American Society of Clinical Oncology: Denileukin Diftitox (Ontak)

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Patients with cutaneous T-cell lymphoma (CTCL) experienced durable major responses with good tolerability when they were treated with denileukin diftitox (Ontak, Seragen/ Ligand), according to results of a phase 3 clinical trial. A recombinant DNA-derived cytotoxic protein, denileukin diftitox (Dd) was approved by the Food and Drug Administration (FDA) for patients with persistent or recurrent cutaneous T-cell lym-phoma whose malignant cells express the CD25 component of the interleukin-2 (IL-2) receptor.

Professor Prince reported that Dd was evaluated at two dose levels: 9 mcg/kg per day or 18 mcg/kg per day. Both doses were given as a 30-minute infusion over five days of a 21-day cycle to 144 patients who had biopsy-confirmed CTCL (stage IA-III) with 20% or more CD25-positive T cells. The primary endpoint was the overall response rate (RR). canadian buy prescription drugs online

For placebo patients, the overall RR was 15.9% (7/44); for patients receiving Dd 9 mcg/kg per day, the rate was 37.8%; and for those receiving 18 mcg/kg per day, it was 49.1%, compared with placebo (P = 0.029 and P = 0.0015, respectively).

Progressive disease was reported in 52.3% of the placebo patients, in 26.7% of those receiving Dd 9 mcg/kg per day, and in 16.4% of the patients treated with 18 mcg/kg per day.

For secondary endpoints of progression-free survival and time to treatment failure, the pattern of dose response favoring the higher Dd dose persisted. The duration of response and the time to the first response, however, favored the 9-mcg/kg dose. Both Dd doses were significantly superior to placebo for all of these parameters.

Although adverse events were reported at similar rates for placebo (90.9%) and Dd (97.0%), discontinuations of treatment attributable to adverse events were more frequent in the Dd groups (20%) than in the placebo group (9.0%), as were serious adverse events (36% with Dd vs. 22.7% with placebo). Dr. Prince emphasized, however, that serious adverse events decreased over time in both Dd groups, reaching levels similar to those of the placebo group.

He explained that mild-to-moderate vascular leak syndrome, characterized by fever, edema, and reduced albumin levels, dropped off sharply after the second cycle of therapy.

“Importantly, we didn’t use dexamethasone in this trial. But in day-to-day practice, we do give steroids, which increases response rates and reduces side effects.” canadian cialis

He concluded: “The key thing is that we demonstrated major responses that are durable with a very good toxicity profile. Denileukin diftitox represents a way of avoiding the side effects of chemotherapy.”

Capecitabine (Xeloda)

The Xeloda in Combination with Avastin as First-Line Treatment for HER2-Negative Metastatic Breast Cancer (XCAL-IBr) trial examined capecitabine (Xeloda, Roche), an oral prodrug of 5-FU, plus bevacizumab (Avastin, Roche) as a first-line treatment for metastatic breast cancer. The combination was more active in women with estrogen receptor-positive (ER-positive) tumors, Dr. Sledge reported.

Patients with HER2-negative metastatic breast cancer received first-line therapy with capecitabine 1,000 mg/m² twice daily for 14 days with seven days off plus bevacizumab 15 mg/kg IV in three-week cycles. Patients whose disease progressed went on to second-line treatment consisting of beva-cizumab plus paclitaxel (Taxol, Bristol-Myers Squibb) or vinor-elbine (Navelbine tartrate, GlaxoSmithKline) on four-week cycles. The primary study endpoint was time to progression.

Among 106 women (mean age, 56.8 years), hormonal status was ER-positive in 57 patients (54%) and ER-negative in 49 (46%); 62 subjects (58%) were postmenopausal. Forty-eight patients (45%) had lung metastases; 56 (53%) had a primary liver tumor, and 60 (57%) had a primary lung tumor. Enrolled patients had not received any previous chemotherapy, except for that given in the neoadjuvant (16%) or adjuvant (65%) setting at least six months before their entry into the trial.

Table 2 Efficacy of Capecitabine plus Bevacizumab According to Hormonal Status of Patients with Metastatic Breast Cancer

	Total No.	ER-Negative	ER-Positive
	of Patients	Status*	Status*
	(N = 106)	(n = 49)	(n = 57)
Median time to disease progression (months)	5.7 months	4.0 months	8.9 months
Median overall survival	16.0+ months	7.5 months	16.6+ months
Overall response rate (complete responses + partial responses)	38%	27%	47%
* ER-positive versus ER-negative status (P < 0.0001).

At a median follow-up of 12.9 months, the median time to progression was 5.7 months; median overall survival had not yet been reached, but it was beyond 16 months.

The overall response rate, consisting of complete and partial responses, was 38%. Dr. Sledge said that although the trial met its primary endpoint, he found the results “somewhat disappointing, ” compared with an earlier trial. (The initial assumption had been that the time to progression would be 5.6 months.) This finding spurred an exploratory analysis of the impact of hormone receptor status (Table 2). buy tadacip

As an unplanned analysis, Dr. Sledge indicated, the finding can be used only to generate a hypothesis; however, he suggested that the combination of capecitabine and bevacizumab would be more active in ER-positive patients.