Neoplasms

Skin and Connective Tissue Diseases

All Conditions

Symptoms and General Pathology

Breast Neoplasms

Recurrence

Breast Diseases

Skin Diseases

Central Nervous System Depressants

All Drugs and Chemicals

Antineoplastic Agents

Other Dietary Supplements

Benzocaine

Tetrathiomolybdate

Chelating Agents

Enzyme Inhibitors

Angiogenesis Inhibitors

Growth Inhibitors

Tannic Acid

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.

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.

Linda Vahdat, MD

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

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.

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

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.

Weill Medical College of Cornell University

Memorial Sloan Kettering Cancer Center

Tetrathiomolybdate: Induction with Tetrathiomolybdate (TM)

When target Cp window is reached, then the maintenance phase begins.

Tetrathiomolybdate (TM)

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

United States

Region of Enrollment

Dr. Tiffany Traina MD

Time to Progression for Patients With Breast Cancer Treated With Study Drug

Overall Study

Respiratory Tract (Lung and Bronchial) Diseases

Lung Neoplasms

Carcinoma, Non-Small-Cell Lung

Adenocarcinoma

Carcinoma

Respiratory Tract Neoplasms

Thoracic Neoplasms

Lung Diseases

Respiratory Tract Diseases

Carcinoma, Bronchogenic

Bronchial Neoplasms

Micronutrients

Mineral

Carboplatin

Pemetrexed

Copper

Copper Supplement

Dose Escalation - It is aimed at determining the maximum tolerated dose of TM in combination with carboplatin and pemetrexed.

Dose Expansion - The dose expansion portion of the study will begin after completion of the dose escalation phase.

Dose Escalation - Dose level -1: 20 mg TM orally 3 x daily x 21 days in combination with carboplatin IV area under the curve (AUC) = 6 and pemetrexed IV 500/mgm2 day 1 x 1 cycle.

Dose level 1: 40 mg TM orally 3 x daily x 21 days in combination with carboplatin IV AUC = 6 and pemetrexed IV 500 mg/m2 day 1 x 1 cycle.

Dose level 2: 60 mg TM orally 3 x daily x 21 days in combination with carboplatin IV AUC = 6 and pemetrexed IV 500 mg/m2 day 1 x 1 cycle.

Patients in the dose-expansion cohort will continue on carboplatin and pemetrexed (without TM) at the discretion of the treating physician.

Dose Expansion - Maximum tolerated dose of TM determined from the dose-escalation cohorts combined with carboplatin IV AUC = 6 and pemetrexed IV 500 mg/m2 day 1 x 4 cycles.

David Dougherty, MD

The main objective of this study is to determine recommended phase II dose and safety of tetrathiomolybdate (TM) in combination with carboplatin and pemetrexed in chemo-naive metastatic or recurrent non-squamous non-small cell lung cancer.

Platinum resistance is a major limitation in the treatment of advanced non-small cell lung cancer. Previous studies suggest that reduced tumor platinum levels may significantly contribute to platinum resistance and thus poor outcome following platinum-based chemotherapy in lung cancer.

Tetrathiomolybdate (TM) is a fast-acting copper chelator that has been under significant investigation as an anti-cancer strategy due to its anti-angiogenic property. Furthermore, more recent preclinical evidence suggests that combining TM with platinum drugs resulted in higher intratumoral platinum concentration and greater tumor response. The oncologists at the University of Rochester are studying addition of TM to commonly used 1st line platinum-based doublet, carboplatin/pemetrexed, in patients with non-squamous non-small cell lung cancer.

Phase I Study of Tetrathiomolybdate in Combination With Carboplatin/Pemetrexed in Metastatic Non-small Cell Lung Cancer

A Phase I Study of Tetrathiomolybdate (TM) in Combination With Carboplatin and Pemetrexed in Chemo-Naive Metastatic or Recurrent Non-Squamous Non-Small Cell Lung Cancer

Determine phase II dose and safety of TM in combination with carboplatin and pemetrexed in chemo-naive metastatic or recurrent non-squamous non-small cell lung cancer.

Determine efficacy of carboplatin and pemetrexed doublet in combination with TM in chemo-naive metastatic or recurrent non-small cell lung cancer.

Determine if pretreatment expression of copper transporter by immunohistochemistry predicts clinical outcome following platinum-based chemotherapy in combination with TM

Determine if ceruloplasmin level (a surrogate marker for copper status) is associated with platinum sensitivity

Determine if ceruloplasmin level is associated with platinum-induced toxicity.

To determine if Tetrathiomolybdate affects serum copper, iron, total iron binding capacity, ferritin or zinc levels when combined with platinum-based chemotherapy.

University of Rochester

Assistant Professor

Triple Negative Breast Neoplasms

Pembrolizumab

Capecitabine

Angiogenesis Inducing Agents

Molybdenum

Antineoplastic Agents, Immunological

Immune Checkpoint Inhibitors

Antimetabolites

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)

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

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.

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

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)

Laurie J Balch, RN

Naomi Kornhauser, MPH

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.

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.

Phase 1 portion is single group. Phase 2 portion is parallel.

A Study of Tetrathiomolybdate (TM) Plus Capecitabine

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

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.

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.

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.

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.

Overall survival (OS) between the two arms via the Kaplan-Meier method

Invasive disease-free survival (iDFS) between the two arms via the Kaplan-Meier method

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.

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

Effect of copper depletion on serial blood-based biomarkers including: VEGFR2+ EPCs, LOXL-2, ctDNA, other biomarkers in process of validation by correlation coefficients

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.

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.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Phase II Study of Tetrathiomolybdate (TM) in Patients With Breast Cancer	NCT00195091	Breast Cancer	Tetrathiomolybd...	18 Years -	Memorial Sloan Kettering Cancer Center
Phase I Study of Tetrathiomolybdate in Combination With Carboplatin/Pemetrexed in Metastatic Non-small Cell Lung Cancer	NCT01837329	Non-Small Cell ...	Tetrathiomolybd...	18 Years -	University of Rochester
Phase I Study of Tetrathiomolybdate in Combination With Carboplatin/Pemetrexed in Metastatic Non-small Cell Lung Cancer	NCT01837329	Non-Small Cell ...	Tetrathiomolybd...	18 Years -	University of Rochester
A Study of Tetrathiomolybdate (TM) Plus Capecitabine	NCT06134375	Triple Negative... Residual Diseas...	Tetrathiomolybd... Capecitabine Pembrolizumab	18 Years - 70 Years	Dartmouth-Hitchcock Medical Center

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