HER2 Molecular Imaging With 89Zr-trastuzumab PET/CT as a Predictive Biomarker for Antibody-drug Conjugate Sequencing in Patients With Advanced HER2-positive Breast Cancer

NCT06595563 | Recruiting Phase 2

• 1 other identifier: IJB-ZEPHIR02-2024
• Study Type: interventional
• Target: 87
• Locations: 1 country
• Sites: 1

Brief Summary

ZEPHIR-02 is a multicentre, open-label phase II study that will enroll subjects with HER2-positive advanced/metastatic breast cancer (mBC) who have experienced disease progression under trastuzumab deruxtecan (T-DXd) in the metastatic setting. All subjects will undergo baseline biopsy, blood collection, FDG-PET/CT and 89Zr-trastuzumab PET/CT (HER2-PET/CT) and will be classified as HER2-PET/CT positive or negative, as previously described in the ZEPHIR trial. Focusing on a central visual "patient-based" classification that captures the entire disease burden, a side-by-side display will be used, comparing baseline FDG-PET/CT (which identifies all FDG-positive metastases regardless of their HER2-imaging status) and HER2-PET/CT. Subjects will be categorized into two HER2-PET/CT patterns (positive vs. negative) based on proportion of FDG-avid tumor load with significant 89Zr-trastuzumab uptake. Subjects classified as "positive" will receive T-DM1 as monotherapy, IV 3.6mg/kg every 3 weeks (21 days +- 3 days) until disease progression, unacceptable toxicity or request of the subject to withdraw from the study. FDG-PET/CT will be performed before cycle 2 of T-DM1 will serve as a research tool to correlate metabolic changes with clinical outcomes. Other FDG-PET/CT will be performed before cycle 4 of T-DM1 for assessment of response. Subjects who demonstrate a partial or complete response (responders) will continue treatment with T-DM1. Subjects who exhibit stable disease or disease progression (non-responders) will discontinue study treatment and enter the survival follow-up period. For responders, subsequent metabolic evaluations will be performed every 3 months, with FDG-PET/CT. Treatment response will be assessed according to metabolic response. For these subjects, mandatory blood samples will be obtained at all metabolic reassessments. Subjects with HER2-PET/CT classified as "negative" will receive treatment of physician's choice (TPC) as per the best local clinical practice and be out of the study. All enrolled subjects will undergo a mandatory biopsy during the pre-treatment period. The study also includes mandatory translational procedures (i.e. collection of tumour biopsy during pre-treatment period and blood samples at pre-specified time points) for exploratory molecular analyses.

Conditions

HER2-positive Advanced Breast Cancer; HER2-positive Metastatic Breast Cancer

Outcome Measures

Primary Outcomes (2)

• Characterization of genomic alterations and HER2 expression.

  To characterize the tumour landscape (molecular alterations on tissue and HER2 expression and its heterogeneity) in HER2-positive mBC after at least 1 line of systemic therapy for advanced disease in order to better inform the oncologist and the subject regarding next treatment options.

  Through study completion, up to 2 years

• Time to treatment failure (TTF)

  The time to treatment failure (TTF), defined as the time from T-DM1 start to discontinuation for any reason, including disease progression (clinical or image-based on 18FDG-PET/CT), treatment toxicity or death in participants classified as "positive" (per metabolic response). Time to Treatment Failure (TTF) of subjects classified as "positive" and its survival probability measures (median survival, survival rate at month 6) will be estimated using Kaplan-Meier method

  During study treatment period (from C1 of T-DM1 until discontinuation), up to 1 year on average

Secondary Outcomes (4)

• Overall Survival under T-DM1

  From study treatment period until death, up to 1 year on average

• Duration of Response under T-DM1

  During study treatment period until disease progression or death, up to 1 year on average

• Disease Control Rate under T-DM1

  From study treatment period until disease progression or death, up to 1 year on average

• Safety of T-DM1

  From study treatment period until progression disease, start of new anti-cancer treatment or death, up to 1 year on average

Other Outcomes (2)

• Correlation between "HER2 positivity" assessments in tumour tissue, HER2-PET/CT and ctDNA

  Through study completion, up to 2 years

• Correlation between genomic and transcriptomic alterations with best overall response

  Through study completion, up to 2 years

Study Arms (2)

HER2 PET/CT "positive"

EXPERIMENTAL

Subjects classified as HER2-PET/CT positive will receive T-DM1, IV 3.6mg/kg every 3 weeks, as monotherapy. HER2-PET/CT positive pattern: The entire or majority of the tumour load shows significant tracer uptake.

Drug: Trastuzumab emtansine

HER2 PET/CT "negative"

NO INTERVENTION

Subjects classified as HER2 PET/CT negative will receive treatment of physician's choice (TPC) as per the best local clinical practice. Subsequent treatment will be collected and the subject will enter survival follow-up. HER2-PET/CT negative pattern: The dominant part or all of the tumour load lacks significant tracer uptake.

Interventions

Trastuzumab emtansine DRUG

T-DM1 will be administered IV at a dose of 3.6 mg/kg every 3 weeks. (21 days +/- 3 days) until disease progression, unacceptable toxicity or request of the subject to withdraw from the study. The total dose will depend on the subject's weight on day 1 of each T-DM1 cycle.

Also known as: T-DM1

HER2 PET/CT "positive"

Eligibility Criteria

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

You may qualify if:

• ECOG performance status ≤ 1
• Must have histologically or cytologically confirmed progressive advanced/metastatic HER2-positive breast carcinoma as per the updated American Society of Clinical Oncology (ASCO) - College of American Pathologists (CAP) guidelines according to local testing. HER2 status may be determined in the primary breast cancer tumour or, when not available, in a metastatic lesion.
• Multifocal unilateral or bilateral breast adenocarcinoma tumours are allowed if all tested HER2-positive, according to local testing
• Life expectancy ≥ 6 months.
• At screening FDG-PET at least two "target" lesions are required to fulfil the following criteria: (1) anatomically transaxial diameter ≥ 1.5 cm and (2) metabolically assessable with a maximum standard uptake value corrected for lean body mass (SUVmax) ≥ 1.5 x SUVmean + 2 standard deviations (SD) of the liver measured in a 3-cm-diameter spherical volume of interest (VOI) in normal liver parenchyma.
• In case of suspected liver metastasis, a lesion should have a SUVmax ≥ 2 x SUVmean + 3 SD of the blood pool measured in a 1 cm-diameter VOI within descending thoracic aorta. Lesions pre-treated with irradiation are not eligible for consideration as "target" lesions.
• Adequate Bone Marrow Function including:
• Absolute Neutrophil Count (ANC) ≥1000/μL or ≥1x109/L.
• Platelets ≥100,000/μL or ≥ 100 x 109/L.
• Haemoglobin ≥ 9 g/dL.
• Adequate Renal Function including serum creatinine ≤ 1.5 x upper limit of normal (ULN) or estimated creatinine clearance ≥ 60 ml/min as calculated using the method standard for the institution.
• Adequate Liver Function, including all the following parameters:
• Total serum bilirubin ≤ 1.5 x ULN unless the patient subject has documented Gilbert syndrome.
• Aspartate and Alanine Aminotransferase (AST and ALT) ≤ 2.5x ULN.
• Current left ventricular ejection fraction (LVEF) ≥ 50% on echocardiography or multiple-gated acquisition scanning and no history of a LVEF \< 40% or symptomatic heart failure or a recent myocardial infarction.

You may not qualify if:

• Prior exposure to T-DM1 for the treatment of metastatic BC. For subjects exposed to T-DM1 for the treatment of early BC, subjects must not have relapsed while on or within 12 months of finishing treatment with T-DM1.
• Brain metastasis as sole metastasis and/or symptomatic or requiring therapy to control symptoms.
• History of interstitial lung disease / pneumonitis (grade 3 or 4) during the prior treatment with T-DXd.
• Cardiopulmonary dysfunction as defined by any of the following:
• Significant symptoms (Grade ≥ 2) relating to LV dysfunction, cardiac arrhythmia, or cardiac ischemia while or since receiving preoperative therapy.
• Uncontrolled hypertension (systolic blood pressure \> 180 mmHg and/or diastolic blood pressure \> 100 mmHg)
• Inadequately controlled angina, serious cardiac arrhythmia not controlled by adequate medication, severe conduction abnormality, or clinically significant valvular disease
• Screening LVEF \< 50% by either ECHO or MUGA
• History of NCI CTCAE (Version 4.0) Grade ≥ 3 symptomatic congestive heart failure (CHF) or New York Heart Association (NYHA) criteria Class ≥ II
• History of a decrease in LVEF to \< 40% or symptomatic CHF with prior trastuzumab treatment (e.g., during preoperative therapy)
• Myocardial infarction within 12 months prior to randomization
• Requirement for continuous oxygen therapy
• Known prior severe hypersensitivity to investigational product or any component in its formulations, including known severe hypersensitivity reactions to trastuzumab or excipients.
• Contra-indication for treatment with T-DM1.
• Any known liver disease, including known carriers of hepatitis B virus, hepatitis C, autoimmune hepatic disorders and sclerosing cholangitis.

Sponsors & Collaborators

• Jules Bordet Institute: lead
• Hoffmann-La Roche: collaborator

Study Sites (1)

Institut Jules Bordet

Anderlecht, Brussels Capital, 1070, Belgium

RECRUITING

MeSH Terms

Interventions

Ado-Trastuzumab Emtansine

Intervention Hierarchy (Ancestors)

Maytansine; Macrolides; Lactones; Organic Chemicals; Lactams, Macrocyclic; Macrocyclic Compounds; Polycyclic Compounds; Trastuzumab; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Study Officials

• Martine Piccart, Md, PhD

  Jules Bordet Institute

  STUDY CHAIR

Central Study Contacts

Margot Morelle

CONTACT

+3225413976; zephir02.ctsu@hubruxelles.be

Ikram El Idrissi

CONTACT

+3225413081; zephir02.ctsu@hubruxelles.be

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 4, 2024
• First Posted: September 19, 2024
• Study Start (Estimated): June 30, 2026
• Primary Completion (Estimated): March 1, 2028
• Study Completion (Estimated): September 1, 2029
• Last Updated: May 7, 2026

Record last verified: 2026-02

Locations

BE (1)