FDA Approval for Temozolomide
- Approved for glioblastoma multiforme
Full prescribing information is available, including clinical trial information, safety, dosing, drug-drug interactions and contraindications.
On March 15, 2005, the U.S. Food and Drug Administration approved temozolomide (Temodar® capsules, made by Schering Corporation) for the treatment of adult patients with newly diagnosed glioblastoma multiforme (GBM) concomitantly with (at the same time as) radiotherapy and then as maintenance treatment. GBM is a severe form of brain cancer.
Temozolomide (TMZ) previously received accelerated approval in 1999 for the treatment of adult patients with refractory anaplastic astrocytoma. This treatment indication is also converted to full approval based on the results of the GBM study described below.
Safety and efficacy were demonstrated in a phase III study conducted by the European Organization for Research and Treatment of Cancer (EORTC) in newly diagnosed GBM patients. Five hundred and seventy-three patients were randomized to receive either TMZ plus radiotherapy (RT) (n= 287) or RT alone (n=286).
Patients in the TMZ + RT arm received concomitant TMZ (75 mg/m2) once daily, starting the first RT day until the last RT day, for 42 days (maximum 49 days). Six cycles of TMZ alone (150 or 200 mg/m2) followed on days 1-5 of every 28-day cycle, starting four weeks after the RT end. Patients in the control arm received RT only.
In both arms RT was delivered as 60 Gy/30 fractions to the tumor bed or resection (surgery) site with a 2-3 cm margin. Pneumocystis carinii pneumonia (PCP) prophylaxis was required during the TMZ + RT treatment, regardless of lymphocyte count, and was to continue until recovery of lymphocytopenia (CTC grade <1). At disease progression, patients in either study arm could receive TMZ treatment.
The TMZ + RT and the RT-only treatment arms were well matched with regard to baseline demographic characteristics. Approximately 60 percent were male and approximately 70 percent were >50 years of age. A total of 88 percent in both treatment groups had a WHO performance status of 0 or 1 and 84 percent had undergone debulking surgery within six weeks of study entry.
At the time of disease progression, TMZ was administered to 161 patients of the 282 (57 percent) in the RT alone arm, and 62 patients of the 277 (22 percent) in the TMZ + RT arm.
Significant improved overall survival in patients receiving concomitant and maintenance TMZ + RT was observed. The hazard ratio was 0.63 (95 percent CI for HR=0.52-0.75) with a log-rank p <0.0001 in favor of the combined modality arm. Median survival was 14.6 months (TMZ + RT) versus 12.1 months (RT alone).
Adverse events during TMZ + RT treatment included thrombocytopenia (an abnormally low number of platelets, which help blood to clot), nausea, vomiting, anorexia, and constipation. The most common adverse events across the total TMZ exposure were alopecia (hair loss), nausea, vomiting, anorexia, headache, and constipation. Forty-nine percent (49 percent) of patients treated with TMZ reported one or more severe or life-threatening events, most commonly fatigue (13 percent), convulsions (6 percent), headache (5 percent), and thrombocytopenia (5 percent).
The FDA is the division of the U.S. Department of Health and Human Services charged with ensuring the safety and effectiveness of new drugs and other products. (See "Understanding the Approval Process for New Cancer Treatments.") The FDA's mission is to promote and protect the public health by helping safe and effective products to reach the market in a timely way, and monitoring products for continued safety after they are in use.