Multicentre Study of Olaparib Maintenance Monotherapy in Platinum Sensitive Relapsed Non gBRCAm Ovarian Cancer Patients

NCT ID: NCT03402841

Last Updated: 2024-08-21

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 279 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2018-01-30
• Study Completion Date: 2022-03-10

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.

Conditions

Non-Germline BRCA Mutated Ovarian Cancer

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Olaparib

Olaparib will be supplied as film-coated tablets containing 150 mg or 100 mg of olaparib.

Patients will be administered olaparib orally twice daily (bid) at 300 mg.

Group Type: EXPERIMENTAL

Olaparib

Intervention Type: DRUG

300 mg twice daily - oral

Interventions

Olaparib

300 mg twice daily - oral

Intervention Type: DRUG

Other Intervention Names

Lynparza

Eligibility Criteria

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

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 95 Years
• Eligible Sex: FEMALE
• Accepts Healthy Volunteers: No

Sponsors

Iqvia Pty Ltd

INDUSTRY

Sponsor Role: collaborator

Myriad Genetics, Inc.

INDUSTRY

Sponsor Role: collaborator

Covance

INDUSTRY

Sponsor Role: collaborator

Theradex

INDUSTRY

Sponsor Role: collaborator

Parexel

INDUSTRY

Sponsor Role: collaborator

AstraZeneca

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Chris Wilks

Role: STUDY_DIRECTOR

AstraZeneca

Locations

Research Site

Graz, , Austria

Research Site

Innsbruck, , Austria

Research Site

Vienna, , Austria

Research Site

Wein, , Austria

Research Site

Brussels, , Belgium

Research Site

Leuven, , Belgium

Research Site

Loverval, , Belgium

Research Site

Namur, , Belgium

Research Site

Wilrijk, , Belgium

Research Site

Plovdiv, , Bulgaria

Research Site

Plovdiv, , Bulgaria

Research Site

Sofia, , Bulgaria

Research Site

Victoria, British Columbia, Canada

Research Site

London, Ontario, Canada

Research Site

Ottawa, Ontario, Canada

Research Site

Toronto, Ontario, Canada

Research Site

Montreal, Quebec, Canada

Research Site

Sherbrooke, Quebec, Canada

Research Site

Brno, , Czechia

Research Site

Nový Jičín, , Czechia

Research Site

Olomouc, , Czechia

Research Site

Ostrava, , Czechia

Research Site

Prague, , Czechia

Research Site

Aalborg, , Denmark

Research Site

Aarhus, , Denmark

Research Site

Kuopio, , Finland

Research Site

Oulu, , Finland

Research Site

Tampere, , Finland

Research Site

Afula, , Israel

Research Site

Beersheba, , Israel

Research Site

Haifa, , Israel

Research Site

Jerusalem, , Israel

Research Site

Kfar Saba, , Israel

Research Site

Ramat Gan, , Israel

Research Site

Ancona, , Italy

Research Site

Brescia, , Italy

Research Site

Lecco, , Italy

Research Site

Milan, , Italy

Research Site

Padua, , Italy

Research Site

Torino, , Italy

Research Site

Torino, , Italy

Research Site

Breda, , Netherlands

Research Site

Tilburg, , Netherlands

Research Site

Bergen, , Norway

Research Site

Oslo, , Norway

Research Site

Gdynia, , Poland

Research Site

Krakow, , Poland

Research Site

Lublin, , Poland

Research Site

Olsztyn, , Poland

Research Site

Poznan, , Poland

Research Site

Warsaw, , Poland

Research Site

Warsaw, , Poland

Research Site

Coimbra, , Portugal

Research Site

Lisbon, , Portugal

Research Site

Bucharest, , Romania

Research Site

Cluj-Napoca, , Romania

Research Site

Cluj-Napoca, , Romania

Research Site

Ljubljana, , Slovenia

Research Site

Badalona, , Spain

Research Site

Barcelona, , Spain

Research Site

Barcelona, , Spain

Research Site

Barcelona, , Spain

Research Site

Córdoba, , Spain

Research Site

Girona, , Spain

Research Site

Hospitalet deLlobregat, , Spain

Research Site

Madrid, , Spain

Research Site

Madrid, , Spain

Research Site

Málaga, , Spain

Research Site

Pamplona, , Spain

Research Site

Seville, , Spain

Research Site

Valencia, , Spain

Research Site

Valencia, , Spain

Research Site

Linköping, , Sweden

Research Site

Lund, , Sweden

Research Site

Basel, , Switzerland

Research Site

Bellinzona, , Switzerland

Research Site

Bern, , Switzerland

Research Site

Frauenfeld, , Switzerland

Research Site

Geneva, , Switzerland

Research Site

Lausanne, , Switzerland

Research Site

Zurich, , Switzerland

Research Site

Aberdeen, , United Kingdom

Research Site

Colchester, , United Kingdom

Research Site

Exeter, , United Kingdom

Research Site

Leeds, , United Kingdom

Research Site

Leicester, , United Kingdom

Research Site

London, , United Kingdom

Research Site

London, , United Kingdom

Research Site

Manchester, , United Kingdom

Research Site

Northampton, , United Kingdom

Research Site

Scarborough, , United Kingdom

Countries

Austria; Belgium; Bulgaria; Canada; Czechia; Denmark; Finland; Israel; Italy; Netherlands; Norway; Poland; Portugal; Romania; Slovenia; Spain; Sweden; Switzerland; United Kingdom

References

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Reference Type: BACKGROUND

PMID: 19553641 (View on PubMed)

Rottenberg S, Jaspers JE, Kersbergen A, van der Burg E, Nygren AO, Zander SA, Derksen PW, de Bruin M, Zevenhoven J, Lau A, Boulter R, Cranston A, O'Connor MJ, Martin NM, Borst P, Jonkers J. High sensitivity of BRCA1-deficient mammary tumors to the PARP inhibitor AZD2281 alone and in combination with platinum drugs. Proc Natl Acad Sci U S A. 2008 Nov 4;105(44):17079-84. doi: 10.1073/pnas.0806092105. Epub 2008 Oct 29.

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Reference Type: BACKGROUND

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Mirza MR, Monk BJ, Herrstedt J, Oza AM, Mahner S, Redondo A, Fabbro M, Ledermann JA, Lorusso D, Vergote I, Ben-Baruch NE, Marth C, Madry R, Christensen RD, Berek JS, Dorum A, Tinker AV, du Bois A, Gonzalez-Martin A, Follana P, Benigno B, Rosenberg P, Gilbert L, Rimel BJ, Buscema J, Balser JP, Agarwal S, Matulonis UA; ENGOT-OV16/NOVA Investigators. Niraparib Maintenance Therapy in Platinum-Sensitive, Recurrent Ovarian Cancer. N Engl J Med. 2016 Dec 1;375(22):2154-2164. doi: 10.1056/NEJMoa1611310. Epub 2016 Oct 7.

Reference Type: BACKGROUND

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Helleday T. The underlying mechanism for the PARP and BRCA synthetic lethality: clearing up the misunderstandings. Mol Oncol. 2011 Aug;5(4):387-93. doi: 10.1016/j.molonc.2011.07.001. Epub 2011 Jul 22.

Reference Type: BACKGROUND

PMID: 21821475 (View on PubMed)

Hay T, Matthews JR, Pietzka L, Lau A, Cranston A, Nygren AO, Douglas-Jones A, Smith GC, Martin NM, O'Connor M, Clarke AR. Poly(ADP-ribose) polymerase-1 inhibitor treatment regresses autochthonous Brca2/p53-mutant mammary tumors in vivo and delays tumor relapse in combination with carboplatin. Cancer Res. 2009 May 1;69(9):3850-5. doi: 10.1158/0008-5472.CAN-08-2388. Epub 2009 Apr 21.

Reference Type: BACKGROUND

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Ledermann J, Harter P, Gourley C, Friedlander M, Vergote I, Rustin G, Scott C, Meier W, Shapira-Frommer R, Safra T, Matei D, Macpherson E, Watkins C, Carmichael J, Matulonis U. Olaparib maintenance therapy in platinum-sensitive relapsed ovarian cancer. N Engl J Med. 2012 Apr 12;366(15):1382-92. doi: 10.1056/NEJMoa1105535. Epub 2012 Mar 27.

Reference Type: BACKGROUND

PMID: 22452356 (View on PubMed)

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.

Reference Type: BACKGROUND

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Barnicle A, Ray-Coquard I, Rouleau E, Cadoo K, Simpkins F, Aghajanian C, Leary A, Poveda A, Lheureux S, Pujade-Lauraine E, You B, Ledermann J, Matulonis U, Gourley C, Timms KM, Lai Z, Hodgson DR, Elks CE, Dearden S, Egile C, Lao-Sirieix P, Harrington EA, Brown JS. Patterns of genomic instability in > 2000 patients with ovarian cancer across six clinical trials evaluating olaparib. Genome Med. 2024 Dec 18;16(1):145. doi: 10.1186/s13073-024-01413-5.

Reference Type: DERIVED

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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.

Reference Type: DERIVED

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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.

Reference Type: DERIVED

PMID: 31553234 (View on PubMed)

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

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Related Info

Other Identifiers

2017-002767-17

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

D0816C00020

Identifier Type: -

Identifier Source: org_study_id