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

• ClinicalTrials.gov Identifier: NCT02445391
• Recruitment Status: Active, not recruiting
• First Posted: May 15, 2015
• Results First Posted: October 5, 2022
• Last Update Posted: July 10, 2023
• Sponsor: ECOG-ACRIN Cancer Research Group
• Collaborator: National Cancer Institute (NCI)
• Information provided by (Responsible Party): Eastern Cooperative Oncology Group ( ECOG-ACRIN Cancer Research Group )

Tracking Information

• First Submitted Date: May 13, 2015
• First Posted Date: May 15, 2015
• Results First Submitted Date: December 9, 2021
• Results First Posted Date: October 5, 2022
• Last Update Posted Date: July 10, 2023
• Actual Study Start Date: October 20, 2015
• Actual Primary Completion Date: April 7, 2021 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: September 7, 2022)

3-year Invasive Disease-Free Survival (IDFS) Rate in Basal-Subtype Patients [ Time Frame: 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. ]

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.

Original Primary Outcome Measures (submitted: May 14, 2015)

IDFS of patients with basal-like TNBC [ Time Frame: From randomization to the earliest of documented disease recurrence (local, regional and/or distant), invasive contralateral breast cancer, invasive any other second primary cancer, or death, assessed up to 86 months after study activation ]

The distributions of IDFS will be estimated using the Kaplan- Meier method, with 95% confidence intervals (CI) calculated using Greenwood's formula. The primary analysis of IDFS comparisons between two treatment arms will be performed using stratified log-rank tests, stratifying on the randomization stratification factors. Stratified Cox proportional-hazard models will also be built to estimate the hazard ratios for treatment effect for IDFS as a supportive analysis.

Current Secondary Outcome Measures (submitted: September 7, 2022)

• 3-year Recurrence-Free Survival (RFS) Rate in Basal-Subtype Patients [ Time Frame: 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. ]
  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.
• 3-year Overall Survival (OS) Rate in Basal-Subtype Patients [ Time Frame: Assessed every 3 months within 2 years from randomization, every 6 months if 2-3 years ]
  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.
• Proportion of Basal Subtype [ Time Frame: Assessed at registration to step 0 (baseline) ]
  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.
• Health-related Quality of Life (HRQL) at 6-month Assessment [ Time Frame: Assessed at 6 months after randomization ]
  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.
• Health-related Quality of Life (HRQL) at 15-month Assessment [ Time Frame: Assessed at 15 months after randomization ]
  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.

Original Secondary Outcome Measures (submitted: May 14, 2015)

• Incidence of toxicity graded using the National Cancer Institute CTCAE v. 4.0 [ Time Frame: Up to 86 months after study activation ]
  All treatment-emergent and baseline adverse events and hematological/biochemical toxicities based on laboratory measurements will be summarized for patients on platinum agent. The incidence of deaths and treatment-emergent serious adverse events will be calculated along with exact 95% CI based on binomial distribution. Also, the incidence of adverse events leading to discontinuation of chemotherapy and/or withdrawal from the study will be summarized and listed as well.
• Overall survival (OS) of patients with basal-like TNBC with residual disease after neoadjuvant chemotherapy [ Time Frame: Time from randomization to death from any cause, assessed up to 116 months after study activation ]
  The distributions of OS will be estimated using the Kaplan- Meier method, with 95% CI calculated using Greenwood's formula. The primary analysis of OS comparisons between two treatment arms will be performed using stratified log-rank tests, stratifying on the randomization stratification factors.
• Rate of basal-like gene expression using PAM50 analysis by digital mRNA quantification [ Time Frame: Baseline ]
  The proportion of basal-like TNBC in all screened TNBC patients will be calculated with exact 95% CI based on binomial distribution.
• RFS [ Time Frame: Up to 86 months after study activation ]
  The distributions of RFS will be estimated using the Kaplan- Meier method, with 95% CI calculated using Greenwood's formula. The primary analysis of RFS comparisons between two treatment arms will be performed using stratified log-rank tests, stratifying on the randomization stratification factors.

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Platinum in Treating Patients With Residual Triple-Negative Breast Cancer Following Neoadjuvant Chemotherapy
• Official Title: 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
• Brief Summary: 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

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.

• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• 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

• Drug: Capecitabine
  Given PO
  Other Name: Xeloda
• Drug: Carboplatin
  Given IV
  Other Names:

  • Paraplatin
  • Carboplatin Novaplus
• Drug: Cisplatin
  Given IV
  Other Names:

  • Platinol-AQ
  • Platinol

Study Arms

• No Intervention: Arm A (observation) (closed to accrual 05/16/2016)
  Patients undergo observation.
• Experimental: Arm B (cisplatin or carboplatin)
  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.
  Interventions:

  • Drug: Carboplatin
  • Drug: Cisplatin
• Active Comparator: Arm C (capecitabine)
  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.
  Intervention: Drug: Capecitabine

• Publications *: Mayer IA, Zhao F, Arteaga CL, Symmans WF, Park BH, Burnette BL, Tevaarwerk AJ, Garcia SF, Smith KL, Makower DF, Block M, Morley KA, Jani CR, Mescher C, Dewani SJ, Tawfik B, Flaum LE, Mayer EL, Sikov WM, Rodler ET, Wagner LI, DeMichele AM, Sparano JA, Wolff AC, Miller KD. Randomized Phase III Postoperative Trial of Platinum-Based Chemotherapy Versus Capecitabine in Patients With Residual Triple-Negative Breast Cancer Following Neoadjuvant Chemotherapy: ECOG-ACRIN EA1131. J Clin Oncol. 2021 Aug 10;39(23):2539-2551. doi: 10.1200/JCO.21.00976. Epub 2021 Jun 6.

Recruitment Information

• Recruitment Status: Active, not recruiting
• Actual Enrollment (submitted: September 7, 2022): 415
• Original Estimated Enrollment (submitted: May 14, 2015): 558
• Estimated Study Completion Date: March 29, 2031
• Actual Primary Completion Date: April 7, 2021 (Final data collection date for primary outcome measure)

Eligibility Criteria

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: South Africa, United States

Administrative Information

• NCT Number: NCT02445391
• Other Study ID Numbers: EA1131; NCI-2014-01820 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) ); EA1131 ( Other Identifier: ECOG-ACRIN Cancer Research Group ); EA1131 ( Other Identifier: CTEP ); U10CA180820 ( U.S. NIH Grant/Contract ); U24CA196172 ( U.S. NIH Grant/Contract )
• Has Data Monitoring Committee: No
• U.S. FDA-regulated Product: Not Provided

IPD Sharing Statement

• Plan to Share IPD: Yes
• Plan Description: Individual participant data may be made available upon request as per the ECOG-ACRIN Data Sharing Policy

• Current Responsible Party: Eastern Cooperative Oncology Group ( ECOG-ACRIN Cancer Research Group )
• Original Responsible Party: Same as current
• Current Study Sponsor: ECOG-ACRIN Cancer Research Group
• Original Study Sponsor: Same as current
• Collaborators: National Cancer Institute (NCI)

Investigators

• Principal Investigator: Ingrid Mayer; ECOG-ACRIN Cancer Research Group

• PRS Account: Eastern Cooperative Oncology Group
• Verification Date: June 2023