Liquid Biopsy: Intercepting Mutational Trajectories of HER2 (Human Epidermal Growth Factor Receptor 2) Breast Cancer (GIM21 Trial)

Not Applicable

Completed

• Conditions: Metastatic Breast Cancer
• Interventions: Other: Both blood and tissues collection for patients with metastatic breast cancer HER2+ pretreated with no more than one line of anti-HER2 therapy for advanced breast cancer.

• Registration Number: NCT05735392
• Lead Sponsor: Consorzio Oncotech

Brief Summary

This is an open, interventional, non-pharmacological, prospective study. Patients will receive trastuzumab emtansine (T-DM1) at 3.6 mg/kg intravenously every 21 days, as per Summary of Product Characteristics (SmPC). This is a no-profit study.

Detailed Description

T-DM1 effects will be monitored by a combination of Next Generation Sequencing (NGS, tumor tissue) and Liquid Biopsy (LB, blood), as described below, to capture molecular events (gene aberrations, mainly mutations) associated with (or causative of) relapse as well as primary/adaptive resistance to HER2 blockade.

This study will prospectively monitor these events throughout the clinical history of the patients (archival tissues, blood collection, aimed biopsies). No investigational drugs will be administered.

This protocol is classified as "interventional" for two reasons:

1. dedicated, additional blood drawings (liquid biopsies)are collected in addition to the routine bloodtests being requested as per standard clinical practice;

2. the study involves occasional fine-needle biopsy on accessible (e.g. cutaneous) metastatic foci in selected patients to confirm their HER2 status, as per good medical practice.

These will represent an additional opportunity of targeted NGS.

Both blood (a) and tissues (b) will be obtained during T-DM1 treatment of enrolled patients at the participating Sites at the study specific timelines.

Study Timeline

• Study Start: 2018-11-07
• Primary Completion: 2022-01-12
• Study Completion: 2022-01-12
• Status Verified: 2023-01
• Study First Submitted: 2023-01-31
• Study First Submitted QC: 2023-02-09
• Last Update Submitted: 2023-02-09
• Study First Posted: 2023-02-21
• Last Update Posted: 2023-02-21

Recruitment & Eligibility

• Status: COMPLETED
• Sex: Female
• Target Recruitment: 48

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Trastuzumab emtansine as per SmPC for liquid biopsy and tissue collection	Both blood and tissues collection for patients with metastatic breast cancer HER2+ pretreated with no more than one line of anti-HER2 therapy for advanced breast cancer.	Patients will receive trastuzumab emtansine (T-DM1) at 3.6 mg/kg intravenously every 21 days, as perSummary of Product Characteristics (SmPC). Peripheral blood samples will be taken by venipuncture prior to initiation of study therapy (T0), and at designated time-points after the first (T1) the second (T2), the third(T3)and after the sixth(T6), the ninth(T9), until the 12thcycle of T-DM1(see Fig.1) on-treatment and finally at progression.

Primary Outcome Measures

Name	Time	Method
Number of de novo mutations	About 4 years	3. Number of de novo mutations arising during T-DM1 treatment. Few mutations and gene aberrations (see above) are known to associate with primary and acquired resistance to Trastuzumab (TTZ) and Pertuzumab (PTZ), and none is specifically associated with T-DM1 escape, to our knowledge. Possibly, this is due to the rather recent introduction of this antibody-drug conjugate in human therapy.
Rate of response/anticipation of relapse	About 4 years	2. Changes form baseline in thr response rate. First detection of index mutations in blood will be compared with first imaging and medical evidence of relapse (response rate) to determine whether and how the LiqERBcept protocol can lead to earlier detection and improvement in medical care.
Number of index mutations	About 4 years	1. Number of index mutations and resistance-associated mutations in the bloodstream. Index mutations are defined as the number of mutation detected in tissue biopsies from either or both the primary lesions and the most recent recurrence, whenever available. Resistance mutations known to arise during non-T-DM1 HER2-blockade include mutations of PIK3CA (phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha), PIK3R1 (Phosphoinositide-3-Kinase Regulatory Subunit 1), AKT1 (AKT1 AKT serine/threonine kinase 1), and EGF1R (Epidermal Growth Factor Receptor 1).These may be a special case of index mutations. Other known genomic aberrations occurring under HER2 blockade and potentially testable in bloodier PTEN (Phosphatase and tensin homolog) loss and overexpression of p95HER2 (p95HER2/611 carboxy terminal fragment), MUC4 (Mucin 4, Cell Surface Associated), and PDK1 (3-Phosphoinositide-dependent kinase 1)

Secondary Outcome Measures

Name	Time	Method
Number of actionable mutations	About 4 years	Number of actionable mutations occur during treatment with T-DM1 .

Trial Locations

Locations (9)

I.R.C.C.S. A.O.U San Martino - IST; 🇮🇹 Genova, Italy

A.O. Ospedale Papa Giovanni XXIII - Oncologia; 🇮🇹 Bergamo, Italy

A.O.U. Policlinico di Modena; 🇮🇹 Modena, Italy

Azienda Ospedaliera Universitaria Federico II; 🇮🇹 Napoli, Italy

Ospedale S. Cuore Don Calabria; 🇮🇹 Negrar, Italy

Fondazione Policlinico Universitario A. Gemelli - Oncologia Medica; 🇮🇹 Roma, Italy

Fondazione Policlinico Universitario A. Gemelli - Senologia Oncologica; 🇮🇹 Roma, Italy

Policlinico Umberto I; 🇮🇹 Rome, Italy

Istituto Nazionale Tumori "Regina Elena"; 🇮🇹 Roma, Italy