Clinical trial NCT03402841: Multicentre Study of Olaparib Maintenance Monotherapy in Platinum Sensitive Relapsed Non gBRCAm Ovarian Cancer Patients
Official title: A Phase IIIb, Single-arm, Open-label Multicentre Study of Olaparib Maintenance Monotherapy in Platinum Sensitive Relapsed Non-Germline BRCA Mutated Ovarian Cancer Patients Who Are in Complete or Partial Response Following Platinum Based Chemotherapy
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Non-Germline BRCA Mutated Ovarian Cancer
Keywords: Ovarian cancer
non-gBRCA
Platinum
Chemotherapy
Lead sponsor: AstraZeneca
Sponsor class: INDUSTRY
Collaborators: name: Iqvia Pty Ltd
name: Myriad Genetics, Inc.
name: Covance
name: Theradex
name: Parexel
First posted: 2018-01-18
Enrollment: 279
Sex: FEMALE
Minimum age (years): 18
Maximum age (years): 95
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Intervention model description: Single arm study
Primary purpose: TREATMENT

Brief summary: The purpose of the study is to assess the efficacy and safety of single-agent olaparib as a maintenance treatment in patients with relapsed High Grade Serous Ovarian Cancer (including patients with primary peritoneal and/or fallopian tube cancer) or high grade endometrioid cancer who do not have known deleterious or suspected deleterious germline BRCA mutations (non-gBRCAm) and who had responded following platinum based chemotherapy

Detailed description: Maintenance monotherapy with the potent polyadenosine 5'diphosphoribose \[Poly (ADP-ribose)\] polymerisation (PARP) inhibitor (PARPi) olaparib will significantly prolong progression-free survival (PFS) in platinum sensitive relapsed non-germline breast cancer susceptibility gene (BRCA) mutated ovarian cancer patients who are in complete or partial response following platinum based chemotherapy.

Olaparib is a potent PARPi (PARP-1, -2 and -3) that is being developed as an oral therapy, both as a monotherapy (including maintenance) and for combination with chemotherapy and other anticancer agents. PARP inhibition is a novel approach to targeting tumours with deficiencies in DNA repair mechanisms. PARP enzymes are essential for repairing DNA single strand breaks (SSBs). Inhibiting PARP enzymes leads to the persistence of SSBs, which are then converted to the more serious DNA double strand breaks (DSBs) during the process of DNA replication. During the process of cell division, DSBs can be efficiently repaired in normal cells by homologous recombination (HR) repair. Tumours with HR deficiencies (HRDs), such as ovarian cancers in patients with BRCA1/2 mutations, cannot accurately repair the DNA damage, which may become lethal to cells as it accumulates. In such tumour types, olaparib may offer a potentially efficacious and less toxic cancer treatment compared with currently available chemotherapy regimens.

While multiple randomized controlled trials (RCTs) have demonstrated that platinum sensitive BRCAm patients have profound response to maintenance treatment with PARP inhibitors, PARP inhibitors target cells with homologous recombination deficiency (HRD), of which BRCA mutation is only one type. Consistent with the mechanism of action of PARP inhibition, response has also been seen in multiple RCTs in patients who are platinum sensitive but whose tumours do not harbor BRCA mutations. Presumably these responders have defects in other components of HRR pathways, though currently available diagnostic technology is not adequate to reliably identify the full spectrum of HRR deficiencies. Instead, these data support the hypothesis that platinum sensitivity itself is a clinical selection factor for HRD.

Eligibility criteria: Key Inclusion Criteria:

* Female patients with histologically diagnosed relapsed HGSOC (including primary peritoneal and / or fallopian tube cancer) or high grade endometrioid ovarian cancer
* Documented gBRCA1/2 mutation status
* Patients must have completed at least 2 previous courses of platinum containing therapy
* Patients must have normal organ and bone marrow function measured within 28 days of starting study treatment
* ECOG performance status 0-1 (see Appendix E)
* Patients must have a life expectancy ≥16 weeks
* 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
* At least one lesion (measurable and/or non-measurable) that can be accurately assessed at baseline with computed tomography (CT) or magnetic resonance imaging (MRI) and is suitable for repeated assessment OR No evidence of disease following a complete response to chemotherapy
* An appropriately prepared tumour sample from the cancer, of sufficient quantity and quality (as specified in the Central Laboratory Services Manual) must be available for future central testing of tumour genetic status

Exclusion Criteria:

* Patients receiving any systemic hormonal therapy, chemotherapy or radiotherapy (except for palliative reasons) within 3 weeks prior to start of study treatment
* Any previous treatment with PARP inhibitor, including olaparib
* Patients with a germline BRCA mutation that is predicted to be deleterious or suspected deleterious (known or predicted to be detrimental / lead to loss of function)
* 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.
* Concomitant use of known strong CYP3A inhibitors and strong (or moderate CYP3A inducers
* Persistent toxicities (≥ Grade 2 Common Terminology Criteria for Adverse Event (CTCAE) adverse event) caused by previous cancer therapy, excluding alopecia
* Patients with myelodysplastic syndrome (MDS)/acute myeloid leukaemia (AML) or with features suggestive of MDS/AML
* Patients with symptomatic uncontrolled brain metastases

Primary outcomes:
measure: Progression Free Survival (PFS)
timeFrame: Up to maximum of 32 months
Secondary outcomes:
measure: Time to First Subsequent Therapy or Death (TFST)
timeFrame: Up to a maximum of 43 months
measure: Time to Treatment Discontinuation or Death (TDT)
timeFrame: Up to a maximum of 43 months
measure: PFS by Homologous Recombination Deficiency (HRD)/ Breast Cancer Susceptibility Gene Mutation (Mutated) (BRCAm) Status
timeFrame: Up to maximum of 32 months
measure: Chemotherapy-free Interval (CT-FI)
timeFrame: Up to a maximum of 43 months
measure: Overall Survival (OS)
timeFrame: Up to a maximum of 43 months
measure: Percentage of Patients With Any Improvement From Baseline in Trial Outcome Index (TOI) Score at Any Point During the Treatment Period
timeFrame: Baseline up to a maximum of 32 months
measure: Percentage of Patients With a 10-Point Deterioration From Baseline in TOI Score at Any Point During the Treatment Period
timeFrame: Baseline up to a maximum of 32 months
Other outcomes:
Locations:
city: Graz
country: Austria
facility: Research Site
city: Innsbruck
country: Austria
facility: Research Site
city: Vienna
country: Austria
facility: Research Site
city: Wein
country: Austria
facility: Research Site
city: Bruxelles
country: Belgium
facility: Research Site
city: Leuven
country: Belgium
facility: Research Site
city: Loverval
country: Belgium
facility: Research Site
city: Namur
country: Belgium
facility: Research Site
city: Wilrijk
country: Belgium
facility: Research Site
city: Plovdiv
country: Bulgaria
facility: Research Site
city: Plovdiv
country: Bulgaria
facility: Research Site
city: Sofia
country: Bulgaria
facility: Research Site
city: Victoria
country: Canada
facility: Research Site
state: British Columbia
city: London
country: Canada
facility: Research Site
state: Ontario
city: Ottawa
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: Sherbrooke
country: Canada
facility: Research Site
state: Quebec
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: Arhus
country: Denmark
facility: Research Site
city: Ålborg
country: Denmark
facility: Research Site
city: Kuopio
country: Finland
facility: Research Site
city: Oulu
country: Finland
facility: Research Site
city: Tampere
country: Finland
facility: Research Site
city: Afula
country: Israel
facility: Research Site
city: Beer Sheva
country: Israel
facility: Research Site
city: Haifa
country: Israel
facility: Research Site
city: Jerusalem
country: Israel
facility: Research Site
city: Kfar Saba
country: Israel
facility: Research Site
city: Ramat Gan
country: Israel
facility: Research Site
city: Ancona
country: Italy
facility: Research Site
city: Brescia
country: Italy
facility: Research Site
city: Lecco
country: Italy
facility: Research Site
city: Milano
country: Italy
facility: Research Site
city: Padova
country: Italy
facility: Research Site
city: Torino
country: Italy
facility: Research Site
city: Torino
country: Italy
facility: Research Site
city: Breda
country: Netherlands
facility: Research Site
city: Tilburg
country: Netherlands
facility: Research Site
city: Bergen
country: Norway
facility: Research Site
city: Oslo
country: Norway
facility: Research Site
city: Gdynia
country: Poland
facility: Research Site
city: Kraków
country: Poland
facility: Research Site
city: Lublin
country: Poland
facility: Research Site
city: Olsztyn
country: Poland
facility: Research Site
city: Poznań
country: Poland
facility: Research Site
city: Warszawa
country: Poland
facility: Research Site
city: Warszawa
country: Poland
facility: Research Site
city: Coimbra
country: Portugal
facility: Research Site
city: Lisboa
country: Portugal
facility: Research Site
city: Bucuresti
country: Romania
facility: Research Site
city: Cluj Napoca
country: Romania
facility: Research Site
city: Cluj-Napoca
country: Romania
facility: Research Site
city: Ljubljana
country: Slovenia
facility: Research Site
city: Badalona
country: Spain
facility: Research Site
city: Barcelona
country: Spain
facility: Research Site
city: Barcelona
country: Spain
facility: Research Site
city: Barcelona
country: Spain
facility: Research Site
city: Córdoba
country: Spain
facility: Research Site
city: Girona
country: Spain
facility: Research Site
city: Hospitalet deLlobregat
country: Spain
facility: Research Site
city: Madrid
country: Spain
facility: Research Site
city: Madrid
country: Spain
facility: Research Site
city: Málaga
country: Spain
facility: Research Site
city: Pamplona
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: Linköping
country: Sweden
facility: Research Site
city: Lund
country: Sweden
facility: Research Site
city: Basel
country: Switzerland
facility: Research Site
city: Bellinzona
country: Switzerland
facility: Research Site
city: Bern
country: Switzerland
facility: Research Site
city: Frauenfeld
country: Switzerland
facility: Research Site
city: Genève 14
country: Switzerland
facility: Research Site
city: Lausanne
country: Switzerland
facility: Research Site
city: Zürich
country: Switzerland
facility: Research Site
city: Aberdeen
country: United Kingdom
facility: Research Site
city: Colchester
country: United Kingdom
facility: Research Site
city: Exeter
country: United Kingdom
facility: Research Site
city: Leeds
country: United Kingdom
facility: Research Site
city: Leicester
country: United Kingdom
facility: Research Site
city: London
country: United Kingdom
facility: Research Site
city: London
country: United Kingdom
facility: Research Site
city: Manchester
country: United Kingdom
facility: Research Site
city: Northampton
country: United Kingdom
facility: Research Site
city: Scarborough
country: United Kingdom
facility: Research Site
Study officials:
affiliation: AstraZeneca
name: Chris Wilks
role: STUDY_DIRECTOR
References:
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citation: Pujade-Lauraine E, Ledermann JA, Selle F, Gebski V, Penson RT, Oza AM, Korach J, Huzarski T, Poveda A, Pignata S, Friedlander M, Colombo N, Harter P, Fujiwara K, Ray-Coquard I, Banerjee S, Liu J, Lowe ES, Bloomfield R, Pautier P; SOLO2/ENGOT-Ov21 investigators. Olaparib tablets as maintenance therapy in patients with platinum-sensitive, relapsed ovarian cancer and a BRCA1/2 mutation (SOLO2/ENGOT-Ov21): a double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Oncol. 2017 Sep;18(9):1274-1284. doi: 10.1016/S1470-2045(17)30469-2. Epub 2017 Jul 25.
citation: Poveda A, Lheureux S, Colombo N, Cibula D, Lindemann K, Weberpals J, Bjurberg M, Oaknin A, Sikorska M, Gonzalez-Martin A, Madry R, Perez MJR, Ledermann J, Davidson R, Blakeley C, Bennett J, Barnicle A, Skof E. Olaparib maintenance monotherapy in platinum-sensitive relapsed ovarian cancer patients without a germline BRCA1/BRCA2 mutation: OPINION primary analysis. Gynecol Oncol. 2022 Mar;164(3):498-504. doi: 10.1016/j.ygyno.2021.12.025. Epub 2022 Jan 19.
citation: Poveda AM, Davidson R, Blakeley C, Milner A. Olaparib maintenance monotherapy in platinum-sensitive, relapsed ovarian cancer without germline BRCA mutations: OPINION Phase IIIb study design. Future Oncol. 2019 Nov;15(32):3651-3663. doi: 10.2217/fon-2019-0343. Epub 2019 Sep 25.