Olaparib treatment in patients with ovarian cancer.

Phase 1

Conditions: Ovarian Carcinoma
MedDRA version: 20.0Level: LLTClassification code 10033131Term: Ovarian carcinomaSystem Organ Class: 100000004864
Therapeutic area: Diseases [C] - Cancer [C04]

Registration Number: EUCTR2017-003183-13-ES

Lead Sponsor: GEICO - Grupo Español de Investigación en Cáncer de Ovario

Brief Summary: Not available

Detailed Description: Not available

Recruitment & Eligibility

Status: Authorised-recruitment may be ongoing or finished

Sex: Female

Target Recruitment: 66

Inclusion Criteria

1. Provision of informed consent prior to any study specific procedures.
2. Female aged =18 years.
3. Patients with high-grade serous or endometrioid ovarian carcinoma.
4. Treatment-free interval of last platinum (TFIp) higher than 6 months.
5. BRCA1/2 germline or somatic deleterious mutation.
6. 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.
7. 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.
8. 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
- Platelet count = 100 x 109/L
- Total bilirubin = 1.5 x institutional upper limit of normal (ULN)
- Aspartate aminotransferase (AST) (Serum Glutamic Oxaloacetic Transaminase
(SGOT)) / Alanine aminotransferase (ALT) (Serum Glutamic Pyruvate Transaminase (SGPT)) = 2.5 x institutional upper limit of normal unless liver metastases are present in which case they must be = 5x ULN
- Patients must have creatinine clearance estimated using the Cockcroft-Gault
equation of =51 mL/min: Estimated creatinine clearance = (140-age [years]) x weight (kg) (x F)a serum creatinine (mg/dL) x 72 a where F=0.85 for females.
9. Eastern Cooperative Oncology Group (ECOG) performance status 0-1.
10. Life expectancy = 16 weeks.
11. 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. Postmenopausal is defined as:
- Amenorrheic for 1 year or more following cessation of exogenous hormonal
treatments.
- Luteinizing hormone (LH) and Follicle stimulating hormone (FSH) levels in the
post menopausal range for women under 50
- Radiation-induced oophorectomy with last menses >1 year ago
- Chemotherapy-induced menopause with >1 year interval since last menses
- Surgical sterilisation (bilateral oophorectomy or hysterectomy)
12. Patient is willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations.
13. Formalin fixed, paraffin embedded (FFPE) tumour sample from the primary cancer must be available for central testing if sBRCA analysis is not available at study site. If there is not written confirmation of the availability of an archived tumour sample or gBRCA test performed prior to enrolment the patient is not eligible for the study. For inclusion in i) the optional exploratory genetic research and ii) the optional biomarker research, patients must fulfil the following criteria:
- Provision of informed consent for genetic research.
- Provision of informed consent for biomarker research.
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 50
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 16

Exclusion Criteria

1. Involvement in the planning and/or conduct of the study (applies to both sponsor staff
and/or staff at the study site).
2. Any previous treatment with PARP inhibitor.
3. 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.
4. 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 1.
5. Resting ECG with QTc > 470 msec on 2 or more time points within a 24 hour period
or family history of long QT syndrome.
6. 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.
7. 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.
8. Persistent toxicities (> Common Terminology Criteria for Adverse Event (CTCAE) grade 2) caused by previous cancer therapy, excluding alopecia.
9. Patients with myelodysplastic syndrome/acute myeloid leukaemia or with features suggestive of these diseases.
10. 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.
11. Patients with spinal cord compression unless considered to have received definitive treatment for this and evidence of clinically stable disease for 28 days.
12. Major surgery within 2 weeks of starting study treatment and patients must have recovered from any effects of any major surgery.
13. Patients considered a poor medical condition due to a serious, uncontrolled medical disorder, non-malignant systemic disease or active, uncontrolled infection. Examples include, but are not limited to, uncontrolled ventricular arrhythmia, recent (within 3 months) myocardial infarction, uncontrolled major seizure disorder, unstable spinal cord compression, superior vena cava syndrome, extensive interstitial bilateral lung disease on High Resolution Computed Tomography (HRCT) scan or any psychiatric disorder that prohibits obtaining informed consent.
14. Patients unable to swallow orally administered medication and patients with
gastrointestinal disorders likely to interfere with absorption of the study medication.

Study & Design

Study Type: Interventional clinical trial of medicinal product

Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Main Objective: Effect of maintenance treatment with olaparib on progression free survival (PFS) in patients with recurrent ovarian carcinoma, treatment-free interval of platinum (TFIp) higher than 6 months, and BRCA1/2 germline or somatic deleterious mutation, who have received treatment with trabectedin + pegylated liposomal doxorubicin (PLD) and reached a partial or complete response, assessed by RECIST 1.1 criteria.;Secondary Objective: - Effect of maintenance treatment with olaparib on Time to First Subsequent Treatment (TFST).<br> - Effect of maintenance treatment with olaparib on Time to Second Subsequent Treatment (TSST).<br>- Effect of maintenance treatment with olaparib on PFS2.<br>- Safety and tolerability of maintenance treatment with olaparib.<br>- Evaluate predictive biomarkers of long PFS with olaparib and molecular response.;Primary end point(s): Progression free survival (PFS);Timepoint(s) of evaluation of this end point: Every 12 weeks

Secondary Outcome Measures

Name	Time	Method
Secondary end point(s): - Time to First Subsequent Treatment (TFST)<br>- Time to Second Subsequent Treatment (TSST)<br>- PFS2<br>- Number of Adverse Events<br>- Predictive biomarkers of long PFS with olaparib and molecular response.;Timepoint(s) of evaluation of this end point: - Time to First Subsequent Treatment (TFST): every 4 weeks<br>- Time to Second Subsequent Treatment (TSST): Every 4 weeks<br>- PFS2: Every 12 weeks<br>- Safety and tolerability will be evaluated in a onging basis during the treatment.<br>- At the end of the study