Double-Blind Randomized Phase I Study on the Clinical Tolerance and Pharmacodynamics of Natural and Recombinant Interferon-β Given Intravenously

Interferons manifest diverse immunomodulatory and antiproliferative characteristics. Since their spectrum of toxicities includes primarily fatigue and anorexia rather than the myelosuppression concomitant with cytotoxic therapies, it is conceptually appealing to combine both modalities. We conducted a phase I trial among 18 patients using the combination of leukocyte A recombinant interferon (IFN-rA) and BCNU. The intramuscular (IM) IFN-rA dose for the initial 12 patients was 12 X 10(6) U/m2 three times a week for an anticipated duration of 12 weeks. Among these patients, we escalated the monthly intravenous (IV) BCNU dose from 50 mg/m2 to 150 mg/m2. Six subsequent patients received IFN-rA 12 X 10(6) U/m2, days 1 to 3, and BCNU 150 mg IV on day 3 of each monthly cycle. Dose-limiting toxicities from both regimens were fatigue and myelosuppression. We recognize the limitation of small sample sizes. Nevertheless, in the absence of a significant number of life-threatening toxicities, it appears that near maximal doses of BCNU and concomitant IFN-rA can be administered with safety in an outpatient setting.

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A large multicenter, randomized, double-blind, crossover study in healthy volunteers, comparing pharmacokinetics and pharmacodynamics of Sandoz proposed biosimilar pegfilgrastim with European and United States reference pegfilgrastim.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.e23118 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. e23118-e23118

Author(s):

Gordon P. Otto ◽

Roumen Nakov ◽

Steven Schussler ◽

Stefanie Schier-Mumzhiu ◽

Celine Schelcher ◽

...

Keyword(s):

Single Dose ◽

Phase I ◽

Crossover Study ◽

Healthy Volunteers ◽

Phase I Study ◽

Geometric Mean ◽

Primary Objective ◽

Local Tolerability ◽

Pivotal Phase ◽

Double Blind

e23118 Background: Similarity of the pharmacokinetic (PK)/pharmacodynamic (PD) profiles of Sandoz proposed biosimilar pegfilgrastim and EU-reference biologic was confirmed in a pivotal Phase I study. In order to confirm PK/PD similarity to the US reference biologic, and to bridge between the two references, a 3-way study was conducted. Methods: A randomized, double-blind, single-dose, 3-treatment, 6-sequence crossover Phase I study was performed in healthy volunteers (HVs) to demonstrate similarity in PK, PD, safety and immunogenicity between Sandoz proposed biosimilar, US reference, and EU reference pegfilgrastim administered subcutaneously (6 mg/0.6 mL) in each treatment period. The primary objective was to demonstrate PK (AUC0-inf, AUC0-last, Cmax) and PD similarity (ANC AUEC0-last, ANC Emax). The study was powered (90%) to achieve confidence intervals (CIs) within biosimilarity margins 0.8─1.25 in pairwise comparisons. Secondary objectives were additional PK/PD parameters, safety and immunogenicity. Results: The study included 577 male and female HVs. PK and PD similarity were demonstrated between Sandoz proposed biosimilar and US reference (Table), as well as EU reference and between both reference biologics since the 90% CIs of the geometric mean ratios were contained within the pre-defined margins of 0.80‒1.25. Safety, immunogenicity and secondary PK/PD parameters were also similar across treatment groups. Conclusions: This large randomized, double-blind, single-dose, 3-treatment, 6-sequence crossover study demonstrated PK and PD similarity between Sandoz proposed biosimilar, US reference and EU reference pegfilgrastim with similar safety, local tolerability and immunogenicity. Clinical trial information: 2016-003549-27. [Table: see text]

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