The purpose of this study is to test the safety and effectiveness of a sequence of drugs (a Taxane plus Trastuzumab plus Pertuzumab followed by Trastuzumab Deruxtecan, followed by Tucatinib plus Ado-Trastuzumab Emtansine (T-DM1), followed by Trastuzumab plus Pertuzumab plus Tucatinib) in HER2+ Breast Cancer. The study will help investigators understand whether first intensifying therapy for a specific period and then stopping treatment is safe and effective for participants.
The names of the study drugs involved in this study are:
* Paclitaxel (a type of anti-microtubule agent) * Docetaxel (a type of anti-microtubule agent) * Nab-Paclitaxel (a type of anti-microtubule agent) * Trastuzumab (a type of IgG1 kappa monoclonal antibody) * Pertuzumab (a type of monoclonal antibody) * Trastuzumab Deruxtecan (a type of HER2-directed antibody drug conjugate) * Tucatinib (Tyrosine Kinase HER2 Inhibitor) * Ado-trastuzumab emtansine or T-DM1 (a type of HER2-targeted antibody-drug conjugate)
Participants must have histologically or cytologically confirmed unresectable locally advanced or metastatic invasive breast carcinoma. Patients must have stage IV breast carcinoma at diagnosis (i.e., de novo metastatic) with unequivocal evidence of metastasis on imaging.
Diagnosis of HER2-positive invasive breast carcinoma and 3+ by immunohistochemistry on both breast and metastatic biopsies, as defined by the current American Society of Clinical Oncology - College of American Pathologists (ASCO/CAP) guidelines. HER2 status must be determined at a Clinical Laboratory Improvements Amendments (CLIA)-certified or International Organization for Standardization (ISO)-accredited laboratory (central testing not required). Patients with HER2 1+ or 2+ disease which is HER2 FISH positive are not eligible to enroll.
No prior systemic therapy for invasive breast cancer, aside from first-line trastuzumab/pertuzumab/taxane (THP) within 6 weeks from treatment start. Prior endocrine therapy for non-invasive breast carcinoma or non-cancerous lesions is allowed if it has been completed at least 5 years prior to study entry.
Age ≥18 years. Because no dosing or adverse event data are currently available on the use of trastuzumab, pertuzumab, paclitaxel, trastuzumab deruxtecan, T-DM1 and tucatinib in Participants <18 years of age, children are excluded from this study, but will be eligible for future pediatric trials.
Prior history of invasive breast carcinoma
Treatment with any other investigational agents for this condition.
Major surgical procedure (excluding placement of vascular access) or significant traumatic injury within 28 days of study entry or an anticipated need for major surgery during the study.
Extracranial palliative radiotherapy within 7 days prior to enrollment.
Single group
Nab-Paclitaxel
DrugAnti-microtubule agent, via intravenous (into the vein) infusion per institutional guidelines.
Paclitaxel
DrugAnti-microtubule agent, via intravenous infusion per institutional guidelines.
Docetaxel
DrugAnti-microtubule agent, via intravenous infusion per institutional guidelines.
Phesgo
DrugPertuzumab plus trastuzumab plus hyaluronidase-zzxf, 10 or 15mL single-dose vial, via subcutaneous (under the skin) injection per protocol.
T-DM1
DrugHER2-targeted antibody-drug conjugate, 16 or 100 mg single-use vials, via intravenous infusion per institutional guidelines.
Pertuzumab
DrugRecombinant humanized monoclonal antibody, 20mL single-use vial, via intravenous infusion per institutional guidelines.
Trastuzumab Deruxtecan
DrugHER2-directed antibody drug conjugate, 100mg vial, via intravenous infusion per institutional guidelines.
Trastuzumab Subcutaneous Subcutaneous
DrugHumanized IgG1 kappa monoclonal antibody, 6mL vial, via subcutaneous injection per institutional guidelines.
Tucatinib
DrugTyrosine Kinase HER2 Inhibitor, 50 or 150mg tablet taken orally per institutional guidelines.
Trastuzumab
DrugHumanized IgG1 kappa monoclonal antibody, 150 mg single-dose vial, via intravenous infusion per institutional guidelines.
Disease Free Survival at 4 Years (DFS4)
DFS4 is the probability estimate 4 years based on Kaplan-Meier Method. DFS is defined the time from registration to disease progression (including death from any cause) or resumption of anti-cancer therapy (not including endocrine therapy). Participants that are alive, progression free and off all anti-cancer therapy are censored at the date of their last disease evaluation.
Median Overall Survival (OS)
Overall survival based on the Kaplan-Meier method is defined as the time from randomization to death. Participants alive are censored at the last date of contact (including lost-to-follow-up) or at the date of withdrawal of consent, if relevant.
Objective Response Rate (ORR)
Objective response rate (ORR), defined as best overall response of either complete or partial response, will be assessed among participants who start protocol therapy and have measurable disease at screening. Radiographic response will be assessed using RECIST 1.1 criteria as defined in section 11.1. The objective response rate by RECIST 1.1 (CR + PR) will be reported with 95% exact confidence interval. ORR will be calculated as best cumulative response achieved with each Part of therapy, taking as baseline, the measurements taken prior to C1D1 of Part A of therapy, and as best cumulative response at the completion of Part D of therapy.
Grade 3-5 Treatment-Related Toxicity Rate
The percentage of participants who experienced a maximum grade 3-5 treatment-related adverse event based on the Common Toxicity Criteria for Adverse events Version 5.0 (CTCAEv5) as reported on case report forms.
Complete Rate of Each Treatment Part
Sequential therapy includes (A) taxane, trastuzumab, pertuzumab, (B) trastuzumab deruxtecan, (C) ado-trastuzumab emtansine, tucatinib, and (D) trastuzumab, pertuzumab, tucatinib. The proportion of participants who complete each part of therapy will be tabulated as the complete rate.
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Dana-Farber Cancer Institute
Lead sponsor
Translational Breast Cancer Research Consortium
Collaborator
Johns Hopkins University
Collaborator
