A phase I study of recombinant interferon-beta in patients with advanced malignant disease

To evaluate the safety, toxicity, and maximum tolerated dose (MTD) of IFN b eta-1a (Rebif, Serono Laboratories, Inc) in patients with malignant disease s unresponsive to standard therapies and to assess the pharmacodynamics and pharmacokinetics associated with IFN beta-1a administration, an open-label , single-center phase I study was designed. Thirty-four patients were enrol led and treated with IFN beta-1a. All had measurable solid neoplasms or eva luable hematological malignancies. All patients received a single i.v. bolu s dose of IFN-beta-1a on day 1, followed 7 days later by daily s.c. injecti ons for 28 consecutive days. Successive groups of three patients received i ncreasingly higher doses (in geometric progression from 1.5 million interna tional units (MIU)/m(2) to 24 MIU/m(2)) until dose-limiting toxicities were noted. Pharmacokinetic and biological studies, including measurement of th e activity of 2',5'-oligoadenylate synthetase (2',5'-OAS) in peripheral blo od mononuclear cells and serum levels of soluble Tac (CD 25) and beta-2 mic roglobulin, were performed on patients who agreed to participate, i.v. and s.c. doses of IFN beta-1a up to 24 MIU/m(2) were administered. The most fre quent adverse events (AEs) were constitutional symptoms. Grade III AEs duri ng i.v. dosing included fever, elevation of bilirubin, and infection unrela ted to therapy. No grade IV events were seen. AEs noted during continuous s .c therapy included fever, liver transaminase increase, albuminuria, fatigu e, nausea, myalgia, and rigors. Dose-limiting toxicities were encountered d uring s.c. dosing at the 24-MIU/m(2) and 18-MIU/m(2) dose levels and includ ed gastrointestinal toxicity, elevations of aspartate aminotransferase and alanine aminotransferase, and albuminuria. The s.c. MTD was determined to b e 12 MIU/m(2), although there was great variability in the individual patie nt's ability to tolerate IPN P-la 2',5'-OAS activity, thought to be indicat ive of IFN activity, increased within hours after i.v. and s.c. dosing, wit h the level remaining persistently elevated during the s.c. daily injection s. The highest peak level was attained in the 6-MIU/m(2) group. There was n o evidence that the increase in 2',5'-OAS activity decayed with repetitive dosing, nor was there evidence of accumulation in this pharmacodynamic mark er. Serum beta-2-microglobulin levels showed a modest time- and dose-depend ent increase after s.c. administration of IFN beta-1a, with the largest inc rease seen at the 24-MIU/m(2) dose level. There were no clear dose-dependen t responses noted in soluble Tac serum levels. IFN beta-1a was well-tolerat ed when administered by a single i.v. bolus injection at doses up to and in cluding 24 MIU/m(2). Daily s.c. injections for at least 28 days were well-t olerated at doses up to and including 12 MIU/m(2), with some patients toler ating doses twice as high as this. The MTD for the i.v, route could not be clearly determined according to the guidelines of the protocol. However, i. v. bolus doses up to 24 MIU/m(2) were relatively well-tolerated. For the s. c. route, the MTD was determined to be 12 MIU/m(2), but there was great int erpatient variability with some patients able to tolerate higher doses.