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
Dartmouth-Hitchcock Medical Center
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. 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.
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…
Eligibility
- Age range
- 18–80 years
- Sex
- All
- Healthy volunteers
- No
Inclusion Criteria: 1. 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 2. The patient must have completed standard neoadjuvant chemotherapy which constitutes at least 6 cycles of chemotherapy. 3. 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) Lo…
Interventions
- DrugTetrathiomolybdate
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.
- DrugCapecitabine
1000mg/m2 twice daily, Days 1-14 Q21days for 6 months
- DrugPembrolizumab
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)
Locations (3)
- Indiana University Simon Cancer CenterIndianapolis, Indiana
- Dartmouth Hitchcock Medical CenterLebanon, New Hampshire
- NYU Langone perimutter Cancer CenterNew York, New York