Phase I evaluation of a 40-kDa branched-chain long-acting pegylated IFN-α-2a with and without cytarabine in patients with chronic myelogenous leukemia

Purpose: Pegasys (PEG-IFN) is a modified form of recombinant human IFN-α-2a in which IFN-α is attached to a branched methoxypolyethylene glycol (PEG) moiety of large molecular weight (40 kDa). Such molecular modification results in sustained absorption after s.c, drug administration and a prolonged half-life. A phase I study of PEG-IFN was conducted in patients with chronic myelogenous leukemia (CML) who were previously treated with IFN-α to evaluate the effect of sustained exposure to IFN on patients with CML. Experimental Design: Twenty-seven patients with long-term or IFN-refractory CML were enrolled in cohorts of three or six patients. PEG-IFN was given once weekly by s.c. injections starting at a dose of 270 μg/wk to a maximum dose of 630 μg/wk. Sixteen additional patients were treated with escalating doses of PEG-IFN ranging from 450 to 540 μg/wk in combination with two different schedules of low-dose cytarabine (1-β-D-arabinofuranosylcytosine, ara-C). Serial venous blood samples were collected to evaluate the pharmacokinetic and pharmacodynamic characteristics of PEG-IFN in these patients. Results: The dose-limiting toxicity (DLT) as defined by the protocol was not achieved at the highest dose tested of 630 μg/wk. With the addition of ara-C, the DLT was reached at 540 μg/ wk. The safety profile was similar to that of unmodified IFNs. Of 27 patients treated with PEG-IFN, 14 (52%) achieved or maintained a complete hematologic response and three (11%) achieved a complete cytogenetic response. Among 16 patients treated with the combination of PEG-IFN and ara-C, 11 (69%) achieved or maintained complete hematologic remission and two (13%) achieved complete cytogenetic remission. The mean serum peak concentration (C_max) of PEG-IFN increased from 9.4 to 28 ng/mL as the dose increased from 270 to 450 μg/wk, with no further increases in C_max at higher dose levels. Serum concentration reached peak value starting about 48 hours after drug administration and was maintained at close to peak value throughout the dosing interval. The mean ± SD area under the serum concentration-time curve (AUC) calculated after the first dose also increased from 1,022 ± 694 to 3,343 ± 2,728 ng hour/mL as dose was increased from 270 to 450 μg/wk, showing a dose-related increase in systemic exposure of PEG-IFN. As with C _max, the AUC did not increase at higher dose levels. The maximum induction (E_max) of neopterin, the surrogate marker of the pharmacodynamic activity of PEG-IFN, increased from 120% to 361% over baseline values as the dose was increased from 270 to 540 μg/wk. On the once-weekly multiple dosing schedule, both the PEG-IFN and neopterin concentration seemed to reach steady state by week 5 and the steady-state values were maintained with chronic dosing over 6 months. Conclusion: Pegasys provided a significant advantage over standard IFN-α by enabling once-weekly dosing while maintaining acceptable safety, tolerability, and activity profiles. This branched 40-kDa PEG-IFN was well tolerated both as a monotherapy as well as in combination with ara-C. Demonstration of its sustained exposure, pharmacodynamic activity, hematologic response, and evidence of cytogenetic response in several patients in this limited study with either IFN-refractory or INF-intolerant patients provides a promise for further investigation in combination with new agents like imatinib.