A phase 1b study of humanized KS-interleukin-2 (huKS-IL2) immunocytokine with cyclophosphamide in patients with EpCAM-positive advanced solid tumors.

BACKGROUND: Humanized KS-interleukin-2 (huKS-IL2), an immunocytokine with specificity for epithelial cell adhesion molecule (EpCAM), has demonstrated favorable tolerability and immunologic activity as a single agent. METHODS: Phase 1b study in patients with EpCAM-positive advanced solid tumors to determine the maximum tolerated dose (MTD) and safety profile of huKS-IL2 in combination with low-dose cyclophosphamide. Treatment consisted of cyclophosphamide (300 mg/m2 on day 1), and escalating doses of huKS-IL2 (0.5-4.0 mg/m2 IV continuous infusion over 4 hours) on days 2, 3, and 4 of each 21-day cycle. Safety, pharmacokinetic profile, immunogenicity, anti-tumor and biologic activity were evaluated. RESULTS: Twenty-seven patients were treated for up to 6 cycles; 26 were evaluable for response. The MTD of huKS-IL2 in combination with 300 mg/m2 cyclophosphamide was 3.0 mg/m2. At higher doses, myelosuppression was dose-limiting. Transient lymphopenia was the most common grade 3/4 adverse event (AE). Other significant AEs included hypotension, hypophosphatemia, and increase in serum creatinine. All patients recovered from these AEs. The huKS-IL2 exposure was dose-dependent, but not dose-proportional, accumulation was negligible, and elimination half-life and systemic clearance were independent of dose and time. Most patients had a transient immune response to huKS-IL2. Immunologic activity was observed at all doses. Ten patients (38%) had stable disease as best response, lasting for ≥ 4 cycles in 3 patients. CONCLUSION: The combination of huKS-IL2 with low-dose cyclophosphamide was well tolerated. Although no objective responses were observed, the combination showed evidence of immunologic activity and 3 patients showed stable disease for ≥ 4 cycles.

Investigation of the impact of sarizotan on the pharmacokinetics of levodopa.

OBJECTIVE: To investigate the effect of sarizotan on the pharmacokinetics of levodopa in fixed combination with carbidopa or benserazide. METHODS: In this open-label, randomized, crossover study, healthy male subjects (n=16) received levodopa 100 mg t.i.d. over two 5-day periods, alone or in combination with sarizotan 5 mg b.i.d. Levodopa was administered with a dopa-decarboxylase inhibitor (carbidopa 25 mg, n=8 or benserazide 25 mg, n=8). Pharmacokinetic parameters of levodopa were obtained on days 1 and 5. RESULTS: ANOVA showed the C(max) values for levodopa were not significantly different with or without sarizotan after single doses (1001 vs 1082 ng/ml; point estimate [PE] 1.10, 90% confidence intervals [CI] 0.83-1.45) or at steady-state (1549 vs 1663 ng/ml; PE 1.06, 90% CI 0.89-1.27); nor were AUC values for single doses (1661 vs 1665 ng h/ml; PE 1.01, 90% CI 0.91-1.11) or at steady-state (2462 vs 2482 ng h/ml; PE 1.01, 90% CI 0.97-1.05). Seven subjects reported adverse events of mild-to-moderate intensity; the most frequent were headaches and dizziness. CONCLUSION: Coadministration of sarizotan with levodopa, in combination with a dopa-decarboxylase inhibitor had no effect on the pharmacokinetics or adverse event profile of levodopa.

Investigation of sarizotan's impact on the pharmacokinetics of probe drugs for major cytochrome P450 isoenzymes: a combined cocktail trial.

OBJECTIVE: The 5HT(1A) receptor agonist sarizotan is in clinical development for the treatment of dyskinesia, a potentially disabling complication in Parkinson's disease. We investigated the effect of sarizotan on the clinical pharmacokinetics of probe drugs for cytochrome P450 (CYP) to evaluate the risk of CYP-related drug-drug interactions. METHODS: This was a double-blind, randomised, two-period cross-over interaction study with repeated administration of 5 mg sarizotan HCl or placebo b.i.d. for 8 days in 18 healthy volunteers. On day 4, a single dose of 100 mg metoprolol (CYP2D6 probe) was administered. On day 8, single doses of 100 mg caffeine (CYP1A2 probe), 50 mg diclofenac (CYP2C9 probe), 100 mg mephenytoin (CYP2C19 probe) and 7.5 mg midazolam (CYP3A4 probe) were simultaneously applied. Pharmacokinetic parameters for probe drugs and their metabolites in plasma and urinary recovery were determined. RESULTS: Concentration-time profiles and pharmacokinetic parameters of all probes and their metabolites remained unchanged after co-administration of sarizotan, compared with placebo. Analysis of variance of the area under the plasma concentration-time curve for probe drugs/metabolites, metabolic ratios and urinary excretion resulted in 90% confidence intervals within the acceptance range (0.8-1.25), indicating the absence of drug-drug interactions. CONCLUSIONS: At a dose higher than that intended for clinical use (1 mg b.i.d.), sarizotan had no effect on the metabolism and pharmacokinetics of specific probe drugs for CYP isoenzymes 1A2, 2C19, 2C9, 2D6 and 3A4. Pharmacokinetic interactions with co-administered drugs metabolised by these CYP isoforms are not expected, and dose adjustment of co-administered CYP substrates is not necessary.