Bryostatin and Vincristine in Relapsed B Cell Cancers

[Guest guest]

Cancer Research Clinical Cancer Research

Clinical Cancer Research Vol. 9, 5929-5935, December 1, 2003

© 2003 American Association for Cancer Research

Clinical Trials

Phase I and Correlative Study of Combination Bryostatin 1 and

Vincristine in Relapsed B-Cell Malignancies

Afshin Dowlati1, Hillard M. Lazarus1, Hartman1, W.

berger1, Cecilia Whitacre1, Stanton L. Gerson1, Pamela Ksenich1,

W. 1, Phyllis S. Frisa1, Gottlieb1, J.

Murgo2 and Scot C. Remick1

1 Developmental Therapeutics Program and the Division of

Hematology/Oncology, Department of Medicine, Case Western Reserve

University School of Medicine and University Hospitals of Cleveland,

Cleveland, Ohio, and

2 National Cancer Institute, Bethesda, land

Purpose: Bryostatin 1 activates protein kinase C (PKC) with short-

term exposure and results in depletion of PKC with prolonged

exposure. Preclinical in vitro and in vivo studies demonstrate

synergistic activity and increased tumor apoptosis in B-cell

malignancies when a prolonged infusion of bryostatin 1 is followed by

vincristine.

Experimental Design: We embarked on a Phase I trial of bryostatin 1

as a 24-h continuous infusion followed by bolus vincristine in

patients with refractory B-cell malignancies other than acute

leukemias. Twenty-four evaluable patients were enrolled.

Results: The dose-limiting toxicity was myalgia*. The MTD (maximum

tolerated dose) and recommended Phase II dose of bryostatin 1 was 50

µg/m2/24 h followed by vincristine 1.4 mg/m2 (maximum total dose of 2

mg) repeated every 2 weeks.

Significant antitumor activity was observed in this relapsed

population, including patients who had failed high-dose chemotherapy.

This included 5 durable complete and partial responses and 5 patients

with stable disease lasting 6 months (range, 6–48+ months). Median

time to response was 8 months.

Correlative studies demonstrated a progressive increase in serum

interleukin-6 with bryostatin 1 infusion followed by an additional

increase after vincristine. Flow cytometry for detection of apoptosis

in B and T cells showed an initial decrease in apoptotic frequency in

CD5+ cells within 6 h of bryostatin 1 infusion compatible with its

known increase in PKC activity in the majority of patients followed

by a return to baseline or overall increase in apoptotic frequency

after completion of infusion. All (5 of 5) patients who had an

overall increase in apoptotic frequency in CD5+ cells achieved either

a clinical response or prolonged stable disease. Four of these 5

patients did not have the initial decrement in apoptosis at 6 h.

Conclusions: Given the lack of myelosuppression and early evidence of

clinical efficacy, additional exploration of this regimen in non-

Hodgkin's lymphoma and multiple myeloma is warranted.

*muscle pain