title: Weekly and twice-weekly bortezomib in patients with systemic AL amyloidosis: results of a phase 1 dose-escalation study.
abstract: New treatment options are required for primary systemic AL amyloidosis (AL). This phase 1 dose-escalation component of a phase 1/2 study in relapsed AL aimed to determine the maximum tolerated dose (MTD) of bortezomib once weekly (0.7-1.6 mg/m(2); days 1, 8, 15, and 22; 35-day cycles) and twice weekly (0.7-1.3 mg/m(2); days 1, 4, 8, and 11; 21-day cycles) and assess preliminary hematologic responses. Thirty-one patients with relapsed AL were enrolled across 7 cohorts. Dose-limiting toxicity included grade 3 congestive heart failure in 2 patients (1 at once weekly, 1.6 mg/m(2), and 1 at twice weekly, 1.0 mg/m(2)). MTD was not defined for either schedule; the maximum doses of 1.6 mg/m(2) (once weekly) and 1.3 mg/m(2) (twice weekly) are being used in phase 2 evaluation. Most commonly reported toxicities on both schedules included gastrointestinal events, fatigue, and nervous system disorders. Discontinuations and dose reductions for toxicity were reported in 12 and 4 patients, respectively. No treatment-related deaths occurred. Hematologic responses occurred in 15 (50%) of 30 evaluable patients, including 6 (20%) complete responses. Median time to first response was 1.2 months. Once-weekly and twice-weekly bortezomib appear generally well tolerated in relapsed AL, with promising hematologic responses. This study is registered with http://ClinicalTrials.Gov under identifier NCT00298766.
authors.affiliation: Princess Margaret Hospital, University Health Network, Toronto, ON, Canada. donna.reece@uhn.on.ca
authors.forename: Donna E
authors.initials: DE
authors.lastname: Reece
authors.forename: Vaishali
authors.initials: V
authors.lastname: Sanchorawala
authors.forename: Ute
authors.initials: U
authors.lastname: Hegenbart
authors.forename: Giampaolo
authors.initials: G
authors.lastname: Merlini
authors.forename: Giovanni
authors.initials: G
authors.lastname: Palladini
authors.forename: Jean-Paul
authors.initials: JP
authors.lastname: Fermand
authors.forename: Robert A
authors.initials: RA
authors.lastname: Vescio
authors.forename: Xiangyang
authors.initials: X
authors.lastname: Liu
authors.forename: Yusri A
authors.initials: YA
authors.lastname: Elsayed
authors.forename: Andrew
authors.initials: A
authors.lastname: Cakana
authors.forename: Raymond L
authors.initials: RL
authors.lastname: Comenzo
mesh_terms: D000328:Adult; D000368:Aged; D000686:Amyloidosis / Q000188:drug therapy*; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects; D001897:Boronic Acids / Q000008:administration & dosage* / Q000009:adverse effects; D000069286:Bortezomib; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D011719:Pyrazines / Q000008:administration & dosage* / Q000009:adverse effects; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D001897:Boronic Acids; D011719:Pyrazines; D000069286:Bortezomib