Platinum in Treating Patients With Residual Triple-Negative Breast Cancer Following Neoadjuvant Chemotherapy

Study Overview
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Brief Summary
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This randomized phase III trial studies how well cisplatin or carboplatin (platinum based chemotherapy) works compared to capecitabine in treating patients with remaining (residual) basal-like triple-negative breast cancer following chemotherapy after surgery (neoadjuvant). Drugs used in chemotherapy, such as cisplatin, carboplatin and capecitabine, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. It is not yet known whether cisplatin or carboplatin is more effective than capecitabine in treating patients with residual triple negative basal-like breast cancer.

Detailed Description
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PRIMARY OBJECTIVES: I. To compare the invasive disease-free survival (IDFS) in triple-negative breast cancer (TNBC) patients with residual basal-like disease after neoadjuvant chemotherapy who are randomized to post-preoperative platinum based chemotherapy with those who are randomized to capecitabine. SECONDARY OBJECTIVES: I. To evaluate overall survival (OS) and response-free survival (RFS) in the two arms in patients with TNBC with residual basal-like disease after neoadjuvant chemotherapy. II. To characterize the side effects and tolerability of platinum agent as well as capecitabine in patients with TNBC with residual disease after neoadjuvant chemotherapy. III. To identify the rate of basal-like gene expression using prediction analysis of microarray 50 (PAM50) analysis by digital messenger ribonucleic acid (mRNA) quantitation amongst drug-resistant residual TNBC after neoadjuvant chemotherapy. IV. To assess the difference in health-related quality of life (HRQL) between the platinum based and capecitabine chemotherapy arms. EXPLORATORY OBJECTIVES: I. To compare the IDFS in TNBC patients with residual non-basal-like disease after neoadjuvant chemotherapy who are randomized to post-preoperative platinum based chemotherapy with those who are randomized to capecitabine. II. To describe the rate of neurotoxicity over time in the platinum arm, the rate of medication adherence in the capecitabine arm and the rates of amenorrhea in both arms. III. To evaluate the association of genomic alterations identified via profiling of the surgical tumor specimen with RFS in patients with TNBC after neoadjuvant chemotherapy. IV. To explore whether any of the genomic alterations identified via profiling of the surgical tumor specimen can predict treatment benefit in patients with basal subtype TNBC. V. To determine the frequency of CTC positivity at baseline and after completion of study therapy in patients with TNBC with residual basal subtype disease after neoadjuvant chemotherapy. VI. To evaluate the associations between CTC levels at baseline, and after completion of chemotherapy, with RFS. VII. To evaluate the association between CTC change in status posttreatment (i.e. negative to negative, negative to positive, positive to negative, positive to positive) and RFS. VIII. To explore significance of CTC number/phenotype and ctDNA detected mutations (mutational burden, specific mutations) in predicting RFS. IX. To determine the frequency of plasma tumor cell-free DNA (cfDNA) positivity at baseline and after completion of study therapy in patients with TNBC with residual basal subtype disease after neoadjuvant chemotherapy. X. To evaluate the associations between plasma tumor cfDNA tumor specific mutations (baseline and after therapy) with RFS. XI. To explore optimal biomarker combination for RFS prediction. XII. To determine the effects of tobacco, operationalized as combustible tobacco (1a), other forms of tobacco (1b), and environmental tobacco exposure (ETS) (1c) on provider-reported cancer-treatment toxicity (adverse events (both clinical and hematologic) and dose modifications). XIII. To determine the effects of tobacco on patient-reported physical symptoms and psychological symptoms. XIV. To examine quitting behaviors and behavioral counseling/support and cessation medication utilization. XV. To explore the effect of tobacco use and exposure on treatment duration, relative dose intensity, and therapeutic benefit. OUTLINE: Patients are randomized to 1 of 3 treatment arms. ARM A (closed to accrual 05/16/2016): Patients undergo observation. ARM B: Patients receive cisplatin intravenously (IV) or carboplatin IV on day 1. Treatment repeats every 3 weeks for 4 courses in the absence of disease progression or unacceptable toxicity. ARM C: Patients receive capecitabine orally (PO) twice daily (BID) on days 1-14. Treatment repeats every 3 weeks for up to 6 courses in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up for up to 10 years.

Official Title
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A Randomized Phase III Post-operative Trial of Platinum Based Chemotherapy vs. Capecitabine in Patients With Residual Triple-Negative Basal-Like Breast Cancer Following Neoadjuvant Chemotherapy

Conditions
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Estrogen Receptor Negative, HER2/Neu Negative, Invasive Breast Carcinoma, Progesterone Receptor Negative, Stage II Breast Cancer, Stage IIA Breast Cancer, Stage IIB Breast Cancer, Stage III Breast Cancer, Stage IIIA Breast Cancer, Stage IIIB Breast Cancer, Stage IIIC Breast Cancer, Triple-Negative Breast Carcinoma

Intervention / Treatment
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* Drug: Capecitabine
* Drug: Carboplatin
* Drug: Cisplatin


Participation Criteria
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Eligibility Criteria
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ELIGIBILITY CRITERIA FOR SCREENING AND MOLECULAR PROFILING (STEP 0) Inclusion Criteria: Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 within 2 weeks prior to screening Female and male patients must have histologically confirmed invasive breast cancer that meets the following criteria: Clinical stage II-III (American Joint Committee on Cancer [AJCC] 7th edition) at diagnosis, based on initial evaluation by clinical examination and/or breast imaging; no metastatic disease allowed ER- and PR- should meet one of the following criteria: =< 10% cells stain positive, with weak intensity score (equivalent to Allred score =< 3) =< 1% cells stain positive, with weak or intermediate intensity score (equivalent to Allred score =< 3) HER2 negative (not eligible for anti-HER2 therapy) will be defined as: Immunohistochemistry (IHC) 0, 1+ without in situ hybridization (ISH) HER2/neu chromosome 17 ratio OR IHC 2+ and ISH HER2/neu chromosome 17 ratio non-amplified with ratio less than 2.0 and if reported average HER2 copy number < 6 signals/cells OR ISH HER2/neu chromosome 17 ratio non-amplified with ratio less than 2.0 and if reported average HER2 copy number < 6 signals/cells without IHC NOTE: Patients that originally present with synchronous bilateral tumors are eligible provided both tumors are TNBC, and at least one of them fulfills the remainder eligibility criteria of the protocol; multifocal or multicentric breast cancers are eligible as long as all tumors fulfill eligibility criteria NOTE: Patients that have a discrepancy in ER/PR/HER2 status between original diagnosis and surgical specimen (if ER/PR/HER2 status were repeated) are not eligible for study participation (i.e. ER/PR/HER2 has to fulfill above criteria in both scenarios) Patients must have completed neoadjuvant taxane +/- anthracycline; patients must NOT have received cisplatin or carboplatin or capecitabine as part of their neoadjuvant therapy regimen NOTE: Patients who received preoperative therapy as part of a clinical trial may enroll NOTE: Patients that were not able to complete their planned neoadjuvant chemotherapy for any reason (i.e. toxicities, etc.) are eligible to participate as long as no further systemic standard of care therapy is planned by the treating physician Must have completed definitive resection of primary tumor Negative margins for both invasive and ductal carcinoma in situ (DCIS) are desirable, however patients with positive margins may enroll if the treatment team believes no further surgery is possible and patient has received radiotherapy; patients with margins positive for lobular carcinoma in situ (LCIS) are eligible Either mastectomy or breast conserving surgery (including lumpectomy or partial mastectomy) is acceptable Sentinel node biopsy either pre or post neoadjuvant chemotherapy (i.e. at the time of definitive surgery) are allowed; axillary dissection is encouraged in patients with lymph node involvement, but is not mandatory Post neoadjuvant chemotherapy, patients must be found to have residual invasive cancer in the breast at the time of definitive surgery; residual cancer is defined as a contiguous focus of residual invasive cancer, in the breast, measuring >= 1 cm in diameter, and with more than minimal cellularity, as per local pathologist determination; this is required due to constraints in deoxyribonucleic acid (DNA) extraction for PAM50 analysis NOTE: The presence of ductal carcinoma in situ (DCIS) without invasion does not qualify as residual invasive disease in the breast NOTE: Despite lymph node involvement if residual invasive cancer in the breast is < 1 cm in diameter patients are not eligible for participation Radiotherapy may be given before or after protocol treatment per standard of care guidelines; when radiotherapy is planned prior to protocol treatment administration, patients may be registered and screened while receiving radiation Post-mastectomy radiotherapy is required for all patients with the following: Primary tumor >= 5 cm (prior to neoadjuvant chemotherapy [clinically] or at the time of definitive surgery) or involvement of 4 or more lymph nodes at the time of definitive surgery For patients with primary tumors < 5 cm or with < 4 involved lymph nodes prior to neoadjuvant chemotherapy and at the time of definitive surgery, provision of post-mastectomy radiotherapy is at the discretion of the treating physician Radiation of regional nodal basins is at the discretion of the treating radiation oncologist NOTE: Breast radiotherapy (whole breast or partial) is required for patients who underwent breast-conserving therapy, including lumpectomy or partial mastectomy Hemoglobin (Hgb) > 9.0 g/dL Platelets > 100,000 mm^3 Absolute neutrophil count (ANC) > 1500 mm^3 Calculated creatinine clearance of > 50 mL/min using the Cockcroft-Gault formula Bilirubin =< 1.5 x ULN upper limit of normal (except in patients with documented Gilbert?s disease, who must have a total bilirubin =< 3.0 mg/dL) Aspartate aminotransferase (AST, serum glutamic oxaloacetic transaminase [SGOT]) =< 2.5 x upper limit of normal (ULN) Alanine aminotransferase (ALT, serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x ULN Patients with active >= Common Terminology Criteria for Adverse Events (CTCAE) version (v.) 4 grade 2 neuropathy are ineligible Adjuvant chemotherapy after surgery other than that specified in this protocol is not allowed; luteinizing hormone-releasing hormone (LHRH) agonists and adjuvant bisphosphonate or denosumab use is allowed Patients must have archived formalin-fixed paraffin-embedded (FFPE) tumor tissue specimen from the residual disease on the definitive surgical specimen available for PAM50 analysis for stratification Tumor tissue specimen from the definitive surgery has been collected and is ready to ship to the ECOG-American College of Radiology Imaging Network (ACRIN) Central Biorepository and Pathology Facility (CBPF) within 21 weeks post-surgery The Molecular Diagnostics Laboratory (MDL) at MD Anderson Cancer Center will perform the PAM50 analysis and notify the ECOG-American College of Radiology Imaging Network (ACRIN) operations office within three (3) weeks of receipt of the tumor tissue specimen via secure electronic messaging to the ECOG-ACRIN database; results will not be reported to the submitting institution NOTE: Tissue must be submitted any time during screening period, even if patient is getting radiation NOTE: Every effort should be made to submit the tumor tissue specimen to the ECOG-ACRIN CBPF immediately Exclusion Criteria: History of TNBC invasive breast cancer within 5 years of enrollment, no concurrent malignancies of any sort Clinically significant infections as judged by the treating investigator ELIGIBILITY CRITERIA FOR RANDOMIZATION (STEP 1): No specific timeframe between registration and randomization needs to be observed, as long as: Patients randomized to the chemotherapy arms have their cycle 1/ day 1 (platinum based or capecitabine) start within 3 weeks (15 working days) following randomization date Randomization occurs no more than 24 weeks from surgery date Must have PAM50 analysis by digital mRNA quantitation on the formalin-fixed paraffin-embedded tumor tissue specimen (FFPE) of the residual disease in the breast or axilla resected at the time of definitive surgery completed ECOG performance status 0 or 1 within 2 weeks prior to randomization Radiotherapy may be given before or after protocol treatment. when radiotherapy is planned prior to protocol treatment administration, patients must have completed adjuvant radiotherapy >= 2 weeks prior to randomization for protocol therapy, if applicable Patients must have completed treatment with any investigational agent >= 30 days prior to randomization for protocol therapy, if applicable Patients must be randomized within 24 weeks from surgery Women must not be pregnant or breast-feeding; all females of childbearing potential must have a blood test or urine study within 2 weeks prior to randomization to rule out pregnancy A female of childbearing potential is any woman, regardless of sexual orientation or whether they have undergone tubal ligation, who meets the following criteria: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months Women of childbearing potential and sexually active males must be strongly advised to use an accepted and effective method of contraception or to abstain from sexual intercourse for the duration of their participation in the study Hemoglobin (Hgb) > 9.0 g/dL Platelets > 100,000 mm^3 Absolute neutrophil count (ANC) > 1500 mm^3 International normalized ratio (INR) =< 3 (to be done/tested only for subjects on warfarin) Calculated creatinine clearance of > 50 mL/min using the Cockcroft-Gault formula Bilirubin =< 1.5 x ULN (except in patients with documented Gilbert?s disease, who must have a total bilirubin =< 3.0 mg/dL) Aspartate aminotransferase (AST, SGOT) =< 2.5 x ULN Alanine aminotransferase (ALT, SGPT) =< 2.5 x ULN

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| No Intervention: Arm A (observation) (closed to accrual 05/16/2016)<br>Patients undergo observation. | |
| Experimental: Arm B (cisplatin or carboplatin)<br>Patients receive cisplatin IV or carboplatin IV on day 1. Treatment repeats every 3 weeks for 4 courses in the absence of disease progression or unacceptable toxicity. | Drug: Carboplatin<br>* Given IV<br>* Other names: Carboplatin Novaplus;Drug: Cisplatin<br>* Given IV<br>* Other names: Platinol;|
| Active Comparator: Arm C (capecitabine)<br>Patients receive capecitabine PO BID on days 1-14. Treatment repeats every 3 weeks for up to 6 courses in the absence of disease progression or unacceptable toxicity. | Drug: Capecitabine<br>* Given PO<br>* Other names: Xeloda;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 3-year Invasive Disease-Free Survival (IDFS) Rate in Basal-Subtype Patients | IDFS was defined to be time from randomization to the earliest of documented disease recurrence (local, regional and/or distant), invasive contralateral breast cancer, invasive any other second cancer, or death. Cases with incomplete follow up or without adequate disease evaluations were censored at the date last documented to be free of IDFS events. 3-year IDFS rate was estimated using Kaplan-Meier method. | No mandatory timeline, assessed at any time as a standard of care procedure or at the investigator's discretion; data reported every 3 months within 2 years from randomization, every 6 months if 2-3 years. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 3-year Recurrence-Free Survival (RFS) Rate in Basal-Subtype Patients | RFS was defined as time from randomization to local/regional recurrence, distant recurrence or death, whichever occurred first. Cases with incomplete follow up or without adequate disease evaluations were censored at the date last documented to be free of RFS events. 3-year RFS rate was estimated using Kaplan-Meier method. | No mandatory timeline, assessed at any time as a standard of care procedure or at the investigator's discretion; data reported every 3 months within 2 years from randomization, every 6 months if 2-3 years. | 
| 3-year Overall Survival (OS) Rate in Basal-Subtype Patients | OS was defined as time from randomization to death from any cause. Patient alive were censored at date of known alive. The 3-year OS rate was estimated using Kaplan-Meier method. | Assessed every 3 months within 2 years from randomization, every 6 months if 2-3 years | 
| Proportion of Basal Subtype | Proportion of basal subtype was calculated as number of patients who had basal subtype disease divided by all triple-negative breast cancers who were randomized to arms B and C after 6/22/2016 and had intrinsic subtype results. | Assessed at registration to step 0 (baseline) | 
| Health-related Quality of Life (HRQL) at 6-month Assessment | HRQL was measured by the Functional Assessment of Cancer Therapy Breast Symptom Index (FBSI) Treatment Side Effects (TSE) subscale score, an aggregate score of 4 items (GP2, GP5, N6 and B5) from the FBSI-16 scale. The FBSI TSE subscale score was calculated based on the scoring manual, score ranges from 0 to 16, higher scores indicate better quality of life. | Assessed at 6 months after randomization | 
| Health-related Quality of Life (HRQL) at 15-month Assessment | HRQL was measured by the Functional Assessment of Cancer Therapy Breast Symptom Index (FBSI) Treatment Side Effects (TSE) subscale score, an aggregate score of 4 items (GP2, GP5, N6 and B5) from the FBSI-16 scale. The FBSI TSE subscale score was calculated based on the scoring manual, score ranges from 0 to 16, higher scores indicate better quality of life. | Assessed at 15 months after randomization | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Platinum, Capecitabine, Triple-negative breast cancer, Basal subtype, Neoadjuvant