Gene modulatory effects, pharmacokinetics, and clinical tolerance of interferon-alpha1b: a second member of the interferon-alpha family.

Interferon-alpha1 (IFN-alpha1), which may have a primary role in innate immunity, differs significantly in amino-acid sequence from IFN-alpha2, the only recombinant IFN-alpha with substantial clinical evaluation. Patients with metastatic malignancies received daily subcutaneous doses of 1.5-270 mug/m(2) of recombinant IFN-alpha1b. Gene modulation, pharmacokinetics, tolerability, and disease response were determined. Significant (P<0.01) dose and gene-dependent increases of 2-10 fold occurred in IFN-stimulated genes, including four (tumor necrosis factor-related apoptosis-inducing ligand, cig 5, p56, GEM) never previously identified as increased in patients; significant increases (P<0.01) resulted at the lowest dose (1.5 microg/m(2); 1.5 x 10(4) human antiviral units/m(2)). Increases (P<0.01) were sustainable for >4 weeks. Peak levels of IFN-alpha1b were at 3 h; an increase of approximately eightfold in both C(max) and AUC occurred between 15 microg/m(2) and 270 microg/m(2). Chronic toxicities of anorexia, weight loss, and fatigue were relatively uncommon. Eighteen patients were treated for >8 weeks; none experienced >grade 1 weight loss. Three patients at the highest dose developed grade 3 fatigue after > or =3 months, which required dose reduction or discontinuation. Patient acceptability of fatigue defined a dose for initiation of Phase II trials, 270 microg/m(2). Six patients (five with renal cell carcinoma) had progression-free survival for >1 year, including two who had partial responses. IFN-alpha1b resulted in potent stimulation of IFN-regulated genes and tumor regressions in renal cell carcinoma. Unique gene modulatory effects, when coupled with the moderate severity of side effects and a potentially central role in innate immunity, provide rationale for further clinical evaluation of IFN-alpha1 in virus infections and cancer.