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

Platinum Sensitive Relapsed Ovarian Cancer Clinical Trial

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

Clinical Trial Details — Status: Withdrawn

Administrative data

• NCT number: NCT02392676
• Other study ID #: D0816C00009
• Status: Withdrawn
• Phase: Phase 3
• First received: February 23, 2015
• Last updated: April 29, 2016
• Start date: July 2016
• Est. completion date: June 2019

Study information

• Verified date: April 2016
• Source: AstraZeneca
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Withdrawn
• Enrollment: 0
• Est. completion date: June 2019
• Est. primary completion date: June 2019
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 18 Years to 96 Years

Eligibility

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

Study Design

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Investigator, Outcomes Assessor), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Ovarian Neoplasms
• Platinum Sensitive Relapsed Ovarian Cancer

Intervention

Drug:
• OLAPARIB
Patients should continue with therapy until objective radiological disease progression as per RECIST 1.1 despite rises in CA-125. All patients should continue to receive study treatment until objective radiological disease progression as per RECIST 1.1 as assessed by the investigator or the patient experiences unacceptable toxicity or they meet any other discontinuation criteria
• PLACEBO
Patients should continue with therapy until objective radiological disease progression as per RECIST 1.1 despite rises in CA-125. All patients should continue to receive study treatment until objective radiological disease progression as per RECIST 1.1 as assessed by the investigator or the patient experiences unacceptable toxicity or they meet any other discontinuation criteria

Locations

Country	Name	City	State
Korea, Republic of	Research Site	Goyang-si
Korea, Republic of	Research Site	Seongnam-si
Korea, Republic of	Research Site	Seoul
Peru	Research Site	Chiclayo
Peru	Research Site	Lima
Philippines	Research Site	Quezon City
United Kingdom	Research Site	Birmingham
United Kingdom	Research Site	Cambridge
United Kingdom	Research Site	Coventry
United Kingdom	Research Site	Edinburgh
United Kingdom	Research Site	London
United Kingdom	Research Site	Manchester
United Kingdom	Research Site	Oxford
United Kingdom	Research Site	Sutton
United States	Research Site	Albany	New York
United States	Research Site	Augusta	Georgia
United States	Research Site	Baltimore	Maryland
United States	Research Site	Covington	Louisiana
United States	Research Site	Iowa City	Iowa
United States	Research Site	Los Angeles	California
United States	Research Site	Louisville	Kentucky
United States	Research Site	Milwaukee	Wisconsin
United States	Research Site	Mobile	Alabama
United States	Research Site	Oklahoma City	Oklahoma
United States	Research Site	Park Ridge	Illinois
United States	Research Site	Philadelphia	Pennsylvania
United States	Research Site	Phoenix	Arizona
United States	Research Site	Scarborough	Maine
United States	Research Site	Stanford	California

Sponsors (2)

Lead Sponsor	Collaborator
AstraZeneca	Myriad Genetic Laboratories, Inc.

Countries where clinical trial is conducted

United States,  Korea, Republic of,  Peru,  Philippines,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Number of AEs in all patients who received at least one dose of randomised investigational product, olaparib or placebo	To assess the safety and tolerability of olaparib maintenance monotherapy by assessment of AEs	assessed up to 60 months	Yes
Other	Changes in Vital signs in all patients who received at least one dose of randomised investigational product, olaparib or placebo	To assess the safety and tolerability of olaparib maintenance monotherapy by assessment of vital signs	assessed up to 60 months	Yes
Other	Changes in Physical examination results in all patients who received at least one dose of randomised investigational product, olaparib or placebo	To assess the safety and tolerability of olaparib maintenance monotherapy by assessment of physical examination parameters	assessed up to 60 months	Yes
Other	Changes in safety laboratory parameters in all patients who received at least one dose of randomised investigational product, olaparib or placebo	To assess the safety and tolerability of olaparib maintenance monotherapy by safety laboratory (consisting of clinical chemistry and haematology)parameters assessment	assessed up to 60 months	Yes
Primary	Progression Free Survival (PFS) using modified RECIST 1.1 in the cohort of patients with sBRCA ovarian cancer	To determine the efficacy of olaparib maintenance monotherapy compared to placebo by assessment of progression free survival (PFS) using blinded independent central review (BICR)	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	No
Secondary	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	To determine the efficacy of olaparib maintenance monotherapy compared to placebo by assessment of progression free survival (PFS)using blinded independent central review (BICR)	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	No
Secondary	Overall Survival (OS) in patients with sBRCAm ovarian cancer and in the ITT population consisting of all randomised patients	To determine the efficacy of olaparib maintenance monotherapy compared to placebo by assessment of overall survival (OS)	From the date of randomisation until death due to any cause, assessed up to 60 months	No
Secondary	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	To determine the efficacy of olaparib maintenance monotherapy compared to placebo by assessment of Time from randomisation to first subsequent therapy or death	From the date of randomisation to the earlier of first subsequent therapy start date, assessed up to 60 months	No
Secondary	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	To compare the effects of olaparib maintenance monotherapy compared to placebo on Health-related Quality of Life (HRQoL)	Administered at baseline, at day 29 then every 8 weeks (+/- 1 week) regardless of treatment discontinuation or disease progression, assessed up to 24 months	No
Secondary	Plasma mutation status	To determine if p53, somatic BRCA and other HRR mutations are present in plasma prior to chemotherapy	cfDNA sample collected during pre-screening, assessed up to 40 months	No
Secondary	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	To determine the efficacy of olaparib maintenance monotherapy compared to placebo by assessment of Time to earliest progression by RECIST 1.1 or CA-125 or Death. Progression or recurrence based on serum CA-125 levels will be defined on the basis of a progressive serial elevation of serum CA-125	From randomisation to the earliest date of investigator assesed RECIST or CA-125 progression or death by any cause, assessed up to 60 months	No
Secondary	Time from randomisation to second progression (PFS2) in patients with sBRCAm ovarian cancer and in the ITT population consisting of all randomised patients	To determine the efficacy of olaparib maintenance monotherapy compared to placebo by assessment of Time from randomisation to second progression	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	No
Secondary	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	To determine the efficacy of olaparib maintenance monotherapy compared to placebo by assessment of Time from randomisation to second subsequent therapy of death	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	No
Secondary	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	To determine the efficacy of olaparib maintenance monotherapy compared to placebo by assessment of Time from randomisation to study treatment discontinuation or death	From the date of randomisation to the earlier of the date of study treatment discontinuation or death, assessed up to 60 months	No