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Background:: Low-dose cyclosporine therapy for severe plaque psoriasis is effective. Most side effects can be controlled by patient monitoring, with appropriate dose adjustment or pharmacologic intervention, or both, if indicated. Prevention or reversibility of laboratory and chemical abnormalities may be achieved by discontinuation of therapy after the induction of clearing. However, relapse occurs rapidly on discontinuation. Maintenance therapy with cyclosporine after induction has not been fully evaluated. Objective:: Our purpose was to compare a regimen of 3.0 mg/kg per day of oral cyclosporine with placebo in maintaining remission or improvement in patients with psoriasis. Methods:: After a 16-week unblinded induction phase in which 181 patients received cyclosporine, 5.0 mg/kg per day (an increase up to 6.0 mg/kg per day and a decrease to 3.0 mg/kg per day were allowed, if required, to achieve efficacy or tolerability, respectively), those patients showing a 70% decrease or more in involved body surface area (BSA) entered the 24-week maintenance phase and were randomly assigned to either placebo, cyclosporine, 1.5 mg/kg per day, or cyclosporine, 3.0 mg/kg per day. Patients were considered to have had a relapse when BSA returned to 50% or more of the prestudy baseline value. Clinical efficacy, adverse effects, and laboratory values were monitored regularly throughout both study phases. Results:: During induction, cyclosporine at approximately 5.0 mg/kg per day produced a reduction in BSA of 70% or more in 86% of the patients. During maintenance, the median time to relapse was 6 weeks in both the placebo and cyclosporine 1.5 mg/kg per day groups, but was longer than the 24-week maintenance period in the 3.0 mg/kg per day group (p < 0.001 vs placebo). By the end of the maintenance period, 42% of the patients in the 3.0 mg/kg per day cyclosporine group had a relapse compared with 84% in the placebo group. Changes in laboratory values associated with the higher induction dosage generally exhibited partial or complete return toward mean prestudy baseline values during the maintenance phase, with the greatest degree of normalization in the placebo group. Conclusion:: Cyclosporine, 3.0 mg/kg per day, adequately and safely maintained 58% of patients with psoriasis for a 6-month period after clearing of their psoriasis with doses of approximately 5.0 mg/kg per day.

AMN107 is a novel aminopyrimidine ATP-competitive inhibitor of Bcr-Abl. In proliferation assays AMN107 ≥10-fold more is potent than IM against Bcr-Abl expressing cell lines. AMN107 is effective against cell lines expressing the following IM-resistant Bcr-Abl mutants: Glu255Val, Phe317Leu, and Met351Thr. In addition, preliminary studies indicate that AMN107 has similar potency to IM against c-Kit and PDGFR-dependent cell proliferation. The ↑ potency and broader spectrum of activity of AMN107 against Bcr-Abl, relative to IM, may result in clinical benefit for pts with CML or Ph+ ALL. In the phase I portion of this phase I/II study, pts with IM-resistant CML-AP, CML-BC, and Ph+ ALL were eligible for treatment with AMN107 as an oral daily dose. 21 pts [median age:61 yrs (range 29–77); 15 male 6 female; performance status: 0(12 pts), 1(6 pts) or 2(3 pts)] have been enrolled in the following dose cohorts (mg/day): 50(7 pts), 100(7 pts), 200(7 pts) and have been on treatment for 8–70 days. Disease types: CML-AP (12 pts), CML-BC (6 pts), Ph+ ALL (3 pts). Intra-pts dose escalations were permitted for persistent disease in peripheral blood and/or marrow. 6/7 pts in the 50mg dose level, and 7/7 pts in the 100mg dose level have dose-escalated. No AMN107-related AE have been observed. Biologic activity, defined as at least a 50% ↓ in blasts or basophils in the peripheral blood and/or marrow lasting for at least 7 days was observed in 0/7 pts treated with 50mg/day, 4/13 pts treated with 100mg/day, and 7/15 pts treated with 200mg/day. Of the 7 pts who demonstrated biologic activity at 200mg/day, 2 pts with CML-AP had complete hematologic responses in marrow, and 1 pts with CML-AP had return to CP in marrow. Pts were not pre-selected for treatment based on mutational status of Bcr-Abl. Mutational analysis is being performed on all pts and will be correlated with response. Initial data reveal Bcr-Abl mutations in the majority (> 80%) of baseline pts samples. Preliminary data from the 50mg cohort comparing baseline peripheral blood samples with day 2 samples showed: significant ↑ in apoptosis as determined by mitochondrial potential, reduction in proliferation of CD34+ cells as measured by BrdU incorporation, and significant reductions in STAT1 phosphorylation. Reduction in CRKL phosphorylation in CD34+ cells was observed. Similar changes were noted in marrow. PK samples were collected on days 1, 2, 8, 15, 22 & 28 of cycle 1 and at time of any intra-pts dose escalation. Pharmacokinetics after 1 daily oral dose of AMN107 were characterized as little accumulation after multiple administrations with moderate inter-pts variability in exposure. Peak concentrations of AMN107 were generally achieved by 3 hrs post-dose. Preliminary PK data support 1-daily dosing. This phase I study, AMN107 given orally appears to be well tolerated with biologic effects in some pts treated with ≥100mg/day & marrow responses in some pts treated with 200mg/day. Once MTD has been determined, pts will be enrolled to multiple expansion cohorts in the phase II portion to assess activity.

AMN107 is a novel aminopyrimidine ATP-competitive inhibitor of Bcr-Abl. In proliferation assays AMN107 ≥10-fold more is potent than IM against Bcr-Abl expressing cell lines. AMN107 is effective against cell lines expressing the following IM-resistant Bcr-Abl mutants: Glu255Val, Phe317Leu, and Met351Thr. In addition, preliminary studies indicate that AMN107 has similar potency to IM against c-Kit and PDGFR-dependent cell proliferation. The ↑ potency and broader spectrum of activity of AMN107 against Bcr-Abl, relative to IM, may result in clinical benefit for pts with CML or Ph+ ALL. In the phase I portion of this phase I/II study, pts with IM-resistant CML-AP, CML-BC, and Ph+ ALL were eligible for treatment with AMN107 as an oral daily dose. 21 pts [median age:61 yrs (range 29–77); 15 male 6 female; performance status: 0(12 pts), 1(6 pts) or 2(3 pts)] have been enrolled in the following dose cohorts (mg/day): 50(7 pts), 100(7 pts), 200(7 pts) and have been on treatment for 8–70 days. Disease types: CML-AP (12 pts), CML-BC (6 pts), Ph+ ALL (3 pts). Intra-pts dose escalations were permitted for persistent disease in peripheral blood and/or marrow. 6/7 pts in the 50mg dose level, and 7/7 pts in the 100mg dose level have dose-escalated. No AMN107-related AE have been observed. Biologic activity, defined as at least a 50% ↓ in blasts or basophils in the peripheral blood and/or marrow lasting for at least 7 days was observed in 0/7 pts treated with 50mg/day, 4/13 pts treated with 100mg/day, and 7/15 pts treated with 200mg/day. Of the 7 pts who demonstrated biologic activity at 200mg/day, 2 pts with CML-AP had complete hematologic responses in marrow, and 1 pts with CML-AP had return to CP in marrow. Pts were not pre-selected for treatment based on mutational status of Bcr-Abl. Mutational analysis is being performed on all pts and will be correlated with response. Initial data reveal Bcr-Abl mutations in the majority (> 80%) of baseline pts samples. Preliminary data from the 50mg cohort comparing baseline peripheral blood samples with day 2 samples showed: significant ↑ in apoptosis as determined by mitochondrial potential, reduction in proliferation of CD34+ cells as measured by BrdU incorporation, and significant reductions in STAT1 phosphorylation. Reduction in CRKL phosphorylation in CD34+ cells was observed. Similar changes were noted in marrow. PK samples were collected on days 1, 2, 8, 15, 22 & 28 of cycle 1 and at time of any intra-pts dose escalation. Pharmacokinetics after 1 daily oral dose of AMN107 were characterized as little accumulation after multiple administrations with moderate inter-pts variability in exposure. Peak concentrations of AMN107 were generally achieved by 3 hrs post-dose. Preliminary PK data support 1-daily dosing. This phase I study, AMN107 given orally appears to be well tolerated with biologic effects in some pts treated with ≥100mg/day & marrow responses in some pts treated with 200mg/day. Once MTD has been determined, pts will be enrolled to multiple expansion cohorts in the phase II portion to assess activity.