ABSTRACT
International Society for Biological Therapy of Cancer
October 2008
PHASE 1, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, SINGLE-DOSE, DOSE-ESCALATION STUDY OF IMPRIME PGG® INJECTION (IMPRIME PGG) IN HEALTHY SUBJECTS
Halstenson CE,(1) Gargano MA,(2) Kurman MR,(3) Walsh R,(2) Theoharis N,(2) and Patchen ML(2)
Imprime PGG is a beta 1,3/1,6 glucose polymer immunomodulator being developed for the treatment of cancer., Preclinical in vivo tumor model studies demonstrate neutrophil-mediated anti-tumor activity and survival enhancement when Imprime PGG is administered in combination with complement-activating monoclonal antibodies.
In a Phase 1 study, 24 healthy subjects (subs) received a single intravenous infusion of placebo or Imprime PGG at doses of 0.5, 1.0, 2.0, 4.0 or 6.0 mg/kg in separate cohorts. In each cohort, 3 subs were randomized to Imprime PGG and 1 to placebo; safety in the previous cohort was determined before dose escalation. Subs were monitored for adverse events (AEs) as well as, physical exam (PE), vital sign, electrocardiogram (ECG) and clinical laboratory results, with last evaluation 7 days after dosing. Serum Imprime PGG levels were determined by an enzyme-linked immunosorbent assay (ELISA). Pharmacokinetic (PK) parameters were analyzed using standard non-compartmental methods.
In total, 15/24 (62.5%) subs experienced AEs, 12/18 (66.7%) Imprime PGG subs and 3/6 (50.0%) placebo subs. The most common AEs were headache (4 subs; 16.7%) and dyspnea (3 subs; 12.5%). There were no deaths, and none of the AEs were serious, severe in intensity, or clustered in a particular system organ class. Four subs (16.7%) prematurely discontinued Imprime PGG infusion because of AEs. Original plans maintained a 1-hr infusion at all dose levels. Following infusion-related AEs at 4.0 mg/kg, the infusion plan was revised, limiting dosing to 2.5 mg/min (at a concentration of 0.6 mg/mL); this resulted in longer infusion times for the 4.0 and 6.0 mg/kg cohorts. Four additional subs dosed at 4.0 mg/kg over 2 hours experienced no infusion-related AEs. Study drug was also generally well tolerated in subs given 6 mg/kg over 3 hours. Treatment-related (TR) AEs were not reported in placebo subs but were reported in 9/18 (50%) Imprime PGG subs. An increase in the number of TR AEs from 0 in the 4.0 mg/kg (2-hr infusion) cohort to 8 in the 6.0 mg/kg cohort, suggested that 6 mg/kg may be approaching a maximum tolerated dose under the conditions administered; the number of TR AEs in the 0.5, 1.0 and 2.0 mg/kg cohorts were 2, 1, and 1, respectively. No clinically significant changes from baseline were observed at end of study for PE, vital signs, ECG or clinical laboratories. PK area under the curve (AUC) assessments indicated that Imprime PGG concentration was linear over the doses administered. Mean T½β values ranged from 23.36 - 32.75 hours. Overall, after adjusting infusion rates, Imprime PGG was safe and well tolerated at single doses up to 6.0 mg/kg.
(1) Prism Research, Minneapolis, MN
(2) Biothera, Eagan, MN
(3) MKConsulting, Upper Saddle River, NJ