Dataset Information

P17.04RANO CRITERIA APPLIED TO A PHASE II RANDOMIZED, MULTICENTER TRIAL COMPARING TEMOZOLOMIDE (TMZ) VS TMZ-PLUS-BEVACIZUMAB (BEV) BEFORE STANDARD TREATMENT IN UNRESECTABLE GLIOBLASTOMA (GBM) PATIENTS (P).GENOM 009 STUDY BY THE GEINO GROUP

ABSTRACT: BACKGROUND: RANO criteria were applied to evaluate differences in response between the 2 arms: TMZ or TMZ + BEV in a randomized study. We evaluate here the RANO sub-criterion (PI) to evaluate response. METHODS: Between December 2009 and April 2013, p with unresectable GBM, PS < 3 and MMS ?25 were randomly assigned to receive eitherTMZ (200 mg/m2, days 1–5,for 2 28-day cycles), followed by standard TMZ with concomitant radiotherapy (60Gy) and then adjuvant TMZ for 6 cycles (TMZ Arm), or the same regimen but with the addition of BEV (10mg/kg /15 days) during pre-radiotherapy and concomitant treatment (BEV Arm). The primary endpoint was response according to RANO criteria after the 2 pre-radiotherapy cycles. The study was powered to detect a 30% difference between arms. A centralized revision of MRI's blinded to clinical status of p is ongoing. (ClinicalTrials.gov NCT01102595). RESULTS:103 p were registered and 93 randomized – 45 to the TMZ Arm and 48 to the BEV Arm. All p who received at least one dose of treatment were included in the analysis. Overall response rate (ORR) was evaluated after the 2-pre-radiotherapy cycles. Patients completed pre-radiotherapy treatment in 48.9% (TMZ Arm) vs 66.7% (BEV Arm), p = 0.08. Response was not evaluable in 3p (TMZ arm) and 5p (BEV arm) because of previous toxicity or refuse to continue. ORR by RANO criteria for evaluable p was: Arm TMZ: PR 3 (7.1%) SD 8 (19%) PD 31 (73.8%)., Arm B: PR 11 (25.6%) SD 17 (39.5%) 15 (34.9%) P = 0.001. Response by individual RANO sub criterion (Arm TMZ% vs Arm BEV%).1- MRI IP: PR (8.3 vs 26.2), SD (22.2 vs 42.8), P (69.4 vs 31) (P = 0.003), 2-Neurological status: SD (54.8 vs 79.5), No SD (45.2 vs 20.5) (P = 0.014), 3-Dexametasone dose: stable (60.5 vs 51.2), increase (28.9 vs 4.7), reduction (10.5 vs 44.2) (P < 0.001). CONCLUSION: ORR was significantly higher in the BEV Arm for both for general RANO criteria as for each individual criterion (MRI, clinical stability and dexametasone doses.

SUBMITTER: Balana C

PROVIDER: S-EPMC4185699 | biostudies-literature | 2014 Sep

REPOSITORIES: biostudies-literature

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Project description:BackgroundDespite multimodality treatments including neurosurgery, radiotherapy and chemotherapy, glioblastoma (GBM) prognosis remains poor. GBM is classically considered as a radioresistant tumor, because of its high local recurrence rate, inside the irradiation field. The development of new radiosensitizer is crucial to improve the patient outcomes. Pre-clinical data showed that Poly (ADP-ribose) polymerase inhibitors (PARPi) could be considered as a promising class of radiosensitizer. The aim of this study is to evaluate Olaparib, a PARPi, as radiosensitizing agent, combined with the Stupp protocol, namely temozolomide (TMZ) and intensity modulated radiotherapy (IMRT) in first line treatment of partially or non-resected GBM.MethodsThe OLA-TMZ-RTE-01 study is a multicenter non-randomized phase I/IIa trial including unresectable or partially resectable GBM patients, from 18 to 70 years old. A two-step dose-escalation phase I design will first determine the recommended phase 2 dose (RP2D) of olaparib, delivered concomitantly with TMZ plus conventional irradiation for 6 weeks and as single agent for 4 weeks (radiotherapy period), and second, the RP2D of olaparib combined with adjuvant TMZ (maintenance period). Phase IIa will assess the 18-month overall survival (OS) of this combination. In both phase I and IIa separately considered, the progression-free survival, the objective response rate, the neurocognitive functions of patients, emotional disorders among caregivers, the survival without toxicity, degradation nor progression, the complications onset and the morphologic and functional MRI (magnetic resonance imaging) parameters will be also assessed as secondary objectives. Ancillary objectives will explore alteration of the DNA repair pathways on biopsy tumor, proton magnetic resonance spectroscopy parameters to differentiate tumor relapse and radionecrosis, and an expanded cognition evaluation. Up to 79 patients will be enrolled: 30 patients in the phase I and 49 patients in the phase IIa.DiscussionCombining PARP inhibitors, such as olaparib, with radiotherapy and chemotherapy in GBM may improve survival outcomes, while sparing healthy tissue and preserving neurocognitive function, given the replication-dependent efficacy of olaparib, and the increased PARP expression in GBM as compared to non-neoplastic brain tissue. Ancillary studies will help to identify genetic biomarkers predictive of PARPi efficacy as radiosensitizer.Trial registrationNCT03212742 , registered June, 7, 2017. Protocol version: Version 2.2 dated from 2017/08/18.

Dataset Information

P17.04RANO CRITERIA APPLIED TO A PHASE II RANDOMIZED, MULTICENTER TRIAL COMPARING TEMOZOLOMIDE (TMZ) VS TMZ-PLUS-BEVACIZUMAB (BEV) BEFORE STANDARD TREATMENT IN UNRESECTABLE GLIOBLASTOMA (GBM) PATIENTS (P).GENOM 009 STUDY BY THE GEINO GROUP

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