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, 12 healthy subjects (subs) received seven consecutive daily intravenous infusions of placebo or Imprime PGG at doses of 1.0, 2.0 or 4.0 mg/kg in separate cohorts. The 1.0 and 2.0 mg/kg Imprime PGG doses were infused over 1 hour and the 4 mg/kg dose infused over 2 hours. 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 signs, electrocardiogram (ECG) and clinical laboratory results, with last evaluation on Day 30. 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, 8/12 (66.7%) subs experienced AEs, 6/9 (66.7%) Imprime PGG subs and 2/3 (66.7%) placebo subs. The most common AE was headache (2 subs; 16.7%). There were no deaths, and none of the AEs were serious, severe in intensity, or clustered in a particular system organ class. One placebo sub and one 4.0-mg/kg sub prematurely discontinued the study because of moderate AEs. Treatment-related (TR) AEs were reported in 1/3 (33.3%) placebo subs and in 2/9 (22.2%) Imprime PGG subs, both of which received Imprime PGG at 4.0 mg/kg. Compared with 1.0 or 2.0 mg/kg Imprime PGG treatment, the occurrence of AEs at the 4 mg/kg treatment (one which resulted in discontinuation), suggested that 4.0 mg/kg may be approaching a maximum tolerated dose under the conditions administered. Minor deviations from the normal range were observed for clinical measures at various time points, but were not assessed as related to Imprime PGG. One exception was a transient, dose-dependent increase in total neutrophil counts, which was considered a pharmacodynamic activity. There were no PE or ECG results that were considered AEs. PK parameters were assessed on Day 0 (final draw 24 hours after first dosing) and on Day 6 (final draw on Day 30, 24 days after final dosing). Steady state was attained at Day 6. PK area under the curve (AUC) assessments indicated that Imprime PGG concentration was linear over the doses administered at both evaluation times. Comparison of Day 0 vs. Days 6-30 AUC(0-last) parameters revealed significantly larger values at Days 6-30 for all three treatment groups; T½β values also tended to be larger at Days 6-30 vs. Day 0. Overall Imprime PGG was safe and well tolerated at multiple doses up to 4.0 mg/kg.
(1) Prism Research, Minneapolis, MN
(2) Biothera, Eagan, MN
(3) MKConsulting, Upper Saddle River, NJ