title: Phase 1b trial of proteasome inhibitor carfilzomib with irinotecan in lung cancer and other irinotecan-sensitive malignancies that have progressed on prior therapy (Onyx IST reference number: CAR-IST-553).
abstract: Introduction Proteasome inhibition is an established therapy for many malignancies. Carfilzomib, a novel proteasome inhibitor, was combined with irinotecan to provide a synergistic approach in relapsed, irinotecan-sensitive cancers. Materials and Methods Patients with relapsed irinotecan-sensitive cancers received carfilzomib (Day 1, 2, 8, 9, 15, and 16) at three dose levels (20/27 mg/m2, 20/36 mg/m2 and 20/45 mg/m2/day) in combination with irinotecan (Days 1, 8 and 15) at 125 mg/m2/day. Key eligibility criteria included measurable disease, a Zubrod PS of 0 or 1, and acceptable organ function. Patients with stable asymptomatic brain metastases were eligible. Dose escalation utilized a standard 3 + 3 design. Results Overall, 16 patients were enrolled to three dose levels, with four patients replaced. Three patients experienced dose limiting toxicity (DLT) and the maximum tolerated dose (MTD) was exceeded in Cohort 3. The RP2 dose was carfilzomib 20/36 mg/m2(given on Days 1, 2, 8, 9, 15, and 16) and irinotecan 125 mg/m2 (Days 1, 8 and 15). Common Grade (Gr) 3 and 4 toxicities included fatigue (19%), thrombocytopenia (19%), and diarrhea (13%). Conclusions Irinotecan and carfilzomib were well tolerated, with common toxicities of fatigue, thrombocytopenia and neutropenic fever. Objective clinical response was 19% (one confirmed partial response (PR) in small cell lung cancer (SCLC) and two unconfirmed); stable disease (SD) was 6% for a disease control rate (DCR) of 25%. The recommended phase II dose was carfilzomib 20/36 mg/m2and irinotecan125 mg/m2. The phase II evaluation is ongoing in relapsed small cell lung cancer.
authors.affiliation: University of Kentucky Markey Cancer Center, 800 Rose Street CC445, Lexington, KY, 40536, USA. susanne.arnold@uky.edu.|University of Kentucky Department of Internal Medicine, Lexington, KY, USA. susanne.arnold@uky.edu.
authors.forename: Susanne M
authors.initials: SM
authors.lastname: Arnold
authors.affiliation: Cancer Research and Biostatistics (CRAB), Seattle, WA, USA.
authors.forename: Kari
authors.initials: K
authors.lastname: Chansky
authors.affiliation: University of Kentucky Markey Cancer Center, 800 Rose Street CC445, Lexington, KY, 40536, USA.|University of Kentucky Department of Pharmaceutical Sciences, Lexington, KY, USA.
authors.forename: Markos
authors.initials: M
authors.lastname: Leggas
authors.affiliation: Aurora Research Institute, Milwaukee, WI, USA.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Thompson
authors.affiliation: University of Kentucky Markey Cancer Center, 800 Rose Street CC445, Lexington, KY, 40536, USA.|University of Kentucky Department of Medicine, Lexington, KY, USA.
authors.forename: John L
authors.initials: JL
authors.lastname: Villano
authors.affiliation: Norton Cancer Institute, Louisville, KY, 40202, USA.
authors.forename: John
authors.initials: J
authors.lastname: Hamm
authors.affiliation: Providence Cancer Center, Portland, OR, USA.
authors.forename: Rachel E
authors.initials: RE
authors.lastname: Sanborn
authors.affiliation: Cancer Treatment Centers of America At Western Regional Medical Center, Goodyear, AZ, USA.
authors.forename: Glen J
authors.initials: GJ
authors.lastname: Weiss
authors.affiliation: Roswell Park Cancer Institute, Buffalo, NY, USA.
authors.forename: Gurkamal
authors.initials: G
authors.lastname: Chatta
authors.affiliation: Washington University School of Medicine Department of Internal Medicine, St. Louis, MO, USA.
authors.forename: Maria Q
authors.initials: MQ
authors.lastname: Baggstrom
mesh_terms: D000293:Adolescent; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D000077146:Irinotecan; D008175:Lung Neoplasms / Q000188:drug therapy*; D008297:Male; D020714:Maximum Tolerated Dose; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy; D009842:Oligopeptides / Q000008:administration & dosage; D061988:Proteasome Inhibitors / Q000008:administration & dosage
chemical_list: D009842:Oligopeptides; D061988:Proteasome Inhibitors; C524865:carfilzomib; D000077146:Irinotecan; D002166:Camptothecin
keywords: Carfilzomib; Irinotecan; Lung cancer; Phase I