title: A phase I/II study of the pan Bcl-2 inhibitor obatoclax mesylate plus bortezomib for relapsed or refractory mantle cell lymphoma.
abstract: Obatoclax, a BH3 mimetic inhibitor of anti-apoptotic Bcl-2 proteins, demonstrates synergy with bortezomib in preclinical models of mantle cell lymphoma (MCL). This phase I/II study assessed obatoclax plus bortezomib in patients with relapsed/refractory MCL. Twenty-three patients received obatoclax 30 or 45 mg plus bortezomib 1.0 or 1.3 mg/m(2), administered intravenously on days 1, 4, 8 and 11 of a 21-day cycle. In phase I, the combination was feasible at all doses. Obatoclax 45 mg plus bortezomib 1.3 mg/m(2) was selected for phase II study. Common adverse events were somnolence (87%), fatigue (61%) and euphoric mood (57%), all primarily grade 1/2. Grade 3/4 events included thrombocytopenia (21%), anemia (13%) and fatigue (13%). Objective responses occurred in 4/13 (31%) evaluable patients (three complete and one partial response). Six patients (46%) had stable disease lasting ≥ 8 weeks. Obatoclax plus bortezomib was feasible, but the synergy demonstrated in preclinical models was not confirmed.
authors.affiliation: John Theurer Cancer Center, Hackensack University Medical Center , Hackensack, NJ , USA.
authors.forename: André
authors.initials: A
authors.lastname: Goy
authors.forename: Francisco J
authors.initials: FJ
authors.lastname: Hernandez-Ilzaliturri
authors.forename: Brad
authors.initials: B
authors.lastname: Kahl
authors.forename: Peggy
authors.initials: P
authors.lastname: Ford
authors.forename: Ewelina
authors.initials: E
authors.lastname: Protomastro
authors.forename: Mark
authors.initials: M
authors.lastname: Berger
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D001897:Boronic Acids / Q000008:administration & dosage; D000069286:Bortezomib; D003131:Combined Modality Therapy; D018450:Disease Progression; D005260:Female; D006801:Humans; D007211:Indoles; D020522:Lymphoma, Mantle-Cell / Q000188:drug therapy* / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D009367:Neoplasm Staging; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors*; D011719:Pyrazines / Q000008:administration & dosage; D011758:Pyrroles / Q000008:administration & dosage; D016896:Treatment Outcome
chemical_list: D001897:Boronic Acids; D007211:Indoles; D019253:Proto-Oncogene Proteins c-bcl-2; D011719:Pyrazines; D011758:Pyrroles; D000069286:Bortezomib; C520962:obatoclax
keywords: Lymphoma and Hodgkin disease; bortezomib; chemotherapeutic approaches; drug resistance; mantle cell; obatoclax