First line treatment of patients with unresectable high-grade gliomas MedDRA version: 19.1 Level: PT Classification code 10018336 Term: Glioblastoma System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Conditions
Interventions
Product Name: Lymparza
Product Code: Olaparib
Pharmaceutical Form: Capsule, hard
INN or Proposed INN: Olaparib
CAS Number: 763113-22-0
Current Sponsor code: Lynparza
Concentration unit: mg milligram(s
Sponsors
Centre François baclesse
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: For inclusion in the study subjects should fulfill the following criteria: • Provision of signed informed consent prior to any study specific procedures • Histologically-confirmed diagnosis of glioblastoma (IDH-wildtype, IDH-mutant or NOS, except gliosarcoma), non resectable or partially resectable with a residual tumor on pre-radiotherapy MRI. The presence of a residual disease will be assessed by the radiologist on the pre-radiotherapy imaging as compared with initial imaging. • IMRT must start within 6 weeks after histological diagnosis • Age between 18 and 70 years ; • Adequate bone marrow and organ function measured within 15 days prior to administration of study treatment as defined below: - Haemoglobin = 10.0 g/dL with no blood transfusions (packed red blood cells and platelet transfusions) in the past 28 days before start of treatment - Absolute neutrophil count (ANC) = 1.5 x 109/L o No features suggestive of MDS/AML on peripheral blood smear - Platelet count = 100 x 109/L - White blood cells (WBC) > 3x109/L - Total bilirubin = 1.5 x institutional upper limit of normal - AST (SGOT)/ALT (SGPT) = 2.5 x institutional upper limit of normal - Creatinine clearance estimated using the Cockcroft-Gault equation of =51 mL/min: estimated creatinine clearance = [(140-age(years)) x weight(kg) (x Fsex) ] / [serum creatinine (mg/dL) x 72] where Fsex=0.85 for females and Fsex=1 for males. • ECOG performance status 0-2 • Neurologically asymptomatic or pauci-symptomatic patients. Patients with moderated neurological symptoms without systemic corticosteroids treatment or with a stable dose of corticosteroids during the study as long as these were started at least 4 weeks prior to treatment can be included. • Patients must have a life expectancy = 16 weeks. • Women of childbearing potential (WOCBP) and men under efficient contraception during treatment and at least 6 months after the end of treatment. • Evidence of non-childbearing status for women of childbearing potential: negative urine or serum pregnancy test within 28 days of study treatment, confirmed prior to treatment on day 1. • Postmenopausal is defined as: - Amenorrheic for 1 year or more following cessation of exogenous hormonal treatments, - LH and 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, - or surgical sterilisation (bilateral oophorectomy or hysterectomy). • Patient is willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations including follow up. • Subjects affiliated to an appropriate social security system Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 82 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 82
Exclusion criteria
Exclusion criteria: Patients should not enter the study if any of the following exclusion criteria are fulfilled • Any prior radiotherapy to brain • Any prior chemotherapy or immunotherapy • Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site) • Candidate for a concomitant therapy with Tumor-Treating Fields during the maintenance treatment • Previous enrolment in the present study • Participation in another clinical trial protocol within 30 days prior to enrolment; • Any previous treatment with a PARP inhibitor, including olaparib. • Patients with second primary cancer, except: adequately treated non-melanoma skin cancer, curatively treated in-situ cancer of the cervix, or other solid tumours curatively treated with no evidence of disease for = 5 years • Gadolinium hypersensitivity, or any contraindication to undergo MRI examination (Pacemaker, brain aneurysms clips) • Patients who had no initial pre-surgery contrast enhanced MRI scan including the standard sequences (T1 non enhanced, T1 contrast enhanced, T2 FLAIR) • Patients receiving any systemic chemotherapy, radiotherapy (except for palliative reasons), within 2 weeks from the last dose prior to study treatment. The patient can receive a stable dose of bisphosphonates for bone metastases, before and during the study as long as these were started at least 4 weeks prior to treatment with study drug. • Concomitant use of known CYP3A4 inhibitors such as ketokonazole, itraconazole, ritonavir, indinavir, saquinavir, telithromycin, clarithromycin and nelfinavir • Resting ECG with QTc > 470 msec detected on 2 or more time points within a 24 hour period or family history of long QT syndrome. If ECG demonstrates QTc > 470 msec, patient will be eligible only if repeat ECG demonstrates QTc =470 msec; • Blood transfusions within 1 month prior to study start • Patients with myelodysplastic syndrome/acute myeloid leukaemia. • Major surgery within 14 days of starting study treatment and patients must have recovered from any effects of any major surgery. • 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, unstable spinal cord compression (untreated and unstable for at least 28 days prior to study entry), superior vena cava syndrome, extensive bilateral lung disease on HRCT scan or any psychiatric disorder that prohibits obtaining informed consent. • Patients unable to swallow orally administered medication and patients with gastrointestinal disorders likely to interfere with absorption of the study medication (inflammatory bowel disease, major bowel resection …) • Pregnant or breast feeding women. • Immunocompromised patients, e.g., patients who are known to be serologically positive for human immunodeficiency virus (HIV) and are receiving antiviral therapy. • Patients with known active hepatic disease (i.e., Hepatitis B or C) due to risk of transmitting the infection through blood or other body fluids. • Patients with a known hypersensitivity to olaparib or any of the excipients of the product. • For temozolomide treatment, patients with a known galactose intolerance, a Lapp lactase deficit or a glucose or galactose malabsorption syndrome (rare hereditary diseases) • Patients with uncontro
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: Phase I: To determine the Recommended Phase II Dose (RP2D) of olaparib combined with the Stupp protocol (TMZ and concomitant fractionated radiotherapy: 60Gy/30 fractions/6 weeks) in first line treatment of patients with unresectable high-grade gliomas. Phase IIa: To assess the 18-month overall survival of the combination (olaparib and Stupp protocol) in the treatment of unresectable high-grade gliomas patients. ;Secondary Objective: In both phase I and phase IIa part, separately considered: To evaluate olaparib combined with the Stupp protocol in first line treatment of patients with unresectable high-grade gliomas, with regard to: - the progression-free survival, - the objective response rate, - the neuro-cognitive functions and quality of life, - the survival without toxicity, without degradation (quality of life and / or cognitive disorders) nor progression (Q-TWIST for Quality-Adjusted Time Without Symptoms or Toxicity) and the prevalence of complications, - the evolution of corticosteroids use - the morphologic and functional MRI parameters ;Primary end point(s): Phase I: RP2D of olaparib associated with Stupp protocol, defined by 2 successive maximum tolerated doses (MTD) for each two treatment periods: i. the MTD1 during radiation phase, defined as the highest dose level (DL) to which 25% or less of the patients developed dose-limiting toxicity (DLT) during this treatment period, and ii. MTD2 during the maintenance phase, defined by the highest dose level (DL) and the remaining =MTD1 for which 30% or less of patients experienced a DLT during this maintenance period (first 2 cycles). Phase IIa: Overall survival, defined as the time between start of treatment and death from any cause (censored at the date of last follow-up for patients alive);Timepoint(s) of evaluation of this end point: Phase I: At the end of each period (radiotherapy and maintenance) Phase IIa: patient death | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): • Type and grade of adverse events • Progression free survival • Objective response rate • Cognitive functions and quality of life for different scores • Survival without toxicity, without alteration • Use of corticosteroids in terms of molecules used, dosage, frequency of catches and routes of administration • Morphological and functional MRI Parameters;Timepoint(s) of evaluation of this end point: Safety : during all the study Up to desease progression for survival ,response rate and MRI Survey 3 months after the start of maintenance period for cognitive functions and quality of life | — |
Countries
France
Contacts
Public ContactProject manager
Centre François Baclesse
Outcome results
None listed