Clinical Trials /

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

NCT03402841

Description:

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.

Related Conditions:
  • Endometrial Carcinoma
  • Fallopian Tube Carcinoma
  • High Grade Ovarian Serous Adenocarcinoma
  • Primary Peritoneal Carcinoma
Recruiting Status:

Active, not recruiting

Phase:

Phase 3

Trial Eligibility

Document

Title

  • Brief Title: 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

Clinical Trial IDs

  • ORG STUDY ID: D0816C00020
  • NCT ID: NCT03402841

Conditions

  • Non-Germline BRCA Mutated Ovarian Cancer

Interventions

DrugSynonymsArms
OlaparibLynparzaOlaparib

Purpose

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.
    

Trial Arms

NameTypeDescriptionInterventions
OlaparibExperimentalOlaparib 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.
  • Olaparib

Eligibility Criteria

        Key Inclusion Criteria:

          -  Female patients with histologically diagnosed relapsed HGSOC (including primary
             peritoneal and / or fallopian tube cancer) or high grade endometrioid 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:

          -  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 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)

          -  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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:Female
Healthy Volunteers:No

Primary Outcome Measures

Measure: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.
Safety Issue:
Description: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

Measure: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).
Safety Issue:
Description: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.
Measure: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).
Safety Issue:
Description: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.
Measure: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.
Safety Issue:
Description: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)
Measure: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)
Safety Issue:
Description: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 .
Measure: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.
Safety Issue:
Description:Proportion of patients with any improvement from baseline in TOI score.
Measure: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.
Safety Issue:
Description:Will be assessed in terms of AEs, deaths and laboratory data.

Details

Phase:Phase 3
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:AstraZeneca

Trial Keywords

  • Ovarian cancer
  • non-gBRCA
  • Platinum
  • Chemotherapy

Last Updated

April 5, 2018