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Cancer clinical trial

Window study of the PARP inhibitor rucaparib in patients with primary triple negative or BRCA1/2 related breast cancer

Summary:
Approximately 6,000 women per year in the UK are diagnosed with triple negative breast cancer (TNBC). TNBC makes
up 10-15%
of all breast cancers. It is a highly proliferative, aggressive form of breast cancer and comes with a high risk
of tumour spread and death. Unlike other types of breast cancer, TNBC does not respond to targeted drugs such as
those used in hormone therapy or trastuzumab. Chemotherapy is currently the only treatment available and although
some patients respond well, those who do not have a poor prognosis.
A family of drugs called PARP inhibitors currently present a promising potential treatment for breast cancer, especially
those in the TNBC group. There is also evidence that PARP inhibitors are effective in patients with BRCA1 / BRCA2
related breast cancers.
The aim of the RIO trial is to determine the percentage of primary TNBCs or BRCA1/2 related breast cancers that
display sensitivity to the PARP inhibitor rucaparib by measuring change in tumour cells multiplying after 12-14
days of
rucaparib treatment. RIO will also aim to identify biomarkers that can identify patient groups sensitive to this medication
to allow further analysis of rucaparib in these cancers.
RIO will recruit 91 patients with primary TNBC or known germline BRCA1/2 related primary breast cancer. All patients
will receive 2 weeks of treatment with rucaparib in a ‘window of opportunity’ before starting their routine treatment (surgery or neoadjuvant chemotherapy). Research tumour biopsies will be taken at baseline and after 2 weeks of
treatment. Patients will be followed up for 28 days after completion of trial treatment.

Inclusion criteria:
• Male or female patients aged 16 years or older
• Histologically proven carcinoma of the breast amenable to biopsy
• Either breast tumour size 2cm or greater OR <2cm tumour with cytologically or histologically confirmed axillary lymph
node metastases
• WHO performance status 0, 1 or 2
• Either
Primary sporadic triple negative breast cancer defined as oestrogen receptor (ER) negative, progesterone receptor
(PgR) negative (as defined by Allred score 0/8 or 2/8 or stain in <1% of cancer cells) and HER2 negative
(immunohistochemistry 0/1+ or negative in situ hybridization) as determined by local laboratory. Patients should not be
known to have a germline pathogenic BRCA1 or BRCA2 mutation at study entry.
OR
Primary BRCA1/2 related breast cancer as defined by a breast carcinoma of any phenotype (ER +ve or –ve, PgR +ve or
–ve, HER2 +ve or –ve) occurring in a patient with a known germline pathogenic BRCA1 or BRCA2 mutation
• Adequate organ function confirmed by the following laboratory values obtained within 14 days prior to the first dose of
rucaparib:
bone marrow function: ANC ≥ 1.5 x 109/L; Platelets >100×109/L; Hemoglobin ≥9 g/dL
hepatic function: Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5 x upper limit of normal
(ULN); Bilirubin ≤1.5 x ULN
renal function: serum creatinine ≤1.5 x ULN
• Patients or patients with partners of childbearing potential must use adequate contraception during trial participation.
A negative pregnancy test is required by female patients prior to the start of therapy. Female patients will be deemed
not of childbearing potential if they are postmenopausal (aged >50 and amenorrhoeic for at least 12 months) or have
had irreversible surgical sterilization
• ER negative patients may enter the trial whether or not they have taken hormone replacement therapy (HRT) or the
oral contraceptive pill (OCP) within the last four weeks. ER positive patients on HRT or the OCP must either continue
HRT/OCP for the duration of the study or must not have taken HRT/OCP within the last four weeks before trial entry.
The possible benefits and risks of continuing HRT/OCP must be discussed with the patient
• Patients with primary breast cancer and evidence of metastatic disease on first presentation are eligible providing
they have not had prior treatment
• Patients must be willing and able to provide informed consent and to comply with all study procedures (including
providing additional tumour biopsies for research purposes) and visit schedules

Exclusion criteria:
• Any prior or concurrent treatment for the current diagnosis of breast cancer.
• Any anti-cancer treatment within the previous 12 months for prior diagnosis of cancer other than for basal cell
carcinoma of the skin or cervical carcinoma in situ.
• Prior history of ipsilateral breast cancer within the previous 5 years.
• Impaired cardiac function or clinically significant cardiac disease, including any of the following:
o unstable angina pectoris ≤3 months prior to first scheduled dose of rucaparib
o acute myocardial infarction ≤3 months prior to first scheduled dose of rucaparib
• Presence of any systemic illness incompatible with participation in the clinical trial or inability to provide written
informed consent.
• Treatment with an unlicensed or investigational drug within 4 weeks prior to trial entry.
• Prior treatment with any PARP inhibitor, including oral or intravenous rucaparib.
• Administration of strong CYP1A2 and CYP3A4 inhibitors or inducers (as detailed in Appendix 1) ≤7 days prior to first
scheduled dose of rucaparib.
• Females who are pregnant or breastfeeding.

Principal Investigator for this trial: Dr Stephen Y Chan

Research Ethics Committee Reference: 14/LO/2181

Contact us about participating in this study by emailing R&IActiveStudyEnquiries@nuh.nhs.uk or telephoning 0115 924 9924 Ext. 70076

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