Olaparib beyond progression compared to platinum chemotherapy after secondary cytoreductive surgery in recurrent ovarian cancer patients. The phase III randomized, open label MITO 35b study: a project of the MITO-MANGO groups.
- Conditions
- Recurrent ovarian cancer patientsMedDRA version: 21.1Level: PTClassification code 10066697Term: Ovarian cancer recurrentSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)Therapeutic area: Diseases [C] - Cancer [C04]
- Registration Number
- EUCTR2021-000245-41-IT
- Brief Summary
Not available
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- Authorised-recruitment may be ongoing or finished
- Sex
- Female
- Target Recruitment
- 200
•Signed informed consent prior to any study specific procedures;
•Female, age = 18 years at time of signing informed consent;
•Patients with high-grade serous or endometroid ovarian, fallopian tube, or primary peritoneal cancer recurrent or progressive after first line PARPi maintenance are allowed;
•Patients must have received only one previous line of a platinum containing regimen not containing bevacizumab;
•Patient must have received a first-line maintenance therapy with a PARPi for at least 6 months; if the prior PARPi used was olaparib then patients must have received treatment without significant toxicity or the need for a permanent dose reduction. Patients who experience disease relapse after the end of the 24 months maintenance therapy are eligible;
•Patients must have undergone secondary cytoreductive surgery. The cytoreduction must result in complete resection (absence of macroscopic residual tumor) or at least resection of the progressive lesion(s) occurring during maintenance;
•Documented BRCA1/2 status. Both mutated and wild type patients are eligible. Patient with unknown status of BRCA genes agrees to undergo analysis of their germline and somatic BRCA status (testing must be completed prior to enrolment in the study);
•Patients must have a life expectancy = 16 weeks;
•Patients must start the experimental treatments in the current study within 3 to 8 weeks from second surgery;
•ECOG performance status of 0 to 1;
•Patient must provide archival tumor samples formalin fixed, paraffin embedded (FFPE) from both the primary and secondary surgeries for paired analysis. A quality control analysis of samples will be performed before patient’s randomization;
•Patient must be able to take oral medications;
•Patients must have normal organ and bone marrow function measured within 28 days prior to administration of study treatment as defined below:
oHaemoglobin = 10.0 g/dL with no blood transfusion in the past 28 days
oAbsolute neutrophil count (ANC) = 1.5 x 109/L
oPlatelet count = 100 x 109/L
oTotal bilirubin = 1.5 x institutional upper limit of normal (ULN)
oAspartate aminotransferase (AST) (Serum Glutamic Oxaloacetic Transaminase (SGOT)) and Alanine aminotransferase (ALT) (Serum Glutamic Pyruvate Transaminase (SGPT)) = 2.5 x ULN for institution (or = 5x ULN if liver metastases are present.
oPatients must have creatinine clearance estimated of =51 mL/min using the Cockcroft-Gault equation or based on a 24 hour urine test: 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 and F=1 for males.)
•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:
-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).
•Women of childbearing potential and their partners, who are sexually active, must agree to the use of one highly effective forms of contraception and their partners must use a male condom, during the treatment (for both treatment arms) and for at least 1 months after last dose of
•Patients considered a poor medical risk due to a serious, uncontrolled medical disorder, non-malignant systemic disease and /or active, uncontrolled infection that may interfere with planned treatment, affect patient compliance or place the patient at high risk from treatment related complications [Examples include, but are not limited to, uncontrolled ventricular arrhythmia, recent (within 3 months) myocardial infarction, New York Heart Association (NYHA) grade II or greater congestive heart failure, uncontrolled hypertension, severe peripheral vascular disease, 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 illness ]
•Patients unable to swallow orally administered medication and patients with gastrointestinal disorders likely to interfere with absorption of the study medication;
•Patients eligible for a platinum based chemotherapy doublet and bevacizumab
•Patients receiving any systemic chemotherapy or radiotherapy (except for palliative reasons) within 3 weeks prior to study treatment;prior palliative radiation must have been completed at least 7 days prior to the start of study drugs, and patients must have recovered from any acute adverse effects prior to the start of study treatment
•Major surgery within 2 weeks of starting study treatment and patients must have recovered from any effects of major surgery;
•Previous allogenic bone marrow transplant or double umbilical cord blood transplantation (dUCBT);
•Breast feeding women;
•Patients with symptomatic uncontrolled brain metastases. A TC/ RMN scan of brain is required at baseline. 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.
•Other malignancy unless curatively treated with no evidence of disease for =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;
•Whole blood transfusions in the last 120 days prior to entry to the study (packed red blood cells and platelet transfusions are acceptable) except for transfusion done during surgery
•Persistent toxicities (>CTCAE grade 2) caused by previous cancer therapy, excluding alopecia.
•Resting ECG indicating uncontrolled, potentially reversible cardiac conditions, as judged by the investigator (eg., unstable ischemia, uncontrolled symptomatic arrhythmia, congestive heart failure, QTcF prolongation >500 ms, electrolyte disturbances, etc.), or patients with congenital long QT syndrome
•Concomitant use of known strong CYP3A inhibitors (e.g. itraconazole, telithromycin, clarithromycin, protease inhibitors boosted with ritonavir or cobicistat, indinavir, saquinavir, nelfinavir, boceprevir, telaprevir) or moderate CYP3A inhibitors (e.g. ciprofloxacin, erythromycin, diltiazem, fluconazole, verapamil). The required washout period prior to starting olaparib is 2 weeks.
•Concomitant use of known strong (e.g. phenobarbital, enzalutamide, phenytoin, rifampicin, rifabutin, rifapentine, carbamazepine, nevirapine and St John’s Wort) or moderate CYP3A inducers (eg. bosentan,
Study & Design
- Study Type
- Interventional clinical trial of medicinal product
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method Main Objective: •To determine the efficacy (in terms of progression-free survival) of olaparib maintenance beyond progression when compared to standard chemotherapy in patients with recurrent ovarian cancer undergone secondary cytoreductive surgery for recurrent or progressive disease.<br>•To determine the efficacy of the experimental therapies on subsequent treatment (in terms of progression-free survival 2) after progression.;Secondary Objective: To compare the two arms in terms of: <br><br>•Overall Survival<br>•Safety and tolerability (CTCAE 5.0 version and PRO-CTCAE questionnaire)<br>•Quality of Life (EORTC QLQ-C30 questionnaire)<br>•Financial toxicity (PROFFIT questionnaire);Primary end point(s): 1) progression-free survival<br>2) progression-free survival 2;Timepoint(s) of evaluation of this end point: Every 12 weeks from C1D1± 7 days
- Secondary Outcome Measures
Name Time Method Secondary end point(s): 1) Overall Survival<br>2) Safety and tolerability (CTCAE 5.0 version and PRO-CTCAE questionnaire)<br>3) Quality of Life (EORTC QLQ-C30 questionnaire)<br>4) Financial toxicity (PROFFIT questionnaire;Timepoint(s) of evaluation of this end point: 1)time from enrollement to death for any cause<br>2) At screening (within 7 days prior to randomization), on Day 1 of each Cycle (during treatment) until 6 months, then at 9 and 12 months, from randomization for both arms or until progression<br>2)At screening (within 7 days prior to randomization), on Day 1 of each Cycle (during treatment) until 6 months, then at 9 and 12 months, from randomization for both arms or until progression<br>3) At screening (within 7 days prior to randomization), on Day 1 of each Cycle (during treatment) until 6 months, then at 9 and 12 months, from randomization for both arms or until progression