A Study of Tetrathiomolybdate (TM) Plus Capecitabine

Phase

1/2

Condition

Breast Cancer

Treatment

Pembrolizumab

Capecitabine

Tetrathiomolybdate

Clinical Study ID

NCT06134375

STUDY02001837|22VAH837

Ages 18-70
All Genders

Study 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 Criteria

Inclusion

Inclusion Criteria:

Patients must have histologically confirmed breast malignancy that is Triplenegative tumors as defined as ER and PR <1% and HER2 negative as per ASCO/CAPguidelines
The patient must have completed standard neoadjuvant chemotherapy which constitutesat least 6 cycles of chemotherapy.
Phase Ib: Patients must have residual invasive carcinoma, at minimum in one of thefollowing capacities: (1) node positive disease after treatment without residualinvasive carcinoma in the breast; (2) RCB 2 or RCB 3 MDAH Calculator; Standardtherapy consists of the following: (1) Local therapy: (a) Lumpectomy or mastectomyto negative margins. (b) Sentinel lymph node biopsy or axillary node dissection; (c)Radiation therapy to breast if patient received a lumpectomy and per investigatorchoice if considering chest wall/extended field RT. (2) Systemic therapy: Priorchemotherapy is required for patients entered on the trial. Neoadjuvant treatmentshould consist of the following standard therapy: Anthracycline and taxane-basedtherapy (i.e. AC->T, AC->Tcarbo, Keynote 522 regimen) or a non-anthracycline basedchemo and immunotherapy regimen (NeoPACT). Patients must have received neoadjuvantPembrolizumab for the phase Ib only and plan to continue it in the adjuvant settingfor at least the first cycle of treatment. Randomized Phase 2: Patients must have residual invasive carcinoma, at minimum inone of the following capacities: (1) node positive disease after treatment withoutresidual invasive carcinoma in the breast; (2) RCB 2 or RCB 3 MDAH Calculator;Standard therapy consists of the following: (1) Local therapy: (a) Lumpectomy ormastectomy to negative margins. (b) Sentinel lymph node biopsy or axillary nodedissection; (c) Radiation therapy to breast if patient received a lumpectomy and perinvestigator choice if considering chest wall/extended field RT. (2) Systemictherapy: 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 variablesthat are known to affect outcome for patients with TNBC.
At least two weeks must have elapsed from last chemotherapy or radiation therapy. Atleast 4 weeks must have elapsed from most recent surgery.
No clinical or radiologic evidence of disease after surgery and/or systemictreatment (by CT scan of chest, abdomen and pelvis and bone scan or PET scan priorto enrollment).
Previous treatment with capecitabine is not allowed.
Because no dosing or adverse event data are currently available on the use of TM inpatients <18 years of age, children are excluded from this study.
KPS 90 or 100.
Life expectancy of greater than 3 months.
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

Antiresorptive therapy and denosumab may be administered.
Patients must be on stable medical therapy for at least 2 weeks if they are beingtreated medically for their chemotherapy induced peripheral neuropathy.
The effects of TM on the developing human fetus are unknown. For this reason, womenof childbearing potential and men must agree to use adequate contraception (hormonalor barrier method of birth control; abstinence) prior to study entry and for theduration of study participation. Should a woman become pregnant or suspect she ispregnant while participating in this study, she should inform her treating physicianimmediately.
Ability to understand and the willingness to sign a written informed consentdocument.
Normal B12 levels.

Exclusion

Exclusion Criteria:

Patients who have had chemotherapy or radiotherapy within 2 weeks prior to enteringthe 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 notplan to continue treatment with immunotherapy for at least the first cycle of studytreatment.
Objective evidence of breast cancer.
Metastatic disease
Carcinomatous meningitis or active parenchymal brain metastases.
Estimated creatinine clearance < 60 ml/min
History of allergic reactions attributed to compounds of similar chemical orbiologic composition to TM or capecitabine.
Pregnant women are excluded from this study because TM has the potential to haveteratogenic or abortifacient effects. Because there is an unknown but potential riskfor 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 infectionswhen treated with marrow-suppressive therapy, HIV-positive patients receivingcombination anti- retroviral therapy are excluded from the study because of possiblepharmacokinetic interactions with TM.

Study Design

Pembrolizumab

1/2

November 26, 2024

November 26, 2034

Study 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 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 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.

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.

Connect with a study center

Dartmouth Hitchcock Medical Center
Lebanon, New Hampshire 03756
United States
Active - Recruiting

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