Cancer Medications : Temodar, Velcade

by National Cancer Institute

(Page 17 of 18)

Temodar

On March 15, 2005, the FDA 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).

Thalomid®

On May 26, 2006, the FDA granted accelerated approval for thalidomide (THALOMID®, made by the Celgene Corporation) in combination with dexamethasone for the treatment of newly diagnosed multiple myeloma (MM) patients.

Because of thalidomide's known teratogenicity, the FDA is controlling thalidomide's marketing in the United States via the System for Thalidomide Education and Prescribing Safety (S.T.E.P.S.®) program. This mandatory registry includes authorized patients, prescribers and pharmacies, extensive patient education regarding thalidomide's safety, and is designed to prevent fetal exposure to thalidomide during pregnancy.

Thalidomide was evaluated in 207 patients with newly diagnosed MM in one open-label, multicenter, cooperative group trial. Patients were randomized to four cycles of thalidomide 200 mg daily plus dexamethasone (Thal/Dex) or to dexamethasone (Dex) alone. Response rates based on serum or urine paraprotein measurements were significantly higher in the combination arm than Dex alone (51.5 percent vs. 35.6 percent, respectively, p = 0.025). After completing treatment, patients were encouraged to undergo stem cell transplantation.

The incidence of grade 3 or 4 adverse events was 84.3 percent on the Thal/Dex arm and 73.5 percent on the Dex alone arm. The most common toxicities associated with thalidomide were somnolence, constipation, neuropathy, venous thromboembolism (VTE), and rash.

The incidence of VTE was significantly higher in the Thal/Dex arm than with Dex alone (22.5 percent vs. 4.9 percent, respectively, p = 0.002). Prophylactic antithrombotic therapy prescribed with thalidomide may reduce VTE; however, the decision to prescribe antithrombotic therapy should be made after a careful assessment of the patient's underlying risk factors.

This approval is based on objective response rates and is approved under accelerated approval regulations (Subpart H) requiring further clinical trials to demonstrate thalidomide's clinical benefit in the treatment of multiple myeloma.

Velcade

On May 13, 2003, under accelerated approval provisions, the FDA approved bortezomib (Velcade®, a trademark of Millennium Pharmaceuticals, Inc.) for the treatment of multiple myeloma patients who have received at least two prior therapies and have demonstrated disease progression on the last therapy.

Subsequently, on March 25, 2005, the FDA approved bortezomib for the treatment of patients with multiple myeloma who have received at least one prior therapy.

Clinical data for May 13, 2003, accelerated approval

Bortezomib was evaluated in 256 patients with multiple myeloma in two open-label multicenter studies conducted in the United States. In the primary efficacy study, 202 patients were entered after having received at least two prior therapies and progressing on the most recent therapy. Bortezomib was administered intravenously at 1.3 milligrams (mg) /m2/dose twice weekly for two weeks, followed by a 10-day rest period (21 day treatment cycle) for a maximum of eight treatment cycles. In the study population, the median number of prior therapies was six, and 64 percent of patients had received stem cell transplant or other high dose therapy. Results (Blade criteria) in the 188 eligible and evaluable patients included complete responses in five patients, for a complete response rate of 2.7 percent (95 CI: 1 percent, 6 percent); partial responses occurred in 47 patients for a PR rate of 25 percent (95 CI: 19 percent, 32 percent). Clinical remissions by SWOG criteria were observed in 17.6 percent of patients (95CI: 12 percent, 24 percent). Median duration of response was 365 days.

Adverse events (AEs) occurring in greater than 50 percent of patients included fatigue or malaise, nausea, and diarrhea. AEs occurring in greater than 30 percent of patients were anorexia, constipation, thrombocytopenia, peripheral neuropathy, pyrexia, vomiting, and anemia. Severe AEs with incidences greater than 10 percent were thrombocytopenia, peripheral neuropathy, neutropenia and asthenia.

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