First-in-human phase 1/2a trial of CRLX101, a cyclodextrin-containing polymer-camptothecin nanopharmaceutical in patients with advanced solid tumor malignancies

Abstract

Patients with advanced solid malignancies were enrolled to an open-label, single-arm, dose-escalation study, in which CRLX101 was administered intravenously over 60 min among two dosing schedules, initially weekly at 6, 12, and 18 mg/m(2) and later bi-weekly at 12, 15, and 18 mg/m(2). The maximum tolerated dose (MTD) was determined at 15 mg/m(2) bi-weekly, and an expansion phase 2a study was completed. Patient samples were obtained for pharmacokinetic (PK) and pharmacodynamic (PD) assessments. Response was evaluated per RECIST criteria v1.0 every 8 weeks. Sixty-two patients (31 male; median age 63 years, range 39-79) received treatment. Bi-weekly dosing was generally well tolerated with myelosuppression being the dose-limiting toxicity. Among all phase 1/2a patients receiving the MTD (n = 44), most common grade 3/4 adverse events were neutropenia and fatigue. Evidence of systemic plasma exposure to both the polymer-conjugated and unconjugated CPT was observed in all treated patients. Mean elimination unconjugated CPT Tmax values ranged from 17.7 to 24.5 h, and maximum plasma concentrations and areas under the curve were generally proportional to dose for both polymer-conjugated and unconjugated CPT. Best overall response was stable disease in 28 patients (64 %) treated at the MTD and 16 (73 %) of a subset of NSCLC patients. Median progression-free survival (PFS) for patients treated at the MTD was 3.7 months and for the subset of NSCLC patients was 4.4 months. These combined phase 1/2a data demonstrate encouraging safety, pharmacokinetic, and efficacy results. Multinational phase 2 clinical development of CRLX101 across multiple tumor types is ongoing.

Fig. 1

a Characterization of CRLX101 - self assembly of CDP-CPT conjugates into nanoparticles. b Characterization of CRLX101 -enhanced tumor permeability

Fig. 2

a Mean plasma concentration versus time for polymer-conjugated camptothecin (CPT) following administration of CRLX101 by dose. Abbreviations MTD maximum tolerated dose. b Mean plasma concentration versus time for polymer-unconjugated camptothecin (CPT) following administration of CRLX101 by dose. Abbreviations MTD maximum tolerated dose. Error Bars indicate standard deviations

Fig. 3

Mean AUCall for polymer-conjugated and unconjugated camptothecin by dose. Abbreviations AUC area under the curve, MTD maximum tolerated dose. Error bars indicate standard deviations

Fig. 4

a Urinary camptothecin (CPT) analysis by collection time period. b Urinary camptothecin (CPT) analysis by dosing cohort. Error Bars indicate standard deviations

Fig. 5

Computed tomography scans of a patient with metastatic pancreatic cancer a before treatment and b after 6 months of treatment with 3-weekly doses of 6 mg/m² CRLX101

Fig. 6

Immunohistochemical analysis of tumor topoisomerase-1 expression levels a before treatment and b on day 2 after infusion with CRLX101 in a patient with ovarian cancer. c Tumor cell topoisomerase-1 activity in whole-cell lysates before treatment and on day 2 and day 25 of treatment with CRLX101 in a patient with ovarian cancer. d Confocal fluorescence microscopy of tumor-localized CRLX101 nanoparticles modified with Au-PEG-AD (green) and DAPI-stained nuclei (blue; left panels, 507-nm emission) and camptothecin (right panels, 440-nm emission) in a patient with triple-negative breast cancer after 2 weeks (top panels) or before (bottom panels) CRLX101 treatment. Abbreviations: Au-PEG-AD, PEG-adamantane-modified gold; DAPI, 4′,6-diamidino-2-phenylindole; PEG, polyethyleneglycol