Lenalidomide and Alvocidib in Treating Patients With Relapsed or Refractory B-cell Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma

PRIMARY OBJECTIVES:

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.

SECONDARY OBJECTIVES:

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
lenalidomide therapy.

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
targets.

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
unacceptable toxicity.

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.

Inclusion Criteria:

- Histologically confirmed B-cell chronic lymphocytic leukemia (CLL), small lymphocytic
lymphoma (SLL) according to WHO criteria, or B-cell prolymphocytic leukemia (B-PLL)
arising from CLL with at least one of the following indications for treatment:

- Progressive disease or marked splenomegaly and/or lymphadenopathy

- Anemia (hemoglobin < 11 mg/dL) or thrombocytopenia (platelets < 100,000/mm^3)

- Unexplained weight loss exceeding 10% of body weight over the preceding 6 months

- NCI common terminology criteria for adverse events version 4.0 (CTCAE v 4.0)
grade 2 or 3 fatigue

- Fevers > 100.5°F or night sweats for more than 2 weeks without evidence of
infection

- Progressive lymphocytosis, with an increase exceeding 50% over a 2-month period
or a doubling time of less than 6 months

- Must have at least one prior therapy that includes either fludarabine (or equivalent
nucleoside analogue) or an alternative regimen if a contraindication to fludarabine
exists (i.e., autoimmune hemolytic anemia)

- Prior lenalidomide allowed provided it has been > 6 months since the last dose

- No other concurrent investigational agents

- ECOG performance status (PS) 0-2 OR Karnofsky PS 60-100%

- WBC ≤ 150,000/mm^3

- Absolute neutrophil count ≥ 1,000/mm^3

- Platelet count ≥ 30,000/mm^3

- Total bilirubin ≤ 1.5 times upper limit of normal (ULN)

- AST/ALT ≤ 2.5 times ULN

- Creatinine ≤ 1.5 mg/dL OR creatinine clearance ≥ 60 mL/min

- Not pregnant or nursing

- Negative pregnancy test

- Fertile patients must use 2 methods of effective contraception 4 weeks prior to
beginning and during study therapy and up to 28 days after completion of study
therapy

- Must agree not to donate blood, semen, or sperm/ova during and for 28 days after
completion of lenalidomide treatment

- No glucose-6-phosphate deficiency

- HIV-positive patients meeting all of the following criteria are eligible:

- CD4 count > 500/mm^3

- Not receiving highly active antiretroviral therapy or anti-HIV viral therapy

- HIV viral load < 10,000 HIV mRNA copies/mm^3

- No history of AIDS-defining illness

- No uncontrolled intercurrent illness including, but not limited to, any of the
following:

- Ongoing or active infection

- Symptomatic congestive heart failure

- Unstable angina pectoris

- Cardiac arrhythmia

- Psychiatric illness/social situations that would preclude compliance with study
requirements

- No prior alvocidib or lenalidomide

- Recovered from prior therapy