Ph2 Study for Optimization of Adjunct Systemic Therapy in HER2+ Patients, MolecularPCR Trial

PRIMARY OBJECTIVES:

I. To determine the 3-year event free survival (EFS) after breast surgery in patients with early triple negative breast cancer (TNBC) that achieve a pathologic complete response (pCR) after neoadjuvant systemic therapy (NST) with a pembrolizumab plus chemotherapy-based regimen and are minimal residual disease (MRD)-negative (negative circulating tumor deoxyribonucleic acid [ctDNA] with the NeXT Personal™ assay) at 4-6 weeks after breast surgery and discontinue standard of care (SOC) adjuvant pembrolizumab.

II. To determine the 3-year EFS after breast surgery in patients with early HER2+ breast cancer that achieve a pCR after NST with a trastuzumab and pertuzumab plus chemotherapy-based regimen and are MRD-negative (negative ctDNA with the NeXT Personal™ assay) at 4-6 weeks after breast surgery and discontinue SOC adjuvant trastuzumab and pertuzumab.

SECONDARY OBJECTIVES:

I. To estimate the rate of conversion from negative to positive ctDNA and time to conversion from negative to positive ctDNA among patients who undergo de-escalation of SOC adjuvant systemic therapy.

II. To establish the prevalence of patients with early TNBC or early HER2+ breast cancer who achieve a pCR after receiving NST and have a positive ctDNA with the NeXT Personal™ assay at 4-6 weeks after breast surgery.

III. To determine the 3-year EFS after breast surgery in patients with early HER2+ breast cancer or early TNBC that achieve a pCR after NST and have a positive ctDNA with the NeXT Personal™ assay at 4-6 weeks after breast surgery.

OUTLINE: Patients with triple negative breast cancer are assigned to cohort 1, patients with HER2 positive breast cancer are assigned to cohort 2.

COHORT 1: Patients may receive 1 to 3 cycles of standard of care treatment with pembrolizumab. Patients with a positive ctDNA test 4-6 weeks after surgery continue to receive standard of care treatment per their treating physician in the absence of disease progression or unacceptable toxicity. Patients with a negative ctDNA test will not receive further treatment with pembrolizumab and will undergo monitoring with ctDNA tests every 3 months for 3 years in the absence of disease progression.

COHORT 2: Patients may receive 1 to 3 cycles of standard of care treatment with trastuzumab with or without pertuzumab. Patients with a positive ctDNA test 4-6 weeks after surgery continue to receive standard of care treatment per their treating physician in the absence of disease progression or unacceptable toxicity. Patients with a negative ctDNA test will not receive further treatment with pembrolizumab and will undergo monitoring with ctDNA tests every 3 months for 3 years in the absence of disease progression. Patients may receive standard of care endocrine therapy per their treating physician throughout the study.

Inclusion criteria

• EARLY HER2 POSITIVE (+) BREAST CANCER COHORT: Female or male with a diagnosis of biopsy proven invasive breast cancer HER2+, hormone (estrogen and progesterone)-receptor positive or negative. The HER2 status (following American Society of Clinical Oncology [ASCO]/College of American Pathologists [CAP] guidelines) and hormone-receptor status will be determined according to institutional (local) guidelines
• EARLY TNBC COHORT: Female or male with a diagnosis of biopsy proven invasive TNBC (estrogen and progesterone receptor < 10%). The HER2 status (following ASCO/CAP guidelines) and hormone-receptor status will be determined according to institutional (local) guidelines
• FOR BOTH HER2+ AND TNBC COHORTS: Invasive breast cancer of any tumor histologic grade and/or nuclear grade, and any tumor histological subtype including but not limited to infiltrating ductal carcinoma, infiltrating lobular carcinoma, mucinous carcinoma, papillary carcinoma, tubular carcinoma, metaplastic carcinoma, and mixed histology
• FOR BOTH HER2+ AND TNBC COHORTS: Clinical tumor stage (per American Joint Committee on Cancer [AJCC] 8th edition): T1-4, N0-2a, M0. Patients who have a diagnosis of inflammatory breast cancer are eligible. Patients should not have clinical evidence of locoregional or distant metastatic breast cancer
• EARLY HER2+ BREAST CANCER COHORT: Have completed NST with a trastuzumab plus pertuzumab and chemotherapy-based regimen (for example, docetaxel plus minus carboplatin plus trastuzumab plus pertuzumab known as the docetaxel/pertuzumab/trastuzumab [THP]/carboplatin/paclitaxel/pertuzumab/trastuzumab [TCHP] regimens) followed by definitive breast surgery where the surgical pathology reports a pCR (ypT0-Tis, ypN0) and are willing to discontinue adjuvant trastuzumab plus pertuzumab
• EARLY TNBC COHORT: Have completed NST with a pembrolizumab plus chemotherapy-based regimen (for example, the KEYNOTE-522 regimen which is paclitaxel plus carboplatin plus pembrolizumab followed by doxorubicin plus cyclophosphamide plus pembrolizumab) followed by definitive breast surgery where the surgical pathology reports a pCR (ypT0-Tis, ypN0) and are willing to discontinue adjuvant pembrolizumab
• The surgical pathology report needs to show a pCR (ypT0-Tis, ypN0) for a patient to be able to participate in this study and all enrolled patients should be willing to discontinue standard adjuvant systemic therapy
• FOR BOTH HER2+ AND TNBC COHORTS: Adequate archival tumor tissue from the core diagnostic biopsy (per Personalis)
• FOR BOTH HER2+ AND TNBC COHORTS: Age ≥ 18 years
• FOR BOTH HER2+ AND TNBC COHORTS: Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 (Karnofsky ≥ 60%)
• FOR BOTH HER2+ AND TNBC COHORTS: Absolute neutrophil count ≥ 1,000/mcL
• FOR BOTH HER2+ AND TNBC COHORTS: Hemoglobin ≥ 9.0 g/dL
• FOR BOTH HER2+ AND TNBC COHORTS: Platelets ≥ 100,000/mcL
• FOR BOTH HER2+ AND TNBC COHORTS: Total bilirubin ≤ 1.5 institutional upper limit of normal (ULN); patients with Gilbert's syndrome (if direct bilirubin <1.5 x institutional ULN)
• FOR BOTH HER2+ AND TNBC COHORTS: Aspartate aminotransferase (AST)(serum glutamic oxaloacetic transaminase [SGOT])/ alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT]) ≤ 3 × institutional ULN
• FOR BOTH HER2+ AND TNBC COHORTS: Creatinine ≤ 1.5 mg/dL
• FOR BOTH HER2+ AND TNBC COHORTS: For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated
• FOR BOTH HER2+ AND TNBC COHORTS: Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load
• FOR BOTH HER2+ AND TNBC COHORTS: Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible
• FOR BOTH HER2+ AND TNBC COHORTS: Pre- and postmenopausal women are eligible
• FOR BOTH HER2+ AND TNBC COHORTS: Ability to understand and the willingness to sign a written informed consent document

Exclusion criteria

• Patients with tumor stage of cN2b or cN3 are not eligible
• History of other malignancies besides breast cancer within the past 5 years, except cervical cancer in situ, melanoma in situ, basal cell carcinoma of the skin, or squamous cell carcinoma of the skin
• Patients who are receiving any other anti-cancer investigational agents
• Patients with known cancer metastases from any site
• Patients with uncontrolled intercurrent illness including but not limited to active infection, symptomatic congestive heart failure, unstable angina pectoris, symptomatic cardiac arrythmias
• Patients with psychiatric illness/social situations that would limit compliance with study requirements
• Blood transfusion within 2 weeks before collection of blood for ctDNA testing
• Patients who have received 4 or more cycles of SOC adjuvant trastuzumab/pertuzumab (HER2+) or 4 or more cycles of SOC adjuvant pembrolizumab (TNBC)
• Pregnant women are not eligible to participate in this study