Phase-II Study of Olaparib as Maintenance Therapy After Response to Trabectedin-pegylated Liposomal Doxorubicin in Recurrent Ovarian Carcinoma
Overview
- Phase
- Phase 2
- Intervention
- Olaparib
- Conditions
- Ovarian Cancer
- Sponsor
- Grupo Español de Investigación en Cáncer de Ovario
- Enrollment
- 9
- Locations
- 16
- Primary Endpoint
- Progression free survival (PFS)
- Status
- Completed
- Last Updated
- 3 years ago
Overview
Brief Summary
Epithelial ovarian cancer harbours 20% Breast Cancer gene (BRCA)1/2 mutations independently of family history. Poly ADP ribose polymerase (PARP) inhibitors (PARPi) have shown clinical activity among patients with homologous recombination deficiency (HRD) and specifically among BRCA1/2 mutation carriers.
The European Medicines Agency (EMA) approved the use of olaparib as maintenance therapy "as monotherapy for the maintenance treatment of adult patients with platinum sensitive relapsed BRCA mutated (germline and/or somatic) high-grade serous epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in response (complete response or partial response) to platinum-based chemotherapy".
Trabectedin and Pegylated liposomal doxorubicin (PLD) have shown relevant activity in relapsed epithelial ovarian cancer. In the relapse with Treatment-free interval of last platinum (TFIp) between 6 and 12 months this efficacy translated into an increase in Overall survival (OS) and Progression free survival (PFS).
There is an increase of hypersensitivity reactions (HSR) among platinum sensitive patients, that reaches 44% in third line and does not always allow for platinum use despite desensitization protocols. In relapse with TFIp between 6-12 months the use of Trabectedin+PLD is accepted in guidelines and consensus.
Following clinical BRCAness criteria a group of patients that harbours up to 50% of BRCA1/2 mutations can be selected. Olaparib has been licensed according to EMA for maintenance in BRCA mutated patients after response to platinum following Study 19 phase II trial and further confirmed with phase III SOLO-2 data. However there is no evidence of the benefit of adding olaparib after Trabectedin+PLD response among BRCA1/2 carriers.
The combination of Trabectedin+PLD, as well as both single drugs, have shown higher activity among BRCA1/2 carriers.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Provision of informed consent prior to any study specific procedures.
- •Female aged ≥18 years.
- •Patients with high-grade serous or endometrioid ovarian carcinoma.
- •Treatment-free interval of last platinum (TFIp) higher than 6 months.
- •BRCA1/2 germline or somatic deleterious mutation.
- •Patient must have received two or more previous chemotherapy (CT) regimens, including first line platinum based CT and last trabectedin + PLD. There is no limit of previous number of CT lines.
- •Last CT prior to the inclusion in the trial must be trabectedin + PLD. Patients must have received at least 4 cycles of treatment, and have reached a partial or complete response, assessed by RECIST 1.1 criteria and no evidence of a rising CA 125, following the chemotherapy course.
- •Patients must have normal organ and bone marrow function measured within 28 days prior to administration of study treatment as defined below:
- •Haemoglobin ≥ 10.0 g/dL with no blood transfusion in the past 28 days
- •Absolute neutrophil count (ANC) ≥ 1.5 x 109/L
Exclusion Criteria
- •Involvement in the planning and/or conduct of the study (applies to both sponsor staff and/or staff at the study site).
- •Any previous treatment with PARP inhibitor.
- •Rising CA125 after chemotherapy is finished until inclusion. Pre-treatment CA-125 measurements must meet criterion specified below:
- •If the first value is within upper limit of normal (ULN) the patient is eligible to be randomised and a second sample is not required.
- •If the first value is greater than ULN a second assessment must be performed at least 7 days after the first. If the second assessment is ≥ 15% more than the first, the patient is not eligible.
- •Other malignancy within the last 3 years except: adequately treated non-melanoma skin cancer, curatively treated cervical carcinoma in situ, breast carcinoma in situ, and grade 1 endometrial carcinoma in stage
- •Resting ECG with QTc \> 470 msec on 2 or more time points within a 24 hour period or family history of long QT syndrome.
- •Concomitant use of known strong CYP3A inhibitors (eg. itraconazole, telithromycin, clarithromycin, protease inhibitors boosted with ritonavir or cobicistat, 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.
- •Concomitant use of known strong (eg. phenobarbital, enzalutamide, phenytoin, rifampicin, rifabutin, rifapentine, carbamazepine, nevirapine and St Johns 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.
- •Persistent toxicities (\> Common Terminology Criteria for Adverse Event (CTCAE) grade 2) caused by previous cancer therapy, excluding alopecia.
Arms & Interventions
Olaparib
Olaparib orally twice daily at 150 mgs bid continually
Intervention: Olaparib
Outcomes
Primary Outcomes
Progression free survival (PFS)
Time Frame: Up to 24 months
Time from date of first olaparib dose until the date of objective radiological disease progression according to modified RECIST 1.1 or death (by any cause in the absence of progression).
Secondary Outcomes
- Time to First Subsequent Treatment (TFST)(Up to 24 months)
- Progression free survival 2 (PFS2)(Up to 24 months)
- Time to Second Subsequent Treatment (TSST)(Up to 24 months)
- Incidence of Treatment Adverse Events(Up to 24 months)