"Sabahaddin Akman, owner of the Istanbul, Turkey, firm Ozay Pharmaceuticals, has pleaded guilty to charges of smuggling misbranded and adulterated cancer treatment drugs into the United States.
Akman pleaded guilty in the U.S. District Court"...
Mechanism of Action
The activity of GLIADEL Wafer is due to release of cytotoxic concentrations of carmustine, a DNA and RNA alkylating agent, into the tumor resection cavity. On exposure to the aqueous environment of the resection cavity, the anhydride bonds in the copolymer are hydrolyzed, releasing carmustine, carboxyphenoxypropane, and sebacic acid into the surrounding brain tissue.
Carmustine concentrations delivered by GLIADEL Wafer in human brain tissue have not been determined.
Following an intravenous infusion of carmustine at doses ranging from 30 to 170 mg/m², the average terminal half-life, clearance and steady-state volume of distribution were 22 minutes, 56 mL/min/kg and 3.25 L/kg, respectively. Approximately 60% of the intravenous 200-mg/m² dose of 14C-carmustine was excreted in the urine over 96 hours and 6% was expired as CO2. Carmustine degrades both spontaneously and metabolically. The relevance of these data to elimination of intracranial implant-delivered carmustine are unknown.
GLIADEL Wafers are biodegradable when implanted into the human brain. Wafer remnants may be observed on brain imaging scans or at re-operation. Wafer remnants were visible in 11 of 18 patients on CT scans obtained 49 days after implantation of GLIADEL Wafer. More than 70% of the copolymer degrades within three weeks. Wafer remnants have been present at re-operation and autopsy up to 232 days after GLIADEL Wafer implantation, and consisted mostly of water and monomeric components with minimal detectable carmustine present.
Newly-Diagnosed High-Grade Malignant Glioma
Study 1 was a multicenter, double-blind, placebo-controlled, clinical trial in adult patients with newly-diagnosed high-grade malignant glioma. A total of 240 patients were randomized (1:1) to receive up to eight GLIADEL Wafers or matched placebo wafers following maximal tumor resection. Patients received post-operative radiation therapy (5560 Gy delivered in 28 to 30 fractions over six weeks) starting three weeks after surgery. Patients with anaplastic oligodendroglioma also received systemic chemotherapy (6 cycles of PCV- lomustine 110 mg/m² day 1, procarbazine 60 mg/m² days 8-21, vincristine 1.4 mg/m² days 8 and 29).
The population in Study 1 was 67% male, 97% white, the median age was 53 years (range: 21-72). Eighty-seven per cent had a Karnofsky performance status ≥ 70% and 71% had a Karnofsky performance status of ≥ 80%. Seventy-eight percent had a histologic subtype of glioblastoma multiforme as determined by central pathology review. Thirty-eight percent of patients received 8 wafers and 78% received ≥ 6 wafers. Starting three weeks after surgery, 80% of patients received standard limited field radiation therapy (RT) described as 55-60 Gy delivered in 28 to 30 fractions over six weeks; 11% received radiotherapy and the remainder received non-standard radiotherapy or a combination of standard and non-standard radiotherapy. At the time of progression, 12% received systemic chemotherapy. Patients were followed for at least three years or until death.
Efficacy results for patients randomized in Study 1 are summarized in Table 6 and Figure 6. Overall survival among all patients with newly diagnosed high grade glioma, the primary outcome measure, was prolonged in the GLIADEL arm. Overall survival in the subset of patients with glioblastoma multiforme, a secondary outcome measure, was not significantly prolonged.
Table 6: Overall Survival in Patients with Newly
Diagnosed Glioma, Study 1.
|Overall Survival – ITT*||Gliadel Wafer
|Number of deaths, n (%)||111 (93%)||117(98%)|
|Median overall survival, months (95% CI)||13.9 (12.1, 15.1)||11.6 (10.2, 12.7)|
|Hazard ratio (95% CI)||0.73 (0.56, 0.95)|
|Log-Rank test p-value||< 0.02**|
|*Based on a post-final
analysis, protocol specified non-stratified log-rank test.
**p-value not adjusted for multiple comparisons
Figure 6 : Overall Survival
for Patients with Newly Diagnosed High-Grade Malignant Glioma – Kaplan-Meier
Curves by Treatment Group*
*Based on a post-final analysis, protocol specified non-stratified log-rank test; p-value not adjusted for multiple comparisons
Recurrent Glioblastoma Multiforme
Study 2 was a multicenter, double-blind, placebo controlled, clinical trial in adult patients with recurrent malignant glioma. Patients were required to have had prior definitive external beam radiation therapy sufficient to disqualify them from additional radiation therapy. Following maximal tumor resection and confirmation of malignant glioma, a total of 222 patients were randomized (1:1) to receive a maximum of eight GLIADEL Wafers (n=110) or matched placebo wafers (n=112) positioned to cover the entire resection surface. All patients were eligible to receive chemotherapy which was withheld at least four weeks (six weeks for nitrosoureas) prior to and two weeks after surgery. Patients were followed for up to 71 months.
The population in Study 2 was 64% male, 92% white, and had a median age of 49 years (range: 19-80). Sixty-five percent had a histologic subtype of glioblastoma multiforme, 26% had anaplastic astrocytoma or another anaplastic variant, 73% had a Karnofsky performance status ≥ 70, 53% had a Karnofsky performance status of ≥ 80%, 73% had only one prior surgery, and 46% had prior treatment with nitrosourea. Eighty-one percent of patients received 8 wafers and 96% received ≥ 6 wafers.
Survival and 6-month mortality rate in the subgroup of patients with recurrent glioblastoma multiforme, were exploratory outcome measures and are summarized in Table 7 and Figures 7 and 8. No survival prolongation was observed in patients with pathologic diagnoses other than glioblastoma multiforme.
Table 7: Main Efficacy Outcome Measures in Patients
with Recurrent Gliomablastoma Multiforme, Study 2.
|GLIOBLASTOMA MULTIFORME||Gliadel Wafer
|Number of deaths, n (%)||32||47|
|6-month survival rate (%)||56%||36%|
|Log-Rank test p-value Gehan's generalized||0.013**|
|Wilcoxon Test p-value||0.015**|
|Number of deaths, n (%)||71 (99%)||72 (99%)|
|Median overall survival (95% CI (months)||6.51 (5.32, 7.49)||4.63 (3.78, 5.52)|
|Log-Rank test p-value||0.181**|
|Gehan's generalized Wilcoxin Test p-value||0.021**|
|**p-value not adjusted for multiple comparisons|
Figure 7: 6-Month Survival for Patients with Recurrent Glioblastoma
Multiforme– Kaplan-Meier Curves by Treatment Group
Figure 8: Overall Survival (months) for
Patients with Recurrent Glioblastoma Multiforme– Kaplan-Meier Curves by
Last reviewed on RxList: 9/4/2013
This monograph has been modified to include the generic and brand name in many instances.
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