A phase I study of safety and pharmacokinetics of NanoBB-1-Dox in patients with advanced solid tumors.

Abstract

e13537 Background: NanoBB-1-Dox is a novel drug candidate for systemic chemotherapy of glioblastoma multiforme (GBM). It is a nanoparticle-based formulation of doxorubicin, which enables passage of the drug across the blood-brain barrier and delivery to the tumor inside the brain. Preclinical studies demonstrated that NanoBB-1-Dox enabled considerable growth inhibition of an intracranially implanted 101.8 glioblastoma in rats and long-term remission in >20% animals, whereas the conventional doxorubicin formulation was only marginally effective. Methods: 21 patients with advanced solid tumors (18 with advanced breast cancer, 34 with GBM) were enrolled in the study. The objectives of the study were: 1) to evaluate the safety and pharmacokinetics (PK), 2) to determine the maximum tolerated dose (MTD). A standard “3 + 3” design with 7 dose levels (4, 24, 36, 48, 60, 75 and 90 mg/m2) was used. Each patient received a single i.v. infusion of NanoBB-1-Dox. Doxorubicin serum concentrations were measured immediately before the infusion, and 2 min, 10 min, 20 min, 40 min, 1 h, 2 h, 4 h, 6 h, 8 h, 12 h, 24 h, 48 h, 72 h, 168 h after the infusion. Results: The PK analysis demonstrated that AUC0-t of doxorubicin after the NanoBB-1-Dox infusion increased in parallel with the dose level from 121.7 to 2054.4 h x ng/ml. T1/2 varied from 45 to 75 h without dose dependence. NanoBB-1-Dox was well tolerated without dose limiting toxicity even at the highest dose of 90 mg/m2, so the MTD was not achieved. The most common AEs included leukopenia, lymphopenia, neutropenia, thrombocytopenia, anemia, nausea, and alopecia. In general, the AE rate and intensity increased with the dose level reaching the maximum at a dose of 90 mg/m2. Only hematological AEs were severe according to CTCAE 4.03. No SAEs were reported. Conclusions: NanoBB-1-Dox after a single i.v. infusion in patients with advanced solid tumors is well tolerated and is characterized by a non-linear PK profile. NanoBB-1-Dox will be investigated in a phase II study in patients with GBM as a second line therapy. [Table: see text]

Key for crossing the BBB with nanoparticles: the rational design

“…They are FDA-approved and have a slower degradation rate than PBCA, allowing for a more sustained delivery [148,149]. Furthermore, a formulation of PLGA nanoparticles loaded with doxorubicin (NanoBB-1-Dox) has been investigated in a phase-I clinical trial for the treatment of glioblastoma multiforme through systemic chemotherapy [150]. Following the good tolerance of the treatment, NanoBB-1-Dox will be investigated in a phase-II study, which might prove the ability of PLGA nanoparticles to cross the BBB in humans.…”

Nanomedicine Ex Machina: Between Model-Informed Development and Artificial Intelligence

“…On the one hand, many PK studies have been carried out in nanomedicine and were analyzed by conventional means (55)(56)(57)(58)(59). A common method is non-linear mixed effects (NLME) modeling describing non-linear relationships using a limited number of population parameters and parameter variability.…”

Modeling the Drug delivery Lifecycle of PLG Nanoparticles Using Intravital Microscopy

“…[2,3] On the contrary, most polymer nanoparticles disappear from the blood plasma more rapidly. Still, through a variety of species and disease models, [4][5][6][7][8][9] they led to surprising outcomes and improved the efficacy of drugs significantly. [4][5][6][7][8] Polymer nanoparticles composed of PLG, for instance, were successfully used in the formulation of doxorubicin [10][11][12] and other anticancer drugs.…”

“…[15] The investigational drug product NanoCore-7.4 has been developed for the treatment of glioblastoma multiforme. [4,9,10,16,17] It comprises doxorubicin that is clinically applied in the treatment of solid tumors and hematological malignancies. [18] Blood partitioning studies indicated the binding of >40% of the total dose of this PLG nanoparticle formulation to the cellular fraction of the blood.…”