Neoplasms

Skin and Connective Tissue Diseases

All Conditions

Breast Neoplasms

Breast Diseases

Skin Diseases

Antineoplastic Agents

All Drugs and Chemicals

Anti-Arrhythmia Agents

Vasodilator Agents

Analgesics

Amino Acids

Paclitaxel

Docetaxel

Ado-Trastuzumab Emtansine

Albumin-Bound Paclitaxel

Trastuzumab

Pertuzumab

Tucatinib

Trastuzumab deruxtecan

Antibodies

Antibodies, Monoclonal

Estrogens

Immunoglobulins

Taxane

Adenosine

Tubulin Modulators

Antimitotic Agents

Antineoplastic Agents, Immunological

Immunotoxins

Immunoconjugates

Immunologic Factors

Protein Kinase Inhibitors

Enzyme Inhibitors

Tyrosine

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.

Anti-microtubule agent, via intravenous (into the vein) infusion per institutional guidelines.

Nab-Paclitaxel

Anti-microtubule agent, via intravenous infusion per institutional guidelines.

Pertuzumab plus trastuzumab plus hyaluronidase-zzxf, 10 or 15mL single-dose vial, via subcutaneous (under the skin) injection per protocol.

Phesgo

HER2-targeted antibody-drug conjugate, 16 or 100 mg single-use vials, via intravenous infusion per institutional guidelines.

T-DM1

Recombinant humanized monoclonal antibody, 20mL single-use vial, via intravenous infusion per institutional guidelines.

HER2-directed antibody drug conjugate, 100mg vial, via intravenous infusion per institutional guidelines.

Trastuzumab Deruxtecan

Humanized IgG1 kappa monoclonal antibody, 6mL vial, via subcutaneous injection per institutional guidelines.

Trastuzumab Subcutaneous Subcutaneous

Tyrosine Kinase HER2 Inhibitor, 50 or 150mg tablet taken orally per institutional guidelines.

Humanized IgG1 kappa monoclonal antibody, 150 mg single-dose vial, via intravenous infusion per institutional guidelines.

Heather Parsons, MD, MPH

Heather Parsons, MD, MPD

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)

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.

The SAPPHO Study: A Single-Arm, Phase II Study of Sequential Therapy With Curative Intent in de Novo HER2+ Metastatic Breast Cancer

A Single-Arm, Phase II Study of Sequential Therapy With Curative Intent in de Novo HER2+ Metastatic Breast Cancer: The SAPPHO Study:

The Dana-Farber / Harvard Cancer Center encourages and supports the responsible and ethical sharing of data from clinical trials. De-identified participant data from the final research dataset used in the published manuscript may only be shared under the terms of a Data Use Agreement. Requests may be directed to: \[contact information for Sponsor Investigator or designee\]. The protocol and statistical analysis plan will be made available on Clinicaltrials.gov only as required by federal regulation or as a condition of awards and agreements supporting the research.

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.

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), 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.

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.

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.

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.

DFS4 is defined as primary outcome 1. Participants will be categorized by MRD status (detectable nv non-detectable).

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
The SAPPHO Study: A Single-Arm, Phase II Study of Sequential Therapy With Curative Intent in de Novo HER2+ Metastatic Breast Cancer	NCT06439693	Breast Cancer F... Breast Cancer Breast Cancer M... Estrogen Recept... HER2-positive B... Stage IV Breast...	Nab-Paclitaxel Paclitaxel Docetaxel Phesgo T-DM1 Pertuzumab Trastuzumab Der... Trastuzumab Sub... Tucatinib Trastuzumab	18 Years -	Dana-Farber Cancer Institute
The SAPPHO Study: A Single-Arm, Phase II Study of Sequential Therapy With Curative Intent in de Novo HER2+ Metastatic Breast Cancer	NCT06439693	Breast Cancer F... Breast Cancer Breast Cancer M... Estrogen Recept... HER2-positive B... Stage IV Breast...	Nab-Paclitaxel Paclitaxel Docetaxel Phesgo T-DM1 Pertuzumab Trastuzumab Der... Trastuzumab Sub... Tucatinib Trastuzumab	18 Years -	Dana-Farber Cancer Institute

Spots Global Cancer Trial Database for trastuzumab subcutaneous subcutaneous