Targretin Gel 1% Clinical Protocols

<table bordercolor="#c0c0c0" cellspacing="1" cellpadding="7" width="672" border="1"> <tbody> <tr> <td valign="top" bgcolor="#ffffff" colspan="2"> <br /> <br /> <p> <b><font face="Times" size="5">Targretin Gel 1% Clinical Protocols</font></b> </p> </td> </tr> <tr> <td valign="top" bgcolor="#ffffff" colspan="2"> <p> <b><i><font face="Times" size="1">The Targretin gel NDA was supported by one Phase III pivotal trial and safety data from three Phase I-II trials.</font></i></b> </p> </td> </tr> <tr> <td valign="top" bgcolor="#ffffff" colspan="2"> <p> <b><i><font face="Times">Protocol L1069T-25</font></i></b> </p> </td> </tr> <tr> <td valign="top" width="21%"> </td> <td valign="top" width="79%"> <p> <font face="Helvetica Condensed" size="2">The multicenter, open-label, <i>Phase III</i> pivotal trial evaluated 50 patients with early-stage cutaneous T-cell lymphoma (CTCL) who were intolerant of, refractory to, or had reached a response plateau for at least six months on at least two prior therapies (one of which had to be topical nitrogen mustard, topical carmustine, or phototherapy). Ninety-four percent of study patients had stage IA or IB CTCL. Two patients had stage IIA disease and one had stage IIB.</font> </p> <p> <font face="Helvetica Condensed" size="2">All lesions were treated; however, five lesions representative of the extent of the disease were designated as index lesions. Dosing involved application of study drug to lesions every other day for the first week, escalating weekly thereafter to applications q.d., b.i.d., t.i.d., and q.i.d., as tolerated. Treatment frequency was adjusted for toxicity. Total treatment time was 16 weeks.</font> </p> <p> <font face="Helvetica Condensed" size="2">The primary efficacy endpoint was tumor response (complete clinical response [CCR] + partial response [PR]) determined by the Composite Assessment (CA) of Index Lesion Disease Severity and by the Physician's Global Assessment (PGA) of Clinical Condition. CA was based on a summation of the grades for all index lesions of erythema, scaling, plaque elevation, hypopigmentation or hyperpigmentation, and area of involvement. Tumor response was assessed a minimum of two times at four-week intervals.</font> </p> <p> <font face="Helvetica Condensed" size="2">An overall response rate of 26% (13/50; 95% confidence interval 14.6%, 40.3%) was achieved according to CA. Stage IA and IB patients had a response rate of 28% (13/47; 95% CI 15.6%, 42.6%); 2% of patients (1/50) had a clinical complete response. Stage II patients had a response rate of 0% (0/3), labeling says.</font> </p> <p> <font face="Helvetica Condensed" size="2">CA median time to best response in 13 responders was 85 days (range 36-154 days). Rate of relapse was 23% over a median observation period of 149 days. Fourteen patients out of 50 (28%) developed new lesions in untreated areas, but of these only six were CA responders. Four patients (8%) developed clinically abnormal lymph nodes (<font face="Symbol">³</font> 1 cm diameter) and one patient (2%) developed a cutaneous tumor, labeling notes.</font> </p> <p> <font face="Helvetica Condensed" size="2">PGA results were not included on labeling because FDA was unable to confirm Ligand's calculation of responses, as the company did not submit photographs of non-index lesions. According to Ligand, the overall PGA response was 38% (19/50, 95% CI 25, 53). CCR was 2% (1/50) and PR was 36% (18/50) according to PGA findings.</font> </p> <p> <font face="Helvetica Condensed" size="2">Most common adverse reactions reported in the trials for all frequencies of application of study drug were rash (72%), pruritis (36%), skin disorder (26%) and pain (30%).</font> </p> </td> </tr> <tr> <td valign="top" bgcolor="#ffffff" colspan="2"> <p> <b><i><font face="Times">Protocol L1069T-11, L1069T-12, L1069-94-04T</font></i></b> </p> </td> </tr> <tr> <td valign="top" width="21%"> </td> <td valign="top" width="79%"> <p> <font face="Helvetica Condensed" size="2">Three dose-seeking <i>Phase I-II</i> trials evaluated safety, dose tolerance and potential efficacy of Targretin gel (0.1%, 0.5% and 1%) in 67 stage I and II CTCL patients. PGA was the response criteria used in the trials. According to the firm's analysis, the response rate (CCR + PR) for patients who reached the 1% dose was 64% (37/58; 95% CI).</font> </p> <p> <font face="Helvetica Condensed" size="2">By FDA calculations, the response rate was 44% based on the fact that only 18 of the 67 study patients received the target dose of 1% gel. As FDA was unable to evaluate PGA responses, trial results were accepted as being supportive of safety but not efficacy.</font> </p> </td> </tr> </tbody> </table>