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

NCT06439693 | Recruiting Phase 2 DMC FDA Drug

• 2 other identifiers: 24-223TBCRC065
• Study Type: interventional
• Target: 72
• Locations: 1 country
• Sites: 1

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)

Conditions

Breast Cancer Female; Breast Cancer; Breast Cancer Metastatic; Estrogen Receptor-positive Breast Cancer; HER2-positive Breast Cancer; Stage IV Breast Cancer

Keywords

Breast Cancer; Breast Cancer Female; Breast Cancer Metastatic; Estrogen Receptor-Positive Breast Cancer; HER2-positive Breast Cancer; Stage IV Breast Cancer

Outcome Measures

Primary Outcomes (1)

• 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.

  Up to 4 years

Secondary Outcomes (6)

• Median Overall Survival (OS)

  Up to 5 years

• Objective Response Rate (ORR)

  Up to 54 months

• Grade 3-5 Treatment-Related Toxicity Rate

  Up to 54 months

• Complete Rate of Each Treatment Part

  Up to 54 months

• Non-Completion reasons of each part of the sequential therapy

  Up to 54 months

Study Arms (1)

HER2+ Breast Cancer

EXPERIMENTAL

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.

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

Interventions

Nab-Paclitaxel DRUG

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

Also known as: Abraxane, ABI-007, Albumin-bound paclitaxel

HER2+ Breast Cancer

Paclitaxel DRUG

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

Also known as: Taxol

HER2+ Breast Cancer

Docetaxel DRUG

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

Also known as: Taxotere

HER2+ Breast Cancer

Phesgo DRUG

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

Also known as: pertuzumab plus trastuzumab plus hyaluronidase-zzxf, RG6264, RO7198574

HER2+ Breast Cancer

T-DM1 DRUG

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

Also known as: ado-trastuzumab emtansine, Kadcyla

HER2+ Breast Cancer

Pertuzumab DRUG

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

HER2+ Breast Cancer

Trastuzumab Deruxtecan DRUG

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

Also known as: Enhertu, fam-trastuzumab deruxtecan-nxki, T-DXd, DS-8201a

HER2+ Breast Cancer

Trastuzumab Subcutaneous Subcutaneous DRUG

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

Also known as: Herceptin Hylecta, Trastuzumab and hyaluronidase-oysk

HER2+ Breast Cancer

Tucatinib DRUG

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

HER2+ Breast Cancer

Trastuzumab DRUG

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

HER2+ Breast Cancer

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.
• Eastern Cooperative Oncology Group Performance Status (ECOG PS) 0-1
• Left ventricular ejection fraction (LVEF) ≥50%, as assessed by echocardiogram (ECHO) or multiple-gated acquisition scan (MUGA) documented within 12 weeks prior to first dose of study treatment, or within 12 weeks before starting THP for patients who start metastatic therapy prior to study entry.
• Participants must meet the following organ and marrow function as defined below within 28 days prior to registration:
• Hgb ≥9.0 g/dL
• Absolute Neutrophil Count ≥ 1,000 /mm3
• Platelets ≥100,000/mm3
• Total bilirubin ≤ 1.5 x ULN (institutional) or direct bilirubin within normal limits in patients with a history of Gilbert\'s syndrome.
• AST and ALT ≤ 2.5 x ULN (institutional) or ≤ 5 x ULN for participants with documented liver metastases
• Serum creatinine ≤ 1.5 x ULN (institutional) OR calculated GFR ≥60mL/min
• Participants with concurrent human immunodeficiency virus (HIV) infection are eligible provided the following criteria are met:
• CD4+ T-cell (CD4+) counts \> 350 cells/uL

You may not qualify if:

• 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.
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to trastuzumab, pertuzumab, paclitaxel, trastuzumab deruxtecan, trastuzumab emtansine, tucatinib.
• Participants with a medical history of myocardial infarction within 6 months before enrollment or symptomatic CHF (NYHA Class II to IV).
• Subjects must not have any of the following:
• Any untreated brain lesion on screening MRI, unless approved by the Sponsor Investigator
• Ongoing use of systemic corticosteroids for control of symptoms of brain metastases at a total daily dose of \>2 mg of dexamethasone (or equivalent).
• Known or concurrent leptomeningeal disease on screening MRI
• Poorly controlled (\>1/week) generalized or complex partial seizures
• History of arrhythmia (multifocal premature ventricular contractions, bigeminy, trigeminy, ventricular tachycardia), which is symptomatic or requires treatment (CTCAE Grade 3), symptomatic or uncontrolled atrial fibrillation despite treatment, or asymptomatic sustained ventricular tachycardia. Participants with atrial fibrillation controlled by medication or arrhythmias controlled by pacemakers may be permitted upon discussion with the Sponsor-Investigator.
• History of (non-infectious) ILD/pneumonitis that required steroids, has current ILD/pneumonitis, or where suspected ILD/pneumonitis cannot be ruled out by imaging at screening.
• History of other lung disease, such as:
• Lung-specific intercurrent clinically significant illnesses including, but not limited to, any underlying pulmonary disorder (e.g., pulmonary emboli within 3 months of study enrolment, severe asthma, severe chronic obstructive pulmonary disorder (COPD), restrictive lung disease, pleural effusion etc.).

Sponsors & Collaborators

• Dana-Farber Cancer Institute: lead
• Translational Breast Cancer Research Consortium: collaborator
• Johns Hopkins University: collaborator

Study Sites (1)

Dana-Farber Cancer Institute

Boston, Massachusetts, 02215, United States

RECRUITING

MeSH Terms

Conditions

Breast Neoplasms

Interventions

130-nm albumin-bound paclitaxel; Albumin-Bound Paclitaxel; Paclitaxel; Docetaxel; pertuzumab; Trastuzumab; Ado-Trastuzumab Emtansine; trastuzumab deruxtecan; tucatinib

Condition Hierarchy (Ancestors)

Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases

Intervention Hierarchy (Ancestors)

Taxoids; Cyclodecanes; Cycloparaffins; Hydrocarbons, Alicyclic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Diterpenes; Terpenes; Albumins; Proteins; Amino Acids, Peptides, and Proteins; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Serum Globulins; Globulins; Maytansine; Macrolides; Lactones; Lactams, Macrocyclic; Macrocyclic Compounds; Polycyclic Compounds

Study Officials

• Nancy Lin, MD

  Dana-Farber Cancer Institute

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Nancy Lin, MD

CONTACT

617-632-2335; Nancy_Lin@dfci.harvard.edu

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principle Investigator

Study Record Dates

• First Submitted: May 28, 2024
• First Posted: June 3, 2024
• Study Start: August 8, 2024
• Primary Completion (Estimated): March 30, 2030
• Study Completion (Estimated): March 30, 2033
• Last Updated: June 26, 2025

Record last verified: 2025-06

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP
• Time Frame: Data can be shared no earlier than 1 year following the date of publication
• Access Criteria: Contact the Belfer Office for Dana-Farber Innovations (BODFI) at innovation@dfci.harvard.edu

Locations

US (1)