A Study of Tetrathiomolybdate (TM) Plus Capecitabine
Trial statusRecruiting
Trial phasePhase 1, Phase 2
Trial typeInterventional
Biological sexAll
Age18-80
SponsorDartmouth-Hitchcock Medical Center
About this trial
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.
Eligibility criteria
This trial does not accept healthy volunteersQualifiers
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
The patient must have completed standard neoadjuvant chemotherapy which constitutes at least 6 cycles of chemotherapy.
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) Local therapy: (a) Lumpectomy or mastectomy to negative margins. (b) Sentinel lymph node biopsy or axillary node dissection; (c) Radiation therapy to breast if patient received a lumpectomy and per investigator choice if considering chest wall/extended field RT. (2) Systemic therapy: Prior chemotherapy is required for patients entered on the trial. Neoadjuvant treatment should consist of the following standard therapy: Anthracycline and taxane-based therapy (i.e. AC->T, AC->Tcarbo, Keynote 522 regimen) or a non-anthracycline based chemo and immunotherapy regimen (NeoPACT). Patients must have received neoadjuvant Pembrolizumab for the phase Ib only and plan to continue it in the adjuvant setting for at least the first cycle of treatment.
At least two weeks must have elapsed from last chemotherapy or radiation therapy. At least 4 weeks must have elapsed from most recent surgery.
Disqualifiers
Patients who have had chemotherapy or radiotherapy within 2 weeks prior to entering the study. Patients who have had surgery within 4 weeks.
Patients who have received capecitabine or who are on warfarin
Patients who had their final breast surgery more than 12 weeks prior to study start.
Phase Ib: patients who have not received neoadjuvant immunotherapy and/or do not plan to continue treatment with immunotherapy for at least the first cycle of study treatment.
Trial design
Design model
Parallel
Treatments tested in this trial
Tetrathiomolybdate
DrugTetrathiomolybdate (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.
Capecitabine
Drug1000mg/m2 twice daily, Days 1-14 Q21days for 6 months
Pembrolizumab
DrugIf 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)
Treatment groups
204 Participants
are divided into 2 treatment groupsGroup A: TM and Capecitabine with or without PembrolizumabExperimental treatment 3 interventions
Group B: Capecitabine with or without PembrolizumabActive comparator 2 interventions
Trial outcomes
Primary outcomes
1
Phase 1b: To establish the safety of the combination of adjuvant tetrathiomolybdate with capecitabine and pembrolizumab by the number of dose limiting toxicities
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.
Time frame
3 years2
Phase 2: Distant relapse-free survival (DRFS) between TM and capecitabine versus capecitabine as measured with the STEEP system
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.
Time frame
10 yearsSecondary outcomes
1
Phase 1b: Distant Relapse free survival (DRFS) between TM, capecitabine and pembrolizumab versus capecitabine and pembrolizumab as measured with the STEEP system
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.
Time frame
3 years2
Phase 1b: Plasma concentrations of capecitabine, pembrolizumab and TM will be performed in a sub cohort of at least nine patients enrolled in the phase 1b part of this 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.
Time frame
3 years3
Phase 2: Overall Survival compared by arm in each of the two RCB groups separately
Overall survival (OS) between the two arms via the Kaplan-Meier method
Time frame
10 years4
Phase 2: invasive disease-free survival compared by arm in each of the two RCB groups separately
Invasive disease-free survival (iDFS) between the two arms via the Kaplan-Meier method
Time frame
10 yearsSponsors and contacts
Click on the lead sponsor to view all of their trials.
Dartmouth-Hitchcock Medical Center
Lead sponsor
National Cancer Institute (NCI)
Collaborator
Congressionally Directed Medical Research Programs
Collaborator
Source ClinicalTrials.gov