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

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ClinicalTrials.gov Identifier: NCT03402841
Recruitment Status : Active, not recruiting
First Posted : January 18, 2018
Last Update Posted : October 14, 2019
Sponsor:
Collaborators:
Iqvia Pty Ltd
Myriad Genetics, Inc.
Covance
Theradex
Parexel
Information provided by (Responsible Party):
AstraZeneca

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.

Condition or disease Intervention/treatment Phase
Non-Germline BRCA Mutated Ovarian Cancer Drug: Olaparib Phase 3

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.


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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 279 participants
Intervention Model: Single Group Assignment
Intervention Model Description: Single arm study
Masking: None (Open Label)
Masking Description: Open
Primary Purpose: Treatment
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
Actual Study Start Date : January 30, 2018
Estimated Primary Completion Date : July 19, 2020
Estimated Study Completion Date : January 4, 2021

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Ovarian Cancer
Drug Information available for: Olaparib

Arm Intervention/treatment
Experimental: 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.

Drug: Olaparib
300 mg twice daily - oral
Other Name: Lynparza




Primary Outcome Measures :
  1. Progression-free survival (PFS) [ Time Frame: Visit 1, 4 and on the first day of each 8 week visit period, relative to the date of the 1st olaparib dose, for the first 12 months on treatment, and then each 12-week visit period, until the earlier of progression, death or EOS for up to 30 months. ]
    Time from date of first dose of olaparib to the date of objective radiological disease progression according to investigator assessment via RECIST 1.1 or death (by any cause in the absence of progression)


Secondary Outcome Measures :
  1. Time to first subsequent therapy or death (TFST) [ Time Frame: Visit 2, visit 3, visit 4 and then at every tumour assessment visit. TFST only: at discontinuation of study treatment visit, at 30 days post last dose and every 12 weeks during long term follow-up (for up to 30 months). ]
    Time from date of first dose to date of first subsequent treatment commencement or death due to any cause if this occurs before commencement of first subsequent treatment.

  2. Time to treatment discontinuation or death (TDT) [ Time Frame: Visit 2, visit 3, visit 4 and then at every tumour assessment visit. TFST only: at discontinuation of study treatment visit, at 30 days post last dose and every 12 weeks during long term follow-up (for up to 30 months). ]
    Time from date of first dose to date of study drug discontinuation or death due to any cause if this occurs before study drug discontinuation.

  3. PFS in the following subgroups: 1. Somatic BRCA mutated and HRD scar positive; 2. HRD scar positive, non-BRCA mutated; 3. HRD scar negative, non-BRCA mutated [ Time Frame: Visit 1, 4 and every 8 week for the first 12 months, and each 12 week until earlier progression, death or EOS for up to 30 months. ]
    Time from date of first dose of olaparib to the date of objective radiological disease progression according to investigator assessment via RECIST 1.1 or death (by any cause in the absence of progression)

  4. Chemotherapy-free interval (CT_FI) [ Time Frame: At Screening, Visit 2, 3, 4 and subsequent tumor assessment visits, Visit 5 and subsequent safety visits until 30 days after last dose and then every 12 weeks until EOS (for up to 30 months) ]
    Time from the date of the last dose of platinum chemotherapy prior to olaparib maintenance therapy until the date of the initiation of the next anticancer therapy .

  5. Trial outcome index (TOI) [ Time Frame: At baseline, visit 3, visit 4 and then at every tumor assessment visit until progression, at discontinuation of study treatment visit and at 30 days post last dose. ]
    Proportion of patients with any improvement from baseline in TOI score.

  6. AEs/SAEs [ Time Frame: Screening, Visit 2, 3, 4 and subsequent Tumor Assessment Visit, Visit 5 and subsequent Safety Visit, until 30 days after last dose of study drug. ]
    Will be assessed in terms of AEs, deaths and laboratory data.

  7. Overall Survival (OS) [ Time Frame: Visit 1, 4, first of each 8 week visit period relative to the data of first olaparib dose, for the first 12 months on threatment and then each 12 week visit period, until death or EOS for up to 30 months. ]
    Time from the date of first dose of olaparib to date of death from any cause



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 95 Years   (Adult, Older Adult)
Sexes Eligible for Study:   Female
Gender Based Eligibility:   Yes
Gender Eligibility Description:   Female
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03402841


  Show 59 Study Locations
Sponsors and Collaborators
AstraZeneca
Iqvia Pty Ltd
Myriad Genetics, Inc.
Covance
Theradex
Parexel
Investigators
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Study Director: Chris Wilks AstraZeneca

Publications:

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: AstraZeneca
ClinicalTrials.gov Identifier: NCT03402841     History of Changes
Other Study ID Numbers: D0816C00020
First Posted: January 18, 2018    Key Record Dates
Last Update Posted: October 14, 2019
Last Verified: October 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by AstraZeneca:
Ovarian cancer
non-gBRCA
Platinum
Chemotherapy
Additional relevant MeSH terms:
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Ovarian Neoplasms
Carcinoma, Ovarian Epithelial
Endocrine Gland Neoplasms
Neoplasms by Site
Neoplasms
Ovarian Diseases
Adnexal Diseases
Genital Diseases, Female
Genital Neoplasms, Female
Urogenital Neoplasms
Endocrine System Diseases
Gonadal Disorders
Carcinoma
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Olaparib
Poly(ADP-ribose) Polymerase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents