Summary

This phase III trial compares the effect of cisplatin or carboplatin (platinum-based chemotherapy) to capecitabine after initial chemotherapy (neoadjuvant therapy) followed by surgery for the treatment of residual triple-negative breast cancer. Chemotherapy drugs, 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. At present, upon completion of chemotherapy and surgery, the standard of care for patients with triple-negative breast cancer is observation. However, recent studies have shown that giving capecitabine after completion of chemotherapy and surgery is a better treatment than receiving no treatment and also that platinum-based chemotherapy after neoadjuvant therapy and surgery may prevent residual triple-negative breast cancer from returning. This trial compares the benefit of adding a platinum agent vs. capecitabine to the treatment regimen, following completion of neoadjuvant therapy and surgery in patients with residual triple-negative breast cancer.

Objectives

PRIMARY OBJECTIVE:
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 CLINICAL 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 each platinum agent (cisplatin and carboplatin) 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 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 (exploratory analysis).
V. To assess the difference in health-related quality of life (HRQL) between the platinum based and capecitabine chemotherapy arms.
VI. 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 (exploratory).

SECONDARY CORRELATIVE BIOMARKER OBJECTIVES:
I. To evaluate the association of genomic alterations identified via profiling of the surgical tumor specimen with RFS in patients with TNBC after neoadjuvant chemotherapy.
II. To explore whether any of the genomic alterations identified via profiling of the surgical tumor specimen can predict treatment benefit in patients with basal-like TNBC.
III. To determine the frequency of CTC positivity at baseline and after completion of study therapy in patients with TNBC with residual basal-like disease after neoadjuvant chemotherapy.
IV. To evaluate the associations between CTC levels at baseline, and after completion of chemotherapy, with RFS.
V. To evaluate the association between CTC change in status post-treatment (i.e. negative to negative, negative to positive, positive to negative, positive to positive) and RFS.
VI. To explore significance of CTC number/phenotype and ctDNA-detected mutations (mutational burden, specific mutations) in predicting RFS.

EXPLORATORY CORRELATIVE BIOMARKER OBJECTIVES:
I. 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-like disease after neoadjuvant chemotherapy.
II. To evaluate the associations between plasma tumor cfDNA tumor-specific mutations (baseline and after therapy) with RFS.
III. To explore optimal biomarker combination for RFS prediction.

EXPLORATORY TOBACCO USE OBJECTIVES:
I. 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).
II. To determine the effects of tobacco on patient-reported physical symptoms and psychological symptoms.
III. To examine quitting behaviors and behavioral counseling/support and cessation medication utilization.
IV. 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 cycles 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 cycles in the absence of disease progression or unacceptable toxicity.

Patients undergo blood sample collection while on study and during follow up.

Eligibility

1. ELIGIBILITY CRITERIA FOR SCREENING AND MOLECULAR PROFILING (STEP 0)
2. Age >= 18 years.
3. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 within 2 weeks prior to screening
4. 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] 8th 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: ** 1 to =< 10% cells stain positive, with weak intensity score ** =< 1% cells stain positive * 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 (please note that tumors that were not tested already do not need to be tested for protocol eligibility) ** NOTE: patients that have a discrepancy in ER/PR/HER2 status between original diagnosis and surgical specimen (only applicable if ER/PR/HER2 status were repeated; repeating it is not mandatory) are not eligible for study participation as long as the surgical specimen's ER/PR/HER2 status fulfills eligibility criteria ** NOTE: Special histologies (i.e. metaplastic, adenoid cystic, apocrine, etc.) are eligible as long as ER/PR/HER2 testing fulfills eligibility criteria ** NOTE: Patients with inflammatory TNBC at presentation are eligible
5. Patients must have received 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 * NOTE: Patients must have received a taxane for at least 1 cycle as part of their neoadjuvant therapy regimen
6. 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
7. 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; please note that in patients that have multifocal or multicentric residual tumors these lesions cannot be added up; the biggest lesion has to measure >= 1 cm in diameter; 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
8. 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, and it has to be complete prior to randomization * Post-mastectomy radiotherapy is required for all patients with the following: ** Primary tumor >= 5 cm or involvement of lymph nodes (prior to neoadjuvant chemotherapy [clinically] or at the time of definitive surgery) or involvement of lymph nodes at the time of definitive surgery ** For patients with primary tumors < 5 cm or without lymph node involvement 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
9. Hemoglobin (Hgb) > 9.0 g/dL (must be obtained within 8 weeks prior to screening for protocol therapy)
10. Platelets > 100,000 mm^3 (must be obtained within 8 weeks prior to screening for protocol therapy)
11. Absolute neutrophil count (ANC) > 1500 mm^3 (must be obtained within 8 weeks prior to screening for protocol therapy)
12. Calculated creatinine clearance of > 50 mL/min using the Cockcroft-Gault formula (must be obtained within 8 weeks prior to screening for protocol therapy)
13. 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) (must be obtained within 8 weeks prior to screening for protocol therapy)
14. Aspartate aminotransferase (AST, serum glutamic oxaloacetic transaminase [SGOT]) =< 2.5 x upper limit of normal (ULN) (must be obtained within 8 weeks prior to screening for protocol therapy)
15. Alanine aminotransferase (ALT, serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x ULN (must be obtained within 8 weeks prior to screening for protocol therapy)
16. 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
17. 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 * 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 (EA CBPF) within 21 weeks post-surgery; the EA CBPF will notify the ECOG-ACRIN Operations Office and submitting institution of receipt of the tumor tissue specimen * NOTE: Tissue must and can 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 EA CBPF immediately
18. ELIGIBILITY CRITERIA FOR RANDOMIZATION (STEP 1): No specific timeframe between registration and randomization needs to be observed, as long as: * After assignment of randomization patients must begin cycle 1/ day 1 (platinum based or capecitabine chemotherapy) within 6 weeks (30 working days) of the randomization date * Randomization occurs no more than 24 weeks from surgery date (i.e. subsequent surgeries for re-excision of margins or lymph nodes or reconstruction do not apply)
19. ELIGIBILITY CRITERIA FOR RANDOMIZATION (STEP 1): Must have confirmation from EA CBPF of receipt of formalin-fixed paraffin-embedded tumor tissue specimen (FFPE) of the residual disease in the breast resected at the time of definitive surgery
20. ELIGIBILITY CRITERIA FOR RANDOMIZATION (STEP 1): ECOG performance status 0 or 1 within 2 weeks prior to randomization
21. ELIGIBILITY CRITERIA FOR RANDOMIZATION (STEP 1): Radiotherapy, if applicable, 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
22. ELIGIBILITY CRITERIA FOR RANDOMIZATION (STEP 1): Patients must have completed treatment with any investigational agent >= 30 days prior to randomization for protocol therapy initiation (cycle 1/day 1)
23. ELIGIBILITY CRITERIA FOR RANDOMIZATION (STEP 1): Patients must be randomized within 24 weeks from surgery date (i.e. subsequent surgeries for re-excision of margins or lymph nodes or reconstruction do not apply)
24. ELIGIBILITY CRITERIA FOR RANDOMIZATION (STEP 1): 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
25. ELIGIBILITY CRITERIA FOR RANDOMIZATION (STEP 1): Hemoglobin (Hgb) > 9.0 g/dL (must be obtained within 4 weeks prior to randomization)
26. ELIGIBILITY CRITERIA FOR RANDOMIZATION (STEP 1): Platelets > 100,000 mm^3 (must be obtained within 4 weeks prior to randomization)
27. ELIGIBILITY CRITERIA FOR RANDOMIZATION (STEP 1): Absolute neutrophil count (ANC) > 1500 mm^3 (must be obtained within 4 weeks prior to randomization)
28. ELIGIBILITY CRITERIA FOR RANDOMIZATION (STEP 1): International normalized ratio (INR) =< 3 (to be done/tested only for subjects on warfarin) (must be obtained within 4 weeks prior to randomization)
29. ELIGIBILITY CRITERIA FOR RANDOMIZATION (STEP 1): Calculated creatinine clearance of > 50 mL/min using the Cockcroft-Gault formula (must be obtained within 4 weeks prior to randomization)
30. ELIGIBILITY CRITERIA FOR RANDOMIZATION (STEP 1): Bilirubin =< 1.5 x ULN (except in patients with documented Gilbert’s disease, who must have a total bilirubin =< 3.0 mg/dL) (must be obtained within 4 weeks prior to randomization)
31. ELIGIBILITY CRITERIA FOR RANDOMIZATION (STEP 1): Aspartate aminotransferase (AST, SGOT) =< 2.5 x ULN (must be obtained within 4 weeks prior to randomization)
32. ELIGIBILITY CRITERIA FOR RANDOMIZATION (STEP 1): Alanine aminotransferase (ALT, SGPT) =< 2.5 x ULN (must be obtained within 4 weeks prior to randomization)

Treatment Sites in Georgia