Advanced cancer patients that have a germline mutation or a somatic mutation in their tumor. Prostate and ovarian cancer patients and breast cancer patients who carry a BRCA1/2 mutation will be excluded because there are ongoing or planned sponsored international trials running in these cohorts. All other cancer types with a homologous recombination deficiency will be eligible as well as breast cancers with non-BRCA1/2.
Conditions
Interventions
Trade Name: Olaparib
Pharmaceutical Form:
Sponsors
Belgian Society of Medical Oncology
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1- Provision of informed consent prior to any study specific procedures 2- Female or male aged > 18 years 3- Histologically proven advanced cancer, either locally or metastatic, harboring a specific pathogenic genetic alteration (with the exception of breast, pancreas, ovarian or prostate cancer patients harboring a BRCA1/2 mutation) 4- No approved targeted therapy for the specific genetic alteration in the specific tumor type 5- No other genomic driven phase I, II or III trial available for the specific genomic alteration in the specific tumor type 6- Available tumor tissue for verification of the mutation by Sanger sequencing. 7- Patients must have normal organ and bone marrow function measured within 28 days prior to administration of study treatment. 8- Eastern Cooperative Oncology Group (ECOG) performance status 0-1 9- Patients must have a life expectancy =16 weeks 10- Postmenopausal or evidence of non-childbearing status for women of childbearing potential: negative urine or serum pregnancy test within 28 days of study treatment and confirmed prior to treatment on day 1. 11- Patients are willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations. 12- At least one lesion (measurable and/or non-measurable) that can be accurately assessed at baseline by CT and is suitable for repeated assessment. 13- *Formalin fixed, paraffin embedded (FFPE) tumour sample from the primary cancer must be available for central testing. 14- For patients not entering the trial after identification of a genetic alteration in the Precision 1 trial, 2 samples of 10 ml EDTA tubes should be taken to make germ-line DNA analysis possible. 15- A new biopsy of tumor tissue with consent of the patient at the moment of progressive disease is preferable Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 342 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 171
Exclusion criteria
Exclusion criteria: 1- Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site) 2- Ovarian cancer patients harboring a HRD and breast, prostate and pancreas cancer patients who carry a BRCA1/2 mutation 3- Previous enrolment in the present study 4- Participation in another clinical study with an investigational product during the last 4 weeks or radiotherapy (except for palliative reasons) within three weeks prior to study treatment. 5- History of non-compliance to medical regimens 6- Any previous treatment with PARP inhibitor, including olaparib. 7- Other malignancy within the last 5 years except: adequately treated non-melanoma skin cancer, curatively treated in situ cancer of the cervix, ductal carcinoma in situ (DCIS), Stage 1, grade 1 endometrial carcinoma, or other solid tumours including lymphomas (without bone marrow involvement) curatively treated with no evidence of disease for =5 years. Patients with a history of localized triple negative breast cancer may be eligible, provided they completed their adjuvant chemotherapy more than three years prior to registration, and that the patient remains free of recurrent or metastatic disease 8- Resting ECG with QTc > 470 msec on 2 or more time points within a 24 hour period or indicating uncontrolled, potentially reversible cardiac conditions as judged by the investigator (er., unstable ischemia, uncontrolled symptomatic arrhythmia, congestive heart failure, QTcF prolongation >500ms, electrolyte disturbances, etc.) or patients with congenital long QT syndrome 9- Patients receiving any systemic chemotherapy or radiotherapy (except for palliative reasons) within four weeks prior to study treatment. Patients must have recovered from radiotherapy toxicities prior to enrollment. 10- Concomitant use of known strong CYP3A inhibitors (eg. itraconazole, telithromycin, clarithromycin, protease inhibitors boosted with ritonavir orcobicistat, indinavir, saquinavir, nelfinavir, boceprevir, telaprevir) or moderate CYP3A inhibitors (eg. ciprofloxacin, erythromycin, diltiazem, fluconazole, verapamil). The required washout period prior to starting olaparib is 2 weeks. 11- Concomitant use of known strong (eg. phenobarbital, enzalutamide, phenytoin, rifampicin, rifabutin, rifapentine, carbamazepine, nevirapine and St John’s Wort ) or moderate CYP3A inducers (eg. bosentan, efavirenz, modafinil). The required washout period prior to starting olaparib is 5 weeks for enzalutamide or phenobarbital and 3 weeks for other agents. 12- Persistent toxicities (Common Terminology Criteria for Adverse Event (CTCAE) > grade 2) caused by previous cancer therapy, excluding alopecia 13- Patients with myelodysplastic syndrome/acute myeloid leukaemia or with features suggestive of MDS/AML. 14- Patients with symptomatic uncontrolled brain metastases. A scan to confirm the absence of brain metastases is not required. The patient can receive a stable dose of corticosteroids before and during the study as long as these were started at least 4 weeks prior to treatment. Patients with spinal cord compression unless considered to have received definitive treatment for this and evidence of clinically stable disease for 28 days. 15- Major surgery within 2 weeks of starting study treatment and patients must have recovered from any effects of any major surgery. 16- Patients considered a poor medical risk due to a serious, uncontrolled medical disorder, non-malignant systemic
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: Primary: document anti-tumor activity (measured by response rate and response duration) of olaparib in advanced cancer patients that have a germline mutation or a somatic tumor mutation among a defined list of HR genes: BRCA1/2, ATM, BARD1, BRIP1, CHEK1, CHEK2, MRE11A, NBN, PALB2, RAD50, RAD 51B, RAD51C, RAD51D, RAD54L, FAM175A, CDK12, FANCL, p53 (only germline) and PPP2R2A. This is the minimal list of genes when mutated causing an HRD currently included in the routine genetic panel testing in the Belgian genetics labs. Other gene mutations proven to cause HRD are also eligible pending approval by the PI.;Secondary Objective: Secondary: correlate efficacy with locus-specific LOH in the tumors in case of cancers not routinely associated with the germline mutations (optional and separate informed consents for participants). Although the presence of LOH is not an absolute marker of the relevance of the mutation in a particular cancer, it gives a strong probability against which the response data can be evaluated.;Primary end point(s): Primary: 1) Response rate according to RECIST 1.1 2) Response duration;Timepoint(s) of evaluation of this end point: 1) and 2) every 8 weeks until cycle 7 thereafter every 12 weeks | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Secondary: 1) Correlate efficacy with locus-specific LOH in the tumors in case of cancers atypical for the germline mutations. 2) PFS 3) OS 4) Safety by reporting all adverse events;Timepoint(s) of evaluation of this end point: 1) every 8 weeks until cycle 7 thereafter every 12 weeks 2) and 3) every 3 months 4) every 4 weeks | — |
Countries
Belgium
Contacts
Public ContactDr. Sofie Joris
UZ Brussel
Outcome results
None listed