Tetrathiomolybdate in Treating Patients with Breast Cancer at Moderate to High Risk of Recurrence
This phase II trial studies the side effects of tetrathiomolybdate and to see how well it works in treating patients with breast cancer at moderate to high risk of the breast cancer coming back. Tetrathiomolybdate may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.
Inclusion Criteria
- 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). * Triple negative tumors (ER/PR/HER2/neu negative): Any nodal positivity, node negative and >= 4 cm
- Eligibility for extension study #1 and #2 (months 25 to 72): * Stage 2 triple negative breast cancer (TNBC) * Stage 3C breast cancer * Stage 4 no evidence of disease (NED) * Triple negative breast cancer
- Eligibility for extension study #3 (months 72 to 96) * Stage 4 NED
- Eligibility for extension study #4 (months 97 to 120) * Stage 4 NED
- Eligibility for extension study #5 (months 121 to 144) * Stage 4 NED
- The patient must have completed 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 therapy if they are Stage 4 and without evidence of disease. The patient cannot be actively receiving chemotherapy or any biologic agent to treat their breast cancer
- Six weeks must elapse from last chemotherapy or radiation therapy
- The patient must have had definitive surgical therapy for their breast cancer. This includes lumpectomy and axillary dissection or mastectomy
- No clinical or radiologic evidence of disease after surgery and/or systemic treatment (by computed tomography [CT] scan of chest, abdomen and pelvis and bone scan or positron emission tomography [PET] scan prior to enrollment)
- Karnofsky Performance Status (KPS) 90 or 100
- Life expectancy of greater than 3 months
- Hemoglobin >= 10mg/dL
- Absolute neutrophil count >= 1,500/uL
- Platelets >= 100,000/uL
- Total bilirubin =< 1.5 x normal institutional limits
- Aspartate aminotransferase (AST)(serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT)(serum glutamate pyruvate transaminase [SGPT]) =< 1.5 x institutional upper limit of normal
- Erythropoietin alpha is allowed, as indicated
- Bisphosphonates may be administered
- Patients must be on stable medical therapy for at least 2 weeks if they are being treated medically for their peripheral neuropathy
- Concurrent trastuzumab is not allowed in the adjuvant setting. In the metastatic setting, up to 4 patients will be allowed to receive concurrent tetrathiomolybdate (TM) and trastuzumab in order to assess whether there are any pharmacokinetic interactions
- 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 and folate levels
Exclusion Criteria
- Patients who have had chemotherapy or radiotherapy within 4 weeks prior to entering the study
- Objective evidence of breast cancer
- Carcinomatous meningitis or active parenchymal brain metastases
- Serum creatinine > 1.5 x normal
- History of allergic reactions attributed to compounds of similar chemical or biologic composition to TM
- 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, human immunodeficiency virus (HIV)-positive patients receiving combination anti- retroviral therapy are excluded from the study because of possible pharmacokinetic interactions with TM
Study sponsor and potential other locations can be found on ClinicalTrials.gov for NCT00195091.
PRIMARY OBJECTIVES:
I. To evaluate the effect of tetrathiomolybdate on the tumor microenvironment including VEGFR1+ and VEGFR2+ bone marrow derived progenitor cells and lysyl oxidase 2.
II. To assess the safety and tolerability of tetrathiomolybdate in patients with breast cancer at high risk of tumor recurrence.
III. To observe the event-free and overall survival of patients enrolled in this trial.
EXPLORATORY OBJECTIVES:
I. To assess single nucleotide polymorphisms of the ceruloplasmin gene and correlate it to the ability to be copper depleted with tetrathiomolybdate.
II. To perform whole exome sequencing of tumor and normal tissue from copper depleted patients and then identify mutations in circulating tumor deoxyribonucleic acid (DNA) and serially monitor.
III. To investigate predictors of response to copper depletion as a therapeutic strategy including assessing ATOX 1 in tumor samples.
OUTLINE:
INDUCTION: Patients receive tetrathiomolybdate orally (PO) 3 or 4 times daily (TID or QID) until target ceruloplasmin level is reached in the absence of disease progression or unacceptable toxicity.
MAINTENANCE: Patients receive tetrathiomolybdate PO TID for up to 2-4 years in the absence of disease progression or unacceptable toxicity. Patients with no evidence of disease may continue on maintenance therapy for up to 12 years at the discretion of the treating physician.
After completion of study treatment, patients are followed up for 10 years.
Trial PhasePhase II
Trial Typetreatment
Lead OrganizationMemorial Sloan Kettering Cancer Center
Principal InvestigatorLinda T Vahdat
- Primary ID18-023
- Secondary IDsNCI-2019-03180
- ClinicalTrials.gov IDNCT00195091