A Study to Assess the Efficacy of Rucaparib in Metastatic Breast Cancer Patients With a BRCAness Genomic Signature

This is a single arm, open-label, multicentric, phase II trial, with a Simon two-stage design, assessing the efficacy of a PARP inhibitor, rucaparib, in 41 progressing breast cancer patients with at least one line of chemotherapy at the metastatic setting., and who are carrying a BRCAness profile defined by Clovis genomic signature or a BRCA1 or 2 somatic mutation, without known BRCA1 or 2 germline mutation.

Inclusion criteria

• Women with histologically proven breast cancer.
• No Her2 over-expression.
• Progressive metastatic disease previously treated with at least one line of chemotherapy at the metastatic setting.
• Molecular analysis using the Affymetrix (CytoScan HD, SNP 6.0, or OncoScan) array available from the SAFIR02 protocol, or from other programs.
• BRCAness profile as defined by the Clovis genomic signature or BRCA1/2 somatic mutation (without known germline BRCA).
• Age ≥ 18 years
• WHO Performance Status 0/1
• Presence of measurable target lesion according to RECIST criteria v1.1
• Patients will have had at least a 21-day wash-out period from last chemotherapy or targeted therapy administration prior to inclusion and should have recover (grade ≤1) from all residual toxicities, excluding alopecia.
• Potentially reproductive patients must agree to use an effective contraceptive non-hormonal method or practice adequate methods of birth control or practice complete abstinence while on treatment, and for at least 6 months after the last dose of study drug.
• Women of childbearing potential must have a negative serum pregnancy test done within 14 days of enrollment and/or urine pregnancy test 72 hours prior to the administration of the study drug.
• Women who are breastfeeding should discontinue nursing prior to the first dose of study drug and until 6 months after the last dose.
• Provision of signed and dated, written informed consent prior to any study specific procedures, sampling and analyses
• Patient with social insurance coverage.

Exclusion criteria

• BRCA1 or 2 germline known mutation.
• Life expectancy <3 months.
• Less than 14 days from radiotherapy (whatever the indication). Fields should not have involved all target lesions.
• Patients previously treated with a PARP inhibitor.
• Spinal cord compression and/or symptomatic or progressive brain metastases (unless asymptomatic or treated and stable off steroids for at least 30 days prior to start of study drug).
• Patients with all target lesions in a previously irradiated region, except if clear progression has been observed prior to study in at least one of them
• Inability to swallow
• Major problem with intestinal absorption
• Previous or current malignancies of other histologies within the last 5 years, with the exception of in situ carcinoma of the cervix, and adequately treated basal cell or squamous cell carcinoma of the skin.
• Evidence of severe or uncontrolled systemic disease (active bleeding diatheses, or active Hepatitis B, C and HIV)
• Previous history of myelodysplastic syndrome
• History of hypersensitivity to active or inactive excipients of the rucaparib.
• Toxicities of grade ≥2 from any previous anti-cancer therapy, with the exception of alopecia.
• Altered haematopoietic or organ function, as indicated by the following criteria:

• Polynuclear neutrophils <1.5 x 10⁹/L
• Platelets <100 x 10⁹/L
• Haemoglobin <90 g/L
• ALAT/ASAT >2.5 x upper limit of normal (ULN) in the absence of or >5 x ULN in the presence of liver metastases
• Bilirubin >1.5 x ULN
• Creatinine clearance ≤30 mL/min (measured or calculated by Cockcroft and Gault formula
• Women who are pregnant.
• Patients using drugs that are known potent inhibitors or potent inducers of CYP1A2 or CYP3A4 are not eligible if those treatments cannot be substituted before inclusion
• Any condition which in the Investigator's opinion makes it undesirable for the subject to participate in the trial or which would jeopardize compliance with the protocol.
• Individuals deprived of liberty or placed under the authority of a tutor.