The SAPPHO Study: Sequential Therapy With Curative Intent in de Novo HER2+ Metastatic Breast Cancer

Phase 2

Recruiting

• Conditions: Stage IV Breast Cancer; Breast Cancer Metastatic; Breast Cancer Female; Breast Cancer; Estrogen Receptor-positive Breast Cancer; HER2-positive Breast Cancer
• Interventions: Drug: Nab-Paclitaxel; Drug: Paclitaxel; Drug: Docetaxel; Drug: Phesgo; Drug: T-DM1; Drug: Pertuzumab; Drug: Trastuzumab Deruxtecan; Drug: Trastuzumab Subcutaneous Subcutaneous; Drug: Tucatinib; Drug: Trastuzumab

• Registration Number: NCT06439693
• Lead Sponsor: Dana-Farber Cancer Institute

Brief Summary

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)

Detailed Description

This is an open-label phase II single-arm study to test the efficacy of a regimen of human epidermal growth factor receptor 2 (HER2)-targeted study drugs in participants with HER2-Positive metastatic Breast Cancer (HER2+ MBC).

The U.S. Food and Drug Administration (FDA) has approved all the study drugs as a treatment option for metastatic, HER2+ breast cancer. In this study, investigators are planning to give a series of treatments in a row without waiting for disease worsening and then stopping HER2 treatment.

The research study procedures include screening for eligibility, study treatment visits, blood tests, tumor biopsies, questionnaires, Computed Tomography (CT) scans, Magnetic Resonance Imaging (MRI) scans, echocardiograms, and electrocardiograms.

Participation in this research study is expected to last about 93 weeks (12 weeks for Part A, 18 weeks for Part B, 12 weeks for Part C, and 51 weeks for Part D) for study treatment and approximately three months to ten years for follow up.

It is expected that about 72 people will take part in this research study.

Seagen Inc. is supporting this study by providing the study drug, tucatinib, and funding.

Study Timeline

• Study First Submitted: 2024-05-28
• Study First Submitted QC: 2024-05-28
• Study First Posted: 2024-06-03
• Study Start: 2024-08-08
• Status Verified: 2025-04
• Last Update Submitted: 2025-04-01
• Last Update Posted: 2025-04-03
• Primary Completion: 2030-03-30
• Study Completion: 2033-03-30

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 72

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
HER2+ Breast Cancer	Phesgo	Participants will complete: * Screening visit with tumor biopsy and imaging. * Imaging on Day I of cycles for Parts A through D. * Part A: * Day 1 of 21 day cycle: Predetermined dose of Trastuzumab (or biosimilar) 1X daily * Day 1 of 21 day cycle: Predetermined dose of Pertuzumab 1X daily * Predetermined dose of Taxane (Paclitaxel, Docetaxel, or Nab-Paclitaxel) * Part B: --Day 1 of 21 day cycle: Predetermined dose of trastuzumab deruxtecan 1X daily * Part C: * Day 1 of 21 day cycle: Predetermined dose of T-DM1 1X daily * Days 1 through 21 of 21 day cycle: Predetermined dose of Tucatinib 2X daily * Part D: * Imaging every 9 weeks * Days 1 through 21 of 21 day cycle: Predetermined dose of Tucatinib 2X daily * Day 1 of 21 day cycle: Predetermined dose of Trastuzumab (biosimilar or SC) 1X daily * Day 1 of 21 day cycle: Predetermined dose of Pertuzumab (or PHESGO) 1X daily * Follow Up: visits every 12 weeks with imaging every 9 weeks.
HER2+ Breast Cancer	Trastuzumab Subcutaneous Subcutaneous	Participants will complete: * Screening visit with tumor biopsy and imaging. * Imaging on Day I of cycles for Parts A through D. * Part A: * Day 1 of 21 day cycle: Predetermined dose of Trastuzumab (or biosimilar) 1X daily * Day 1 of 21 day cycle: Predetermined dose of Pertuzumab 1X daily * Predetermined dose of Taxane (Paclitaxel, Docetaxel, or Nab-Paclitaxel) * Part B: --Day 1 of 21 day cycle: Predetermined dose of trastuzumab deruxtecan 1X daily * Part C: * Day 1 of 21 day cycle: Predetermined dose of T-DM1 1X daily * Days 1 through 21 of 21 day cycle: Predetermined dose of Tucatinib 2X daily * Part D: * Imaging every 9 weeks * Days 1 through 21 of 21 day cycle: Predetermined dose of Tucatinib 2X daily * Day 1 of 21 day cycle: Predetermined dose of Trastuzumab (biosimilar or SC) 1X daily * Day 1 of 21 day cycle: Predetermined dose of Pertuzumab (or PHESGO) 1X daily * Follow Up: visits every 12 weeks with imaging every 9 weeks.
HER2+ Breast Cancer	Nab-Paclitaxel	Participants will complete: * Screening visit with tumor biopsy and imaging. * Imaging on Day I of cycles for Parts A through D. * Part A: * Day 1 of 21 day cycle: Predetermined dose of Trastuzumab (or biosimilar) 1X daily * Day 1 of 21 day cycle: Predetermined dose of Pertuzumab 1X daily * Predetermined dose of Taxane (Paclitaxel, Docetaxel, or Nab-Paclitaxel) * Part B: --Day 1 of 21 day cycle: Predetermined dose of trastuzumab deruxtecan 1X daily * Part C: * Day 1 of 21 day cycle: Predetermined dose of T-DM1 1X daily * Days 1 through 21 of 21 day cycle: Predetermined dose of Tucatinib 2X daily * Part D: * Imaging every 9 weeks * Days 1 through 21 of 21 day cycle: Predetermined dose of Tucatinib 2X daily * Day 1 of 21 day cycle: Predetermined dose of Trastuzumab (biosimilar or SC) 1X daily * Day 1 of 21 day cycle: Predetermined dose of Pertuzumab (or PHESGO) 1X daily * Follow Up: visits every 12 weeks with imaging every 9 weeks.
HER2+ Breast Cancer	Paclitaxel	Participants will complete: * Screening visit with tumor biopsy and imaging. * Imaging on Day I of cycles for Parts A through D. * Part A: * Day 1 of 21 day cycle: Predetermined dose of Trastuzumab (or biosimilar) 1X daily * Day 1 of 21 day cycle: Predetermined dose of Pertuzumab 1X daily * Predetermined dose of Taxane (Paclitaxel, Docetaxel, or Nab-Paclitaxel) * Part B: --Day 1 of 21 day cycle: Predetermined dose of trastuzumab deruxtecan 1X daily * Part C: * Day 1 of 21 day cycle: Predetermined dose of T-DM1 1X daily * Days 1 through 21 of 21 day cycle: Predetermined dose of Tucatinib 2X daily * Part D: * Imaging every 9 weeks * Days 1 through 21 of 21 day cycle: Predetermined dose of Tucatinib 2X daily * Day 1 of 21 day cycle: Predetermined dose of Trastuzumab (biosimilar or SC) 1X daily * Day 1 of 21 day cycle: Predetermined dose of Pertuzumab (or PHESGO) 1X daily * Follow Up: visits every 12 weeks with imaging every 9 weeks.
HER2+ Breast Cancer	Docetaxel	Participants will complete: * Screening visit with tumor biopsy and imaging. * Imaging on Day I of cycles for Parts A through D. * Part A: * Day 1 of 21 day cycle: Predetermined dose of Trastuzumab (or biosimilar) 1X daily * Day 1 of 21 day cycle: Predetermined dose of Pertuzumab 1X daily * Predetermined dose of Taxane (Paclitaxel, Docetaxel, or Nab-Paclitaxel) * Part B: --Day 1 of 21 day cycle: Predetermined dose of trastuzumab deruxtecan 1X daily * Part C: * Day 1 of 21 day cycle: Predetermined dose of T-DM1 1X daily * Days 1 through 21 of 21 day cycle: Predetermined dose of Tucatinib 2X daily * Part D: * Imaging every 9 weeks * Days 1 through 21 of 21 day cycle: Predetermined dose of Tucatinib 2X daily * Day 1 of 21 day cycle: Predetermined dose of Trastuzumab (biosimilar or SC) 1X daily * Day 1 of 21 day cycle: Predetermined dose of Pertuzumab (or PHESGO) 1X daily * Follow Up: visits every 12 weeks with imaging every 9 weeks.
HER2+ Breast Cancer	T-DM1	Participants will complete: * Screening visit with tumor biopsy and imaging. * Imaging on Day I of cycles for Parts A through D. * Part A: * Day 1 of 21 day cycle: Predetermined dose of Trastuzumab (or biosimilar) 1X daily * Day 1 of 21 day cycle: Predetermined dose of Pertuzumab 1X daily * Predetermined dose of Taxane (Paclitaxel, Docetaxel, or Nab-Paclitaxel) * Part B: --Day 1 of 21 day cycle: Predetermined dose of trastuzumab deruxtecan 1X daily * Part C: * Day 1 of 21 day cycle: Predetermined dose of T-DM1 1X daily * Days 1 through 21 of 21 day cycle: Predetermined dose of Tucatinib 2X daily * Part D: * Imaging every 9 weeks * Days 1 through 21 of 21 day cycle: Predetermined dose of Tucatinib 2X daily * Day 1 of 21 day cycle: Predetermined dose of Trastuzumab (biosimilar or SC) 1X daily * Day 1 of 21 day cycle: Predetermined dose of Pertuzumab (or PHESGO) 1X daily * Follow Up: visits every 12 weeks with imaging every 9 weeks.
HER2+ Breast Cancer	Pertuzumab	Participants will complete: * Screening visit with tumor biopsy and imaging. * Imaging on Day I of cycles for Parts A through D. * Part A: * Day 1 of 21 day cycle: Predetermined dose of Trastuzumab (or biosimilar) 1X daily * Day 1 of 21 day cycle: Predetermined dose of Pertuzumab 1X daily * Predetermined dose of Taxane (Paclitaxel, Docetaxel, or Nab-Paclitaxel) * Part B: --Day 1 of 21 day cycle: Predetermined dose of trastuzumab deruxtecan 1X daily * Part C: * Day 1 of 21 day cycle: Predetermined dose of T-DM1 1X daily * Days 1 through 21 of 21 day cycle: Predetermined dose of Tucatinib 2X daily * Part D: * Imaging every 9 weeks * Days 1 through 21 of 21 day cycle: Predetermined dose of Tucatinib 2X daily * Day 1 of 21 day cycle: Predetermined dose of Trastuzumab (biosimilar or SC) 1X daily * Day 1 of 21 day cycle: Predetermined dose of Pertuzumab (or PHESGO) 1X daily * Follow Up: visits every 12 weeks with imaging every 9 weeks.
HER2+ Breast Cancer	Trastuzumab Deruxtecan	Participants will complete: * Screening visit with tumor biopsy and imaging. * Imaging on Day I of cycles for Parts A through D. * Part A: * Day 1 of 21 day cycle: Predetermined dose of Trastuzumab (or biosimilar) 1X daily * Day 1 of 21 day cycle: Predetermined dose of Pertuzumab 1X daily * Predetermined dose of Taxane (Paclitaxel, Docetaxel, or Nab-Paclitaxel) * Part B: --Day 1 of 21 day cycle: Predetermined dose of trastuzumab deruxtecan 1X daily * Part C: * Day 1 of 21 day cycle: Predetermined dose of T-DM1 1X daily * Days 1 through 21 of 21 day cycle: Predetermined dose of Tucatinib 2X daily * Part D: * Imaging every 9 weeks * Days 1 through 21 of 21 day cycle: Predetermined dose of Tucatinib 2X daily * Day 1 of 21 day cycle: Predetermined dose of Trastuzumab (biosimilar or SC) 1X daily * Day 1 of 21 day cycle: Predetermined dose of Pertuzumab (or PHESGO) 1X daily * Follow Up: visits every 12 weeks with imaging every 9 weeks.
HER2+ Breast Cancer	Trastuzumab	Participants will complete: * Screening visit with tumor biopsy and imaging. * Imaging on Day I of cycles for Parts A through D. * Part A: * Day 1 of 21 day cycle: Predetermined dose of Trastuzumab (or biosimilar) 1X daily * Day 1 of 21 day cycle: Predetermined dose of Pertuzumab 1X daily * Predetermined dose of Taxane (Paclitaxel, Docetaxel, or Nab-Paclitaxel) * Part B: --Day 1 of 21 day cycle: Predetermined dose of trastuzumab deruxtecan 1X daily * Part C: * Day 1 of 21 day cycle: Predetermined dose of T-DM1 1X daily * Days 1 through 21 of 21 day cycle: Predetermined dose of Tucatinib 2X daily * Part D: * Imaging every 9 weeks * Days 1 through 21 of 21 day cycle: Predetermined dose of Tucatinib 2X daily * Day 1 of 21 day cycle: Predetermined dose of Trastuzumab (biosimilar or SC) 1X daily * Day 1 of 21 day cycle: Predetermined dose of Pertuzumab (or PHESGO) 1X daily * Follow Up: visits every 12 weeks with imaging every 9 weeks.
HER2+ Breast Cancer	Tucatinib	Participants will complete: * Screening visit with tumor biopsy and imaging. * Imaging on Day I of cycles for Parts A through D. * Part A: * Day 1 of 21 day cycle: Predetermined dose of Trastuzumab (or biosimilar) 1X daily * Day 1 of 21 day cycle: Predetermined dose of Pertuzumab 1X daily * Predetermined dose of Taxane (Paclitaxel, Docetaxel, or Nab-Paclitaxel) * Part B: --Day 1 of 21 day cycle: Predetermined dose of trastuzumab deruxtecan 1X daily * Part C: * Day 1 of 21 day cycle: Predetermined dose of T-DM1 1X daily * Days 1 through 21 of 21 day cycle: Predetermined dose of Tucatinib 2X daily * Part D: * Imaging every 9 weeks * Days 1 through 21 of 21 day cycle: Predetermined dose of Tucatinib 2X daily * Day 1 of 21 day cycle: Predetermined dose of Trastuzumab (biosimilar or SC) 1X daily * Day 1 of 21 day cycle: Predetermined dose of Pertuzumab (or PHESGO) 1X daily * Follow Up: visits every 12 weeks with imaging every 9 weeks.

Primary Outcome Measures

Name	Time	Method
Disease Free Survival at 4 Years (DFS4)	Up to 4 years	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.

Secondary Outcome Measures

Name	Time	Method
Non-Completion reasons of each part of the sequential therapy	Up to 54 months	Sequential therapy includes (A) taxane, trastuzumab, pertuzumab, (B) trastuzumab deruxtecan, (C) ado-trastuzumab emtansine, tucatinib, and (D) trastuzumab, pertuzumab, tucatinib. The reasons of non-completion will be tabulated.
Complete Rate of Each Treatment Part	Up to 54 months	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.
DFS4 by Minimal Residual Disease (MRD) status	Up to 4 years	DFS4 is defined as primary outcome 1. Participants will be categorized by MRD status (detectable nv non-detectable).
Objective Response Rate (ORR)	Up to 54 months	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	Up to 54 months	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.
Median Overall Survival (OS)	Up to 5 years	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.

Trial Locations

Locations (1)

Dana-Farber Cancer Institute; 🇺🇸 Boston, Massachusetts, United States