A dose-finding pharmacokinetic study of IT-101, the first de novo designed nanoparticle therapeutic, in refractory solid tumors

Abstract

Background: IT-101 is the first de novo designed experimental nanoparticle therapeutic for cancer and is comprised of a cyclodextrin-based polymer conjugate of camptothecin (CPT) that self-assembles into nanoparticles with diameter of ca. 40 nm and near neutral surface charge. The nanoparticle properties have been designed to accomplish extended circulation, tumor penetration, and slow intracellular drug release to enhance the mechanism of action of the CPT. Methods: Patients with refractory solid tumors received IT-101 by 90 minute IV infusions on days 1, 8, and 15 of a 28 day cycle over a dose range of 6 mg/m^2/wk to 18 mg/m^2/wk. Dose escalation was conducted with a Simon’s design. Dose limiting toxicity (DLT) was determined over the first cycle. Progressive disease (PD) was defined by RECIST (CT) results. Pharmacokinetics of free and total CPT in blood and urine were collected over after the 1st dose. Patients completing 6 cycles with stable disease (SD) or better were eligible to receive compassionate IT-101 at the same dose level every other week (QOW). Results: Twelve patients [6 (6 mg/m^2), 3 (12 mg/m^2), and 3 (18 mg/m^2)] were enrolled. 4 of 12 (33%) had PD by CT. 8 of 12 (66%) did not have PD. (6-SD and 2 clinical deterioration (CD). Hematologic toxicity was the DLT. The MTD was 2 cycles, SD was observed at cumulative doses of 18 mg/m^2/mo to 27 mg/m^2/mo. Three patients (pancreatic, renal cell, NSCLC) completed 6 cycles and received treatment QOW with a PFS of ≥18, 14, and 11 months, respectively. Over 7 days, the mean plasma total CPT and free CPT t_(½ β) were 39 ± 1.1 and 51 ± 1.5 hrs, respectively. The AUC of free and total CPT were linear with 9.9 ± 4.0 % of the CPT dose free. Urinary excretion averaged 16 ± 9.1% of the total CPT dose in the first 48 hrs. Conclusions: These data appear to demonstrate that IT-101 is safe, tolerable, and is associated with acceptable toxicity at the MTD. SD was maintained in patients treated beyond 6 cycles QOW at doses of 6 to 9 mg/m^2/wk. In addition, twice monthly regimens maintained SD with minimal drug-related toxicity. A QOW schedule (allowing for 99% elimination of CPT) is warranted in future clinical trial.