REPARP: Study Evaluating DNA Double-strand Breaks (DSBs) REpair Factors (POLQ, Shieldin Complex and 53BP1) Expression as Biomarker of PARP Inhibitor Resistance in Patients With Deleterious Germline Mutation in BRCA 1/2 and HER2-negative, Metastatic or Locally Advanced Breast Cancer.

Sponsor

Institut Claudius Regaud (Other)

Overall Status

Recruiting

CT.gov ID

NCT05378204

Collaborator

Artios Pharma Ltd (Industry)

120

Enrollment

Locations

Arm

35.3

Anticipated Duration (Months)

5.7

Patients Per Site

0.2

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The purpose of this study is to assess whether expression of not only POLQ/Polθ, but also Shieldin complex and/or 53BP1 are correlated with primary and/or acquired resistance to PARPi (Poly(ADP-Ribose) Polymerases inhibitors) in a sub-population of locally advanced or metastatic breast cancer patients and vary regarding type and location of gBRCA1/2 mutations.

This translational research program is composed of two multicentric, non-randomized prospective studies in patients with HER2-negative locally advanced or metastatic breast cancer:

The main study concerns 80 patients eligible for PARPi (according to the investigators).PARPi treatments (talazoparib or olaparib) will be administered and dosed according to the standard of care administration.
The sub-study concerns 40 patients in progression disease under PARPi alone.

For each included patient in the main study or sub-study, tumor biopsy specimen and blood samples will be collected at different times during the study.

Condition or Disease	Intervention/Treatment	Phase
Breast Cancer	Other: Main study: Other: Sub-study:	N/A

Study Design

Study Type:

Interventional

Anticipated Enrollment :

120 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Other

Official Title:

Prospective and Multicentric Study Evaluating DNA Double-strand Breaks (DSBs) REpair Factors (POLQ, Shieldin Complex and 53BP1) Expression as Biomarker of PARP Inhibitor Resistance in Patients With Deleterious Germline Mutation in BRCA 1/2 and HER2-negative, Metastatic or Locally Advanced Breast Cancer.

Actual Study Start Date :

Jun 23, 2022

Anticipated Primary Completion Date :

Jan 1, 2025

Anticipated Study Completion Date :

Jun 1, 2025

Arms and Interventions

Arm	Intervention/Treatment
Other: Patients with breast cancer Patients With Deleterious Germline Mutation in BRCA 1/2 and HER2-negative, Metastatic or Locally Advanced Breast Cancer.	Other: Main study: For each included patient, tumor biopsy specimen and blood samples will be collected at baseline visit (before the first dose of PARPi treatment). During the treatment period: blood samples will be scheduled every 8 weeks (i.e. 2 cycles). At the time of progression: tumor biopsy and blood samples will be collected. Other: Sub-study: For each included patient, tumor biopsy specimen and blood samples will be collected as soon as possible after progression (before initiation of the post PARPi anti-tumoral treatment).

Arm

Intervention/Treatment

Other: Patients with breast cancer

Patients With Deleterious Germline Mutation in BRCA 1/2 and HER2-negative, Metastatic or Locally Advanced Breast Cancer.

Other: Main study:

For each included patient, tumor biopsy specimen and blood samples will be collected at baseline visit (before the first dose of PARPi treatment). During the treatment period: blood samples will be scheduled every 8 weeks (i.e. 2 cycles). At the time of progression: tumor biopsy and blood samples will be collected.

Other: Sub-study:

For each included patient, tumor biopsy specimen and blood samples will be collected as soon as possible after progression (before initiation of the post PARPi anti-tumoral treatment).

Outcome Measures

Primary Outcome Measures

Main study: the primary endpoint is the Area under the Receiver Operating Characteristic Curve (ROC Curve) of POLQ expression to identify patients presenting progressive disease or death at 6 months under PARPi alone (primary resistance). [6 months for each patient]
Progression will be determined using RECIST v1.1 criteria.
Sub-study: the primary end point is the rate of patients presenting loss of Shieldin complex and/or 53BP1. [1 month for each patient]

Secondary Outcome Measures

Main study: Progression-Free Survival defined as the time from inclusion until progression according to RECIST v1.1 criteria or death from any cause, whichever occurs first. [12 months for each patient]
Main study: Objective Response (i.e. complete or partial response) defined using RECIST v1.1 criteria. [12 months for each patient]
Main study: Duration Of Response defined as the time from initial objective response until progression according to RECIST v1.1 criteria or death from any cause. [12 months for each patient]
Sub-study: expression of the Shieldin complex and 53BP1. [1 month for each patient]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

MAIN STUDY

INCLUSION CRITERIA:

Women (or men) aged ≥ 18 years with histologically proven breast cancer
Metastatic relapse or locally advanced breast cancer
No-HER2 overexpression or amplification
Triple-negative (defines as ER<1%, PR<1% and HER2-negative as per ASCO CAP guidelines) or hormone receptor positive (defines as ER and/or PR ≥ 1%) breast cancer
Patients with metastases that can be biopsied except bone metastases. At baseline, if patients already have an archived biopsy from a secondary or a primary site (if stage

of their current disease, this material can be used for the study, provided that, it was collected within 3 months prior enrollment and a frozen and a FFPE sample are both available for research

ECOG Performance Status ≤ 2
Patients must have measurable or evaluable disease according to RECIST v1.1
Patient with deleterious germline BRCA 1 and/or 2 mutation, eligible for PARP inhibitor therapy (olaparib or talazoparib), according each investigator
Any number of prior lines therapy are allowed
Current treatment with PARP inhibitor not yet started
Women should be post-menopaused or willing to accept the use of an effective contraceptive regimen during the treatment period by PARP inhibitor
Patient able to participate and willing to give informed consent prior performance of any study-related procedures and to comply with the study protocol
Patient affiliated to a Social Health Insurance in France

NON-INCLUSION CRITERIA:

Abnormal coagulation contraindicating biopsy
Bone metastases when this is the only site of biopsiable disease
Patients with all target in a previously irradiated region, except if clear progression has been observed prior to study in at least one of them
Patients with known additional malignancy that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer
Patients with known untreated CNS metastases and/or carcinomatous meningitis
Patients with a known history of Human Immunodeficiency Virus (HIV)
Patients with known active Hepatitis B or C
Patients should not be on any other anti-cancer therapy (chemotherapy, endocrine therapy, immunotherapy, tailored therapy or alternative investigational therapy)
Patient pregnant, or breast-feeding
Any psychological, familial, geographic or social situation, according to the judgment of investigator, potentially preventing the provision of informed consent or compliance to study procedure
Patient who has forfeited his/her freedom by administrative or legal award or who is under legal protection (curatorship and guardianship, protection of justice)

SUB-STUDY

INCLUSION CRITERIA:

Women (or men) aged ≥ 18 years with histologically proven breast cancer
Metastatic relapse or locally advanced breast cancer
No-HER2 overexpression or amplification
Triple-negative (defines as ER<1%, PR<1% and HER2-negative as per ASCO CAP guidelines) or hormone receptor positive (defines as ER and or PR ≥ 1%) breast cancer
Patients with metastases that can be biopsied except bone metastases
ECOG Performance Status ≤ 2
Patients, with deleterious germline BRCA 1 and/or 2, in progression under PARPi alone (talazoparib or olaparib)
Patient able to participate and willing to give informed consent prior performance of any study-related procedures and to comply with the study protocol
Patient affiliated to a Social Health Insurance in France

NON-INCLUSION CRITERIA:

Abnormal coagulation contraindicating biopsy
Bone metastases when this is the only site of biopsiable disease
Patient pregnant, or breast-feeding
Patients with a known history of Human Immunodeficiency Virus (HIV)
Patients with known active Hepatitis B or C
Any psychological, familial, geographic or social situation, according to the judgment of investigator, potentially preventing the provision of informed consent or compliance to study procedure
Patients already participating in the main REPARP study
Patient who has forfeited his/her freedom by administrative or legal award or who is under legal protection (curatorship and guardianship, protection of justice)

Contacts and Locations

Locations

	Site	City	Country
1	Institut Bergonie	Bordeaux	France
2	Centre Francois Baclesse	Caen	France
3	Centre Jean Perrin	Clermont-Ferrand	France
4	Centre Georges Francois Leclerc	Dijon	France
5	Centre Oscar Lambret	Lille	France
6	Centre Leon Berard	Lyon	France
7	Institut Paoli Calmettes	Marseille	France
8	Centre de Cancerologie Du Grand Montpellier	Montpellier	France
9	Institut Regional Du Cancer de Montpellier	Montpellier	France
10	CHU de Nimes	Nîmes	France
11	Hopital Pitie Salpetriere	Paris	France
12	Hopital Saint Louis	Paris	France
13	Hopital Tenon	Paris	France
14	INSTITUT CURIE - Site de Paris	Paris	France
15	CENTRE ARMORICAIN DE RADIOTHERAPIE, IMAGERIE MEDICALE ET ONCOLOGIE - Hôpital privé des Côtes d'Armor	Plérin	France
16	Centre Eugene Marquis	Rennes	France
17	INSTITUT DE CANCEROLOGIE DE L'OUEST St-Herblain	Saint-Herblain	France
18	IUCT-O	Toulouse	France
19	Chru de Tours	Tours	France
20	Institut de Cancerologie de Lorraine	Vandoeuvre-les-nancy	France
21	Institut Gustave Roussy	Villejuif	France