Clinical Trials /

Multi-maintenance Olaparib After Disease Recurrence in Participants With Platinum Sensitive BRCAm High Grade Serous Ovarian Cancer

NCT02855697

Description:

PARP inhibitors, such as olaparib, significantly improve progression free survival (PFS) in participants with recurrent, platinum-sensitive high-grade serous/endometrioid ovarian cancer (HGS/EOC), who harbour a germline mutation in BRCA 1 or 2 genes. Despite some of the most impressive hazard ratios seen in ovarian oncology, such improvements in PFS have not translated into improved overall survival (OS) advantage potentially because maintenance poly ADP ribose polymerase inhibitors (PARPi) are only being administered during a single remission. Here the investigators will test the feasibility of administering a second course of olaparib in participants who have recurrent platinum-sensitive HGS/EOC.

Related Conditions:
  • Fallopian Tube Carcinoma
  • Ovarian Carcinoma
  • Primary Peritoneal Carcinoma
Recruiting Status:

Recruiting

Phase:

Early Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Multi-maintenance Olaparib After Disease Recurrence in Participants With Platinum Sensitive BRCAm High Grade Serous Ovarian Cancer
  • Official Title: Single Arm Feasibility of Multi-maintenance Olaparib After Disease Recurrence in Participants With Platinum Sensitive BRCAm High Grade Serous Ovarian Cancer

Clinical Trial IDs

  • ORG STUDY ID: 15_DOG01_142
  • NCT ID: NCT02855697

Conditions

  • Ovarian Cancer

Interventions

DrugSynonymsArms
OlaparibLynparza, AZD2281, KU-0059436Olaparib +/- cediranib
CediranibAZD2171Olaparib +/- cediranib
Platinum-based ChemotherapyOlaparib +/- cediranib

Purpose

PARP inhibitors, such as olaparib, significantly improve progression free survival (PFS) in participants with recurrent, platinum-sensitive high-grade serous/endometrioid ovarian cancer (HGS/EOC), who harbour a germline mutation in BRCA 1 or 2 genes. Despite some of the most impressive hazard ratios seen in ovarian oncology, such improvements in PFS have not translated into improved overall survival (OS) advantage potentially because maintenance poly ADP ribose polymerase inhibitors (PARPi) are only being administered during a single remission. Here the investigators will test the feasibility of administering a second course of olaparib in participants who have recurrent platinum-sensitive HGS/EOC.

Detailed Description

      Epithelial ovarian cancer presents in most participants at an advanced stage when curative
      surgery is not possible because of extensive pelvic, abdominal or distant metastases.
      Immediate or delayed surgery combined with platinum-based chemotherapy are the standards of
      care but even with complete surgical cytoreductive techniques and the prescription of
      combination platinum-based chemotherapy, the 5 year survival rate remains approximately 35%.

      Approximately 50% of ovarian cancers harbour defects in HR. Defects in the pathway can arise
      as a result of genomic or epigenetic events in any one of up to 33 genes.

      Phase I and II clinical trials with the PARPi, olaparib, have shown promising results in BRCA
      mutated (BRCAm) recurrent EOC and in a proportion of HGSOC participants with wild type
      germline BRCA (BRCA wt). Additionally the favourable toxicity profile of olaparib has
      prompted the long-term use of PARPi as a maintenance strategy. The results of a randomized
      placebo-controlled phase II clinical trial of olaparib maintenance therapy showed an
      improvement in progression free survival (PFS) and time to progression in participants with
      recurrent platinum-sensitive HGSOC6. Recent data have confirmed that the increase in median
      PFS is most marked in BRCAm participants who received olaparib as maintenance treatment
      compared with the BRCAm participants who received placebo treatment (11.2 vs 4.3 months
      respectively; HR, 0.18; 95% CI, 0.11-0.31; p<0.00001). These studies were performed with the
      original capsule formulation of olaparib at a dose of 400mg bd.

      Rationale for this study The improvement in PFS with maintenance olaparib in participants
      with germline BRCA-mutation (g-BRCAm), although particularly striking, has not translated
      into improved overall survival, presumably because subsequent salvage therapy obscures this
      effect. Emerging data indicate that a significant proportion of BRCAm HGSOC participants
      retain sensitivity to platinum agents or other chemotherapies following progression on
      olaparib. Thus it is appropriate to offer further platinum-containing therapy to participants
      whose disease progresses more than 6 months after previous platinum therapy. In those whose
      disease benefits from further platinum chemotherapy, a further course of olaparib might
      consolidate the gains from the first course of olaparib, improving PFS to the point that OS
      is increased as well. However, to date no trial has tested the feasibility of successive
      treatments with 2 or more courses of maintenance olaparib and this issue will be addressed
      here, in participant who harbour a germline BRCA defect and whose disease has recurred and
      which is at least stabilised by subsequent platinum-based chemotherapy.

      Functional testing remains the gold standard test for HR status and has greater predictive
      accuracy than non-functional tests. The Rad51 functional assay involves the recognition of
      completion of HR by the formation of Rad51 foci in viable cells that have undergone DNA
      damage, recognised by γH2AX focus formation. The assay is robust and reproducible but
      requires viable cells derived from either participant ascites or solid tumour deposits.
    

Trial Arms

NameTypeDescriptionInterventions
Olaparib +/- cediranibExperimentalPatients are administered two courses of maintenance olaparib following chemotherapy. It is possible for patients to take cediranib during the second course of olaparib if recommended as per the protocol.
  • Olaparib
  • Cediranib
  • Platinum-based Chemotherapy

Eligibility Criteria

        Inclusion Criteria:

          1. Progressive, measureable high grade serous or endometrioid ovarian cancer, fallopian
             tube or primary peritoneal cancer

               -  Participants who have not been treated with PARP inhibitor previously will be
                  treated with two maintenance courses of olaparib.

               -  Participants, who have received one course of maintenance olaparib before entry
                  to the trial, will only receive one further course of treatment.

          2. Aged 18 or over

          3. Measureable disease by RECIST 1.1

          4. ECOG performance status 0-2 and life expectancy of over 12 weeks

          5. Adequate haematological function: Hb ≥ 10.0 g/l, Neutrophils ≥ 1.5 x 109/l, Platelets
             ≥ 100 x 109/l; coagulation: INR <1.4 (unless therapeutically anti-coagulated) and/or
             APPT ratio <1.4

          6. Adequate liver function: bilirubin ≤1.5 x ULN, Transaminases (ALT and AST) ≤2.5x ULN
             unless liver metastases are present in which case they must be ≤ 5x ULN

          7. Adequate renal function defined as GFR ≥ 51ml/min

          8. Written, informed consent that includes genetic research on tissue derived from
             biopsies.

          9. Pathogenic germline BRCA-1 or -2 gene mutation

         10. Ability to swallow oral medication (tablets).

        Exclusion Criteria:

          1. Concurrent medical illness that would impact on compliance with the protocol including
             MDS/ AML

          2. Uncontrolled brain metastases or seizures. A scan to confirm the absence of brain
             metastases is not required.

          3. Known positivity for Hep B, Hep C or HIV.

          4. Resting ECG with QTc > 470msec on 2 or more time points within a 24 hour period or
             family history of long QT syndrome

          5. Concomitant use of known strong CYP3A inhibitors (eg. itraconazole, telithromycin,
             clarithromycin, protease inhibitors boosted with ritonavir or cobicistat, indinavir,
             saquinavir, nelfinavir, boceprevir, telaprevir) or moderate CYP3A inhibitors (eg.
             ciprofloxacin, erythromycin, diltiazem, fluconazole, verapamil). The required washout
             period prior to starting olaparib is 2 weeks.

          6. Concomitant use of known strong (eg. phenobarbital, enzalutamide, phenytoin,
             rifampicin, rifabutin, rifapentine, carbamazepine, nevirapine and St John's Wort) or
             moderate CYP3A inducers (eg. bosentan, efavirenz, modafinil). The required washout
             period prior to starting olaparib is 5 weeks for enzalutamide or phenobarbital and 3
             weeks for other agents.

          7. Another cancer, which has been active within the previous 5 years, with the exception
             of adequately treated cone-biopsied in situ carcinoma of the cervix uteri and basal or
             squamous cell carcinoma of the skin and no evidence of recurrence of other malignancy.

          8. Female participants who are able to become pregnant (or are already pregnant or
             lactating) unless the following apply: Those who have a negative serum or urine
             pregnancy test before enrolment and agree to use two highly effective forms of
             contraception (oral, injected or implanted hormonal contraception and condom, have an
             intra-uterine device and condom, diaphragm with spermicidal gel and condom) for four
             weeks before entering the trial, during the trial and for one month afterwards are
             considered eligible. Alternatively if the participant can abstain from sexual
             intercourse for the same interval, then they are eligible to participate.

          9. Participants who are planning to receive maintenance bevacizumab.

         10. Participants will be excluded if the side effects of previous treatments have not
             resolved to grade I or less, with the exception of alopecia or grade 2 neurotoxicity
             that is considered related to cytotoxic chemotherapy.

         11. Radiotherapy, surgery or tumour embolization within 28 days before the cycle 1 day 1
             of the platinum-containing chemotherapy.

         12. Additional concurrent anti-cancer therapy.

         13. Causes of malabsorption e.g. uncontrolled diarrhoea or poorly controlled stoma is not
             permitted.

         14. Participants who have contra-indications to VEGF inhibitors will not be eligible to
             receive cediranib (second treatment). These contra-indications include concurrent or
             past history of malignant fistula, uncontrolled hypertension, recent arterial
             thrombosis (cerebrovascular accident or myocardial infarction) within the past 6
             months, participants who are at risk of bowel perforation, proteinuria greater than
             2g/24 hours or a past history of VEGF inhibitor-associated reversible posterior
             leukoencephalopathy.

         15. Any participant that is participating in another interventional clinical trial within
             30 days or 5-lives prior to signing of consent. Participation in an observational
             trial would be acceptable.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:Female
Healthy Volunteers:No

Primary Outcome Measures

Measure:To determine the feasibility of administering a second course of maintenance olaparib for more than 6 months (26 weeks) to participants with recurrent platinum-sensitive HGS/EOC who have been previously treated with olaparib.
Time Frame:6 months after the last patient has started the second course of olaparib
Safety Issue:
Description:The proportion of participants who remain on olaparib for more than 6 months (26 weeks) in the second course of maintenance olaparib.

Secondary Outcome Measures

Measure:Impact of multi-maintenance olaparib treatment on time to first subsequent therapy (TFST) in participants with platinum sensitive recurrent BRCAm HGS/EOC.
Time Frame:6 months after the last event
Safety Issue:
Description:Secondary endpoints will include time to first subsequent chemotherapy (TFST), which is defined as the interval from the last day of the last cycle of a prior regimen of chemotherapy to the first day of the first cycle of the subsequent regimen for each course of chemotherapy, following the first course of olaparib.
Measure:Impact of multi-maintenance olaparib treatment on time to second subsequent therapy (TSST) in participants with platinum sensitive recurrent BRCAm HGS/EOC.
Time Frame:6 months after the last event
Safety Issue:
Description:Secondary endpoints will include time to second subsequent chemotherapy (TSST), which is defined as the interval from the last day of the last cycle of a prior regimen of chemotherapy to the first day of the first cycle of the subsequent regimen for each course of chemotherapy, following the second course of olaparib.
Measure:Progression-free survival (PFS) for each course of chemotherapy followed by olaparib
Time Frame:6 months after the last event
Safety Issue:
Description:Secondary endpoints will include PFS for each course of chemotherapy, which is followed by olaparib.

Details

Phase:Early Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Rozalia Lubiatowska

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