Clinical Trials /

Olaparib in Recurrent IDH-mutant Glioma

NCT03561870

Description:

Recent data demonstrate that in IDH-mutant gliomas, 2 hydroxy-glutarate production induces a homologous recombination defect that renders tumor cells exquisitely sensitive to poly(adenosine 5'-diphosphate-ribose) polymerase (PARP) inhibitors, including olaparib (Lynparza; AstraZeneca). The aim of this open-label phase 2 study is to evaluate the efficacy of olaparib in in recurrent IDH-mutant high grade gliomas based on 6 months progression-free survival.

Related Conditions:
  • Malignant Glioma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Olaparib in Recurrent IDH-mutant Glioma
  • Official Title: A Phase II Study of Olaparib in Recurrent IDH-mutant High Grade Gliomas OLAGLI

Clinical Trial IDs

  • ORG STUDY ID: 69HCL18_0132
  • SECONDARY ID: 2018-002584-25
  • NCT ID: NCT03561870

Conditions

  • Recurrent IDH
  • Mutant High Grade Glioma

Interventions

DrugSynonymsArms
Olaparib 150 MGOlaparib

Purpose

Recent data demonstrate that in IDH-mutant gliomas, 2 hydroxy-glutarate production induces a homologous recombination defect that renders tumor cells exquisitely sensitive to poly(adenosine 5'-diphosphate-ribose) polymerase (PARP) inhibitors, including olaparib (Lynparza; AstraZeneca). The aim of this open-label phase 2 study is to evaluate the efficacy of olaparib in in recurrent IDH-mutant high grade gliomas based on 6 months progression-free survival.

Trial Arms

NameTypeDescriptionInterventions
OlaparibExperimental
  • Olaparib 150 MG

Eligibility Criteria

        Inclusion Criteria:

          1. Affiliation to a French social security system (recipient or assign) excluding AME.

          2. Histological confirmation of grade III or IV high-grade glioma or evidence of
             anaplastic transformation (based on histological or radiological analysis) of a
             previous grade II glioma

          3. Tumor is mutated for IDH1 or IDH2 gene (detected by R132HIDH immunochemistry or
             IDH1/IDH2 sequencing)

          4. Recurrence after radiotherapy and at least one line of alkylating chemotherapy
             (Temozolomide or PCV (Procarbazine, CCNU, Vincristine) (Surgery at recurrence is
             allowed before trial inclusion)

          5. Recurrence occurring more than 12 weeks from the end of the radiotherapy or occurring
             outside the irradiated volume

          6. Provision of informed consent prior to any study specific procedures

          7. Age ≥ 18 years old

          8. Patients must have normal organ and bone marrow function measured within 28 days prior
             to administration of study treatment as defined below:

             Haemoglobin ≥ 10.0 g/dL with no blood transfusion in the past 28 days Absolute
             neutrophil count (ANC) ≥ 1.5 x 109/L Platelet count ≥ 100 x 109/L total bilirubin ≤
             1.5 x institutional upper limit of normal (ULN) Aspartate aminotransferase (AST)
             (Serum Glutamic Oxaloacetic Transaminase (SGOT)) / Alanine aminotransferase (ALT)
             (Serum Glutamic Pyruvate Transaminase (SGPT)) ≤ 2.5 x institutional upper limit of
             normal

             Patients must have creatinine clearance estimated using the Cockcroft-Gault equation
             of ≥51 mL/min:

             Estimated creatinine clearance = (140-age [years]) x weight (kg) (x F)a serum
             creatinine (mg/dL) x 72 a where F=0.85 for females and F=1 for males.

          9. KPS ≥ 70

         10. Patients must have a life expectancy ≥ 16 weeks.

         11. 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.

             Postmenopausal is defined as:

             Amenorrheic for 1 year or more following cessation of exogenous hormonal treatments
             Luteinizing hormone (LH) and Follicle stimulating hormone (FSH) levels in the post
             menopausal range for women under 50 radiation-induced oophorectomy with last menses >1
             year ago chemotherapy-induced menopause with >1 year interval since last menses
             surgical sterilisation (bilateral oophorectomy or hysterectomy)

         12. Male patients and their partners, who are sexually active and of childbearing
             potential, must agree to the use of two highly effective forms of contraception in
             combination [see appendix B for acceptable methods], throughout the period of taking
             study treatment and for 3 months after last dose of study drug(s) to prevent pregnancy
             in a partner.

         13. Patients is willing and able to comply with the protocol for the duration of the study
             including undergoing treatment and scheduled visits and examinations.

         14. Radiologically measurable disease based on RANO criteria, i. e. at least one lesion
             (measurable and/or non-measurable) that can be accurately assessed at baseline by MRI
             and is suitable for repeated assessment. Tumor lesions situated in a previously
             irradiated area are considered measurable if progression has been demonstrated in such
             lesions.

         15. Formalin fixed, paraffin embedded (FFPE) tumour sample from the primary cancer must be
             available for central testing. If there is not written confirmation of the
             availability of an archived tumour sample prior to enrolment the patient is not
             eligible for the study.

         16. For inclusion in the optional biomarker research, patients must fulfil the following
             criteria:

        Provision of informed consent for biomarker research If a patient declines to participate
        in the optional exploratory genetic research or the optional biomarker research, there will
        be no penalty or loss of benefit to the patient. The patient will not be excluded from
        other aspects of the study.

        Exclusion Criteria:

          1. Involvement in the planning and/or conduct of the study (applies to both AstraZeneca
             staff and/or staff at the study site)

          2. Previous enrolment in the present study

          3. Participation in another clinical study with an investigational product during the
             last month

          4. Any previous treatment with PARP inhibitor, including olaparib.

          5. Other malignancy within the last 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, or other solid tumours including
             lymphomas (without bone marrow involvement) curatively treated with no evidence of
             disease for ≥5 years. Patients with a history of localised triple negative breast
             cancer may be eligible, provided they completed their adjuvant chemotherapy more than
             three years prior to registration, and that the patient remains free of recurrent or
             metastatic disease.

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

          7. Patients receiving any systemic chemotherapy or radiotherapy (except for palliative
             reasons) within 3 weeks prior to study treatment

          8. 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.

          9. 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.

         10. Persistent toxicities (>Common Terminology Criteria for Adverse Event (CTCAE) grade 2)
             caused by previous cancer therapy, excluding alopecia.

         11. Patients with myelodysplastic syndrome/acute myeloid leukaemia or with features
             suggestive of MDS/AML.

         12. Major surgery within 2 weeks of starting study treatment and patients must have
             recovered from any effects of any major surgery.

         13. Patients considered a poor medical risk due to a serious, uncontrolled medical
             disorder, non-malignant systemic disease or active, uncontrolled infection. Examples
             include, but are not limited to, uncontrolled ventricular arrhythmia, recent (within 3
             months) myocardial infarction, uncontrolled major seizure disorder, unstable spinal
             cord compression, superior vena cava syndrome, extensive interstitial bilateral lung
             disease on High Resolution Computed Tomography (HRCT) scan or any psychiatric disorder
             that prohibits obtaining informed consent.

         14. Patients unable to swallow orally administered medication and patients with
             gastrointestinal disorders likely to interfere with absorption of the study
             medication.

         15. Breast feeding women.

         16. Immunocompromised patients, e.g., patients who are known to be serologically positive
             for human immunodeficiency virus (HIV).

         17. Patients with a known hypersensitivity to olaparib or any of the excipients of the
             product.

         18. Patients with known active hepatitis (i.e. Hepatitis B or C) due to risk of
             transmitting the infection through blood or other body fluids

         19. Previous allogenic bone marrow transplant or double umbilical cord blood
             transplantation (dUCBT)

         20. Whole blood transfusions in the last 120 days prior to entry to the study (packed red
             blood cells and platelet transfusions are acceptable, for timing refer to inclusion
             criteria no.8)
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:progression free survival
Time Frame:6 months
Safety Issue:
Description:

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Hospices Civils de Lyon

Trial Keywords

  • IDH-mutant
  • recurrent
  • glioma

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