title: Correlating animal and human phase Ia/Ib clinical data with CALAA-01, a targeted, polymer-based nanoparticle containing siRNA.
abstract: Nanoparticle-based experimental therapeutics are currently being investigated in numerous human clinical trials. CALAA-01 is a targeted, polymer-based nanoparticle containing small interfering RNA (siRNA) and, to our knowledge, was the first RNA interference (RNAi)-based, experimental therapeutic to be administered to cancer patients. Here, we report the results from the initial phase I clinical trial where 24 patients with different cancers were treated with CALAA-01 and compare those results to data obtained from multispecies animal studies to provide a detailed example of translating this class of nanoparticles from animals to humans. The pharmacokinetics of CALAA-01 in mice, rats, monkeys, and humans show fast elimination and reveal that the maximum concentration obtained in the blood after i.v. administration correlates with body weight across all species. The safety profile of CALAA-01 in animals is similarly obtained in humans except that animal kidney toxicities are not observed in humans; this could be due to the use of a predosing hydration protocol used in the clinic. Taken in total, the animal models do appear to predict the behavior of CALAA-01 in humans.
authors: Chemical Engineering, California Institute of Technology, Pasadena, CA 91125;
authors: Jonathan E
authors: JE
authors: Zuckerman
authors: College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan;
authors: Ismael
authors: I
authors: Gritli
authors: South Texas Accelerated Research Therapeutics, San Antonio, TX 78229;
authors: Anthony
authors: A
authors: Tolcher
authors: Informulate, Madison, WI 53704;
authors: Jeremy D
authors: JD
authors: Heidel
authors: Department of Medical Oncology and Therapeutics Research, City of Hope Comprehensive Cancer Center, Duarte, CA 91010;
authors: Dean
authors: D
authors: Lim
authors: Department of Medical Oncology and Therapeutics Research, City of Hope Comprehensive Cancer Center, Duarte, CA 91010;
authors: Robert
authors: R
authors: Morgan
authors: Department of Medicine, Division of Hematology Oncology, David Geffen School of Medicine, University of California, Los Angeles, CA 90095; and.
authors: Bartosz
authors: B
authors: Chmielowski
authors: Department of Medicine, Division of Hematology Oncology, David Geffen School of Medicine, University of California, Los Angeles, CA 90095; andJonsson Comprehensive Cancer Center, Los Angeles, CA 90095.
authors: Antoni
authors: A
authors: Ribas
authors: Chemical Engineering, California Institute of Technology, Pasadena, CA 91125; mdavis@cheme.caltech.edu yyen@coh.org.
authors: Mark E
authors: ME
authors: Davis
authors: College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan;Department of Medical Oncology and Therapeutics Research, City of Hope Comprehensive Cancer Center, Duarte, CA 91010; mdavis@cheme.caltech.edu yyen@coh.org.
authors: Yun
authors: Y
authors: Yen
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D001777:Blood Coagulation / Q000187:drug effects; D003165:Complement System Proteins / Q000378:metabolism; D016207:Cytokines / Q000097:blood; D003710:Demography; D005260:Female; D000882:Haplorhini; D006801:Humans; D007114:Immunization; D007668:Kidney / Q000187:drug effects / Q000473:pathology; D008099:Liver / Q000187:drug effects / Q000473:pathology; D008297:Male; D051379:Mice; D008875:Middle Aged; D053758:Nanoparticles / Q000009:adverse effects / Q000627:therapeutic use*; D010976:Platelet Count; D011092:Polyethylene Glycols / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D011108:Polymers / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D034741:RNA, Small Interfering / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D051381:Rats; D013045:Species Specificity; D016896:Treatment Outcome
chemical_list: C000591995:CALAA-01; D016207:Cytokines; D011108:Polymers; D034741:RNA, Small Interfering; D011092:Polyethylene Glycols; D003165:Complement System Proteins
keywords: DNA proliferation; DNA replication; dose limiting toxicity; maximum tolerance dose; translational medicine