Phase III Randomized Study of Olaparib Versus Platinum-Based Chemotherapy Post-Secondary Cytoreductive Surgery in Recurrent Ovarian Cancer
- Trial ID
- 2024-516842-21-00
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate the **efficacy** of olaparib maintenance therapy beyond progression in terms of progression-free survival compared to standard chemotherapy in patients with recurrent ovarian cancer who have undergone secondary cytoreductive surgery. This is clinically relevant as it may offer an alternative therapeutic strategy that could potentially extend the time patients remain free from disease progression, thereby improving clinical outcomes in this patient population.
Secondary objectives include comparing the two treatment arms in terms of overall survival, safety and tolerability using the CTCAE 5.0 version and PRO-CTCAE questionnaire, quality of life assessed by the EORTC QLQ-C30 questionnaire, and financial toxicity evaluated through the PROFFIT questionnaire. These secondary objectives aim to provide a comprehensive assessment of the treatment's impact on patients' overall health and well-being, as well as the economic burden associated with the treatment.
Participants
The clinical trial focuses on evaluating the efficacy of olaparib maintenance therapy in patients with **recurrent ovarian cancer**. The study population consists exclusively of female participants aged 18 years and older. Participants are required to have undergone secondary cytoreductive surgery for recurrent or progressive disease. The trial does not include male subjects or vulnerable populations. Participants must have a documented BRCA1/2 status, with both mutated and wild-type patients eligible. The trial population was selected based on specific inclusion criteria, including a history of high-grade serous or endometrioid ovarian, fallopian tube, or primary peritoneal cancer, and prior treatment with a platinum-containing regimen. Participants must have received first-line maintenance therapy with a PARP inhibitor for at least six months. The sponsor has not provided information regarding the total number of participants. Lifestyle considerations such as diet and physical activity are not specified. Key inclusion criteria include a life expectancy of at least 16 weeks and an ECOG performance status of 0 to 1. Participants must have normal organ and bone marrow function and be able to take oral medications. The trial excludes individuals with significant toxicity from prior olaparib treatment or those requiring permanent dose reduction. The sponsor has not provided additional data regarding the trial population.
Plans and Procedures
The clinical trial is a **randomized**, open-label, phase III study designed to evaluate the efficacy of **olaparib** maintenance therapy beyond progression compared to standard platinum-based chemotherapy in patients with **recurrent ovarian cancer** who have undergone secondary cytoreductive surgery. The trial aims to assess progression-free survival as the primary endpoint, with secondary endpoints including overall survival, safety, tolerability, quality of life, and financial toxicity. The study is expected to conclude by December 31, 2026, with recruitment having commenced on March 22, 2023.
Participants will be randomly assigned to receive either olaparib or a comparator chemotherapy regimen, which may include agents such as **carboplatin**, **cisplatin**, **doxorubicin hydrochloride**, **paclitaxel**, **gemcitabine hydrochloride**, or **bevacizumab**. The trial involves multiple study visits, beginning with a screening visit to confirm eligibility based on criteria such as age, previous treatment history, and **BRCA1/2** status. Participants must have completed secondary cytoreductive surgery with complete resection or resection of progressive lesions and must start the experimental treatments within 3 to 8 weeks post-surgery.
Follow-up visits will be scheduled to monitor the participants' health status, treatment efficacy, and any adverse effects. These visits will include assessments of organ and bone marrow function, as well as quality of life evaluations using standardized questionnaires. The end-of-study visit will occur upon completion of the treatment regimen or if the participant experiences disease progression or unacceptable toxicity. The expected length of participant involvement varies depending on the treatment arm, with olaparib administered for a maximum of 1 month and chemotherapy regimens potentially extending up to 24 months.
Participants may be withdrawn from the study early if they experience significant adverse effects, fail to comply with study procedures, or if the investigator deems it in the participant's best interest. The trial is conducted in accordance with ethical guidelines, and informed consent is obtained from all participants prior to any study-specific procedures. The study's design and methodology ensure rigorous evaluation of the investigational treatment's efficacy and safety in the target population.
Treatment
The clinical trial involves the administration of several **experimental medications** and comparator treatments. **Carboplatin** is administered in a pharmaceutical form identified as PHF00230MIG. It is given intravenously with a maximum daily dose of 450 mg and a total dose limit of 3600 mg over a treatment period of up to 8 weeks. **Cisplatin** is also administered intravenously, with a pharmaceutical form of PHF00015MIG. The dosing is calculated based on body surface area, with a maximum daily dose of 75 mg/m² and a total dose limit of 600 mg/m² over a 24-week period.
**Doxorubicin Hydrochloride** is administered intravenously in the form PHF00231MIG. The dosing is 30 mg/m² per day, with a total dose limit of 240 mg/m² over 8 weeks. **Olaparib** is provided as Lynparza film-coated tablets, available in 150 mg and 100 mg strengths. The maximum daily dose for the 150 mg tablets is 600 mg, while for the 100 mg tablets, it is 500 mg. Both forms are administered orally, with a treatment period of 1 week.
**Paclitaxel** is administered intravenously in the form PHF00230MIG, with a dosing of 175 mg/m² per day and a total dose limit of 1400 mg/m² over 24 weeks. **Gemcitabine Hydrochloride** is also administered intravenously in the same form, with a maximum daily and total dose of 1000 mg/m² over a 1-week period. **Bevacizumab** is administered intravenously in the form PHF00230MIG, with a dosing of 15 mg/kg per day and a total dose limit of 315 mg/kg over 21 weeks.
Participant compliance with the dosing schedule is monitored throughout the trial. The trial includes both experimental and comparator treatments, with the primary objective being to evaluate the efficacy of **olaparib** maintenance therapy beyond progression in patients with recurrent ovarian cancer. The trial is designed to compare the efficacy of olaparib with standard chemotherapy regimens, including the aforementioned medications.
Efficacy
The efficacy of the clinical trial will be assessed primarily through the measurement of **progression-free survival** (PFS) and **progression-free survival 2** (PFS2). These endpoints are designed to evaluate the effectiveness of **olaparib** maintenance therapy beyond progression in comparison to standard platinum-based chemotherapy in patients with recurrent ovarian cancer who have undergone secondary cytoreductive surgery. The primary endpoint, progression-free survival, will be measured from the time of randomization until the first documented disease progression or death from any cause, whichever occurs first. Progression-free survival 2 will be assessed from the time of randomization until the second documented disease progression or death.
Secondary endpoints include overall survival, safety and tolerability, quality of life, and financial toxicity. Overall survival will be determined from the time of randomization to death from any cause. Safety and tolerability will be evaluated using the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 and the Patient-Reported Outcomes version of the CTCAE (PRO-CTCAE) questionnaire. Quality of life will be assessed using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30). Financial toxicity will be measured using the PROFFIT questionnaire.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Inclusion criteria: • 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. Regimens containing bevacizumab are allowed; • 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 0 to 1; • Patient must provide archival tumor samples formalin fixed, paraffin embedded (FFPE) from both the primary (before any treatment, chemotherapy naive)) 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: o Haemoglobin = 10.0 g/dL with no blood transfusion in the past 28 days o Absolute neutrophil count (ANC) = 1.5 x 109/L o Platelet count = 100 x 109/L o Total bilirubin = 1.5 x institutional upper limit of normal (ULN) o Aspartate 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). o Patients 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.) o For patients not receiving therapeutic anticoagulation international normalized ratio (INR) or activated partial thromboplastin time (aPTT)= 1.5xULN. Patients receiving heparin treatment should have an aPTT between 1.5 to 2.5 X ULN (or patient value before starting heparin treatment) Patients receiving coumarin derivatives should have an INR have an INR between 2.0 and 3.0 assessed in two consecutive measurements 1 to 4 days apart XML File Identifier: q1p939o9kVegPlsaSqFuuHC+alQ= Page 40/68 • 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). For the remaining inclusion criteria refer to the protocol
Exclusion Criteria
- 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 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 >grade 2 according Common Terminology Criteria for Adverse (CTCAE) version 5.0 caused by previous cancer therapy, excluding alopecia • Resting ECG indicating uncontrolled, potentially irreversible cardiac conditions, as judged by the investigator (eg., unstable ischemia, uncontrolled symptomatic arrhythmia, congestive heart failure, QTcF prolongation >470 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, efavirenz, modafinil). The required washout period prior to starting olaparib is 5 weeks for enzalutamide or phenobarbital and 3 weeks for other agents. Patients with myelodysplastic syndrome (MSD)/acute myeloid leukaemia (AML) or with features suggestive of MDS/AML. • Immunocompromised patients, e.g., patients who are known to be serologically positive for human immunodeficiency virus (HIV). FOR THE REMAINING EXCLUSION CRITERIA REFER TO THE PROTOCOL
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Italy | Recruiting | 22 Mar 2023 | 200 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
DOXORUBICIN | Comparator | PHF00231MIG | INTRAVENOUS USE | 30 | 8 | SCP119562649 |
CISPLATIN | Comparator | PHF00015MIG | INTRAVENOUS USE | 75 | 24 | SCP134220 |
PACLITAXEL | Comparator | PHF00230MIG | INTRAVENOUS USE | 175 | 24 | SCP129816 |
CARBOPLATIN | Comparator | PHF00230MIG | INTRAVENOUS USE | 450 | 8 | SCP10337134 |
Lynparza 150 mg film-coated tablets | Test | FILM-COATED TABLETS | ORAL USE | 600 | 1 | PRD6152224 |
Lynparza 100 mg film-coated tablets | Test | FILM-COATED TABLETS | ORAL USE | 500 | 1 | PRD6163465 |
GEMCITABINE | Comparator | PHF00230MIG | INTRAVENOUS USE | 1000 | 1 | SCP1128788 |
BEVACIZUMAB | Comparator | PHF00230MIG | INTRAVENOUS USE | 15 | 21 | SCP29096188 |