Clinical trial NCT05378204: 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.
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.
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: NA
Conditions: Breast Cancer
Keywords: Breast cancer
Germline BRCA mutation
PARP inhibitor
Biomarkers
POLQ
Polθ
Shieldin complex
53BP1
Lead sponsor: Institut Claudius Regaud
Sponsor class: OTHER
Collaborators: name: Artios Pharma Ltd
First posted: 2022-05-18
Enrollment: 120
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: OTHER

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.


Eligibility criteria: MAIN STUDY

INCLUSION CRITERIA:

1. Women (or men) aged ≥ 18 years with histologically proven breast cancer
2. Metastatic relapse or locally advanced breast cancer
3. No-HER2 overexpression or amplification
4. 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
5. 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 IV) 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
6. ECOG Performance Status ≤ 2
7. Patients must have measurable or evaluable disease according to RECIST v1.1
8. Patient with deleterious germline BRCA 1 and/or 2 mutation, eligible for PARP inhibitor therapy (olaparib or talazoparib), according each investigator
9. Any number of prior lines therapy are allowed
10. Current treatment with PARP inhibitor not yet started
11. Women should be post-menopaused or willing to accept the use of an effective contraceptive regimen during the treatment period by PARP inhibitor
12. Patient able to participate and willing to give informed consent prior performance of any study-related procedures and to comply with the study protocol
13. Patient affiliated to a Social Health Insurance in France

NON-INCLUSION CRITERIA:

1. Abnormal coagulation contraindicating biopsy
2. Bone metastases when this is the only site of biopsiable disease
3. 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
4. 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
5. Patients with known untreated CNS metastases and/or carcinomatous meningitis
6. Patients with a known history of Human Immunodeficiency Virus (HIV)
7. Patients with known active Hepatitis B or C
8. Patients should not be on any other anti-cancer therapy (chemotherapy, endocrine therapy, immunotherapy, tailored therapy or alternative investigational therapy)
9. Patient pregnant, or breast-feeding
10. 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
11. 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:

1. Women (or men) aged ≥ 18 years with histologically proven breast cancer
2. Metastatic relapse or locally advanced breast cancer
3. No-HER2 overexpression or amplification
4. 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
5. Patients with metastases that can be biopsied except bone metastases
6. ECOG Performance Status ≤ 2
7. Patients, with deleterious germline BRCA 1 and/or 2, in progression under PARPi alone (talazoparib or olaparib)
8. Patient able to participate and willing to give informed consent prior performance of any study-related procedures and to comply with the study protocol
9. Patient affiliated to a Social Health Insurance in France

NON-INCLUSION CRITERIA:

1. Abnormal coagulation contraindicating biopsy
2. Bone metastases when this is the only site of biopsiable disease
3. Patient pregnant, or breast-feeding
4. Patients with a known history of Human Immunodeficiency Virus (HIV)
5. Patients with known active Hepatitis B or C
6. 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
7. Patients already participating in the main REPARP study
8. Patient who has forfeited his/her freedom by administrative or legal award or who is under legal protection (curatorship and guardianship, protection of justice)

Primary outcomes:
measure: 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).
timeFrame: 6 months for each patient
measure: Sub-study: the primary end point is the rate of patients presenting loss of Shieldin complex and/or 53BP1.
timeFrame: 1 month for each patient
Secondary outcomes:
measure: 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.
timeFrame: 12 months for each patient
measure: Main study: Objective Response (i.e. complete or partial response) defined using RECIST v1.1 criteria.
timeFrame: 12 months for each patient
measure: 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.
timeFrame: 12 months for each patient
measure: Sub-study: expression of the Shieldin complex and 53BP1.
timeFrame: 1 month for each patient
Other outcomes:
Locations:
city: Bordeaux
country: France
facility: Institut Bergonie
city: Caen
country: France
facility: Centre Francois Baclesse
city: Clermont-Ferrand
country: France
facility: Centre Jean Perrin
city: Dijon
country: France
facility: Centre Georges Francois Leclerc
city: La Roche-sur-Yon
country: France
facility: Centre Hospitalier Départemental Vendée
city: Lille
country: France
facility: Centre Oscar Lambret
city: Limoges
country: France
facility: CHU de LIMOGES
city: Lyon
country: France
facility: Centre Leon Berard
city: Marseille
country: France
facility: Institut Paoli Calmettes
city: Montpellier
country: France
facility: Centre de Cancerologie Du Grand Montpellier
city: Montpellier
country: France
facility: Institut Regional Du Cancer de Montpellier
city: Nîmes
country: France
facility: CHU de Nimes
city: Paris
country: France
facility: Hopital Pitie Salpetriere
city: Paris
country: France
facility: Hopital Saint Louis
city: Paris
country: France
facility: Hopital Tenon
city: Paris
country: France
facility: INSTITUT CURIE - Site de Paris
city: Plérin
country: France
facility: CENTRE ARMORICAIN DE RADIOTHERAPIE, IMAGERIE MEDICALE ET ONCOLOGIE - Hôpital privé des Côtes d'Armor
city: Poitiers
country: France
facility: Chu de Poitiers
city: Rennes
country: France
facility: Centre Eugene Marquis
city: Saint-Herblain
country: France
facility: INSTITUT DE CANCEROLOGIE DE L'OUEST St-Herblain
city: Saint-Étienne
country: France
facility: Chu Saint Etienne
city: Toulouse
country: France
facility: IUCT-O
city: Tours
country: France
facility: Chru de Tours
city: Vandoeuvre-les-nancy
country: France
facility: Institut de Cancerologie de Lorraine
city: Villejuif
country: France
facility: Institut Gustave Roussy
Study officials:
References: