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
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
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
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
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
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.
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
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
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
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
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
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