PHASE-I STUDY OF BRYOSTATIN-1 IN PATIENTS WITH RELAPSED NON-HODGKINS-LYMPHOMA AND CHRONIC LYMPHOCYTIC-LEUKEMIA

Citation
Ml. Varterasian et al., PHASE-I STUDY OF BRYOSTATIN-1 IN PATIENTS WITH RELAPSED NON-HODGKINS-LYMPHOMA AND CHRONIC LYMPHOCYTIC-LEUKEMIA, Journal of clinical oncology, 16(1), 1998, pp. 56-62
Citations number
25
Categorie Soggetti
Oncology
ISSN journal
0732183X
Volume
16
Issue
1
Year of publication
1998
Pages
56 - 62
Database
ISI
SICI code
0732-183X(1998)16:1<56:PSOBIP>2.0.ZU;2-D
Abstract
Purpose: To define, in a phase I study in relapsed non-Hodgkin's lymph oma (NHL) and chronic lymphocytic leukemia (CLL), the maximum-tolerate d dose (MTD), major toxicities, and possible antitumor activity of bry ostatin 1, a macrocyclic lactone. Patients and Methods: Bryostatin 1 w as delivered by 72-hour continuous infusion every 2 weeks to patients with relapsed NHL or CLL, at doses that ranged from 12 mu g/m(2) to 18 0 mu g/m(2) per course. Correlative investigations included evaluation s of total protein kinase C (PKC) in peripheral blood and lymphoid dif ferentiation in patient tumor tissue. Results: Twenty-nine patients we re treated, including three patients with CLL and 26 with NHL. General ized myalgia was the dose-limiting toxicity (DLT) and occurred in two of three patients treated with bryostatin 1 at 180 mu g/m(2) per cours e. Myalgias were dose-related and cumulative, and often started in the thighs and calves, improved with activity, were somewhat responsive t o analgesics, and often took weeks to resolve once taken off study Six patients were treated at the MTD of 120 mu g/m(2) pel course. Myalgia , headache, and fatigue were common, Hematologic toxicity was uncommon . Total cumulative doses of bryostatin 1 up to 1,134 mu g/m(2) have be en administered without untoward toxicity. Eleven patients achieved st able disease for 2 to 19 months. An in vitro assay for total PKC evalu ation in patient peripheral-blood samples demonstrated activation with in the first 2 hours with subsequent down-regulation by 24 hours, whic h was maintained throughout the duration of the 72-hour infusion. Conc lusion: This phase 1 study defined the MTD and recommended phase II do se of bryostatin 1, when administered over 72 hours every 2 weeks, to be 120 mu g/m(2) (40 mu g/m(2)/d for 3 days). Generalized myalgia was the DLT. Future studies will define the precise activity of bryostatin 1 in subsets elf patients with lymphoproliferative malignancies and i ts efficacy in combination with other agents. (C) 1998 by American Soc iety of Clinical Oncology.