Phase I/IIa study of concomitant radiotherapy with olaparib and temozolomide in unresectable high grade gliomas patients

Phase 1

• Conditions: First line treatment of patients with unresectable high-grade gliomas; MedDRA version: 19.1Level: PTClassification code 10018336Term: GlioblastomaSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps); Therapeutic area: Diseases [C] - Cancer [C04]

• Registration Number: EUCTR2016-003468-38-FR
• Lead Sponsor: Centre François baclesse

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Study Start: 2017-03-30
• Last Update Posted: 24 April 2017

Recruitment & Eligibility

• Status: Authorised-recruitment may be ongoing or finished
• Sex: All
• Target Recruitment: Not specified

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

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

Study & Design

• Study Type: Interventional clinical trial of medicinal product
• Study Design: Not specified