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

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Institut Jules Bordet

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Decision date (initial)

2025-02-10

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

F.Hoffmann-La-Roche

External identifiers

EU CT number

2024-516253-49-00

ClinicalTrials.gov

NCT06595563

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Safety

• 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.

• To assess the efficacy of T-DM1 in subjects with a “positive” HER2-PET/CT.

Secondary objectives 5

1. To evaluate the best overall response (bORR, defined as partial response or complete response) to T-DM1 (subjects with a “positive” HER2-PET/CT).
2. To evaluate the overall survival (OS) under T-DM1 subjects with a “positive” HER2-PET/CT
3. To evaluate the duration of response (DoR) under T-DM1 (subjects with a “positive” HER2-PET/CT).
4. To evaluate the disease control rate (DCR) under T-DM1 (subjects with a “positive” HER2-PET/CT).
5. To evaluate the safety of the study treatment regarding adverse events including drug induced liver injury described in the section “9.1.2.2 Recording and reporting of AEs by the investigators” and in the section “9.2.1. Adverse Events of Special Interest – Definitions”.

Conditions and MedDRA coding

advanced/metastatic HER2-positive breast carcinoma

Study design 1 period

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 15

1. Age ≥ 18 years old
2. ECOG performance status ≤ 1
3. 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 [32]. HER2 status may be determined in the primary breast cancer tumour or, when not available, in a metastatic lesion.
4. Multifocal unilateral or bilateral breast adenocarcinoma tumours are allowed if all tested HER2-positive, according to local testing.
5. Prior treatment with taxane, trastuzumab and pertuzumab (early or advanced setting) and T-DXd (metastatic setting). In order to be eligible, subjects must have received T-DXd as the last systemic metastatic treatment line before inclusion, and presented disease progression on this drug. Prior therapy with tucatinib, trastuzumab, and capecitabine, in advanced setting, is permissible, provided that T-DXd serves as the last systemic metastatic treatment line before inclusion, and subject presented disease progression on this drug.
6. Life expectancy ≥ 6 months.
7. 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 [33] 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
8. 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
9. 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
10. Adequate Liver Function, including all the following parameters: • Total serum bilirubin ≤ 1.5 x ULN unless the subject has documented Gilbert syndrome. • Aspartate and Alanine Aminotransferase (AST and ALT) ≤ 2.5 x ULN.
11. Current left ventricular ejection fraction (LVEF) ≥ 50% on echocardiography (ECHO) or multiple-gated acquisition scanning (MUGA) and no history of a LVEF < 40% or symptomatic heart failure or a recent myocardial infarction.
12. Willingness to provide tumour tissue (mandatory biopsy) and blood samples (mandatory) for translational research activities.
13. Willingness to comply with the protocol for the duration of the study including treatment and scheduled visits and examinations.
14. Signed Informed Consent form (ICF) obtained prior to any study related procedure
15. Inclusion criterion applicable to FRANCE only: Affiliated to the French Social Security System

Exclusion criteria 14

1. 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.
2. Brain metastasis as sole metastasis and/or symptomatic or requiring therapy to control symptoms
3. History of interstitial lung disease / pneumonitis (grade 3 or 4) during the prior treatment with T-DXd.
4. 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 > 110 mmHg), despite optimal medical management), 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
5. Known prior severe hypersensitivity to investigational product or any component in its formulations, including known severe hypersensitivity reactions to trastuzumab or excipients
6. Contra-indication for treatment with T-DM1
7. The number of subjects included in this trial, considered as “rapid progressors” (Rapid progressors defined as progressive disease within the first 6 months of TDXd therapy) will be capped at 10% at enrolment (no more than 7 subjects out the 78 subjects planned to be recruited). After the first 7 “rapid progressors” included, progression within the first 6 months of T-DXd therapy will be considered as an exclusion criterion
8. Any known liver disease, including known carriers of hepatitis B virus, hepatitis C, autoimmune hepatic disorders and sclerosing cholangitis.
9. Concurrent, serious, uncontrolled infections or known infection with HIV. Prior history of other invasive cancer in the past 5 years except basal or squamous cell carcinoma of skin that has been definitively treated.
10. Pregnant and/or lactating women, or intending to become pregnant during the study. Serum pregnancy test (for subjects of childbearing potential) positive within 15 days prior to enrolment.
11. Women of childbearing potential refusing to use at least one highly effective method of contraception from ICF signature, during the course of the study and at least 7 months after the last administration of T-DM1.
12. Men with childbearing potential partner refusing to use condom during the course of this study and for at least 7 months after the last administration of T-DM1.
13. Subject with a significant medical, neuro-psychiatric, or surgical condition, currently uncontrolled by treatment, which, in the principal investigator’s opinion, may interfere with completion of the study.
14. Exclusion criterion applicable to FRANCE only: Vulnerable persons according to the article L.1121-6 of the Public Health Code, adults who are the subject of a measure of legal protection or unable to express their consent according to article L.1121-8 of the Public Health Code

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. Characterization of genomic alterations and HER2 expression.
2. 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 with a “positive” HER2-PET/CT (per metabolic response)

Secondary endpoints 5

1. Overall response to T-DM1 assessed by metabolic response (subjects with a “positive” HER2-PET/CT).
2. OS defined from the start of treatment to the date of death from any cause (subjects with a “positive” HER2-PET/CT).
3. DoR defined as the time from the date of first documentation of response (CR or PR) to disease progression or death, in participants who achieve complete or partial response assessed by metabolic response (subjects with a “positive” HER2-PET/CT)..
4. DCR defined as absence of disease progression (subjects with a “positive” HER2-PET/CT).
5. Incidence, nature, and severity of adverse events, including but not limited to drug induced liver injury, described in the section 9.1.2.2 “Recording and reporting of AEs by the investigators” and in the section 9.2.1 “Adverse Events of Special Interest – Definitions”

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 2

Auxiliary 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Institut Jules Bordet

Sponsor organisation

Institut Jules Bordet

Address

Mijlenmeersstraat 90

City

Anderlecht

Postcode

1070

Country

Belgium

Scientific contact point

Organisation

Institut Jules Bordet

Contact name

CTSU

Public contact point

Organisation

Institut Jules Bordet

Contact name

CTSU

Locations

1 EU/EEA country · 7 investigational sites

By country

Investigational sites

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 15 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

1 submissions — initial application plus substantial / non-substantial modifications