Journal of Clinical Oncology, Vol 16, 56-62, Copyright © 1998 by American Society of Clinical Oncology
Phase I study of bryostatin 1 in patients with relapsed non-Hodgkin's lymphoma and chronic lymphocytic leukemia
ML Varterasian, RM Mohammad, DS Eilender, K Hulburd, DH Rodriguez, PA Pemberton, JM Pluda, MD Dan, GR Pettit, BD Chen and AM Al-Katib
Karmanos Cancer Institute and Wayne State University, Detroit, MI, USA. varterasian@oncgate.roc.wayne.edu
PURPOSE: To define, in a phase I study in relapsed non-Hodgkin's lymphoma
(NHL) and chronic lymphocytic leukemia (CLL), the maximum- tolerated dose
(MTD), major toxicities, and possible antitumor activity of bryostatin 1, a
macrocyclic lactone. PATIENTS AND METHODS: Bryostatin 1 was delivered by
72-hour continuous infusion every 2 weeks to patients with relapsed NHL or
CLL, at doses that ranged from 12 microg/m2 to 180 microg/m2 per course.
Correlative investigations included evaluations of total protein kinase C
(PKC) in peripheral blood and lymphoid differentiation in patient tumor
tissue. RESULTS: Twenty-nine patients were treated, including three
patients with CLL and 26 with NHL. Generalized myalgia was the
dose-limiting toxicity (DLT) and occurred in two of three patients treated
with bryostatin 1 at 180 microg/m2 per course. Myalgias were dose-related
and cumulative, and often started in the thighs and calves, improved with
activity, were somewhat responsive to analgesics, and often took weeks to
resolve once taken off study. Six patients were treated at the MTD of 120
microg/m2 per course. Myalgia, headache, and fatigue were common.
Hematologic toxicity was uncommon. Total cumulative doses of bryostatin 1
up to 1,134 microg/m2 have been administered without untoward toxicity.
Eleven patients achieved stable disease for 2 to 19 months. An in vitro
assay for total PKC evaluation in patient peripheral-blood samples
demonstrated activation within the first 2 hours with subsequent
downregulation by 24 hours, which was maintained throughout the duration of
the 72-hour infusion. CONCLUSION: This phase I study defined the MTD and
recommended phase II dose of bryostatin 1, when administered over 72 hours
every 2 weeks, to be 120 microg/m2 (40 microg/m2/d for 3 days). Generalized
myalgia was the DLT. Future studies will define the precise activity of
bryostatin 1 in subsets of patients with lymphoproliferative malignancies
and its efficacy in combination with other agents.
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