RTOG 0913: A phase I study of daily everolimus (RAD001) in combination with radiation therapy and temozolomide in patients with newly diagnosed glioblastoma.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 2047-2047
Author(s):  
Prakash Chinnaiyan ◽  
Minhee Won ◽  
Patrick Y. Wen ◽  
Amyn Rojiani ◽  
Merideth M Wendland ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Radiation Therapy ◽  
Dose Level ◽  
Radiation Therapy Oncology Group ◽  
Newly Diagnosed ◽  
Biomarker Analysis ◽  
Molecular Determinants ◽  
Newly Diagnosed Glioblastoma ◽  
Level 3 ◽  
Clinical Trial Information

2047 Background: To determine the safety of the mTOR inhibitor everolimus (RAD001) administered daily with concurrent radiation and temozolomide in newly diagnosed glioblastoma patients. Methods: Everolimus was administered daily with concurrent radiation (60 Gy in 30 fractions) and temozolomide (TMZ) (75 mg/m2/day). Everolimus was escalated from 2.5 (Dose Level 1), to 5 (Dose Level 2), to 10 mg/day (Dose Level 3). Maintenance TMZ was delivered at 150-200 mg/m2 on days 1 to 5 every 28 days for up to 12 cycles with concurrent everolimus at the previously established daily dose of 10 mg/day. Dose escalation continued if a dose level produced DLTs in ≤ 2 of the first 6 evaluable patients. Results: Between October 28, 2010 and July 2, 2012, the Radiation Therapy Oncology Group (RTOG) 0913 protocol initially registered a total of 35 patients, with 25 patients successfully meeting enrollment criteria, receiving drug and evaluable for toxicity. Everolimus was successfully escalated to the predetermined MTD of 10 mg/day. Two of the first 6 eligible patients experienced a DLT at each dose level. DLTs included: gait disturbance, febrile neutropenia, rash, fatigue, thrombocytopenia, hypoxia, ear pain, headache, and mucositis. Other common toxicities were Grade 1/2 hypercholesterolemia and hypertriglyceridemia. At the time of analysis, there was one death reported, which was attributed to tumor progression. Conclusions: Daily oral everolimus (10 mg) combined with both concurrent radiation therapy and TMZ followed by maintenance TMZ, is well tolerated, with an acceptable toxicity profile. A phase II randomized clinical trial with mandatory correlative biomarker analysis is currently underway, designed to both determine the efficacy of this regimen and identify molecular determinants of response. Supported by RTOG U10 CA21661 and CCOP U10 CA37422 grants from NCI and Novartis. Clinical trial information: NCT01062399.

scholarly journals Does Valproic Acid or Levetiracetam Improve Survival in Glioblastoma? A Pooled Analysis of Prospective Clinical Trials in Newly Diagnosed Glioblastoma

2016 ◽  
Vol 34 (7) ◽  
pp. 731-739 ◽  
Author(s):  
Caroline Happold ◽  
Thierry Gorlia ◽  
Olivier Chinot ◽  
Mark R. Gilbert ◽  
L. Burt Nabors ◽  
...  
Keyword(s):  
Valproic Acid ◽  
Clinical Trials ◽  
Radiation Therapy ◽  
Drug Use ◽  
Antiepileptic Drug ◽  
Randomized Clinical Trials ◽  
Radiation Therapy Oncology Group ◽  
Gene Promoter ◽  
Newly Diagnosed ◽  
Newly Diagnosed Glioblastoma

Purpose Symptomatic epilepsy is a common complication of glioblastoma and requires pharmacotherapy. Several uncontrolled retrospective case series and a post hoc analysis of the registration trial for temozolomide indicated an association between valproic acid (VPA) use and improved survival outcomes in patients with newly diagnosed glioblastoma. Patients and Methods To confirm the hypothesis suggested above, a combined analysis of survival association of antiepileptic drug use at the start of chemoradiotherapy with temozolomide was performed in the pooled patient cohort (n = 1,869) of four contemporary randomized clinical trials in newly diagnosed glioblastoma: AVAGlio (Avastin in Glioblastoma; NCT00943826), CENTRIC (Cilengitide, Temozolomide, and Radiation Therapy in Treating Patients With Newly Diagnosed Glioblastoma and Methylated Gene Promoter Status; NCT00689221), CORE (Cilengitide, Temozolomide, and Radiation Therapy in Treating Patients With Newly Diagnosed Glioblastoma and Unmethylated Gene Promoter Status; NCT00813943), and Radiation Therapy Oncology Group 0825 (NCT00884741). Progression-free survival (PFS) and overall survival (OS) were compared between: (1) any VPA use and no VPA use at baseline or (2) VPA use both at start of and still after chemoradiotherapy. Results of Cox regression models stratified by trial and adjusted for baseline prognostic factors were analyzed. The same analyses were performed with levetiracetam (LEV). Results VPA use at start of chemoradiotherapy was not associated with improved PFS or OS compared with all other patients pooled (PFS: hazard ratio [HR], 0.91; 95% CI, 0.77 to 1.07; P = .241; OS: HR, 0.96; 95% CI, 0.80 to 1.15; P = .633). Furthermore, PFS and OS of patients taking VPA both at start of and still after chemoradiotherapy were not different from those without antiepileptic drug use at both time points (PFS: HR, 0.92; 95% CI, 0.74 to 1.15; P = .467; OS: HR, 1.10; 95% CI, 0.86 to 1.40; P = .440). Similarly, no association with improved outcomes was observed for LEV use. Conclusion The results of this analysis do not justify the use of VPA or LEV for reasons other than seizure control in patients with newly diagnosed glioblastoma outside clinical trials.

A phase III randomized controlled trial of short-course radiotherapy with or without concomitant and adjuvant temozolomide in elderly patients with glioblastoma (CCTG CE.6, EORTC 26062-22061, TROG 08.02, NCT00482677).

2016 ◽  
Vol 34 (18_suppl) ◽  
pp. LBA2-LBA2 ◽  
Author(s):  
James R. Perry ◽  
Normand Laperriere ◽  
Christopher J. O'Callaghan ◽  
Alba Ariela Brandes ◽  
Johan Menten ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Controlled Trial ◽  
Phase Iii ◽  
Newly Diagnosed ◽  
Adjuvant Temozolomide ◽  
Short Course ◽  
Newly Diagnosed Glioblastoma ◽  
To Receive ◽  
Short Course Radiotherapy ◽  
Clinical Trial Information

LBA2 Background: The EORTC (26981-22981)/NCIC CTG (CE.3) RCT in newly diagnosed glioblastoma (GB) showed increased overall survival (OS) with concomitant and adjuvant temozolomide (TMZ) added to radiotherapy (RT). Pts were 18-71 (median 56) years; however, a trend of decreasing benefit from the addition of TMZ with increasing age was noted. Recent RCTs in elderly GB detected non-inferiority of 40 Gy/15 v 60 Gy/30 RT and superior survival was noted for MGMT-methylated pts treated with TMZ alone. However, whether the addition of TMZ to RT improves survival in elderly pts remained unanswered. Methods: We conducted a global randomized phase III clinical trial for patients ≥ 65 yrs with histologically confirmed newly diagnosed GB, ECOG 0-2, randomized 1:1 to receive 40Gy/15 RT v 40Gy/15 RT with 3 weeks of concomitant TMZ plus monthly adjuvant TMZ until progression or 12 cycles. Stratification was by centre, age (65-70, 71-75, or 76+), ECOG 0,1 vs 2, and biopsy vs resection. Results: 562 pts were randomized, 281 on each arm; median age 73 yrs (range 65-90), male 61%, PS 0/1 77%, resection 68%. RT+TMZ significantly improved OS over RT alone (median 9.3m v 7.6m, HR 0.67, 95%CI 0.56-0.80, p < 0.0001) and significantly improved PFS (median 5.3m v 3.9m, HR 0.50, 95%CI 0.41 – 0.60, p < 0.0001). Tissue from 462 pts was provided and adequate for MGMT analysis in 354 to date. In MGMT methylated patients (n = 165) OS for RT+TMZ v RT was 13.5 m and 7.7m respectively (HR: 0.53 (95% C.I. 0.38, 0.73, p = 0.0001). In MGMT unmethylated patients (n = 189) OS for RT + TMZ v RT was 10.0m vs 7.9m respectively (HR 0.75 (95% C.I. 0.56 – 1.01, p = 0.055). QoL analyses showed no differences in functional domains of QLQC30 and BN20 but were worse in the RT/TMZ arm for nausea, vomiting, and constipation. Systemic therapy after PD was reported in 39% on RT+TMZ v 41% on RT. Conclusions: The addition of concomitant and adjuvant TMZ to hypofractionated RT for elderly pts with GB significantly improves OS and PFS in all patients and is well tolerated. Patients with MGMT methylated tumors benefit the most from the addition of TMZ to RT where median OS is nearly doubled. Clinical trial information: NCT00482677.

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