Panretin® gel is not a systemic therapy; it therefore cannot treat visceral Kaposi's sarcoma (KS) nor prevent the development of new KS lesions where it has not been applied. Visceral KS disease was not monitored in these trials, and the appearance of new KS lesions was not considered part of the response assessment in clinical trials.
Panretin® gel was evaluated in two multicenter, prospective, randomized, double-blind, vehicle-controlled studies in patients with cutaneous lesions of AIDS-related KS. In both studies the primary efficacy endpoint was the patients' cutaneous KS tumor response rate through 12 weeks of study drug treatment which was assessed by evaluating from 3 to 8 KS index lesions according to the modified AIDS Clinical Trials Group (ACTG) response criteria as applied to topical therapy (i.e., evaluation of height and area reductions of the index lesions only; progressive disease in non-index lesions and new lesions were not considered progressive disease; progressive disease was scored only in the treated index lesions). A global evaluation by physicians was also carried out. It considered all of the patient’s treated lesions (index and other) compared to baseline. In this evaluation, patients with at least a 50% improvement in the KS lesions were considered responders. In addition, photographs of lesions in patients considered responders by the modified ACTG criteria were examined by the FDA for a cosmetically beneficial response, defined as at least a 50% improvement in appearance compared to baseline, considering both the KS lesions and dermal toxicity at the lesion site, in at least 50% of the index lesions and maintained for at least 3 weeks. Patients were also asked about their satisfaction with the treatment.
In Study 1, a total of 268 patients were entered from centers in the U.S. and Canada. Patients were treated topically three to four times a day with either Panretin® gel or a matching vehicle gel for a minimum of 12 weeks, followed by an open-label phase in patients who had not yet progressed on Panretin® gel. Responses during the double-blind phase are shown in Table 1. Responses to Panretin® gel were seen in both previously untreated patients and in patients with prior systemic and/or topical KS treatment. A total of 72 patients responded to Panretin® gel during the randomized or crossover portions of the study. At a median duration of monitoring of 16 weeks, only 15% of the 72 patients had relapsed. Panretin® gel would not be expected to affect development of new lesions in untreated areas and these were seen in about 50% of patients, at similar rates in treated and untreated patients, responders and non-responders. The patients’ assessment of their overall satisfaction with the drug effect on all treated lesions significantly favored Panretin® gel.
Study 2 was an international study with a planned enrollment of 270 patients. Patients were treated topically twice a day with Panretin® gel or a matching vehicle for 12 weeks. The study was stopped early because of positive interim results in the initial 82 patient data set. Results of the study are shown in Table 1. Responses to Panretin® gel were seen both in previously untreated patients and in patients with prior systemic and/or topical KS treatment.
TABLE 1: Summary of Tumor Responses
In the clinical trials, responses were seen as early as two (2) weeks; most patients, however, required four (4) to eight (8) weeks of treatment, and some patients did not experience significant improvement until 14 or more weeks of treatment. The cumulative percentage of patients who achieved a response was less than 1% at 2 weeks, 10% at 4 weeks, and 28% at 8 weeks.
In both studies, responses occurred in patients with a wide range of baseline CD4+ lymphocyte counts, including patients with CD4+ lymphocyte counts less than 50 cells/mm3. Nearly all patients received concomitant combination antiretroviral therapy.
Photographs of patients revealed a substantial erythematous and edematous response in some cases, leading to a cosmetically mixed outcome even in apparent responders. Nonetheless, in Study 1 it appeared that a cosmetically satisfactory result occurred at about the same rate as the Physician’s Global response rate and in both studies such a response was more frequent than in the vehicle control.