BackgroundThe synergistic combination of interferon (IFN) alpha-2b and IFN gamma results in more potent in vitro biological effects mediated by both IFNs. The aim of this investigation was to evaluate by first time the pharmacokinetics and pharmacodynamics of this combination in patients with mycosis fungoides.MethodsAn exploratory, prospective, open-label clinical trial was conducted. Twelve patients, both genders, 18 to 75 years-old, with mycosis fungoides at stages IB to III, were eligible for the study. All of them received intramuscularly a single high dose (23 × 106 IU) of a novel synergistic IFN mixture (HeberPAG®) for pharmacokinetic and pharmacodynamic studies. Serum IFN alpha-2b and IFN gamma concentrations were measured during 96 hours by commercial enzyme immunoassays (EIA) specific for each IFN. Other blood IFN-inducible markers and laboratory variables were used as pharmacodynamics and safety criteria.ResultsThe pharmacokinetic evaluation by EIA yielded a similar pattern for both IFNs that are also in agreement with the well-known described profiles for these molecules when these are administered separately. The average values for main parameters were: Cmax: 263 and 9.3 pg/mL; Tmax: 9.5 and 6.9 h; AUC: 4483 and 87.5 pg.h/mL, half-life (t1/2): 4.9 and 13.4 h; mean residence time (MRT): 13.9 and 13.5 h, for serum IFN alpha-2b and IFN gamma, respectively. The pharmacodynamic variables were strongly stimulated by simultaneous administration of both IFNs: serum neopterin and beta-2 microglobulin levels (β2M), and stimulation of 2’-5’ oligoadenylate synthetase (OAS1) mRNA expression. The most encouraging data was the high increment of serum neopterin, 8.0 ng/mL at 48 h, not been described before for any unmodified or pegylated IFN. Additionally, β2M concentration doubled the pre-dose value at 24–48 hours. For both variables the values remained clearly upper baseline levels at 96 hours.ConclusionsHeberPAG®possesses improved pharmacodynamic properties that may be very useful in the oncologic setting. Efficacy trials can be carried out to confirm these findings.Trial registrationRegistro Público Cubano de Ensayos Clínicos RPCEC00000130

Introduction: Non-melanoma skin cancer is the most common tumor. The combination of IFN-alpha 2b and IFN-gamma has been used as a new therapeutic opportunity to treat basal cell carcinomas and cutaneous squamous cell carcinomas. The aim of this report is to record prospectively the recurrence and new lesions rates in patients participating in phase II clinical trials. Methods Phase II clinical trials (double-blind randomized one center study, InCarbacel-III, in patients with basal cell carcinoma; and open, non-randomized multicenter study, CECIN, in patients with cutaneous squamous cell carcinomas), with the use of the combination of IFN-alpha 2b and IFN-gamma were conducted to evaluate the efficacy, safety and the 5-year duration of clinical responses. Both studies were approved by institutional ethic committees and all the patients given their written informed consent. The investigational treatment was administered, peri- or intralesionally, three times per week, during 3 weeks. Clinical (RECIST 1.0) responses were evaluated three months after the end of treatment. Results The combination of IFNs in InCarbacel-III study showed the best clinical response (complete response of 64.3%, overall response of 85.7%) with the highest doses (10.5 MIU); without patients recurrence at 5 years follow-up (3.5 MUI and 10.5 MUI groups). The frequency of new lesions decreased in the treated patients 8 times. In the CECIN study 14 patients achieved complete response and 4 partial responses (overall response rate 67%). Up to the 5-year follow-up none of the patients with complete response had recurrence or new lesion. In both studies the cosmetic results were excellent and the reported adverse events were mostly of mild intensity. Conclusions: The use of the combination of IFN-alpha 2b and IFN-gamma showed efficacy in basal cell carcinoma and cutaneous squamous cell carcinoma promoting a long term response for at least 5 years and decreasing the rate of new lesions, safely and with excellent cosmetic effects.