is a flow diagram of subjects assessed, enrolled, randomized and followed throughout the trial. summarizes the baseline characteristics of all 260 patients enrolled and demonstrates the similarities in the two treatment arms. Overall, there were 59% men and 41% women with 74% Caucasians, 13% African-Americans and 12% of other race. The median age was 58 (range 11–88). Overall, 54% of the patients had stage IA disease at baseline (59% and 50% for MCH gel and ointment, respectively) and 44% had stage IB disease (40% and 49% for MCH gel and ointment, respectively). Few patients in either arm (2 each) had stage IIA disease at baseline. The median number of prior treatments was 2 (range 1–12).
Flow diagram of subject progress through the randomized trial.
The CAILS RRs are summarized in . In the ITT population the confirmed RR (CR+PR) was higher for 0.02% MCH gel than 0.02% MCH ointment (59% vs. 48%). The ratio of the RR of MCH gel to ointment was 1.23 (95% CI: 0.97–1.55), meeting the pre-specified criterion for non-inferiority (). In the EE population, 77% of patients receiving 0.02% MCH gel vs. 59% of patients receiving 0.02% MCH ointment achieved a confirmed CAILS response (RR ratio 1.30 [95% CI: 1.06–1.61], p=0.011) ().
CAILS Treatment Response, n (%)
Ratios of response rates for primary (CAILS) and secondary (mSWAT) efficacy endpoints in ITT and EE populations with 95% confidence intervals greater than non-inferiority threshold (0.75).
Subset analysis by strata revealed relative balance between stratum 1 (stage IA), n = 141 and stratum 2 (stages IB/IIA), n = 119. A 59% overall CAILS RR (in the ITT population) for 0.02% MCH gel versus 40% for 0.02% MCH ointment was seen in stratum 1(RR ratio 1.48 [95% CI: 1.05–2.14]). Stratum 2 subjects revealed a 57% overall RR for gel versus 55% for ointment (RR ratio 1.04 [95% CI: 0.75–1.43]). There were 8 patients with folliculotropic/syringotropic and LCT variants in the study (5 with folliculotropic, 1 with syringotropic, 1 with LCT and 1 with folliculotropic and LCT changes). Of the 6 who completed the study, 4 demonstrated a CAILS response when treated with MCH 0.02%. The responders included 1 PR in the gel arm (folliculotropic) and 3 PRs in the ointment arm (2 folliculotropic and 1 folliculotropic/LCT).
Time to response was evaluated by K-M analysis and revealed that the estimated time to a 50% RR in the MCH gel arm was 26 (95% CI: 20.71 to 35.14) weeks and 42 (95% CI: 29.14 to 53.00) weeks in the MCH ointment arm. Therefore, the gel attained a 50% RR approximately 16 weeks sooner than the ointment. In addition, the RR improved the longer patients were treated with MCH. Approximately 46% of patients treated with gel achieved a confirmed response at 24 weeks and 76% achieved a confirmed response at 52 weeks. Of patients treated with ointment approximately 37% achieved a confirmed response at 24 weeks and approximately 56% achieved a confirmed response at 52 weeks. Finally, patients treated with 0.02% MCH gel had a higher response rate than patients treated with 0.02% MCH ointment beginning at approximately 16 weeks through 52 weeks of treatment (). Time to response demonstrated superiority of MCH gel to ointment (p<0.012).
Kaplan-Meier curve of time to response by CAILS response in ITT population: 50% RR in the MCH gel arm was at 26 weeks and at 42 weeks in the MCH ointment arm.
Duration of response (DOR) based on CAILS score in the ITT population was analyzed in those patients who achieved a response (76 on gel; 62 on ointment), utilizing both the protocol (PD and/or LOR of < 50% baseline score) and consensus definition (PD and/or increase of greater than nadir plus 50% baseline score) 24
of DOR. The same duration was seen with both definitions for all but 8 patients (4 in each treatment arm) who had a longer duration using the new consensus definition. Sixty-five of seventy-six (86%) patients on the gel arm and 51/62 (82%) patients on the ointment arm maintained their response through the end of the trial (12 months). Based on the K-M analysis, there was no statistically significant difference between the two treatment arms with respect to DOR (p=0.481 log-rank) and based on the Kaplan-
Meier analysis, it is estimated that at least 90% of responses (using new consensus guidelines) will be maintained for 10+ months, the maximum follow-up in the trial ().
Kaplan-Meier curve of duration of response (DOR) by CAILS score in ITT population: at least 90% of responses will be maintained for 10+ months with no statistical significant difference between the two treatment arms (p=0.481 log-rank).
The secondary efficacy endpoint, mSWAT, demonstrated similar results with RR of 47% and 46% for MCH gel and ointment, respectively (RR ratio 1.02 [95% CI = 0.78–1.32]) in the ITT population. In the EE population the RR was 63% and 56% for MCH gel and ointment, respectively (RR ratio 1.14[95% CI = 0.89–1.49]). ().
The CR rate ranged from 12–19% in both arms of the ITT and EE populations. Thirty-three percent (33%) and 24% of MCH gel and ointment, respectively, achieved a 90% reduction in CAILS while 52% and 38% reached a 75% reduction in CAILS. Fifteen patients randomized to the MCH gel arm and 10 patients randomized to the MCH ointment arm had PD at some time during the study. However, the majority of patients remained on treatment. Seven of the patients on the MCH gel arm who stayed on treatment achieved a confirmed response. Only eight patients (5-gel; 3-ointment) met the criterion for PD without impact on their T classification, at the time of their last visit.
Safety and Tolerance
No drug-related severe adverse events were reported during this trial. Sixty-two percent and 50% of patients who received MCH gel and ointment, respectively, reported at least one AE that was considered to be related to study drug. The vast majority of AEs in both arms were skin related, characterized mainly as local dermatitis (skin irritation)(). There was a higher incidence of skin irritation in the gel arm (p=0.040). There were no statistically significant differences in overall incidence of AEs or any other subcategory between the gel and ointment arms.
Adverse Events in the Skin Occurring in ≥5% of Patients
The difference in skin irritation in the MCH gel arm is due primarily to an increased incidence of moderate-moderately severe (grade 2 or 3) local dermal irritation. However, there was no difference between the two treatment arms with respect to the number of patients withdrawn from the trial due to protocol defined treatment limiting skin AE: 26/128 (20.3%) on MCH gel vs. 22/127 (17.3%) on MCH ointment, p=0.631. Examination of the data shows that the majority of withdrawals for treatment limiting skin AE occurred within the first few months, and 90% occurred prior to month six.
Though patch testing was not routinely required in this trial, the incidence of treatment limiting skin AE, 21/128 (16.4%) on the MCH gel arm and 16/127 (12.6%) on the MCH ointment arm, can be used as a conservative estimate of allergic contact dermatitis. Of the 21 patients on the gel arm who withdrew from the study due to treatment limiting skin AE, 13 had a positive patch test, and 8 were not tested; of the 16 patients on the ointment arm withdrawn for a treatment limiting skin AE, 11 had a positive patch test, 2 had a negative patch test, and 3 were not tested.
Clinical laboratory monitoring (hematology and serum chemistry parameters at baseline and months 4, 8 and 12) did not demonstrate any systematic pattern of change in any laboratory value measured, consistent with the lack of systemic absorption. Additionally, HPLC serum assays performed on 16 subjects who received 0.02% MCH gel (0, 1, 3, 6 hours after application on day 1 and at week 4) did not reveal any detectable blood levels or evidence of systemic absorption of MCH (data not shown).
Development of secondary non-melanoma skin cancers was monitored throughout the 12-month trial and an additional 12-month follow-up period. Eleven patients (3-gel; 8-ointment) were diagnosed with 20 non-melanoma skin cancers. These included 9 squamous cell carcinomas of the skin (1/9 occurring in a treatment area), 10 basal cell carcinomas (5/10 occurring in a treatment area) and 1 Merkel cell carcinoma (not occurring in a treatment area). Most non-melanoma skin cancers occurred on sun exposed areas and in patients with a prior history of skin cancers or who had received prior skin-directed therapies, including phototherapy, for the treatment of MF.