Clinical trial NCT02392676: Olaparib Maintenance Treatment Versus Placebo in Patients With PSR Ovarian Cancer Who Are in CR or PR to Platinum-based Chemotherapy and Whose Tumours Carry sBRCAm or HRR-associated Genes Mutations
Official title: A Phase III, Randomised, Double Blind, Placebo Controlled, Multicentre Study of Olaparib Maintenance Monotherapy in Patients With Platinum Sensitive Relapsed Ovarian Cancer Who Are in Complete or Partial Response Following Platinum Based Chemotherapy and Whose Tumours Carry Loss of Function Somatic BRCA Mutation(s) or Loss of Function Mutation(s) in Tumour Homologous Recombination Repair -Associated Genes
Study type: INTERVENTIONAL
Overall status: WITHDRAWN
Phase: PHASE3
Conditions: Platinum Sensitive Relapsed Ovarian Cancer
Keywords: Ovarian cancer
Platinum
Somatic BRCA mutation
Homologous recombination repair
Lead sponsor: AstraZeneca
Sponsor class: INDUSTRY
Collaborators: name: Myriad Genetic Laboratories, Inc.
First posted: 2015-03-19
Enrollment: 0
Sex: FEMALE
Minimum age (years): 18
Maximum age (years): 96
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Olaparib administered as monotherapy in the maintenance setting improves progression free survival compared to placebo in patients whose tumours carry loss of function (deleterious or suspected deleterious) somatic BRCA mutations or loss of function (deleterious or suspected deleterious) mutation in non-BRCA Homologous Recombination Repair (HRR) -associated genes who have a complete or partial response to platinum-based chemotherapy.

Detailed description: This is a phase III, randomised, double-blind, placebo-controlled, multi-centre study to assess the efficacy of olaparib maintenance monotherapy in relapsed high grade epithelial ovarian cancer patients (including patients with primary peritoneal and / or fallopian tube cancer) who have responded following platinum based chemotherapy. The study population will be enrolled as two separate cohorts that will enrol simultaneously. The confirmatory cohort will consist of patients who carry a somatic BRCA mutation (documented mutation in BRCA1 or BRCA2 that is predicted to be deleterious or suspected deleterious) which are detected in tumour material but absent from germline blood testing ; the exploratory cohort will include patients with a mutation (documented mutation predicted to be deleterious or suspected deleterious) in non BRCA HRR-associated genes which are detected in tumour material regardless of their germline status.

Eligibility criteria: Inclusion Criteria:

* Patients must be ≥ 18 years of age
* Histologically diagnosed relapsed high grade epithelial ovarian cancer (including primary peritoneal and/ or fallopian tube cancer)
* Documented deleterious or suspected deleterious somatic BRCA 1 and/or BRCA 2 somatic mutation or evidence of non- BRCA HRR-associated gene mutation in the tumour.
* At least 2 previous lines of platinum containing therapy prior to randomisation.
* CA-125 measurements prior to randomised treatment
* Patients must have normal organ and bone marrow function measured within 28 days of randomisation
* Eastern Cooperative Oncology Group (ECOG) performance status 0-1
* Postmenopausal or evidence of non-childbearing status for women of childbearing potential
* Patient is willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations
* Provision of a blood sample for cfDNA biomarker analysis in Pre-Screening Part 1
* Formalin fixed, paraffin embedded (FFPE) tumour sample from the primary or recurrent cancer must be available for central testing. If archival tumour sample is not available tumour sample from fresh biopsy is acceptable, for all patients eligible to participate in Pre-Screening part 2.

Exclusion Criteria:

* Documented germline mutation in BRCA1 and/or BRCA2 that is predicted to be deleterious or suspected deleterious (known or predicted to be detrimental/lead to loss of function).
* Patients who have had drainage of their ascites from the final 2 cycles of their last chemotherapy regimen prior to randomisation on the study
* Participation in another clinical study with an investigational product during the chemotherapy course immediately prior to randomisation
* Any previous treatment with a PARP inhibitor, including olaparib
* Patients with a known hypersensitivity to olaparib or any of the excipients of the product
* Prior malignancy in the last 5 years, unless curatively treated and recurrence free (few exceptions apply)
* Patients receiving any systemic chemotherapy (including chemotherapy received as the most recent anticancer therapy) or radiotherapy (except for palliative reasons) within 3 weeks prior to study randomised treatment
* Persistent toxicities (\>Common Terminology Criteria for Adverse Event (CTCAE) CTCAE grade 2) caused by previous cancer therapy, excluding CTCAE grade 2 peripheral neuropathy
* Patients with myelodysplastic syndrome/acute myeloid leukaemia (t-AML) or with features suggestive of MDS/AML
* Patients with symptomatic uncontrolled brain metastases
* Major surgery within 2 weeks of starting study randomised treatment and patients must have recovered from any effects of any major surgery
* Patients considered a poor medical risk

Primary outcomes:
measure: Progression Free Survival (PFS) using modified RECIST 1.1 in the cohort of patients with sBRCA ovarian cancer
timeFrame: From date of randomization until the date of first documented progression or date of death (by any cause, in the absence of disease progression) whichever came first, assessed up to 40 months
Secondary outcomes:
measure: Progression Free Survival (PFS) using modified RECIST 1.1. in the Intent to Treat Population (ITT) consisting of all randomised patients with sBRCAm or HRR-associated gene mutations
timeFrame: From date of randomization until the date of first documented progression or date of death (by any cause, in the absence of disease progression), whichever came first, assessed up to 60 months
measure: Overall Survival (OS) in patients with sBRCAm ovarian cancer and in the ITT population consisting of all randomised patients
timeFrame: From the date of randomisation until death due to any cause, assessed up to 60 months
measure: Time from randomisation to first subsequent therapy or death (TFST) in patients with sBRCAm ovarian cancer and in the ITT population consisting of all randomised patients
timeFrame: From the date of randomisation to the earlier of first subsequent therapy start date, assessed up to 60 months
measure: Trial outcome index (TOI) of the Functional Assessment of Cancer Therapy - Ovarian (FACT-O) in sBRCA and HRR associated gene mutated relapsed ovarian cancer patients who are in complete or partial response following platinum based chemotherapy
timeFrame: Administered at baseline, at day 29 then every 8 weeks (+/- 1 week) regardless of treatment discontinuation or disease progression, assessed up to 24 months
measure: Plasma mutation status
timeFrame: cfDNA sample collected during pre-screening, assessed up to 40 months
measure: Time to earliest progression by RECIST 1.1 or CA-125 or Death in patients with sBRCAm ovarian cancer and in the ITT population consisting of all randomised patients
timeFrame: From randomisation to the earliest date of investigator assesed RECIST or CA-125 progression or death by any cause, assessed up to 60 months
measure: Time from randomisation to second progression (PFS2) in patients with sBRCAm ovarian cancer and in the ITT population consisting of all randomised patients
timeFrame: From the date of randomisation to the earliest of the progression event subsequent to that used for the primary variable PRS or death, assessed up to 60 months
measure: Time from randomisation to second subsequent therapy or death (TSST) in patients with sBRCAm ovarian cancer and in the ITT population consisting of all randomised patients
timeFrame: From the date of randomisation to the earlier of the date of second subsequent chemotherapy start date or death date, assessed up to 60 months
measure: Time from randomisation to study treatment discontinuation or death (TDT) in patients with sBRCAm ovarian cancer and in the ITT population consisting of all randomised patients
timeFrame: From the date of randomisation to the earlier of the date of study treatment discontinuation or death, assessed up to 60 months
Other outcomes:
measure: Number of AEs in all patients who received at least one dose of randomised investigational product, olaparib or placebo
timeFrame: assessed up to 60 months
measure: Changes in Vital signs in all patients who received at least one dose of randomised investigational product, olaparib or placebo
timeFrame: assessed up to 60 months
measure: Changes in Physical examination results in all patients who received at least one dose of randomised investigational product, olaparib or placebo
timeFrame: assessed up to 60 months
measure: Changes in safety laboratory parameters in all patients who received at least one dose of randomised investigational product, olaparib or placebo
timeFrame: assessed up to 60 months
Locations:
city: Mobile
country: United States
facility: Research Site
state: Alabama
city: Phoenix
country: United States
facility: Research Site
state: Arizona
city: Los Angeles
country: United States
facility: Research Site
state: California
city: Stanford
country: United States
facility: Research Site
state: California
city: Augusta
country: United States
facility: Research Site
state: Georgia
city: Park Ridge
country: United States
facility: Research Site
state: Illinois
city: Iowa City
country: United States
facility: Research Site
state: Iowa
city: Louisville
country: United States
facility: Research Site
state: Kentucky
city: Covington
country: United States
facility: Research Site
state: Louisiana
city: Scarborough
country: United States
facility: Research Site
state: Maine
city: Baltimore
country: United States
facility: Research Site
state: Maryland
city: Albany
country: United States
facility: Research Site
state: New York
city: Oklahoma City
country: United States
facility: Research Site
state: Oklahoma
city: Philadelphia
country: United States
facility: Research Site
state: Pennsylvania
city: Milwaukee
country: United States
facility: Research Site
state: Wisconsin
city: Goyang-si
country: Korea, Republic of
facility: Research Site
city: Seongnam-si
country: Korea, Republic of
facility: Research Site
city: Seoul
country: Korea, Republic of
facility: Research Site
city: Chiclayo
country: Peru
facility: Research Site
city: Lima
country: Peru
facility: Research Site
city: Quezon City
country: Philippines
facility: Research Site
city: Birmingham
country: United Kingdom
facility: Research Site
city: Cambridge
country: United Kingdom
facility: Research Site
city: Coventry
country: United Kingdom
facility: Research Site
city: Edinburgh
country: United Kingdom
facility: Research Site
city: London
country: United Kingdom
facility: Research Site
city: Manchester
country: United Kingdom
facility: Research Site
city: Oxford
country: United Kingdom
facility: Research Site
city: Sutton
country: United Kingdom
facility: Research Site
Study officials:
affiliation: University of Edinburgh
name: Charlie Gourley, Prof.
role: PRINCIPAL_INVESTIGATOR
affiliation: MSKCC
name: Carol Aghajanian, MD
role: PRINCIPAL_INVESTIGATOR
References: