title: A phase I safety study of enzastaurin plus bortezomib in the treatment of relapsed or refractory multiple myeloma.
abstract: The purpose of this study was to assess the safety and identify the recommended doses of enzastaurin and bortezomib in combination for future Phase II studies in patients with relapsed or refractory multiple myeloma. Three dose levels (DLs) of oral enzastaurin and intravenous bortezomib were used according to a conventional "3 + 3" design. A loading dose of enzastaurin (250 mg twice/day [BID]) on Day 1 was followed by enzastaurin 125 mg BID for 1 week, after which bortezomib was added (Cycle 1, 28 days, 1.0 mg/m(2) : Days 8, 11, 15, and 18; seven subsequent 21-day cycles, 1.3 mg/m(2) : Days 1, 4, 8, and 11). Twenty-three patients received treatment; all patients received prior systemic therapy. Most patients received ≥3 regimens; 17 patients were bortezomib-refractory. A median of four treatment cycles (range 1-24) was completed. No dose-limiting toxicities were observed; thus, DL 3 was the recommended Phase II dose. The most common drug-related Grade 3/4 toxicities were thrombocytopenia (n = 6) and anemia (n = 2). No patients died on therapy. One patient (DL 1) achieved a very good partial response; three patients (DLs 2 and 3), a partial response; nine patients, stable disease; and four patients, progressive disease. The recommended Phase II doses in patients with relapsed or refractory multiple myeloma are as follows: enzastaurin loading dose of 375 mg three times/day on Day 1 followed by 250 mg BID, with bortezomib 1.3 mg/m(2) on Days 1, 4, 8, and 11 of a 21-day cycle. The combination was well-tolerated and demonstrated some antimyeloma activity.
authors.affiliation: The Multiple Myeloma/Waldenstrom's Macroglobulinemia Program, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA. irene_ghobrial@dfci.harvard.edu
authors.forename: Irene M
authors.initials: IM
authors.lastname: Ghobrial
authors.forename: Nikhil C
authors.initials: NC
authors.lastname: Munshi
authors.forename: Brianna N
authors.initials: BN
authors.lastname: Harris
authors.forename: Peipei
authors.initials: P
authors.lastname: Shi
authors.forename: Nichole M
authors.initials: NM
authors.lastname: Porter
authors.forename: Robert L
authors.initials: RL
authors.lastname: Schlossman
authors.forename: Jacob P
authors.initials: JP
authors.lastname: Laubach
authors.forename: Kenneth C
authors.initials: KC
authors.lastname: Anderson
authors.forename: Durisala
authors.initials: D
authors.lastname: Desaiah
authors.forename: Scott P
authors.initials: SP
authors.lastname: Myrand
authors.forename: James E
authors.initials: JE
authors.lastname: Wooldridge
authors.forename: Paul G
authors.initials: PG
authors.lastname: Richardson
authors.forename: Rafat
authors.initials: R
authors.lastname: Abonour
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects; D001897:Boronic Acids / Q000008:administration & dosage* / Q000009:adverse effects; D000069286:Bortezomib; D017322:Clinical Trials, Phase II as Topic; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007211:Indoles / Q000008:administration & dosage* / Q000009:adverse effects; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma / Q000188:drug therapy*; D011719:Pyrazines / Q000008:administration & dosage* / Q000009:adverse effects; D012008:Recurrence; D013997:Time Factors
chemical_list: D001897:Boronic Acids; D007211:Indoles; D011719:Pyrazines; D000069286:Bortezomib; C504878:enzastaurin