Phase 1 Trial of Flavopiridol in Combination With Lenalidomide in Patients With Relapsed or Refractory B-cell CLL/SLL
I. To determine the maximum-tolerated dose (MTD) of lenalidomide when combined with
alvocidib in patients with relapsed or refractory B-cell chronic lymphocytic leukemia (CLL)
or small lymphocytic lymphoma (SLL).
II. To define the specific toxicities and the dose-limiting toxicity (DLT) of alvocidib in
combination with lenalidomide in these patients.
I. To assess preliminary efficacy of alvocidib combined with lenalidomide in these patients
to justify future, rigorous phase II studies of the combination in CLL.
II. To determine the pharmacokinetics of alvocidib and lenalidomide alone and in combination
in these patients.
III. To correlate select pre-treatment prognostic markers, including interphase cytogenetics
with minimal residual disease, progression-free survival, response, and toxicity after
treatment with this regimen.
IV. To determine patient cytokine-expression profiles immediately pre-treatment, after
alvocidib dosing, and after combination alvocidib and lenalidomide therapy to assess the
impact of lenalidomide on alvocidib-induced cytokine release (interleukin [IL]-6).
V. To assess if pre-treatment ex vivo and in vivo (day 1 and day 3 of lenalidomide) immune
(B-cell, NK cell, and T-cell) activation correlates with response and toxicity of
VI. To assess the in vivo effect of lenalidomide on alvocidib on the modulation of selected
intracellular pharmacodynamic targets including STAT3, Mcl-1, and other downstream IL-6
OUTLINE: This is a dose-escalation study of lenalidomide.
Patients receive alvocidib IV over 4.5 hours on days 1, 8, and 15 in course 1 followed by a
week of rest. Beginning in course 2 and all subsequent courses, patients receive oral
lenalidomide on days 1-21 and alvocidib IV over 4.5 hours on days 3, 10, and 17. Treatment
repeats every 5 weeks for up to 8 courses in the absence of disease progression or
Blood samples are collected at baseline, on day 1 of course 1, and on days 2-3 of course 2
for pharmacokinetic studies, cytokine measurements, intracellular pharmacodynamic targets,
and B-cell surface antigen expression by ELISA assays, quantitative immunoblot analysis,
RT-PCR, and direct immunofluorescence staining.
After completion of study therapy, patients are followed every 3 months for 2 years.
Endpoint Classification: Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
MTD of lenalidomide when combined with alvocidib
We will use the standard method (SM) phase I design of dose escalation using 3-6 patients per dose level. MTD is defined as the maximum dose level with fewer than 2 of 6 patients experiencing dose limiting toxicity (DLT). Toxicities classified as DLT during course 1 will not be considered DLT for the combination of lenalidomide and flavopiridol, but will result in patient removal from the study.
During course 2
Ohio State University
United States: Food and Drug Administration
|Arthur G. James Cancer Hospital and Solove Research Institute at Ohio State University Medical Center||Columbus, Ohio 43210-1240|