To Assess the Efficacy and Safety of Olaparib Maintenance Monotherapy in the Treatment of Ovarian Cancer

Study Overview
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Brief Summary
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This is a prospective, open-label, single arm, multi-center study to assess the real world clinical effectiveness and safety of olaparib maintenance monotherapy as the capsule formulation (in line with the EU approved prescribing information) and will be conducted in platinum-sensitive relapsed high grade epithelial ovarian cancer patients (including patients with primary peritoneal and / or fallopian tube cancer) who carry germline or somatic BRCA mutations (documented mutation in BRCA1 or BRCA2 that is predicted to be deleterious or suspected deleterious [known or predicted to be detrimental/lead to loss of function]).

Detailed Description
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The study will recruit approximately 250 patients with sBRCAm disease or gBRCAm disease, with the aim to accrue a minimum of 50 patients with sBRCAm disease. Patients with an unknown germline BRCA mutated status or gBRCAwt disease or previously identified as having a BRCAm disease by a tumour test will be considered for screening and will undergo, upon informed consent signature, central tumor and blood testing to determine their BRCA mutation status. In addition to central BRCA testing, patients screened for the study with unknown BRCA status or with known gBRCAwt status, for whom an adequate archival tumour tissue sample is available, will be tested for qualifying HRR gene alterations. Patients confirmed to carry a deleterious or suspected deleterious BRCA-independent genetic alteration in any of 13 genes involved in the Homologous Recombination Repair (HRR) pathway (HRRm cohort) will be allowed into an additional exploratory cohort (HRRm cohort). It is expected that approximately 25 patients will be included in the HRRm cohort before the target number of 250 patients with BRCAm disease is reached. Patients will be assigned olaparib capsules orally 400 mg twice daily. They should initiate olaparib treatment within 8 weeks after their last dose of platinum-containing chemotherapy (last dose is the day of the last infusion) and will be assessed every 4 weeks whilst on treatment. All patients will have clinical and objective radiological tumour assessments according to modified Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 guidelines at baseline and every 12 weeks relative to date of enrolment, until objective radiological disease progression as determined by the investigator. Patients could continue to receive olaparib for as long as determined by the investigator, until objective radiological disease progression or as long as in the investigator's opinion they are benefiting from treatment in relation to other clinical assessments and they do not meet any other discontinuation criteria. Once a patient has discontinued olaparib she will be managed as per local clinical practice but will remain in the study and data will be collected on subsequent treatments, progression, overall survival and safety. For exploratory analysis purposes, patients will be asked to provide consent to: Optional tumour samples at baseline and at disease progression An optional blood sample only for patients with a confirmed sBRCAm or HRRm disease

Official Title
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An Open Label, Single Arm, Multicentre Study to Assess the Clinical Effectiveness and Safety of Lynparza (Olaparib) Capsules Maintenance Monotherapy in Platinum Sensitive Relapsed Somatic or Germline BRCA Mutated Ovarian Cancer Patients Who Are in Complete or Partial Response Following Platinum Based Chemotherapy (ORZORA).

Conditions
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BRCA or HRR+ Mutated Ovarian Cancer Patients

Intervention / Treatment
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* Drug: Olaparib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Provision of informed consent prior to any study specific procedures Age 18 years or over Documented germline or somatic mutation in BRCA1 or BRCA2 genes that is predicted to be deleterious or suspected deleterious (known or predicted to be detrimental/lead to loss of function) [Genetic counselling for patients with germline BRCA mutations should be performed according to local regulations] Or Tumour BRCAwt status and documented qualifying mutation in any of 13 genes involved in the HRR pathway, excluding BRCA1 and BRCA2 (ATM, BARD1, BRIP1,CDK12, CHEK1, CHEK2, FANCL, PALB2, PPP2R2A, RAD51B, RAD51C, RAD51D,and RAD54L), identified by the Lynparza HRR Assay in archival tumour tissue (i.e.,BRCA-independent HRRm) Patients with platinum sensitive relapsed high grade epithelial ovarian cancers (including primary peritoneal and/or fallopian tube cancer): - Platinum sensitive disease is defined as disease progression ≥6 months after completion of their last dose of platinum based chemotherapy Patients should have received at least 2 previous lines of platinum containing therapy prior to enrolment: - For the last chemotherapy course immediately prior to enrolment on the study, patients must be, in the opinion of the investigator, in response (partial or complete radiological response) and no evidence of a rising CA-125, following completion of this chemotherapy course. Patients must have normal organ and bone marrow function measured within 28 days of enrolment, as defined below: Haemoglobin ≥ 10.0 g/dL with no blood transfusions 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 ULN unless liver metastases are present in which case they must be ≤ 5x ULN Creatinine clearance > 50 ml/min (calculated) Patients must be postmenopausal or have evidence of non-childbearing status for women of childbearing potential. Postmenopausal is defined as any of the following: Amenorrhoea for 1 year or more following cessation of exogenous hormonal treatments For women under 50 years old, luteinizing hormone (LH) and follicle stimulating hormone (FSH) levels in the post-menopausal range Radiation-induced oophorectomy, with interval of 1 year or more since last menses Chemotherapy-induced menopause, with interval of 1 year or more since last menses Surgical sterilisation (bilateral oophorectomy or hysterectomy). Exclusion Criteria: Patients previously diagnosed with gBRCAm disease Participation in another clinical study with an investigational product during the most recent chemotherapy course Patients with a known hypersensitivity to olaparib or any of the excipients of the product Patients receiving any systemic chemotherapy or radiotherapy (except for palliative reasons) or major surgery within 3 weeks prior to olaparib treatment. Major surgery within 3 weeks of starting study treatment and patients must have recovered from any effects of any major surgery Persistent toxicities Common Terminology Criteria for Adverse Event (CTCAE) grade 2 caused by previous cancer therapy, excluding alopecia Patients with myelodysplastic syndrome/acute myeloid leukaemia Immuno-compromised patients e.g., Human Immunodeficiency Virus (HIV) requiring treatment or active Hepatitis B or C Patients with symptomatic uncontrolled brain metastases. 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 (SD) for 28 days Patients considered to be at a high medical risk due to a serious, uncontrolled medical disorder, systemic disease or active, uncontrolled infection Currently pregnant (confirmed with a positive pregnancy test) or breastfeeding.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 130 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Olaparib<br>Open Label Drug | Drug: Olaparib<br>* Olaparib Capsule - 50 mg. Olaparib capsules will be packed in high-density polyethylene (HDPE) bottles with child-resistant closures. Each bottle will contain 120 capsules and 4 bottles will be dispensed for a 4 weekly visit, with a 2 day overage. Patients will be administered olaparib capsules orally at a dose of 400 mg twice daily. Eight 50 mg olaparib capsules should be taken at the same time each day approximately 12 hours apart with approximately 240 mL of water.<br>* Other names: Lynparza;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-Free Survival (PFS) | To assess the real-world clinical effectiveness of olaparib maintenance monotherapy in patients with BRCAm and sBRCAm ovarian cancer by assessment of PFS. The PFS was defined as the time from the date of enrolment until date of objective radiological disease progression (assessed by the Investigator via Response Evaluation Criteria in Solid Tumors, version 1.1 [RECIST 1.1]), or death (by any cause in absence of disease progression) regardless of whether the patient withdrew from therapy or received another anti-cancer therapy prior to disease progression. Objective progression was defined as at least a 20% increase in the sum of the diameters of the target lesions (compared to previous minimum sum) and an absolute increase of > 5 millimeters, or an overall non-target lesion assessment of progression or a new lesion. The data cut-off (DCO) for the primary analysis of the study occurred after approximately 60% maturity of PFS in the sBRCAm and all BRCAm patient populations. | Tumour assessments at baseline then every 12 weeks relative to date of enrolment until RECIST 1.1-defined progression. Assessed until primary analysis DCO of 17 April 2020 (up to maximum of 55 months). | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS); Assessed at Primary Analysis | To assess the real-world clinical effectiveness of olaparib maintenance monotherapy in patients with BRCAm and sBRCAm ovarian cancer by assessment of OS. The OS was defined as the time from the date of enrolment until death due to any cause regardless of whether the patient withdrew from therapy or received another anti-cancer therapy. Any patient not known to have died at the time of analysis was censored based on the last recorded date on which the patient was known to be alive. Pre-specified analysis of OS was performed at the time of primary analysis of PFS; a further analysis of OS was performed after approximately 60% maturity of OS in the sBRCAm and all BRCAm patient populations (and reported as a separate outcome measure). | From baseline until death due to any cause. Assessed until primary analysis DCO of 17 April 2020 (up to maximum of 55 months). | 
| Time to Second Progression (PFS2) or Death; Assessed at Primary Analysis | To assess the real-world clinical effectiveness of olaparib maintenance monotherapy in patients with BRCAm and sBRCAm ovarian cancer by assessment of PFS2. The PFS2 was defined as the time from the date of enrolment to the earliest progression event subsequent to that used for the primary variable PFS or death (by any cause) in the absence of progression. Patients whose progression event for PFS was death had this counted as a progression event for PFS2 also. The date of second progression was recorded by the Investigator and defined according to local standard clinical practice and could involve any of the following: objective radiological, symptomatic, cancer antigen-125 (CA-125) progression or death. Pre-specified analysis of PFS2 was performed at the time of the primary analysis; a further analysis of PFS2 was performed at the final analysis (and reported as a separate outcome measure). | Tumour assessments (and blood samples for CA-125, if applicable) at baseline then every 12 weeks relative to date of enrolment until second progression. Assessed until primary analysis DCO of 17 April 2020 (up to maximum of 55 months). | 
| Time to First Subsequent Therapy (Treatment) or Death (TFST); Assessed at Primary Analysis | To assess the real-world clinical effectiveness of olaparib maintenance monotherapy in patients with BRCAm and sBRCAm ovarian cancer by assessment of TFST. The TFST was defined as the time from the date of enrolment to the earlier of first subsequent anti-cancer therapy start date (excluding radiotherapy), or death date. Pre-specified analysis of TFST was performed at the time of the primary analysis; a further analysis of TFST was performed at the final analysis (and reported as a separate outcome measure). | From enrolment to first subsequent therapy or death. Assessed every 12 weeks following treatment discontinuation. Assessed until primary analysis DCO of 17 April 2020 (up to maximum of 55 months). | 
| Time to Second Subsequent Therapy (Treatment) or Death (TSST); Assessed at Primary Analysis | To assess the real-world clinical effectiveness of olaparib maintenance monotherapy in patients with BRCAm and sBRCAm ovarian cancer by assessment of TSST. The TSST was defined as the time from the date of enrolment to the earlier of the date of second subsequent anti-cancer therapy start date, or death date. Pre-specified analysis of TSST was performed at the time of the primary analysis; a further analysis of TSST was performed at the final analysis (and reported as a separate outcome measure). | From enrolment to second subsequent therapy or death. Assessed every 12 weeks following treatment discontinuation. Assessed until primary analysis DCO of 17 April 2020 (up to maximum of 55 months). | 
| Time to Discontinuation of Treatment or Death (TDT) | To assess the real-world clinical effectiveness of olaparib maintenance monotherapy in patients with BRCAm and sBRCAm ovarian cancer by assessment of TDT. The TDT was defined as the time from the date of enrolment to the earlier of the date of study treatment discontinuation or death. | From enrolment to study treatment discontinuation or death (up to maximum of 6 years). | 
| Change From Baseline in Functional Assessment of Cancer Therapy - Ovarian (FACT-O) Trial Outcome Index (TOI) Scores Over Time | To assess the Quality of Life (QoL) of patients with BRCAm and sBRCAm ovarian cancer by evaluation of FACT-O TOI. The TOI score was derived from the sum of the scores of the 25 items included in the physical well-being (7 items), functional well-being (7 items), and additional concerns ovarian cancer subscale (11 items) of the FACT-O questionnaire version 4. The FACT-O TOI score ranges from 0-100, with a higher score indicating better QoL. A change (increase or decrease) in score of at least 10 points from baseline was defined as clinically meaningful. A positive change in score from baseline indicates an improvement. | QoL questionnaires at baseline, Day 29 (Week 4), then every 12 weeks for 24 months or DCO for primary analysis, whichever came first. QoL questionnaires also collected at discontinuation of study treatment visit and 30 days post last dose. | 
| Change From Baseline in Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) Total Scores Over Time | To assess the QoL of patients with BRCAm and sBRCAm ovarian cancer by evaluation of FACIT-F. The FACIT-F is a 13-item questionnaire to assess patients' fatigue experience and its impact on their daily lives over the past 7 days. The FACIT-F total score ranges from 0-52, with a higher score indicating a lower level of fatigue (and better QoL). Changes in scores of ≥3 points were defined to be clinically meaningful. A positive change in score from baseline indicates an improvement. | QoL questionnaires at baseline, Day 29 (Week 4), then every 12 weeks for 24 months or DCO for primary analysis, whichever came first. QoL questionnaires also collected at discontinuation of study treatment visit and 30 days post last dose. | 
| Change From Baseline in Functional Living Index-Emesis (FLIE) Questionnaire Total Scores Over Time | The FLIE captures the impact of nausea and vomiting on patient's QoL. The FLIE consists of 18 items (9 nausea-specific and 9 vomiting-specific items), rated from 1 to 7. Two domain scores and a total score are derived; the total score ranges 18-126 and a higher score indicates a lower impact (and better QoL). A positive change in score from baseline indicates an improvement. | FLIE questionnaires at baseline, weekly until Day 29 (Week 4), then every 12 weeks for 24 months or DCO for primary analysis, whichever came first. FLIE questionnaires also collected at discontinuation of study treatment visit and 30 days post last dose. | 
| OS; Assessed at Final Analysis | To assess the real-world clinical effectiveness of olaparib maintenance monotherapy in patients with BRCAm and sBRCAm ovarian cancer by assessment of OS. The OS was defined as the time from the date of enrolment until death due to any cause regardless of whether the patient withdrew from therapy or received another anti-cancer therapy. Any patient not known to have died at the time of analysis was censored based on the last recorded date on which the patient was known to be alive. | From baseline until death due to any cause (up to maximum of 6 years). | 
| PFS2 or Death; Assessed at Final Analysis | To assess the real-world clinical effectiveness of olaparib maintenance monotherapy in patients with BRCAm and sBRCAm ovarian cancer by assessment of PFS2. The PFS2 was defined as the time from the date of enrolment to the earliest progression event subsequent to that used for the primary variable PFS or death (by any cause) in the absence of progression. Patients whose progression event for PFS was death had this counted as a progression event for PFS2 also. The date of second progression was recorded by the Investigator and defined according to local standard clinical practice and could involve any of the following: objective radiological, symptomatic, CA-125 progression or death. | Tumour assessments (and blood samples for CA-125, if applicable) at baseline then every 12 weeks relative to date of enrolment until second progression (up to maximum of 6 years). | 
| TFST; Assessed at Final Analysis | To assess the real-world clinical effectiveness of olaparib maintenance monotherapy in patients with BRCAm and sBRCAm ovarian cancer by assessment of TFST. The TFST was defined as the time from the date of enrolment to the earlier of first subsequent anti-cancer therapy start date (excluding radiotherapy), or death date. | From enrolment to first subsequent therapy or death. Assessed every 12 weeks following treatment discontinuation (up to maximum of 6 years). | 
| TSST; Assessed at Final Analysis | To assess the real-world clinical effectiveness of olaparib maintenance monotherapy in patients with BRCAm and sBRCAm ovarian cancer by assessment of TSST. The TSST was defined as the time from the date of enrolment to the earlier of the date of second subsequent anti-cancer therapy start date, or death date. | From enrolment to second subsequent therapy or death. Assessed every 12 weeks following treatment discontinuation (up to maximum of 6 years). |