Phase I/IIa Study of Concomitant Radiotherapy With Olaparib and Temozolomide in Unresectable High Grade Gliomas Patients

  • STATUS
    Recruiting
  • End date
    Jun 30, 2022
  • participants needed
    79
  • sponsor
    Centre Francois Baclesse
Updated on 22 July 2021
Investigator
Dinu STEFAN, MD
Primary Contact
H pitaux universitaires La Piti Salp tri re - Charles Foix (1.6 mi away) Contact
+8 other location
platelet count
corticosteroids
hysterectomy
tumor necrosis factor
residual tumor
neutrophil count
blood transfusion
glioblastoma multiforme
temozolomide
gliosarcoma
histological diagnosis
gliomas

Summary

The Stupp protocol is the standard treatment of glioblastoma multiform (GBM) which prognosis remains poor.

The non-dividing nature of normal brain cells provides an opportunity to enhance the therapeutic ratio by combining radiation with inhibitors of replication-specific DNA repair pathways such poly(ADP-ribose) polymerase (PARP) inhibitors, thus inducing more cytotoxic effects of DNA-damage related to treatment modalities, including alkylating reagents like temozolomide (TMZ).

Olaparib, a potent PARP inhibitor, overcomes apoptotic resistance and sensitizes GBM cells for death receptor-mediated apoptosis induced by TRAIL (Tumor necrosis factor-Related Apoptosis Inducing Ligand). Moreover, inhibition of PARP activity increases cellular sensitivity to ionizing radiation: it was even suggested to be more pronounced in tumors than in normal tissue.

Lastly, progress in technical imaging and intensity-modulated-radiotherapy (IMRT) techniques provide new possibilities for sparing healthy tissues.

Description

HGGs are the most common and most aggressive primary brain tumor. There is a real need to improve care management of GBM patients. Attempts to achieve cure by increasing radiation dose result in unacceptable neurotoxicity. As for radiosensitizers, they can exacerbate normal tissue damage.

Since GBM represent a rapidly dividing cell population within the nonreplicating normal brain, the therapeutic ratio may be enhanced by specific radiosensitization of proliferating cells. Resistance to apoptosis is a paramount issue in the treatment of HGG. Targeting PARP by the inhibitors like olaparib can reduce proliferation and lowers the apoptotic threshold of HGG (effect showed in vivo and in vitro).

In this context, we propose a phase I-IIa trail to investigate the toxicity and efficacy of olaparib and TMZ concomitantly with radiotherapy in first line treatment of unresectable high risk HGG.

Correlation between treatment response and tumor profiling will allow us to identify biomarkers that can be useful in treatment improvement and/or present a prognostic value. Then, the transfer of this approach will be evaluated in terms of compatibility with the requirements of diagnostic.

Details
Condition Radiation Oncology, Glioma, Radiotherapy, radiotherapeutic, High Grade Glioma, PARP Inhibitor, Gliomas, PARP Inhibitors, malignant glioma, inhibitors, parp
Treatment olaparib, Temozolomide (TMZ), IMRT (Intensity Modulated Radiation Therapy)
Clinical Study IdentifierNCT03212742
SponsorCentre Francois Baclesse
Last Modified on22 July 2021

Eligibility

Yes No Not Sure

Inclusion 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
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
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
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
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 (if applicable) 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)
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, throughout the period of taking study treatment and for 3 months after last dose of study drug(s) to prevent pregnancy in a partner
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

Exclusion Criteria

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 [70]
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 strong CYP3A inhibitors (eg. itraconazole, telithromycin, clarithromycin, protease inhibitors boosted) or moderate CYP3A inhibitors (eg. ciprofloxacin, erythromycin, diltiazem, fluconazole, verapamil). The required washout period prior to starting olaparib is 2 weeks
Concomitant use of known strong (eg. phenobarbital, phenytoin, rifampicin, rifabutin, rifapentine, carbamazepine, and St John's Wort ) or moderate CYP3A inducers (eg. bosentan, modafinil). The required washout period prior to starting olaparib is 5 weeks for phenobarbital and 3 weeks for other agents
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
Previous allogenic bone marrow transplant or double umbilical cord blood transplantation (dUCBT)
Patients with myelodysplastic syndrome/acute myeloid leukaemia or with features suggestive of MDS/AML
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, uncontrolled major seizure disorder, 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 hepatitis (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 uncontrolled epileptic seizures
Neurological, addictive or psychiatric disorder
Lack of availability for clinical follow-up assessments
Persons protected by a legal regime (guardianship, trusteeship)
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