Primary breast cancer MedDRA version: 19.0 Level: PT Classification code 10057654 Term: Breast cancer female System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Conditions
Interventions
Product Name: Rucaparib (camphorsulfonic acid salt form)
Product Code: CO-338
Pharmaceutical Form: Tablet
INN or Proposed INN: Rucaparib
CAS Number: 283173-50-2
Current Sponsor code: 459868-92-9
Conce
Sponsors
The Royal Marsden NHS Foundation Trust
The Insitute of Cancer Research
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: • Male or female patients aged 16 years or older • Histologically proven carcinoma of the breast amenable to biopsy • Either breast tumour size 1.5cm or greater OR 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 72 hours prior to trial entry. 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 Are the trial subjects under 18? yes Number of subjects for this age range: 3 F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 35 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 53
Exclusion criteria
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.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: The main aim of this study is to determine the proportion of triple negative breast cancers (TNBCs) that respond to 12-14 days treatment with the PARP inhibitor rucaparib. The cell proliferation marker Ki67 will be used to measure treatment response. Ki67 has been widely used to measure proliferation in human breast cancer. Preclinical studies have shown that Ki67 levels decrease in response to PARP inhibition in xenografts of an HR deficient cancer cell line and that the degree of suppression of Ki67 is also associated with the magnitude of xenograft response to PARP inhibition in vivo. The exploratory analysis of Ki67 in BRCA1 and BRCA2 germline mutation carriers will be used to assess the validity of fall in Ki67 as a surrogate for sensitivity to rucaparib. From prior work it is anticipated that a majority of untreated BRCA1 and BRCA2 related cancers should show a fall in Ki67 on rucaparib.;Secondary Objective: - To identify a subgroup of TNBCs that are sensitive to rucaparib using baseline biomarkers of BRCA1 gene methylation and a genomic predictor of homologous recombination (HR) deficiency (DNA repair pathway). - To determine the proportion of TNBC cells undergoing apoptosis (cell death) following 12-14 days treatment with rucaparib. - To establish the proportion of TNBCs that display evidence of a defect in HR-based DNA repair as determined by the number of cells that fail to induce RAD51 foci, a cellular indicator of DNA repair. - To determine the extent rucaparib inhibits PARP in TNBC cells following 12-14 days rucaparib treatment. - To establish the safety of rucaparib treatment and how well this is tolerated in patients. ;Primary end point(s): The cell proliferation marker Ki67 will be used to measure treatment response. Response to rucaparib is defined as 50% or greater fall in Ki67 from baseline.;Timepoint(s) of evaluation of this end point: Ki67 levels will be assessed in tumour tissue biopsied at baseline (day 0) and on the last d | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Safety and tolerability will be assessed in all patients. All other secondary endpoints will be performed on patients with sporadic triple negative breast cancer only. • Association between baseline biomarkers of BRCA1 methylation, a genomic predictor of HR deficiency, and a drop in Ki67. • Apoptosis induction following 12-14 days of rucaparib treatment in patients with sporadic triple negative cancers. • Association between sporadic TNBC and evidence of a defect in HR based DNA repair, assessed as the proportion of sporadic TNBC that fail to induce RAD51 foci. • Safety and tolerability of rucaparib • Association of biomarkers with RAD51 score on day 12-14 biopsy;Timepoint(s) of evaluation of this end point: Safety and tolerability will be assessed in patients at day 8, day 12-14, 28 days after end of rucaparib treatment and a final assessment post surgery. All other evaluations will occur in samples taken at baseline (blood and tissue)and after 12-14 days of rucaparib treatment (tissue). | — |
Countries
United Kingdom
Outcome results
None listed