Safe Use of New Bacterially-Derived, Targeted 'Minicells' to Ferry Paclitaxel to Solid Tumors is 'Feasible' in Humans24th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics in Dublin, Ireland.
Minicells are a new investigational class of intravenously-administered targeted anticancer conjugates that package tumor “seeking” engineered antibodies with anticancer agents, using a scaffolding of bacterial cell membrane.
“Minicells are a novel drug-delivery strategy comprised of bacterially-derived nanoparticles that may be packaged with cytotoxic drugs or siRNA and directed to tumor cells via attached targeting antibodies that have demonstrated preclinical efficacy,” explained lead author Benjamin Solomon, PhD, MBBS, FRACP, of the Peter MacCallum Cancer Center's Department of Medical Oncology in Melbourne, Australia, and coauthors.
“Administration of EGFR-Minicells-Pac is feasible and generally well tolerated with a recommended Phase II dose of 1x 1010 minicells per dose,” the team reported.
In the open-label phase 1 dose-escalation-design safety and tolerability study, minicells were “loaded” with paclitaxel and coated with epidermal growth factor receptor (EGFR)-targeting cetuximab, a chimeric engineered mouse/human monoclonal antibody.
A total of 235 doses of EGFR-Minicells-Pac were administered to 28 patients with advanced solid tumors, who received doses ranging from 108 to 5 x 1010 minicells per dose. Although the study was a safety trial, not statistically powered to detect clinical benefits, 10 patients were determined to have stable disease at 6 weeks and continued on the experimental therapy.
“At 2 x 1010 and 5 x 1010, there was a significant elevation of TNFα and IL-6 and IL-10,” the authors reported. “OPS (O-polysaccharide) antibody response showed a 20-fold increase from pre-dose by dose 3 with no further augmentation following subsequent doses.”
Antibiodies to cetuximab “were not detectable” in study participants, they reported.
The most frequent toxicities observed were grade 1-2 fever within 2 hours of infusion and transient, asymptomatic hypophosphatemia, the authors reported. Dose-limiting toxicities included grade 3 reactive arthritis, grade 3 hypotension, grade 3 elevations in AST and ALT liver enzyme levels, and grade 3 fever.
Phase 2 trials are planned, including a study of doxorubicin-loaded minicells for glioblastoma.
By targeting tumor cells, conjugates can ferry high doses of cytotoxic drugs to malignancies with less risk of toxicity to a patient's healthy tissues.
Abstract (Search for Abstract Number 156)