Phase II Study of Tetrathiomolybdate (TM) in Patients With Breast Cancer

A Phase II Study of Tetrathiomolybdate (TM) in Patients With Breast Cancer at Moderate to High Risk of Recurrence

Patients with moderate to high risk primary breast cancer (Stage II with more than 4 lymph nodes involved with cancer) III or Stage IV (without evidence of disease) will take tetrathiomolybdate (TM) pills for two years.

The objectives of the study are to:

• Assess the safety and tolerability of tetrathiomolybdate in patients with breast cancer at high risk of tumor recurrence.
• Observe the disease-free survival of patients in this trial.
• Conduct background scientific experiments on tumor tissue and blood of patients in this study

Study Overview

• Status: Terminated
• Conditions: Breast Cancer
• Intervention / Treatment: Drug: Tetrathiomolybdate

Detailed Description

Patients with moderate to high risk primary breast cancer -Stage III, Triple negative (T= 4 cm N0, any N+), Stage IV (without evidence of disease) will take tetrathiomolydbate (TM) pills for two years.

Extension study 1 - If patients are shown to be copper depleted, they are given the option to continue to receive TM for an additional 2 years.

Extension study 2 - Open to patients who are stage 4 NED, 10 involved lymph nodes or triple negative molecular subtype and candidates will continue for months 49-72.

Extension study 3 - Open to patients who are stage 4 NED receiving a benefit from TM. These subjects can continue receiving TM for 73-96 months.

Extension study 4 - Open to patients who are stage 4 NED receiving a benefit from TM. These subject can continue receiving TM for 97-120 months.

• Study Type: Interventional
• Enrollment (Actual): 16
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • New York
    • New York, New York, United States, 10021
      • Memorial Sloan Kettering Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Patients must have histologically confirmed breast malignancy that is:

   • High risk stage II breast cancer (≥4 positive lymph nodes),
   • Stage III breast cancer, including inflammatory breast cancer
   • Stage IV breast cancer in a complete remission (bone only not allowed unless the bone scan is normal).
2. The patient must have had what is considered standard adjuvant systemic therapy that may include chemotherapy, hormonal therapy and radiation therapy. They may have undergone high dose chemotherapy with stem cell support as part of their therapy in the adjuvant or metastatic setting. The patient is allowed to continue to take adjuvant hormonal therapy (for high risk adjuvant patients) and may be allowed to be on hormonal consolidation post transplant if they are without evidence of disease after a transplant for metastatic breast cancer. The patient cannot be actively receiving chemotherapy or any biologic agent to treat their breast cancer.
3. Six weeks must elapse from last chemotherapy or radiation therapy.
4. The patient must have had definitive surgical therapy for their breast cancer. This includes lumpectomy and axillary dissection or mastectomy.
5. 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)
6. 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.
7. ECOG performance status < 1
8. Life expectancy of greater than 3 months.

9. Patients must have normal organ and marrow function as defined below:

   • hemoglobin >10mg/dL
   • absolute neutrophil count >1,500/mL
   • platelets >100,000/mL
   • total bilirubin < 1.5 x normal institutional limits
   • AST(SGOT)/ALT(SGPT) <1.5 X institutional upper limit of normal
10. Erythropoietin alpha is allowed, as indicated.
11. Bisphosphonates may be administered if they were started prior to starting this therapy.
12. Patients must be on stable medical therapy for at least 2 weeks if they are being treated medically for their peripheral neuropathy.
13. Concurrent herceptin is not allowed.
14. The effects of TM on the developing human fetus are unknown. For this reason, women of child-bearing 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.
15. Ability to understand and the willingness to sign a written informed consent document.

Exclusion Criteria:

1. Patients who have had chemotherapy or radiotherapy within 6 weeks prior to entering the study.
2. Objective evidence of breast cancer.
3. Carcinomatous meningitis or history of neoplastic parenchymal brain disease.
4. Serum creatinine >1.5 x normal.
5. History of allergic reactions attributed to compounds of similar chemical or biologic composition to TM.
6. 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.
7. 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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Tetrathiomolybdate (TM); Induction period - TM 40 mg is administered three x per day with meals and TM 60 mg at bedtime for a total of 4 doses (180 mg) per day. Maintenance Period - Total TM dose per day will be in 20 mg increments to tailor the therapy to individualized patient needs to maintain the Cp level at 5-17mg/dL. Thus all dose modifications will be dependent on individual patient Cp levels. TM 40 mg p.o. BID with meals and TM 20 mg at bedtime. Subjects who have no evidence of disease (NED) and are receiving a benefit of TM can continue taking the drug for up to 120 months.

Drug: Tetrathiomolybdate; Induction with Tetrathiomolybdate (TM) Tetrathiomolybdate 40 mg. p.o. TID with meals and tetrathiomolybdate 60 mg at bedtime for a total of 4 doses (180 mg) per day. Induction goal Total tetrathiomolybdate dose per day = 180 mg until serum ceruloplasmin (Cp) level decreases to 5-15mg/dL. When target Cp window is reached, then the maintenance phase begins. Maintenance with Tetrathiomolybdate Total tetrathiomolybdate dose per day = 100 mg Tetrathiomolybdate 40 mg p.o. BID with meals and tetrathiomolybdate 20 mg at bedtime.; Other Names: TM

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Time to Progression for Patients With Breast Cancer Treated With Study Drug	duration of study

Collaborators and Investigators

• Sponsor: Memorial Sloan Kettering Cancer Center
• Collaborators: Weill Medical College of Cornell University
• Investigators: Principal Investigator: Linda Vahdat, MD, Memorial Sloan Kettering Cancer Center

Publications and helpful links

General Publications

• Ramchandani D, Berisa M, Tavarez DA, Li Z, Miele M, Bai Y, Lee SB, Ban Y, Dephoure N, Hendrickson RC, Cloonan SM, Gao D, Cross JR, Vahdat LT, Mittal V. Copper depletion modulates mitochondrial oxidative phosphorylation to impair triple negative breast cancer metastasis. Nat Commun. 2021 Dec 15;12(1):7311. doi: 10.1038/s41467-021-27559-z.

Helpful Links

• Related Info

Study record dates

Study Major Dates

• Study Start: December 1, 2003
• Primary Completion (Actual): March 2, 2023
• Study Completion (Actual): March 2, 2023

Study Registration Dates

• First Submitted: September 14, 2005
• First Submitted That Met QC Criteria: September 14, 2005
• First Posted (Estimated): September 19, 2005

Study Record Updates

• Last Update Posted (Actual): April 23, 2024
• Last Update Submitted That Met QC Criteria: March 28, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Skin Diseases; Neoplasms; Neoplasms by Site; Breast Diseases; Breast Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Chelating Agents; Sequestering Agents; Tetrathiomolybdate
• Other Study ID Numbers: 18-023; 0309006307 (Other Identifier: Weill Cornell Medical College)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Memorial Sloan Kettering Cancer Center supports the international committee of medical journal editors (ICMJE) and the ethical obligation of responsible sharing of data from clinical trials. The protocol summary, a statistical summary, and informed consent form will be made available on clinicaltrials.gov when required as a condition of Federal awards, other agreements supporting the research and/or as otherwise required. Requests for deidentified individual participant data can be made beginning 12 months after publication and for up to 36 months post publication. Deidentified individual participant data reported in the manuscript will be shared under the terms of a Data Use Agreement and may only be used for approved proposals. Requests may be made to: crdatashare@mskcc.org.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No