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

Summary 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 max...

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Bibliographic Details
Published in:Investigational new drugs 2013-08, Vol.31 (4), p.986-1000
Main Authors: Weiss, Glen J., Chao, Joseph, Neidhart, Jeffrey D., Ramanathan, Ramesh K., Bassett, Dawn, Neidhart, James A., Choi, Chung Hang J., Chow, Warren, Chung, Vincent, Forman, Stephen J., Garmey, Edward, Hwang, Jungyeon, Kalinoski, D. Lynn, Koczywas, Marianna, Longmate, Jeffrey, Melton, Roger J., Morgan, Robert, Oliver, Jamie, Peterkin, Joanna J., Ryan, John L., Schluep, Thomas, Synold, Timothy W., Twardowski, Przemyslaw, Davis, Mark E., Yen, Yun
Format: Article
Language:English
Subjects:
Adult
Aged
Antineoplastic agents
Area Under Curve
Biological and medical sciences
Biopsy
Camptothecin - adverse effects
Camptothecin - blood
Camptothecin - pharmacokinetics
Camptothecin - therapeutic use
Cancer therapies
Cellulose - adverse effects
Cellulose - blood
Cellulose - pharmacokinetics
Cellulose - therapeutic use
Chemotherapy
Clinical trials
Cyclodextrins - adverse effects
Cyclodextrins - blood
Cyclodextrins - pharmacokinetics
Cyclodextrins - therapeutic use
Demography
Disease-Free Survival
Dose-Response Relationship, Drug
Drug dosages
Drug therapy
Female
General aspects
Humans
Immunohistochemistry
Male
Maximum Tolerated Dose
Medical sciences
Medicine
Medicine & Public Health
Middle Aged
Multiple tumors. Solid tumors. Tumors in childhood (general aspects)
Nanoparticles
Nanoparticles - adverse effects
Nanoparticles - therapeutic use
Neoplasm Staging
Neoplasms - diagnostic imaging
Neoplasms - drug therapy
Neoplasms - pathology
Oncology
Ovarian cancer
Patients
Permeability
Pharmaceutical sciences
Pharmacodynamics
Pharmacokinetics
Pharmacology. Drug treatments
Pharmacology/Toxicology
Phase II Studies
Plasma
Polymers
Studies
Tomography, X-Ray Computed
Toxicity
Treatment Outcome
Tumors
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Summary:Summary 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 T max 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.
ISSN:0167-6997
1573-0646
DOI:10.1007/s10637-012-9921-8