chan29@nyulangone.org
Nancy Chen, MD
About this study
Official title: Novel Targeting of the Microenvironment to Decrease Metastatic Recurrence of High-Risk TNBC: A Randomized Phase II Study of Tetrathiomolybdate (TM) Plus Capecitabine in Patients With Breast Cancer at High Risk of Recurrence
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.
Read the detailed description
Scientific Rationale for the study design: Copper depletion is designed to be a complement to standard therapy to overcome resistance mechanisms hence it would be optimal to combine it with standard adjuvant therapy which at the current time is capecitabine and pembrolizumab.
Study Design:
Phase 1b: Patients with triple negative breast cancer who have completed standard neoadjuvant therapy (chemotherapy + pembrolizumab) and who have residual disease at RCB 2, 3 will start adjuvant therapy with standard dose capecitabine, standard dose pembrolizumab and tetrathiomolybdate (TM). Patients must have received neoadjuvant immunotherapy (pembrolizumab) and wish to continue adjuvant immunotherapy for at least one cycle on trial. The capecitabine will be for 6 months with concurrent TM and TM will continue for an additional 2.5 years (for a total of 3 years of treatment). Patients must stay on immunotherapy for at least the first cycle of the study and subsequently as per physician's choice.
This phase of the study is designed to assess safety of TM with capecitabine + immunotherapy (pembrolizumab) as adjuvant therapy for TNBC.
With a standard 3+3 design, the maximum possible total number of patients is 18.
Randomized Phase 2: Patients with triple negative breast cancer who have completed standard neoadjuvant therapy (chemotherapy +/- pembrolizumab) and who have residual disease at RCB 2, 3 will start adjuvant therapy with standard dose capecitabine or capecitabine and tetrathiomolybdate (TM). If they received neoadjuvant pembrolizumab and wish to continue adjuvant immunotherapy, they may continue. The capecitabine will be for 6 months with concurrent TM and TM will continue for an additional 2.5 years (for a total of 3 years of treatment). If they elect to continue immunotherapy, then they should complete one year total or as per physician's choice.
Patients will be randomized with a 1:1 allocation ratio between the two treatment arms.
There will be at most 186 patients accrued to account for 10% loss to follow-up over the course of the approximately 5-year study period.
Study Treatment:
Phase 1b:
- Induction Phase TM dose: as per dose escalation nomogram. Dose Level 1 is 140 mg a day (TM 100 mg + 40 mg QHS) Ceruloplasmin (Cp) target: Will be done at local lab. The Cp target goal is to be 1-6 mg/dL below the lower limit of normal for the reference lab (see Section 7.1).
Capecitabine Dose: 1000 mg per square meter of body-surface area, twice per day, on days 1 to 14 every 3 weeks.
Pembrolizumab: Standard doses will be used (200 mg IV Q3 weeks or 400 mg IV Q6 weeks
- Maintenance Phase TM dose: as per dose escalation nomogram Dose Level 1 is 100 mg a day (TM 100 mg daily) Cp target: Will be done at local lab. Goal is to be 1-6 mg/dL below the lower limit of normal for the reference lab (see Section 7.1). TM dosed according to Cp level and ANC in 20mg TM capsule increments.
Capecitabine Dose: 1000 mg per square meter of body-surface area, twice per day, on days 1 to 14 every 3 weeks for a total of 6 months Pembrolizumab: Standard doses will be used (200 mg IV Q3 weeks or 400 mg IV Q6 weeks for one year total as per package insert or per physician's choice).
Study Duration: TM and capecitabine and pembrolizumab will be administered concurrently for 6 months, and the TM will continue for an additional 2.5 years (total duration of TM treatment is 3 years).
If no DLT is observed at dose level +2 then that is the dose that will proceed to the randomized phase 2 portion of the study.
Randomized Phase 2:
- Randomization: Patients will be randomized 1:1 to the combination of Capecitabine and TM vs. Capecitabine. 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 or per physician's choice)
- Induction Phase TM dose: Will be determined in phase 1b part of this study. If no DLT noted at dose level 2, then will proceed with TM dose 180 mg a day (TM 100 mg qAM + 80 mg QHS) Cp target: Will be done at local lab. Goal is to be 1-6 mg/dL below the lower limit of normal for the reference lab (see Section 7.1) Capecitabine Dose: 1000 mg per square meter of body-surface area, twice per day, on days 1 to 14 every 3 weeks for a total of 6 months Pembrolizumab: optional as per physician's choice. Standard doses will be used (200 mg IV Q3weeks or 400 mg IV Q6 weeks for one year total per package insert or per physician's choice
- Maintenance Phase TM dose: Will be determined in phase 1b part of this study. If no DLT noted at dose level 2, then will proceed with TM dose 100 mg a day (TM 100 mg QD) Cp target: Will be done at local lab. Goal is to be 1-6 mg/dL below the lower limit of normal for the reference lab (see Section 7.1). TM dosed according to Cp level and ANC in 20mg TM capsule increments.
Capecitabine Dose: 1000 mg per square meter of body-surface area, twice per day, on days 1 to 14 every 3 weeks for a total of 6 months Pembrolizumab: optional as per physician's choice. Standard doses will be used (200 mg IV Q3weeks or 400 mg IV Q6 weeks for one year total per package insert or per physician's choice.
Study Duration: TM and capecitabine will be administered concurrently for 6 months, and the TM will continue for an additional 2.5 years (total duration of TM treatment is 3 years). Pembrolizumab is optional and should be administered according to standard guidelines.
- Conditions
- Triple Negative Breast Cancer, Residual Disease
- Being tested
- Tetrathiomolybdate, Capecitabine, Pembrolizumab
- Keywords
- Triple Negative Breast cancer, Residual Disease
- Medical subject headings
- Triple Negative Breast Neoplasms, Neoplasm, Residual
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
TetrathiomolybdateDrug
Also called TM
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.
CapecitabineDrug
Also called Xeloda
1000mg/m2 twice daily, Days 1-14 Q21days for 6 months
PembrolizumabDrug
Also called Keytruda
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)
| Study group | Role | What they receive |
|---|---|---|
| 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) Receives: 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). Receives: Drug: Capecitabine; Drug: Pembrolizumab |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 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.
Measured: 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
Distant Relapse free survival (DRFS) between TM, capecitabine and pembrolizumab versus capecitabine and pembrolizumab. 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. This will be analyzed descriptively due to small sample sizes and possibly different dose levels.
Measured: 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
Pharmacokinetics of capecitabine, pembrolizumab and TM. Capecitabine and 5 fluoro-uracil will be measured in plasma and 5FU intracellular nucleotides will be measured in PBMCs. Plasma pembrolizumab concentrations will be measured using the commercially available ELISA assay.
Measured: 3 years
Phase 2: Overall Survival compared by arm in each of the two RCB groups separately
Overall survival (OS) between the two arms via the Kaplan-Meier method
Measured: 10 years
Phase 2: invasive disease-free survival compared by arm in each of the two RCB groups separately
Invasive disease-free survival (iDFS) between the two arms via the Kaplan-Meier method
Measured: 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
Treatment-related adverse events comparing capecitabine and tetrathiomolybdate +/- pembrolizumab versus capecitabine alone +/- pembrolizumab. Safety will be described by calculating the frequencies and 95% confidence intervals for each adverse event, with the maximum grade per toxicity serving as the patient-specific summary measure. Safety in terms on adverse events will be described over the entire time period, in addition to specific time periods (after 1 year, 2 and 3 years after the start of therapy) to evaluate late onset adverse events.
Measured: 5 years
Phase 2: Survival in patients that complete at least 6 months of treatment
Overall survival (OS) and invasive disease-free survival (iDFS) in patients that complete at least 6 months of TM and capecitabine therapy versus capecitabine alone (+/- pembrolizumab for each arm) (enough time to be copper depleted) via the Kaplan-Meier method
Measured: 10 years
Phase 2: Effect of copper depletion on serial blood-based biomarkers
Effect of copper depletion on serial blood-based biomarkers including: VEGFR2+ EPCs, LOXL-2, ctDNA, other biomarkers in process of validation by correlation coefficients
Measured: 5 years
Phase 2: Patient-reported quality of life measurements to assess whether the addition of TM to capecitabine impacts health-related quality of life and differ between arms over time
Patient-reported quality of life (PROs) including: oral, gastrointestinal, cutaneous, neurological, and treatment-related symptoms will be assessed every 16 weeks in both arms through surveys. The questionnaire uses a 5-point Likert scale to assess severity with a scale from none, never, not at all, etc. to very much, constantly, very severe, etc. or yes and no. Separate mixed linear models will be conducted for each symptom to compare the average difference between the randomized arms.
Measured: 5 years
Phase 2: Plasma concentrations of capecitabine, pembrolizumab and TM will be performed in a sub cohort of patients enrolled in the randomized phase 2 part of this study
Based on the phase 1b pharmacokinetics analyses, a population pharmacokinetic sampling schema will be developed for a sub cohort (the number of participants will be determined based on the phase 1b results) in the randomized phase 2 part of the study. Pharmacokinetics of capecitabine, pembrolizumab and TM. Capecitabine and 5 fluoro-uracil will be measured in plasma and 5FU intracellular nucleotides will be measured in PBMCs. Plasma pembrolizumab concentrations will be measured using the commercially available ELISA assay.
Measured: 5 years
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted18 Nov 2023
- Study start26 Nov 2024
- Primary completion26 Jun 2031 (estimated)
- Study completion26 Jun 2036 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Triple Negative Breast CancerStudies of the same condition, open and under way.
- More trials run by Dartmouth-Hitchcock Medical CenterThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1/2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Model description
- Phase 1 portion is single group. Phase 2 portion is parallel.
- Masking
- None (open label)
- Enrolment
- 204 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Dartmouth-Hitchcock Medical Center
- Sponsor type
- University, hospital or other
- Collaborators
- National Cancer Institute (NCI), Congressionally Directed Medical Research Programs
- Responsible party
- Principal investigator, Linda.T.Vahdat, Dartmouth-Hitchcock Medical Center
- Investigators
- Linda Vahdat, MD, Principal investigator, Study Principal Investigator
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT06134375
- Sponsor's protocol ID
- STUDY02001837
- Other IDs
- R01CA290013, CDMRP-eBRAP BC240345, 22VAH837, NCI-2025-05879
- Status last verified
- Jan 2026
- First submitted
- 3 Oct 2023
- Last updated
- 20 Apr 2026
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- No
Study at a glance
From the registry record, last updated by the sponsor on 20 Apr 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Novel Targeting of the Microenvironment to Decrease Metastatic Recurrence of High-Risk TNBC: A Randomized Phase II Study of Tetrathiomolybdate (TM) Plus Capecitabine in Patients With Breast Cancer at High Risk of Recurrence
- ClinicalTrials.gov ID
- NCT06134375
- Acronym / sponsor ID
- STUDY02001837
- Conditions
- Triple Negative Breast Cancer, Residual Disease
- Keywords
- Triple Negative Breast cancer, Residual Disease
- Phase
- Phase 1/2
- Study type
- Interventional
- Recruitment status
- Recruiting
- Enrolment
- 204 participants (estimated)
- Lead sponsor
- Dartmouth-Hitchcock Medical CenterUniversity, hospital or other
- Collaborators
- National Cancer Institute (NCI), Congressionally Directed Medical Research Programs
- Study start
- 26 Nov 2024 (actual)
- Primary completion
- 26 Jun 2031 (estimated)
- Study completion
- 26 Jun 2036 (estimated)
- First posted
- 18 Nov 2023 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Detailed description
Scientific Rationale for the study design: Copper depletion is designed to be a complement to standard therapy to overcome resistance mechanisms hence it would be optimal to combine it with standard adjuvant therapy which at the current time is capecitabine and pembrolizumab.
Study Design:
Phase 1b: Patients with triple negative breast cancer who have completed standard neoadjuvant therapy (chemotherapy + pembrolizumab) and who have residual disease at RCB 2, 3 will start adjuvant therapy with standard dose capecitabine, standard dose pembrolizumab and tetrathiomolybdate (TM). Patients must have received neoadjuvant immunotherapy (pembrolizumab) and wish to continue adjuvant immunotherapy for at least one cycle on trial. The capecitabine will be for 6 months with concurrent TM and TM will continue for an additional 2.5 years (for a total of 3 years of treatment). Patients must stay on immunotherapy for at least the first cycle of the study and subsequently as per physician's choice.
This phase of the study is designed to assess safety of TM with capecitabine + immunotherapy (pembrolizumab) as adjuvant therapy for TNBC.
With a standard 3+3 design, the maximum possible total number of patients is 18.
Randomized Phase 2: Patients with triple negative breast cancer who have completed standard neoadjuvant therapy (chemotherapy +/- pembrolizumab) and who have residual disease at RCB 2, 3 will start adjuvant therapy with standard dose capecitabine or capecitabine and tetrathiomolybdate (TM). If they received neoadjuvant pembrolizumab and wish to continue adjuvant immunotherapy, they may continue. The capecitabine will be for 6 months with concurrent TM and TM will continue for an additional 2.5 years (for a total of 3 years of treatment). If they elect to continue immunotherapy, then they should complete one year total or as per physician's choice.
Patients will be randomized with a 1:1 allocation ratio between the two treatment arms.
There will be at most 186 patients accrued to account for 10% loss to follow-up over the course of the approximately 5-year study period.
Study Treatment:
Phase 1b:
- Induction Phase TM dose: as per dose escalation nomogram. Dose Level 1 is 140 mg a day (TM 100 mg + 40 mg QHS) Ceruloplasmin (Cp) target: Will be done at local lab. The Cp target goal is to be 1-6 mg/dL below the lower limit of normal for the reference lab (see Section 7.1).
Capecitabine Dose: 1000 mg per square meter of body-surface area, twice per day, on days 1 to 14 every 3 weeks.
Pembrolizumab: Standard doses will be used (200 mg IV Q3 weeks or 400 mg IV Q6 weeks
- Maintenance Phase TM dose: as per dose escalation nomogram Dose Level 1 is 100 mg a day (TM 100 mg daily) Cp target: Will be done at local lab. Goal is to be 1-6 mg/dL below the lower limit of normal for the reference lab (see Section 7.1). TM dosed according to Cp level and ANC in 20mg TM capsule increments.
Capecitabine Dose: 1000 mg per square meter of body-surface area, twice per day, on days 1 to 14 every 3 weeks for a total of 6 months Pembrolizumab: Standard doses will be used (200 mg IV Q3 weeks or 400 mg IV Q6 weeks for one year total as per package insert or per physician's choice).
Study Duration: TM and capecitabine and pembrolizumab will be administered concurrently for 6 months, and the TM will continue for an additional 2.5 years (total duration of TM treatment is 3 years).
If no DLT is observed at dose level +2 then that is the dose that will proceed to the randomized phase 2 portion of the study.
Randomized Phase 2:
- Randomization: Patients will be randomized 1:1 to the combination of Capecitabine and TM vs. Capecitabine. 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 or per physician's choice)
- Induction Phase TM dose: Will be determined in phase 1b part of this study. If no DLT noted at dose level 2, then will proceed with TM dose 180 mg a day (TM 100 mg qAM + 80 mg QHS) Cp target: Will be done at local lab. Goal is to be 1-6 mg/dL below the lower limit of normal for the reference lab (see Section 7.1) Capecitabine Dose: 1000 mg per square meter of body-surface area, twice per day, on days 1 to 14 every 3 weeks for a total of 6 months Pembrolizumab: optional as per physician's choice. Standard doses will be used (200 mg IV Q3weeks or 400 mg IV Q6 weeks for one year total per package insert or per physician's choice
- Maintenance Phase TM dose: Will be determined in phase 1b part of this study. If no DLT noted at dose level 2, then will proceed with TM dose 100 mg a day (TM 100 mg QD) Cp target: Will be done at local lab. Goal is to be 1-6 mg/dL below the lower limit of normal for the reference lab (see Section 7.1). TM dosed according to Cp level and ANC in 20mg TM capsule increments.
Capecitabine Dose: 1000 mg per square meter of body-surface area, twice per day, on days 1 to 14 every 3 weeks for a total of 6 months Pembrolizumab: optional as per physician's choice. Standard doses will be used (200 mg IV Q3weeks or 400 mg IV Q6 weeks for one year total per package insert or per physician's choice.
Study Duration: TM and capecitabine will be administered concurrently for 6 months, and the TM will continue for an additional 2.5 years (total duration of TM treatment is 3 years). Pembrolizumab is optional and should be administered according to standard guidelines.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
- Model description
- Phase 1 portion is single group. Phase 2 portion is parallel.
| Arm | Type | Receives |
|---|---|---|
| TM and Capecitabine with or without Pembrolizumab | Experimental | Drug: Tetrathiomolybdate, Drug: Capecitabine, Drug: PembrolizumabTetrathiomolybdate (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) |
| Capecitabine with or without Pembrolizumab | Active comparator | Drug: Capecitabine, Drug: PembrolizumabCapecitabine +/- Pembrolizumab will be administered for 6 months (participants will remain on study for 2.5 more years). |
Who may qualify
- Ages
- 18 to 80 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (21 listed)
- 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.
Key exclusion criteria (11 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| TetrathiomolybdateAlso: TMTetrathiomolybdate (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. | Drug | TM and Capecitabine with or without Pembrolizumab |
| CapecitabineAlso: Xeloda1000mg/m2 twice daily, Days 1-14 Q21days for 6 months | Drug | Capecitabine with or without Pembrolizumab, TM and Capecitabine with or without Pembrolizumab |
| PembrolizumabAlso: KeytrudaIf 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) | Drug | Capecitabine with or without Pembrolizumab, TM and Capecitabine with or without Pembrolizumab |
Primary outcome
Phase 1b: To establish the safety of the combination of adjuvant tetrathiomolybdate with capecitabine and pembrolizumab by the number of dose limiting toxicities
Time frame: 3 years
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.
Phase 2: Distant relapse-free survival (DRFS) between TM and capecitabine versus capecitabine as measured with the STEEP system
Time frame: 10 years
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.
9 secondary outcomes
Phase 1b: Distant Relapse free survival (DRFS) between TM, capecitabine and pembrolizumab versus capecitabine and pembrolizumab as measured with the STEEP system
Time frame: 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
Time frame: 3 years
Phase 2: Overall Survival compared by arm in each of the two RCB groups separately
Time frame: 10 years
Phase 2: invasive disease-free survival compared by arm in each of the two RCB groups separately
Time frame: 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
Time frame: 5 years
Phase 2: Survival in patients that complete at least 6 months of treatment
Time frame: 10 years
Phase 2: Effect of copper depletion on serial blood-based biomarkers
Time frame: 5 years
Phase 2: Patient-reported quality of life measurements to assess whether the addition of TM to capecitabine impacts health-related quality of life and differ between arms over time
Time frame: 5 years
Phase 2: Plasma concentrations of capecitabine, pembrolizumab and TM will be performed in a sub cohort of patients enrolled in the randomized phase 2 part of this study
Time frame: 5 years
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 20 Apr 2026.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part.
Naomi Kornhauser, MPH contact
Linda Vahdat, MD principal investigator
Study Principal Investigator
3 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1/2 study testing Tetrathiomolybdate, Capecitabine and Pembrolizumab in people with Triple Negative Breast Cancer and Residual Disease, run by Dartmouth-Hitchcock Medical Center at 3 sites in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 21 inclusion and 11 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: looking for participants now, as of the sponsor's last update on 20 Apr 2026. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 3 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this combined phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
Contact Raven J Lavoie, RN ((603) 653-3661, Raven.M.Lavoie@hitchcock.org), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Phase 1b: To establish the safety of the combination of adjuvant tetrathiomolybdate with capecitabine and pembrolizumab by the number of dose limiting toxicities (time frame: 3 years). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 20 Apr 2026.