Tetrathiomolybdate + Capecitabine + Pembrolizumab for Breast Cancer

Overseen By Raven J Lavoie, RN

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Dartmouth-Hitchcock Medical Center

Must be taking: Pembrolizumab

Must not be taking: Capecitabine, Warfarin

Disqualifiers: Metastatic disease, Brain metastases, others

Stay on Your Current Meds You can continue your current medications while participating

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: 6

204 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine if adding tetrathiomolybdate (TM) to existing breast cancer drugs can prevent the recurrence of triple-negative breast cancer. Initially, the study will assess the safety of TM when combined with capecitabine (Xeloda) and pembrolizumab (KEYTRUDA). It will then compare the effectiveness of TM and capecitabine against capecitabine alone. Participants should have triple-negative breast cancer with a high risk of relapse and must have completed chemotherapy and surgery. The trial seeks to discover better methods to prevent breast cancer recurrence and improve patient outcomes. As a Phase 1, Phase 2 trial, this research focuses on understanding the treatment's effects in people and measuring its effectiveness in an initial, smaller group, offering participants a chance to contribute to groundbreaking advancements in breast cancer treatment.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you cannot participate if you are currently taking capecitabine or warfarin. You must also be on stable medical therapy for at least 2 weeks if you are being treated for chemotherapy-induced peripheral neuropathy.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research is investigating the safety of combining three drugs—tetrathiomolybdate (TM), capecitabine, and pembrolizumab—to treat triple-negative breast cancer. Studies have shown that this combination is generally safe, with side effects typically being acceptable.

Capecitabine, already used as an additional treatment after the main one, has proven effective in breast cancer, as demonstrated by the CREATE-X study. Pembrolizumab, an immunotherapy, helps the body's immune system fight cancer and is approved for other cancer types.

Tetrathiomolybdate is under study for its potential to lower copper levels in the body, possibly reducing the risk of cancer spreading. Although TM is not as extensively researched as the other drugs, early findings suggest it could be safe when used with them.

Overall, while more research is needed, current evidence suggests that this treatment combination is generally well-tolerated by patients. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of Tetrathiomolybdate (TM), Capecitabine, and Pembrolizumab for breast cancer because it introduces TM, a novel agent that may enhance treatment efficacy. Unlike standard treatments that mainly involve chemotherapy and hormone therapy, TM has a unique mechanism that targets copper metabolism, potentially inhibiting tumor growth and spread. This approach, when combined with Capecitabine and Pembrolizumab, could offer a more comprehensive attack on cancer cells by addressing both the tumor environment and immune response. Additionally, the extended use of TM for up to three years might provide lasting benefits in maintaining remission and preventing recurrence.

What evidence suggests that this trial's treatments could be effective for high risk for relapse triple negative breast cancer?

This trial will evaluate the effectiveness of different treatment combinations for breast cancer. One arm will administer Capecitabine, with or without Pembrolizumab, for 6 months. Another arm will test the combination of Tetrathiomolybdate (TM) and Capecitabine, with or without Pembrolizumab, with TM continuing for a total of 3 years. Research has shown that adding TM to Capecitabine and Pembrolizumab might help treat triple-negative breast cancer (TNBC). TM can lower copper levels in the body, potentially reducing the risk of cancer spreading. Capecitabine stops cancer cells from growing. Pembrolizumab, a type of immunotherapy, has shown promise in slowing cancer, with some studies indicating it controls the disease in 37% of cases. Using these treatments together could potentially improve outcomes for patients at high risk of cancer recurrence. ^{2 5 6 7 8}

Who Is on the Research Team?

Linda Vahdat, MD

Principal Investigator

Study Principal Investigator

Are You a Good Fit for This Trial?

This trial is for adults with triple-negative breast cancer who have a high risk of the cancer returning. They must have finished at least 6 cycles of specific chemotherapy, had surgery, and possibly radiation therapy. They can't join if they've been treated with capecitabine before or if their performance status is low (KPS less than 90).

Inclusion Criteria

I have had surgery and chemotherapy for breast cancer with some remaining cancer.

My scans show no signs of cancer after treatment.

I have never been treated with capecitabine.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Phase 1b Treatment

Participants receive adjuvant therapy with capecitabine, pembrolizumab, and tetrathiomolybdate (TM) to assess safety.

6 months

Every 3 weeks

Phase 2 Treatment

Randomized treatment with capecitabine and TM, with optional pembrolizumab, to assess efficacy.

3 years

Every 3 weeks for capecitabine, TM continues for 3 years

Follow-up

Participants are monitored for safety and effectiveness after treatment.

5 years

What Are the Treatments Tested in This Trial?

Interventions

• Capecitabine
• Pembrolizumab
• Tetrathiomolybdate

Trial Overview The study tests adding Tetrathiomolybdate (TM) to standard treatment with Capecitabine and Pembrolizumab in patients who still have cancer after initial treatments. It's done in two parts: first to ensure safety, then comparing TM plus Capecitabine against Capecitabine alone.

How Is the Trial Designed?

Group I: TM and Capecitabine with or without Pembrolizumab Experimental Treatment 3 Interventions

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)

Group II: Capecitabine with or without Pembrolizumab Active Control 2 Interventions

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

Capecitabine is already approved in European Union, United States, Canada, Japan for the following indications:

Approved in European Union as Xeloda for:

• Colorectal cancer
• Breast cancer

Approved in United States as Xeloda for:

• Colorectal cancer
• Breast cancer

Approved in Canada as Xeloda for:

• Colorectal cancer
• Breast cancer

Approved in Japan as Xeloda for:

• Colorectal cancer
• Breast cancer

Who Is Running the Clinical Trial?

Dartmouth-Hitchcock Medical Center

Lead Sponsor

Trials

548

Recruited

2,545,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Congressionally Directed Medical Research Programs

Collaborator

Trials

59

Recruited

10,600+

Published Research Related to This Trial

A retrospective study of 12 patients with severe renal impairment (GFR <30 mL/min) showed that capecitabine can be safely administered with close monitoring and dose adjustments, despite previous contraindications from the manufacturer based on a small Phase II trial.

Most patients experienced only mild to moderate adverse effects, and some showed a positive response to treatment, indicating that capecitabine may still be effective in this population when managed carefully.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A retrospective observational study on the use of capecitabine in patients with severe renal impairment (GFR Jhaveri, KD., Flombaum, C., Shah, M., et al.[2022]

Capecitabine (Xeloda) is an oral chemotherapy that delivers 5-FU directly to tumors, offering superior response rates and equivalent survival outcomes compared to intravenous 5-FU in first-line metastatic colorectal cancer (MCRC).

Capecitabine has a favorable safety profile, with manageable side effects like hand-foot syndrome and diarrhea, allowing for prompt dose adjustments without compromising treatment efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Development of and clinical experience with capecitabine (Xeloda) in the treatment of solid tumours. Sternberg, CN., Reichardt, P., Holland, M.[2015]

Pembrolizumab, an immune checkpoint inhibitor, can cause pneumonitis in 1%-5% of patients, and this case report highlights an atypical presentation of this side effect in a patient with metastatic squamous cell carcinoma.

The patient was successfully treated with steroid therapy after ruling out other potential causes, leading to complete resolution of the pneumonitis, emphasizing the importance of recognizing and managing atypical cases of checkpoint inhibitor-pneumonitis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Recurrent and atypical immune checkpoint inhibitor-induced pneumonitis. Jeon, WJ., Nguyen, J., Castillo, DR., et al.[2023]

In a phase II trial involving 15 patients with resectable non-small cell lung cancer (NSCLC), neoadjuvant treatment with pembrolizumab showed a major pathologic response in 27% of patients, indicating promising antitumor activity before surgery.

The treatment was found to be feasible and safe, with only 33% of patients experiencing moderate adverse events, and no postoperative mortality, suggesting that pembrolizumab does not compromise surgical outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neoadjuvant anti-programmed death-1 immunotherapy by pembrolizumab in resectable non-small cell lung cancer: First clinical experience. Eichhorn, F., Klotz, LV., Kriegsmann, M., et al.[2022]

Pembrolizumab, a PD-1 inhibitor used in cancer treatment, can lead to rare but serious immune-related adverse events, including type 1 diabetes mellitus, occurring in about 0.2% of cases.

A review of 42 cases revealed that patients may develop diabetic ketoacidosis during treatment, highlighting the need for blood glucose monitoring and awareness of this potential side effect among clinicians.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Programmed Cell Death-1 Inhibitor-Induced Type 1 Diabetes Mellitus. Clotman, K., Janssens, K., Specenier, P., et al.[2022]

This Phase II study investigates the effectiveness of combining Trastuzumab, a targeted therapy for HER2-positive cancers, with Capecitabine, a chemotherapy drug, to treat patients with specific types of cancer.

The study aims to assess how well this combination works in improving patient outcomes, although specific results and participant details are not provided in the abstract.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Correction to: Phase II study to evaluate the efficacy of Trastuzumab in combination with Capecitabine and Oxaliplatin in first-line treatment of HER2-positive advanced gastric cancer: HERXO trial. Rivera, F., Romero, C., Jimenez-Fonseca, P., et al.[2020]

Pembrolizumab (Keytruda) was approved by the FDA for treating metastatic non-small cell lung cancer (mNSCLC) in patients with tumors expressing PD-L1, showing significant improvements in overall survival (OS) and progression-free survival (PFS) in two major clinical trials with thousands of participants.

In the KEYNOTE-024 trial, pembrolizumab demonstrated a 40% reduction in the risk of death compared to chemotherapy, while in the KEYNOTE-010 trial, it also showed a significant survival advantage over chemotherapy in patients who had previously progressed on treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FDA Approval Summary: Pembrolizumab for Treatment of Metastatic Non-Small Cell Lung Cancer: First-Line Therapy and Beyond. Pai-Scherf, L., Blumenthal, GM., Li, H., et al.[2022]

In a study of 42 patients with advanced breast and colorectal cancer, capecitabine showed a partial response rate of 29.16% for breast cancer and 11.76% for colorectal cancer, indicating its potential efficacy in these pretreated patients.

Capecitabine was well tolerated with low toxicity levels, as most adverse reactions were mild, although 7.14% of patients experienced grade 3 hand-foot syndrome, and hypertriglyceridemia was noted in some patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Capecitabine (Xeloda) as monotherapy in advanced breast and colorectal cancer: effectiveness and side-effects. Stathopoulos, GP., Koutantos, J., Lazaki, H., et al.[2022]

Pembrolizumab (KEYTRUDA) was approved by the FDA for treating advanced melanoma, showing an overall response rate of 24% in a trial of 89 patients, with 86% of responses lasting at least 6 months.

While there are potential immune-mediated side effects, the benefits of prolonged tumor response durations were deemed to outweigh these risks, marking an improvement over existing treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FDA Approval Summary: Accelerated Approval of Pembrolizumab for Second-Line Treatment of Metastatic Melanoma. Chuk, MK., Chang, JT., Theoret, MR., et al.[2021]

Capecitabine is a well-tolerated treatment for metastatic breast cancer, showing minimal side effects like myelosuppression and hair loss, which makes it a promising option for combination therapies with other anticancer drugs.

Ongoing phase II/III trials are investigating the use of capecitabine in early breast cancer treatment, and preliminary results indicate that it may provide significant benefits when used as part of adjuvant and neoadjuvant therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Future options with capecitabine (Xeloda) in (neo)adjuvant treatment of breast cancer. Fumoleau, P., Cameron, D.[2019]

Pembrolizumab, a PD-1 inhibitor, has demonstrated clinical effectiveness in treating various solid tumors, particularly in patients with PD-L1-positive non-small-cell lung cancer and unresectable/metastatic melanoma.

Early-phase trials and ongoing studies are focused on further confirming the clinical benefits of pembrolizumab in thoracic malignancies, highlighting its potential as a significant treatment option in cancer therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab for the treatment of thoracic malignancies: current landscape and future directions. Karim, S., Leighl, N.[2017]

Pembrolizumab (Keytruda) is approved for treating advanced endometrial carcinoma that is microsatellite instability-high or mismatch repair deficient, specifically for patients whose disease has progressed after previous treatments.

This approval is significant for patients who are not candidates for curative surgery or radiation, providing a new therapeutic option for a challenging stage of cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

New Approved Use for Keytruda. Aschenbrenner, DS.[2022]

In a phase II study involving 22 patients with BRCA1/2-related metastatic breast cancer, the combination of pembrolizumab and carboplatin showed an overall response rate (ORR) of 43% and a disease control rate (DCR) of 76%, indicating some level of efficacy, particularly in luminal tumors.

Despite the promising results, the study did not meet its primary aim of achieving an ORR of 70%, leading to its termination; however, the safety profile was acceptable with only 22.7% of patients experiencing grade ≥3 adverse events.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase II study of pembrolizumab plus carboplatin in BRCA-related metastatic breast cancer (PEMBRACA). Cortesi, L., Venturelli, M., Cortesi, G., et al.[2023]

Combining pembrolizumab with trastuzumab and chemotherapy has been shown to reduce tumor size in patients, indicating enhanced efficacy of the treatment.

This combination therapy can also lead to complete responses in some patients, suggesting a potential for significant improvement in cancer treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab Addition Improves Clinical Response in HER2+ Gastric Cancer. [2022]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT06134375

A Study of Tetrathiomolybdate (TM) Plus Capecitabine 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 ...

2. cancer.gov cancer.gov/research/participate/clinical-trials-search/v?id=NCI-2025-05879

Capecitabine with or without Tetrathiomolybdate and ... Giving capecitabine with or without tetrathiomolybdate and pembrolizumab may be safe and effective in treating patients with triple negative breast cancer that ...

3. onclive.com onclive.com/view/copper-depletion-combats-metastatic-recurrence-in-high-risk-tnbc

Copper Depletion Combats Metastatic Recurrence in High- ... Copper depletion with tetrathiomolybdate may decrease the risk of metastatic disease development in patients with triple-negative breast cancer (TNBC) at high ...

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10252021/

Hope and Hype around Immunotherapy in Triple-Negative ... Nevertheless, a subsequent study, the TAPUR trial, showed that pembrolizumab monotherapy had a good DCR (37%) and ORR (21%) in 28 patients with previously ...

5. ctv.veeva.com ctv.veeva.com/study/a-study-of-tetrathiomolybdate-tm-plus-capecitabine

A Study of Tetrathiomolybdate (TM) Plus Capecitabine 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 ...

6. clinicaltrials.gov clinicaltrials.gov/study/NCT06134375

A Study of Tetrathiomolybdate (TM) Plus Capecitabine 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 ...

7. connect.careboxhealth.com connect.careboxhealth.com/en-US/trial/listing/440455

A Study of Tetrathiomolybdate (TM) Plus Capecitabine 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 ...

8. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11987871/

Advanced and Metastatic Triple Negative Breast Cancer— ... Preliminary results showed a manageable safety profile and lasting response rates [49]. The CREATE-X study presented the effectiveness of adjuvant capecitabine ...