An update of phase II results from RTOG 0211: A phase I/II study of gefitinib with radiotherapy in newly diagnosed glioblastoma

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 1527-1527 ◽  
Author(s):  
A. Chakravarti ◽  
B. Berkey ◽  
H. I. Robins ◽  
A. Guha ◽  
W. J. Curran ◽  
...  
Keyword(s):  
Phase I ◽  
Median Survival ◽  
Phase Ii ◽  
Kinase Inhibitor ◽  
Statistical Significance ◽  
Radiation Therapy Oncology Group ◽  
Newly Diagnosed ◽  
Genetic Profiling ◽  
Newly Diagnosed Glioblastoma ◽  
Historical Controls

1527 Background: The epidermal growth factor receptor (EGFR) pathway is commonly deregulated in GBMs and its activity has been associated with treatment resistance in preclinical models. Accordingly, the Radiation Therapy Oncology Group (RTOG) recently conducted a Phase I/II study of Gefitinib, an EGFR tyrosine kinase inhibitor, in combination with radiotherapy for newly-diagnosed glioblastoma (GBM) patients. Methods: 178 GBM patients were entered on RTOG 0211 (Phase I: 31 patients and Phase II: 147 patients). The maximum tolerated dose (MTD) of Gefitinib was determined to be 500mg in non-EIACD patients, and the Phase II component of RTOG 0211 was continued at this dose level during radiation and as maintenance for 18 months afterward or until disease progression. Results: 119/147 patients completed treatment per protocol and/or with acceptable deviation. The median survival time for all patients in the study was 11.0 months. Progression-free survival was 5.1 months for all patients. When considering only patients who were treated per protocol, the median survival of RTOG 0211 patients was 11.5 months, compared to 11.0 months for historical controls treated in previous RTOG studies (p=0.14). RPA Class IV patients appeared to derive the greatest benefit from Gefitinib when combined with radiotherapy compared to historical controls, although not reaching statistical significance. Molecular and genetic profiling efforts are underway to determine which GBM patients derive greatest benefit from Gefitinib in the upfront setting, which will be reported at the time of the annual meeting. These include markers such as EGFRvIII and PTEN, which have been recently reported to be associated with response to anti-EGFR agents in the recurrent setting, and members of key signal transduction pathways regulated by EGFR. Conclusions: The observed survival advantage of newly-diagnosed GBM patients treated with Gefitinib in combination with radiotherapy compared to historical controls treated on previous RTOG studies does not reach statistical significance. Molecular and genetic profiling efforts are underway to identify subsets of GBM patients who might derive the greatest benefit from Gefitinib in the upfront setting. No significant financial relationships to disclose.

EORTC Study 26041–22041: Phase I/II study on concomitant and adjuvant temozolomide (TMZ) and radiotherapy (RT) with or without PTK787/ZK222584 (PTK/ZK) in newly diagnosed glioblastoma—Results of a phase I trial

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 2026-2026 ◽  
Author(s):  
A. A. Brandes ◽  
R. Stupp ◽  
P. Hau ◽  
S. Sleijfer ◽  
D. Lacombe ◽  
...  
Keyword(s):  
Phase I ◽  
Kinase Inhibitor ◽  
Standard Dose ◽  
Dose Finding ◽  
Hepatic Toxicity ◽  
Newly Diagnosed ◽  
Triple Combination ◽  
Adjuvant Temozolomide ◽  
Newly Diagnosed Glioblastoma ◽  
Fixed Standard

2026 Background: VEGF is an essential mediator of angiogenesis. PTK/ZK is an orally available tyrosine kinase inhibitor of all known VEGF receptors. The EORTC has initiated a randomized phase I/II study in which PTK/ZK is being investigated in combination with standard RT and concomitant TMZ. The results of the safety and dose-finding run-in of the triple combination are reported here. Methods: Escalating doses of PTK/ZK QD continuously (using classical 3+3 design) and concomitant RT (60 Gy) and TMZ (75 mg/m2/day) during 6–7 weeks were to be administered. During the adjuvant/maintenance part, PTK/ZK was prescribed at a fixed standard dose of 750mg bid until progression. Dose limiting toxicities (DLT) were defined as >G3 toxicity occurring during RT + 2 weeks. Results: 18 GBM pts (M/F: 11/7, median age: 53 years, PS 0/1) have been enrolled and complete data for 15 pts are currently available. DL1 (500 mg): 4 pts; no DLT; DL2 (1000 mg): 6 pts: 1 DLT: G3, liver enzyme (ALAT) elevation and hyponatremia DL3 (1250 mg); 8 pts: 3 DLTs: G3 hepatic toxicity (2 pts) and G3 platelets and G4 neutrophil (1 pt). In a 4th patient a G3 diarrhea and hepatic DLT leading to PTK/ZK interruption was doubtful therefore it was decided to extend DL3. Frequently observed possibly related non-dose limiting drug adverse events of all grades included: abdominal pain/cramping (2 pts), ALAT/ASAT elevation (10 pts), creatinine elevation (2 pts), allergic reaction (2 pts), constipation (4 pts), diarrhea (5 pts), fatigue (11 pts), hypertension (6 pts), nausea (8 pts), vomiting (3 pts), and weight loss (4 pts). All toxicities were reversible. Conclusions: MTD has been reached at 1250 mg and the recommended dose of PTK/ZK in combination with RT and TMZ is 1000 mg/day. A randomized 3-arm phase II will start accrual in January 2007. Patients will receive standard TMZ/RT alone or with PTK/ZK starting at the beginning of radiotherapy or at the beginning of adjuvant therapy 4 weeks after the end of radiotherapy. [Table: see text]

Phase I trial of vatalanib (PTK787) in combination with standard radiation and temozolomide in patients with newly diagnosed glioblastoma

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 2035-2035
Author(s):  
T. Batchelor ◽  
A. F. Eichler ◽  
S. R. Plotkin ◽  
J. Drappatz ◽  
P. Wen ◽  
...  
Keyword(s):  
Phase I ◽  
Kinase Inhibitor ◽  
Wound Dehiscence ◽  
Recurrent Glioblastoma ◽  
Newly Diagnosed ◽  
Study Results ◽  
Diagnostic Biopsy ◽  
Newly Diagnosed Glioblastoma ◽  
Grade 3 ◽  
Endothelial Growth Factor

2035 Background: Anti-vascular endothelial growth factor (VEGF) agents are hypothesized to work synergistically with chemotherapy and radiation (RT). Vatalanib (MW 347, T1/2 4.6 h) is an oral, pan-VEGFR tyrosine kinase inhibitor that has shown activity in patients with recurrent glioblastoma. Methods: This phase I study was designed to determine the maximal tolerated dose of vatalanib in combination with RT and TMZ for patients with newly diagnosed GBM who were taking enzyme-inducing anti-epileptic drugs. RT and TMZ were administered at standard doses. Vatalanib was initiated 5 days prior to the start of RT and continued daily until tumor progression, unacceptable toxicity or a maximum of up to 12 cycles of post-RT TMZ. Cohorts of 3 patients were treated during RT and TMZ at doses of 250mg daily, 250mg BID, or 500mg BID of vatalanib. Following the completion of RT, patients were treated with vatalanib 750mg BID for the remainder of the study. Results: Nineteen patients were enrolled of which 17 took 5 or more days of vatalanib (1 patient withdrew consent prior to start of vatalanib and 1 withdrew consent after only 1 dose). The median age was 58 and the median KPS was 90. Eight patients had a diagnostic biopsy only. The MTD has not been reached. Potentially related grade 3–4 toxicities included elevated transaminases (2 patients), thrombocytopenia (1 patient), leukopenia (1 patient), neutropenia (1 patient), depressed level of consciousness (1 patient), and fatigue (1 patient). Only 1 patient suffered an asymptomatic intracerebral hemorrhage and no patient experienced wound dehiscence or infection. Five patients remain on vatalanib and the median follow-up for all patients is 6.5 months. Seven patients have died. The best responses for the 13 patients who completed combination RT/TMZ/vatalanib was 2 PR, 7 SD, and 2 PD. Two patients were clinically stable with biopsy proven pseudoprogression. Median PFS is 18.4+ months and OS has not been reached. Conclusions: Vatalanib is safe and well tolerated when added to standard RT and TMZ. The MTD has not been reached and dose escalation continues in this population of patients on enzyme inducing anti-epileptic drugs. [Table: see text]

NABTT 0306: A randomized phase II trial of EMD 121974 in conjunction with concomitant and adjuvant temozolomide with radiation therapy in patients with newly diagnosed glioblastoma multiforme (GBM)

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 2001-2001 ◽  
Author(s):  
L. B. Nabors ◽  
T. Mikkelsen ◽  
T. Batchelor ◽  
G. Lesser ◽  
M. Rosenfeld ◽  
...  
Keyword(s):  
Overall Survival ◽  
Median Survival ◽  
Phase Ii ◽  
Phase Ii Trial ◽  
Methylation Status ◽  
Newly Diagnosed ◽  
Integrin Receptor ◽  
Randomized Phase Ii ◽  
Newly Diagnosed Glioblastoma ◽  
Dose Levels

2001 Background: EMD 121974 (cilengitide) is a selective integrin receptor inhibitor that is well tolerated and has demonstrated biological activity in patients with malignant glioma. The objectives of this phase II trial were to determine safety when combined with chemoradiation and estimate the overall survival for two different doses in newly diagnosed GBM. Methods: A total of 112 patients were accrued onto the trial through the NABTT CNS consortium. Cilengitide was administered by one-hour infusion twice a week with 18 patients treated in a safety run-in phase of 6 patients at the tested dose levels of 500 mg, 1000 mg, and 2000 mg. After safety completion, 94 patients were randomly assigned to either 500 mg or 2000 mg groups. To date, 55 out of 112 (49%) patients have died. Overall survival was estimated using all patients in this trial regardless of their treating dose. Results: The median age was 55 years old (range: 22–88) and the median KPS was 90 (range: 60–100). 86 out of the 112 (76.8%) had a craniotomy as their initial surgical procedure and 25 patients (22%) had a biopsy. There were no DLTs during the safety run-in phase. The estimated median survival time is 18.9 months (95% CI: 16.3 -30.0 months) for patients treated with RT+TMZ+EMD. The trial was closed to accrual on December 31, 2007. To date, 89 out of 112 patients were alive 12 months from their initial diagnosis. The overall survival at 12 months for all patients is 79.5% (95% CI: 71–87%). MGMT methylation status and survival based on dose levels received are not currently available. Conclusions: EMD 121974 (cilengitide) is well-tolerated when combined with standard chemoradiation (TMZ+RT) and may improve survival for patients newly diagnosed with GBM given the substantial differences between the estimated median survival and that seen in the EORTC study (Stupp, N Engl J Med, 2005). [Table: see text]

scholarly journals Talampanel With Standard Radiation and Temozolomide in Patients With Newly Diagnosed Glioblastoma: A Multicenter Phase II Trial

2009 ◽  
Vol 27 (25) ◽  
pp. 4155-4161 ◽  
Author(s):  
Stuart A. Grossman ◽  
Xiaobu Ye ◽  
Marc Chamberlain ◽  
Tom Mikkelsen ◽  
Tracy Batchelor ◽  
...  
Keyword(s):  
Median Survival ◽  
Ampa Receptors ◽  
Dna Methyltransferase ◽  
Karnofsky Performance Score ◽  
Newly Diagnosed ◽  
Methylguanine Dna Methyltransferase ◽  
Newly Diagnosed Glioblastoma ◽  
And Migration ◽  
Historical Controls

Purpose Recent data suggest that the glutamatergic system is important in the proliferation and migration of glioblastoma. Talampanel is a well-tolerated, oral α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor blocker that could be beneficial in this disease. Patients and Methods This trial was designed to estimate overall survival in adults with newly diagnosed glioblastoma treated with talampanel in addition to standard radiation (RT) and temozolomide (TMZ). A secondary purpose was to evaluate talampanel toxicity in this setting. Talampanel was initiated with RT + TMZ and discontinued for toxicity or disease progression. Survival was compared with historical controls. Results Seventy-two patients were enrolled from December 2005 to July 2006. Their median age was 60 years (range, 37 to 85 years, with 17% > 70 years), median Karnofsky performance score was 90 (range, 70 to 100), and 77% had a debulking procedure. With a median follow-up time of 18 months, 55 patients (76%) have died, yielding a median survival time of 18.3 months (95% CI, 14.6 to 22.5 months). When the 60 patients who were 18 to 70 years old were compared with the European Organisation for Research and Treatment of Cancer (EORTC) RT + TMZ data, the median survival (20.3 v 14.6 months, respectively) and percentage of patients surviving at 24 months (41.7% v 26.5%, respectively; P = .02) seemed superior. The percentage of patients methylated at O6-methylguanine–DNA methyltransferase was lower than on the EORTC study (29% v 43%, respectively). Talampanel was well tolerated and did not increase the known hematologic or nonhematologic toxicities of TMZ. Conclusion Talampanel can be added to RT + TMZ without significant additional toxicity. The encouraging survival results in methylated and unmethylated patients suggest that blocking AMPA receptors may be a useful strategy in newly diagnosed glioblastoma.

scholarly journals ATIM-41. PHASE II TRIAL OF A SURVIVIN VACCINE (SurVaxM) For Newly Diagnosed Glioblastoma

2018 ◽  
Vol 20 (suppl_6) ◽  
pp. vi10-vi11 ◽  
Author(s):  
Manmeet Ahluwalia ◽  
David Reardon ◽  
Ajay Abad ◽  
William Curry ◽  
Eric Wong ◽  
...  
Keyword(s):  
Phase Ii ◽  
Phase Ii Trial ◽  
Newly Diagnosed ◽  
Newly Diagnosed Glioblastoma
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