Correlation of Clinical Response to Pathologic Response in Patients With Early Breast Cancer (RESPONSE)

A Phase II Trial to Correlate Early Clinical Response to Pathologic Outcome With Neoadjuvant Systemic Therapy in Patients With Early Stage Breast Cancer

The purpose of this study is to learn whether clinical response (the amount a tumor shrinks based on imaging or tumor measurements obtained by physical exam) predicts pathologic response (the amount of tumor remaining when surgery is performed) in participants with breast cancer who are receiving chemotherapy prior to surgery.

Study Overview

• Status: Recruiting
• Conditions: Breast Cancer; Breast Neoplasm; Triple Negative Breast Cancer; Triple Negative Breast Neoplasms; HER2-positive Breast Cancer; Breast Cancer Stage II; Breast Cancer Female; Breast Cancer Stage III; Estrogen Receptor-positive Breast Cancer; Hormone Receptor-positive Breast Cancer; Breast Cancer Invasive
• Intervention / Treatment: Drug: Paclitaxel; Drug: Carboplatin; Drug: Doxorubicin; Drug: Cyclophosphamide; Drug: Pembrolizumab; Drug: Trastuzumab; Drug: Pertuzumab; Drug: Pertuzumab/Trastuzumab/Hyaluronidase-zzxf

Detailed Description

Neoadjuvant therapy was first introduced to improve surgical outcomes of breast cancer and to be able to assess the pathological responsiveness to therapy at the time of surgery. Over time, it became a useful experimental platform in clinical research in breast cancer, and in recent years became an important part of standard management of certain subtypes and clinical stages in breast cancer.

It has been long established that patients who achieve pathologic complete response (pCR, i.e., the absence of any cancer in the tissue removed during surgery) after receiving neoadjuvant treatment have better outcomes than those who don't, especially in HER2+, and triple-negative breast cancer (TNBC). Many reports add aggressive ER+ breast cancer to these groups. So far, the only way to know whether a patient achieved pCR is to give them a full course of therapy and then proceed to surgery.

One of the areas that has attracted significant research interest has been the effort to develop early predictors of pCR. This way, treatment can be tailored in the future to each patient and each tumor and can spare patients ineffective therapy. Some of these predictors include tissue biomarkers, blood based biomarkers, and imaging biomarkers.

It has been observed in neoadjuvant clinical trials that many patients have an impressive early clinical response to treatment after 1-2 cycles of treatment. Anecdotally, many of those patients go on to have a pCR at the time of surgery. This observation, if validated in a prospective clinical trial, may lead to a simple, inexpensive way to assess tumor responsiveness and predict pCR using clinical exam and simple imaging.

Using imaging or molecular changes to predict pCR will also be explored in this study. A consortium of investigators will be studying image analysis and proteogenomic changes early in the course of treatment to predict clinical response specifically in participants with TNBC. Only participants with TNBC will be required to undergo a research biopsy and research MRI prior to starting treatment, and again after the first cycle of treatment.

The investigators therefore hypothesize that absence of early clinical response, defined as at least a 30% reduction in the size of the breast tumor by Day 21 of treatment (as measured by either imaging or clinical exam), will be associated with absence of pCR at the time of surgery, in 3 subtypes of breast cancer - TNBC, HER2+, high-risk ER+.

All treatment in this study is standard of care (non-investigational).

• Study Type: Interventional
• Enrollment (Estimated): 185
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Maria Rodriguez; Phone Number: (713) 798-8347; Email: bcc-clinicalresearch@bcm.edu

Study Locations

• United States
  • Texas
    • Houston, Texas, United States, 77054
      • Recruiting
      • Harris Health System - Smith Clinic
      • Principal Investigator: Mothaffar Rimawi, MD
      • Contact: Maria Rodriguez; Phone Number: 713-798-8347; Email: bcc-clinicalresearch@bcm.edu
    • Houston, Texas, United States, 77054
      • Recruiting
      • O'Quinn Medical Tower - McNair Campus - Dan L Duncan Comprehensive Cancer Center
      • Principal Investigator: Mothaffar Rimawi, MD
      • Contact: Maria Rodriguez; Phone Number: 713-798-8347; Email: bcc-clinicalresearch@bcm.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• At least 18 years of age, and legally able to provide informed consent. Both men and women are eligible.
• Histologically confirmed, invasive breast cancer. Tumor may be triple negative (as defined by ASCO-CAP guidelines), HER2-positive (as defined by ASCO-CAP guidelines), or high-risk estrogen receptor positive (as defined by ASCO-CAP guidelines).

To be considered "high risk," at least 2 of the following criteria must be met: 1) histologic grade 3; 2) patient age 50 or less; 3) ER Allred score < 6; 4) Ki-67 ≥ 30%.

• Tumors must be at least 2 cm by clinical exam or ultrasound
• Bilateral breast cancers are allowed if the following criteria are met: 1) A lesion on one side (meeting the criteria above) is designated as the index lesion on which study assessments will be performed, and 2) the same treatment regimen is appropriate for both cancers as determined by the treating physician.
• ECOG performance status of 0 or 1
• Left ventricular ejection fraction (LVEF) ≥ the institutional lower limit of normal, as assessed by echocardiogram or Multigated Acquisition (MUGA )scan.

• Adequate organ function, as determined by the following parameters:

  • Absolute Neutrophil Count (ANC) ≥ 1200/mm3
  • Platelets ≥ 100,000/mm3
  • Hemoglobin ≥ 9 g/dL
  • Total bilirubin ≤ institutional upper limit of normal (ULN), unless patient has Gilbert's disease or similar syndrome
  • Alkaline phosphatase (ALP) ≤ 2.5 x institutional ULN
  • Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ≤ 1.5 x institutional ULN
  • Serum creatinine ≤ institutional ULN
• The participant, if of childbearing potential, is willing to use effective, non-hormonal contraception while on treatment.
• Participation in a concurrent clinical trial is permitted, with Principal Investigator approval.

Exclusion Criteria:

• Definitive clinical or radiologic evidence of Stage IV disease
• Inflammatory breast cancer
• Participants who are pregnant or lactating
• History of an excisional biopsy or lumpectomy performed prior to study entry
• Prior treatment with anthracyclines for any malignancy.
• Prior treatment for currently diagnosed breast cancer (i.e., endocrine therapy, chemotherapy, targeted therapy, or radiation.

• History of cardiac disease that would preclude the use of drugs included in these treatment regimens. This includes, but is not limited to:

  • Angina pectoris requiring the use of anti-anginal medication
  • Ventricular arrhythmias except for benign premature ventricular contractions
  • Supraventricular and nodal arrhythmias requiring a pacemaker or not controlled with medication
  • Conduction abnormality requiring a pacemaker
  • Valvular disease with documented compromise in cardiac function
  • Symptomatic pericarditis
  • Documented cardiomyopathy
  • History of documented congestive heart failure (CHF)
  • Myocardial infarction documented by elevated cardiac enzymes, or persistent regional wall abnormalities on assessment of left ventricular function.
• Current HIV, hepatitis B, or hepatitis C infection
• History of non-breast malignancies (with the exception of in situ cancers treated only by local excision, and basal cell or squamous cell carcinoma of the skin) within 5 years prior to enrollment.
• Any other non-malignant systemic disease that would preclude treatment with any of the treatment regimens or prevent required follow-up.
• Any psychiatric or addictive disorders, adverse social situations, or other medical conditions that, in the opinion of the investigator, would preclude the patient from meeting study requirements.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Triple Negative Breast Cancer (for tumors > 5 cm); Paclitaxel IV plus carboplatin IV (+/- pembrolizumab IV) (4 cycles total), followed by doxorubicin IV plus cyclophosphamide IV (+/- pembrolizumab IV) (4 cycles total)	Drug: Paclitaxel; 80 mg/m2 IV administered on Days 1, 8, 15 of each 21-day cycle; Other Names: Taxol; Drug: Carboplatin; Carboplatin AUC 1.5 IV administered on Days 1, 8, 15 of each 21-day cycle; Drug: Doxorubicin; 60 mg/m2 IV administered on Day 1 of each 14-day cycle; Other Names: Adriamycin; Drug: Cyclophosphamide; 600 mg/m2 IV administered on Day 1 of each 14-day cycle; Other Names: Cytoxan; Drug: Pembrolizumab; Either 200 mg IV administered on Day 1 of Cycles 1-4, or 400 mg IV administered on Day 1 of Cycles 1 and 3 of the paclitaxel/carboplatin regimen. 400 mg on Day 1 of Cycles 1 and 4 of the dose-dense AC regimen.; Other Names: Keytruda
Active Comparator: Triple Negative Breast Cancer (for tumors < 5 cm); Paclitaxel IV (4 cycles total), followed by doxorubicin IV plus cyclophosphamide IV (4 cycles total)	Drug: Paclitaxel; 80 mg/m2 IV administered on Days 1, 8, 15 of each 21-day cycle; Other Names: Taxol; Drug: Doxorubicin; 60 mg/m2 IV administered on Day 1 of each 14-day cycle; Other Names: Adriamycin; Drug: Cyclophosphamide; 600 mg/m2 IV administered on Day 1 of each 14-day cycle; Other Names: Cytoxan
Active Comparator: HER2-Positive Breast Cancer; Paclitaxel IV plus Trastuzumab IV plus Pertuzumab IV (or PHESGO) (4 cycles total), followed by doxorubicin IV plus cyclophosphamide IV administered (4 cycles total)	Drug: Paclitaxel; 80 mg/m2 IV administered on Days 1, 8, 15 of each 21-day cycle; Other Names: Taxol; Drug: Doxorubicin; 60 mg/m2 IV administered on Day 1 of each 14-day cycle; Other Names: Adriamycin; Drug: Cyclophosphamide; 600 mg/m2 IV administered on Day 1 of each 14-day cycle; Other Names: Cytoxan; Drug: Trastuzumab; Trastuzumab 8 mg/kg loading dose, followed by 6 mg/kg maintenance dose, administered on Day 1 of each 21-day cycle; Other Names: Herceptin; Drug: Pertuzumab; Pertuzumab 840 mg loading dose, followed by 420 mg maintenance dose, administered on Day 1 of each 21-day cycle; Other Names: Perjeta; Drug: Pertuzumab/Trastuzumab/Hyaluronidase-zzxf; Can be used in place of separate IV formulations of pertuzumab and trastuzumab. 1200 mg pertuzumab/600 mg trastuzumab/30,000 U hyaluronidase administered subcutaneously on Day 1 of the first cycle, followed by a maintenance dose of 600 mg pertuzumab/600 mg trastuzumab/20,000 U hyaluronidase administered subcutaneously every 3 weeks.; Other Names: PHESGO
Active Comparator: Hormone Receptor Positive Breast Cancer; Paclitaxel IV plus Carboplatin IV (4 cycles total), followed by doxorubicin IV plus cyclophosphamide IV (4 cycles total)	Drug: Paclitaxel; 80 mg/m2 IV administered on Days 1, 8, 15 of each 21-day cycle; Other Names: Taxol; Drug: Doxorubicin; 60 mg/m2 IV administered on Day 1 of each 14-day cycle; Other Names: Adriamycin; Drug: Cyclophosphamide; 600 mg/m2 IV administered on Day 1 of each 14-day cycle; Other Names: Cytoxan

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Clinical Tumor Measurement vs. Pathologic Response	Clinical tumor measurements are tumor measurements obtain via imaging (mammogram or ultrasound) or by physical exam. Pathologic response is the amount of tumor remaining at the time of surgery, as determined by the pathologist.	Baseline and at surgery (after 20 weeks)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pathologic Complete Response Rate in each Breast Cancer Subtype	A pathologic complete response (pCR) means that there is no residual invasive cancer identified in the tissue removed at surgery. The frequency of pCR will be estimated for each breast cancer subtype (triple negative, hormone receptor positive, and HER2-positive)	20 weeks
Predictive value of clinical response following 1 cycle of chemotherapy to predict pathologic complete response	This aims to determine whether a 30 percent reduction in tumor size (as measured by physical exam or imaging) following one cycle of chemotherapy can predict whether a patient will have no residual invasive cancer at the time of surgery	20 weeks

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in circulating tumor DNA (ctDNA) levels from baseline to surgery	ctDNA is DNA from a tumor circulating in a patient's bloodstream. The goal of this is to determine whether a decrease in ctDNA levels (as measured from baseline to surgery) correlates to clinical and/or pathologic response	20 weeks

Collaborators and Investigators

• Sponsor: Baylor Breast Care Center
• Investigators: Principal Investigator: Mothaffar Rimawi, MD, Baylor College of Medicine

Study record dates

Study Major Dates

• Study Start (Actual): April 18, 2023
• Primary Completion (Estimated): August 1, 2027
• Study Completion (Estimated): November 1, 2029

Study Registration Dates

• First Submitted: August 19, 2021
• First Submitted That Met QC Criteria: August 19, 2021
• First Posted (Actual): August 25, 2021

Study Record Updates

• Last Update Posted (Actual): January 16, 2024
• Last Update Submitted That Met QC Criteria: January 11, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Skin Diseases; Neoplasms by Site; Breast Diseases; Neoplasms; Breast Neoplasms; Triple Negative Breast Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antirheumatic Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Antineoplastic Agents, Phytogenic; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Antineoplastic Agents, Immunological; Antibiotics, Antineoplastic; Immune Checkpoint Inhibitors; Cyclophosphamide; Carboplatin; Paclitaxel; Trastuzumab; Pembrolizumab; Doxorubicin; Pertuzumab
• Other Study ID Numbers: H-50349

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No