Clinical trial NCT02476968: To Assess the Efficacy and Safety of Olaparib Maintenance Monotherapy in the Treatment of Ovarian Cancer
Official title: 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).
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: BRCA or HRR+ Mutated Ovarian Cancer Patients
Lead sponsor: AstraZeneca
Sponsor class: INDUSTRY
First posted: 2015-06-22
Enrollment: 181
Sex: FEMALE
Minimum age (years): 18
Maximum age (years): 130
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: OTHER

Brief summary: 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: 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:

1. Optional tumour samples at baseline and at disease progression
2. An optional blood sample only for patients with a confirmed sBRCAm or HRRm disease

Eligibility criteria: Inclusion Criteria:

1. Provision of informed consent prior to any study specific procedures
2. Age 18 years or over
3. 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)
4. 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
5. 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.
6. 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
7. 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
8. Creatinine clearance \> 50 ml/min (calculated)
9. 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:

1. Patients previously diagnosed with gBRCAm disease
2. Participation in another clinical study with an investigational product during the most recent chemotherapy course
3. Patients with a known hypersensitivity to olaparib or any of the excipients of the product
4. 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
5. Persistent toxicities Common Terminology Criteria for Adverse Event (CTCAE) grade 2 caused by previous cancer therapy, excluding alopecia
6. Patients with myelodysplastic syndrome/acute myeloid leukaemia
7. Immuno-compromised patients e.g., Human Immunodeficiency Virus (HIV) requiring treatment or active Hepatitis B or C
8. 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
9. Patients considered to be at a high medical risk due to a serious, uncontrolled medical disorder, systemic disease or active, uncontrolled infection
10. Currently pregnant (confirmed with a positive pregnancy test) or breastfeeding.

Primary outcomes:
measure: Progression-Free Survival (PFS)
timeFrame: 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 outcomes:
measure: Overall Survival (OS); Assessed at Primary Analysis
timeFrame: From baseline until death due to any cause. Assessed until primary analysis DCO of 17 April 2020 (up to maximum of 55 months).
measure: Time to Second Progression (PFS2) or Death; Assessed at Primary Analysis
timeFrame: 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).
measure: Time to First Subsequent Therapy (Treatment) or Death (TFST); Assessed at Primary Analysis
timeFrame: 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).
measure: Time to Second Subsequent Therapy (Treatment) or Death (TSST); Assessed at Primary Analysis
timeFrame: 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).
measure: Time to Discontinuation of Treatment or Death (TDT)
timeFrame: From enrolment to study treatment discontinuation or death (up to maximum of 6 years).
measure: Change From Baseline in Functional Assessment of Cancer Therapy - Ovarian (FACT-O) Trial Outcome Index (TOI) Scores Over Time
timeFrame: 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.
measure: Change From Baseline in Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) Total Scores Over Time
timeFrame: 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.
measure: Change From Baseline in Functional Living Index-Emesis (FLIE) Questionnaire Total Scores Over Time
timeFrame: 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.
measure: OS; Assessed at Final Analysis
timeFrame: From baseline until death due to any cause (up to maximum of 6 years).
measure: PFS2 or Death; Assessed at Final Analysis
timeFrame: 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).
measure: TFST; Assessed at Final Analysis
timeFrame: From enrolment to first subsequent therapy or death. Assessed every 12 weeks following treatment discontinuation (up to maximum of 6 years).
measure: TSST; Assessed at Final Analysis
timeFrame: From enrolment to second subsequent therapy or death. Assessed every 12 weeks following treatment discontinuation (up to maximum of 6 years).
Other outcomes:
Locations:
city: Plovdiv
country: Bulgaria
facility: Research Site
city: Plovdiv
country: Bulgaria
facility: Research Site
city: Sofia
country: Bulgaria
facility: Research Site
city: Sofia
country: Bulgaria
facility: Research Site
city: Sofia
country: Bulgaria
facility: Research Site
city: Sofia
country: Bulgaria
facility: Research Site
city: Varna
country: Bulgaria
facility: Research Site
city: Calgary
country: Canada
facility: Research Site
state: Alberta
city: Halifax
country: Canada
facility: Research Site
state: Nova Scotia
city: London
country: Canada
facility: Research Site
state: Ontario
city: Toronto
country: Canada
facility: Research Site
state: Ontario
city: Montreal
country: Canada
facility: Research Site
state: Quebec
city: Montreal
country: Canada
facility: Research Site
state: Quebec
city: Brno
country: Czechia
facility: Research Site
city: Brno
country: Czechia
facility: Research Site
city: Novy Jicin
country: Czechia
facility: Research Site
city: Olomouc
country: Czechia
facility: Research Site
city: Ostrava
country: Czechia
facility: Research Site
city: Praha 2
country: Czechia
facility: Research Site
city: Praha 5
country: Czechia
facility: Research Site
city: Budapest
country: Hungary
facility: Research Site
city: Budapest
country: Hungary
facility: Research Site
city: Budapest
country: Hungary
facility: Research Site
city: Debrecen
country: Hungary
facility: Research Site
city: Kecskemét
country: Hungary
facility: Research Site
city: Nyíregyháza
country: Hungary
facility: Research Site
city: Bari
country: Italy
facility: Research Site
city: Milano
country: Italy
facility: Research Site
city: Napoli
country: Italy
facility: Research Site
city: Perugia
country: Italy
facility: Research Site
city: Bialystok
country: Poland
facility: Research Site
city: Gdansk
country: Poland
facility: Research Site
city: Kielce
country: Poland
facility: Research Site
city: Poznan
country: Poland
facility: Research Site
city: Poznań
country: Poland
facility: Research Site
city: Badalona
country: Spain
facility: Research Site
city: Barcelona
country: Spain
facility: Research Site
city: Burgos
country: Spain
facility: Research Site
city: L'Hospitalet de Llobregat
country: Spain
facility: Research Site
city: Madrid
country: Spain
facility: Research Site
city: Madrid
country: Spain
facility: Research Site
city: San Cristobal de La Laguna
country: Spain
facility: Research Site
city: Sevilla
country: Spain
facility: Research Site
city: Valencia
country: Spain
facility: Research Site
city: Valencia
country: Spain
facility: Research Site
city: Zaragoza
country: Spain
facility: Research Site
city: Belfast
country: United Kingdom
facility: Research Site
city: Birmingham
country: United Kingdom
facility: Research Site
city: Cardiff
country: United Kingdom
facility: Research Site
city: Glasgow
country: United Kingdom
facility: Research Site
city: Leeds
country: United Kingdom
facility: Research Site
city: London
country: United Kingdom
facility: Research Site
city: Manchester
country: United Kingdom
facility: Research Site
city: Newcastle upon Tyne
country: United Kingdom
facility: Research Site
city: Oxford
country: United Kingdom
facility: Research Site
city: Swansea
country: United Kingdom
facility: Research Site
city: Taunton
country: United Kingdom
facility: Research Site
city: Wirral
country: United Kingdom
facility: Research Site
Study officials:
affiliation: Istituto Nazionale Tumori Fondazione G. Pascale, 80131, Napoli, Italy
name: Sandro Pignata, Doctor of Medicine
role: PRINCIPAL_INVESTIGATOR
References: