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
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.