Cancer Medications : Velcade, Vidaza, Xeloda

by National Cancer Institute

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Clinical data for May 25, 2005, approval

The previous accelerated approval was based on response rate and response durability. The post-marketing commitments have been fulfilled with the results of the trial described below.

Safety and efficacy were demonstrated in one multicenter, controlled clinical trial of 669 myeloma patients who had received at least one prior therapy. These patients were randomized to receive either bortezomib, 1.3 mg/m2 intravenous bolus on days 1, 4, 8, 11 of each three week cycle for eight weeks or dexamethasone, 40 mg/day by mouth once daily on Days 1 to 4, 9 to 12, and 17 to 20 every five weeks for four cycles. Each arm also had a reduced-dose schedule for further treatment cycles. The primary endpoint was time-to-progression (TTP). Following a planned interim analysis, the study was terminated early on the advice of a Data Monitoring Committee.

Bortezomib demonstrated a statistically significant improvement in TTP (HR=0.55, [0.44, 0.69], p <0.0001) and response rate (38 percent versus 18 percent; p < 0.0001). Overall survival was prolonged for patients on the bortezomib arm (HR=0.57, p value < 0.05) compared to the dexamethasone arm.

Adverse events were similar to those previously reported for bortezomib. Among the 331 patients treated with bortezomib, the most commonly reported adverse events were asthenic conditions, diarrhea, nausea, fatigue, constipation, peripheral neuropathy, vomiting, pyrexia, thrombocytopenia, anemia, headache, anorexia, cough, and paresthesia. Other adverse events included dyspnea, neutropenia, rash, insomnia, and bone pain. Myelosuppression was moderate in degree and reversible. Neuropathy was slowly reversible. Heart failure and possible tumor lysis syndrome were added to the label warnings in mid-2004.

Vidaza

On May 19, 2004, the FDA approved azacitidine for injectable suspension (Vidaza™, made by Pharmion Corporation) for use in patients with all subtypes of myelodysplastic syndromes. Approval was based on response rates supported by reduction or elimination of transfusion dependence.

Safety and efficacy were demonstrated in one multicenter, randomized trial in 191 patients with all five French, American and British subtypes of myelodysplastic syndromes comparing azacitidine treatment to observation only, and in two multicenter single-arm azacitidine trials in 120 patients.

Azacitidine was administered at a dose of 75 mg/m2/day for 7 days every 28 days subcutaneously in the randomized trial and in one of the single-arm trials. Patients in the "observation only" arm of the randomized trial were permitted to cross over to Vidaza treatment. Greater than 50 percent of observation only patients crossed over to Vidaza treatment at the time of disease progression. Patients with an adjudicated diagnosis of AML at baseline were excluded from the efficacy analysis of response rate.

Clinical response (complete and partial) was observed in approximately 16 percent of the azacitidine patients. The response rates were similar in patients randomized to Vidaza treatment (15.7 percent), in patients who crossed over from the observation arm to Vidaza treatment (12.8 percent), and in patients in the two single arm trials (12.7 percent and 19.1 percent). None of the patients in the observation only arm had clinical response. The difference in response rates between Vidaza treated patients and "observation only" patients was statistically significant (p<0.0001).

Median response duration was greater than 330 days in the randomized trial. The response duration could not be accurately estimated, because most patients remained in response status at the time of study completion. In addition to complete and partial responses, approximately 24 percent of Vidaza-treated patients had either reduction of the need for transfusions and/or ≤50 percent normalization of blood cell counts and/or bone marrow blast percentages.

The major toxicity of azacitidine was myelosuppression, as manifested by thrombocytopenia (and bleeding), neutropenia (and infections), and anemia. Myelosuppression decreased with the onset of a response.

Other common adverse events were gastrointestinal (nausea, vomiting, diarrhea, constipation, anorexia), constitutional (fatigue, weakness, fever, rigors), musculoskeletal (arthralgia, pain in limb), pulmonary (cough, dyspnea), and skin and soft tissue (ecchymoses, rash, erythema).

Xeloda

On June 15, 2005, the FDA approved capecitabine (Xeloda® Tablets, made by Hoffman-LaRoche Inc.) as a single-agent adjuvant treatment for Dukes' stage C colon cancer patients who have undergone complete resection of the primary tumor in those instances when fluoropyrimidine therapy alone would be preferred.

Dukes' stage C colon cancer is when the cancer has spread outside the colon to one or more lymph nodes; also called stage III colon cancer.

Approval is based on non-inferiority in disease-free survival (DFS) to bolus 5-fluorouracil plus leucovorin (5-FU/LV). In 2004, the FDA approved oxaliplatin for injection (Eloxatin™) in combination with infusional 5-FU/LV for adjuvant stage III colon cancer. Although neither capecitabine nor the combination of oxaliplatin plus 5-FU/LV prolonged overall survival in the adjuvant setting, the combination chemotherapy regimen was associated with an improvement in DFS compared to 5-FU/LV in stage III colon cancer. Physicians should consider these results when prescribing single-agent capecitabine in the adjuvant treatment of Dukes' C colon cancer.

Safety and efficacy for capecitabine in the adjuvant indication were demonstrated in one multicenter, randomized, open-label, international clinical trial. There were 1987 patients with stage C colon cancer who had undergone complete resection of the primary tumor. The patients were equally randomized to one of two arms: capecitabine (1250 mg/m2 twice daily for 14 days followed by seven days rest, repeated every 21 days for eight cycles) or bolus 5-FU/LV (Mayo Clinic regimen).

At a median follow-up of 4.4 years, a non-inferiority analysis for the primary endpoint of DFS in the all randomized population showed capecitabine retained at least 75 percent of the active control effect of 5-FU/LV. The three-year DFS rates for capecitabine and 5-FU/LV were 66 percent and 63 percent, respectively (hazard ratio 0.87, 95 percent CI: 0.76-1.00; test for difference: p = 0.055). No statistical difference in overall survival was shown between the treatment arms in the all randomized population (hazard ratio 0.88, 95 percent CI: 0.74-1.05; p = 0.17).

The incidence of grade 3 or 4 adverse events was 36 percent on the capecitabine arm and 35 percent on the 5-FU/LV arm. The most common capecitabine toxicities (diarrhea, stomatitis, nausea, and palmar-plantar erythrodysesthesia) are described in the current label, and in 93 percent of cases were reversible within 30 days. The incidence of febrile neutropenia or neutropenic sepsis was less than 1 percent.

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