LEDAGA Gel Ref.[9059] Active ingredients: Chlormethine

Pharmacotherapeutic group: Antineoplastic agents, nitrogen mustard analogues
ATC code: L01AA05

Mechanism of action

Chlormethine is a bifunctional alkylating agent that inhibits rapidly proliferating cells.

Clinical efficacy and safety

The efficacy and safety of Ledaga were assessed in a randomised, multicentre, observer-blinded, active-controlled, non-inferiority clinical trial (Study 201) of 260 adult patients with Stage IA (141), IB (115), and IIA (4) MF-type CTCL who had received at least one prior skin-directed therapy. Qualifying prior therapies included topical corticosteroids, phototherapy, topical bexarotene, and topical nitrogen mustard. Patients were not required to be refractory to or intolerant of prior therapies. Patients were stratified based on stage (IA vs IB and IIA) and then randomised to receive either Ledaga (equivalent to 0.02% chlormethine HCl) or the comparator (a petroleum-based 0.02% chlormethine HCl ointment).

Study medicinal product was to be applied topically once daily for 12 months. Dosing could be suspended or continued at reduced frequency in the case of skin reactions. The median daily usage of Ledaga was 1.8 g. The maximum individual daily usage in the trial was 10.5 g of gel (i.e., 2.1 mg of chlormethine HCl).

The primary efficacy endpoint in Study 201 was the Composite Assessment of Index Lesion Severity (CAILS) response rate. Assessment was undertaken by a blinded observer. A response was defined as an at least 50% improvement in the baseline CAILS score, confirmed at a subsequent visit at least 4 weeks later. A complete response was defined as a confirmed CAILS score of 0. A partial response was defined as an at least 50% reduction in the baseline CAILS score. Non-inferiority was considered to have been demonstrated if the lower bound of the 95% confidence interval around the ratio of response rates (Ledaga/comparator) was greater than or equal to 0.75. The CAILS score was adjusted by removal of the pigmentation score and simplification of the plaque elevation scale.

As the main secondary endpoint, patients were also evaluated using the Severity Weighted Assessment Tool (SWAT), which was based on an assessment of all lesions. The response criteria were the same as for CAILS.

Efficacy was evaluated in the Efficacy Evaluable (EE) population, which included all 185 patients who were treated for at least 6 months with no major protocol deviations [Table 1], and in the Intent-To-Treat (ITT) population, which included all 260 randomised patients.

Table 1. CAILS and SWAT-confirmed response rates by 12 months in Study 201 (efficacy evaluable population):

CAILS = Composite Assessment of Index Lesion Severity; CI = confidence interval; CR = Complete Response; PR = Partial Response; SWAT = Severity Weighted Assessment Tool.

The ratio of response and the 95% confidence interval in the ITT population were 1.226 (0.974–1.552) for CAILS and 1.017 (0.783–1.321) for SWAT and therefore consistent with those in the EE population for both the overall CAILS and SWAT responses.

Reductions in mean CAILS scores were observed as early as at 4 weeks, with further reductions observed with continuing therapy.

In the EE population, the percentage of patients who achieved a confirmed response by CAILS was similar between disease stages IA (79.6%) and IB–IIA (73.2%).

Results in other secondary endpoints (response in percentage of body surface area affected, time to first confirmed CAILS response, duration of first confirmed CAILS response and time to disease progression) were consistent with those for CAILS and SWAT.

A small number of subjects (6.3%, 8/128) treated with Ledaga utilised topical corticosteroids. Thus, the safety of the concomitant use of Ledaga with topical corticosteroids has not yet been established.

Paediatric population

The European Medicines Agency has waived the obligation to submit the results of studies with Ledaga in all subsets of the paediatric population in cutaneous T-cell lymphoma (see section 4.2 for information on paediatric use).