A Study of Tetrathiomolybdate (TM) Plus Capecitabine

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.

Eligibility

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) 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.

   Randomized Phase 2: 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). Pembrolizumab is allowed. Patients will be stratified by: (1) Treatment (chemotherapy vs chemotherapy + immunotherapy); (2) Age (Age ≤ 40 yrs vs \> 40 yrs); and (3) RCB 2 vs RCB 3. These important stratification factors represent variables that are known to affect outcome for patients with TNBC.
4. At least two weeks must have elapsed from last chemotherapy or radiation therapy. At least 4 weeks must have elapsed from most recent surgery.
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. Previous treatment with capecitabine is not allowed.
7. 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.
8. KPS 90 or 100.
9. Life expectancy of greater than 3 months.
10. Patients must have normal organ and marrow function as defined below:

    * hemoglobin \>10mg/dL
    * absolute neutrophil count \>1,500/ µL
    * platelets \>100,000/µL
    * total bilirubin \<1.5 x normal institutional limits
    * AST (SGOT)/ALT (SGPT) \<1.5 X institutional upper limit of normal
11. Antiresorptive therapy and denosumab may be administered.
12. Patients must be on stable medical therapy for at least 2 weeks if they are being treated medically for their chemotherapy induced peripheral neuropathy.
13. 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.
14. Ability to understand and the willingness to sign a written informed consent document.
15. Normal B12 levels.

Exclusion Criteria:

1. Patients who have had chemotherapy or radiotherapy within 2 weeks prior to entering the study. Patients who have had surgery within 4 weeks.
2. Patients who have received capecitabine or who are on warfarin
3. Patients who had their final breast surgery more than 12 weeks prior to study start.
4. 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.
5. Objective evidence of breast cancer.
6. Metastatic disease
7. Carcinomatous meningitis or active parenchymal brain metastases.
8. Estimated creatinine clearance \< 60 ml/min
9. History of allergic reactions attributed to compounds of similar chemical or biologic composition to TM or capecitabine.
10. 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.
11. 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.

Conditions4

Locations1 site

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