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Phase II Study of Lenalidomide to Repair Immune Synapse Response and Humoral Immunity in Early-Stage, Asymptomatic Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL) With High-Risk Genomic Features


Phase 2
18 Years
N/A
Open (Enrolling)
Both
B-cell Chronic Lymphocytic Leukemia, Bacterial Infection, Contiguous Stage II Small Lymphocytic Lymphoma, Noncontiguous Stage II Small Lymphocytic Lymphoma, Stage 0 Chronic Lymphocytic Leukemia, Stage I Chronic Lymphocytic Leukemia, Stage I Small Lymphocytic Lymphoma, Stage II Chronic Lymphocytic Leukemia, Stage II Small Lymphocytic Lymphoma

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Trial Information

Phase II Study of Lenalidomide to Repair Immune Synapse Response and Humoral Immunity in Early-Stage, Asymptomatic Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL) With High-Risk Genomic Features


PRIMARY OBJECTIVES:

I. To determine the proportion of early-stage, high-risk chronic lymphocytic leukemia (CLL)
patients achieving a response (≥ 4-fold increase from baseline and/or antibody
concentrations ≥ 0.35 μg/mL in 6 of 7 type-specific anti-pneumococcal antibody levels) after
2 doses of pneumococcal 13-valent conjugated vaccine (Prevnar 13, PCV13) administered
concurrently versus sequentially with low-dose lenalidomide.

SECONDARY OBJECTIVES:

I. To determine the complete response (CR) rate after 2 years of lenalidomide therapy.

II. To determine the time to first treatment (TFT), defined as the time from diagnosis to
first non-lenalidomide therapy for progressive CLL as described by IWCLL 2008 criteria.

III. To determine the incidence of infection and invasive pneumococcal infections following
treatment with the PCV13 vaccine and either concurrent or sequential lenalidomide.

IV. To determine the frequency of humoral and cellular immune response to CLL tumor antigens
following treatment with the PCV13 vaccine and either concurrent or sequential lenalidomide.

V. To determine the safety and toxicity associated with long-term lenalidomide exposure.

VI. To perform correlative pharmacodynamic and pharmacokinetic studies and correlate these
with vaccine/tumor immunologic and disease response.

OUTLINE: Patients are stratified according to prior exposure to pneumococcal vaccination
within the past 5 years (yes vs no). Patients are randomized to 1 of 2 treatment arms.

ARM I (concurrent PCV13): Patients receive low-dose lenalidomide orally once daily on days
1-28. Treatment repeats every 28 days for at least 24 courses in the absence of disease
progression or unacceptable toxicity. Patients also receive 13-valent protein-conjugated
pneumococcal vaccine (PCV13) intramuscularly (IM) on days 78 and 134 (courses 3 and 5).

ARM II (sequential PCV13): Patients receive PCV13 IM on days 1 and 78 (courses 1 and 3).
Patients also receive low-dose lenalidomide as in arm 1 beginning on day 106 (course 4).

Blood samples are collected at baseline and periodically during study for humoral and
cellular immune response and pharmacokinetic and pharmacodynamic studies.

After completion of study treatment, patients are followed up every 3 months for 1 year and
then every 6 months thereafter.


Inclusion Criteria:



- Patients must have histologically identified chronic lymphocytic leukemia (CLL) or
small lymphocytic lymphoma (SLL) as defined by the WHO classification of
hematopoietic neoplasms

- CLL/SLL cells must demonstrate one or more of the following high-risk genomic
features:

- Del(17p13.1) as detected by fluorescence in-situ hybridization (FISH) in > 20%
of cells

- Del(11q22.3) as detected by FISH in > 20% of cells

- Complex karyotype (≥ 3 cytogenetic abnormalities on stimulated karyotype)

- Unmutated IgVH (≥ 98% sequence homology compared with germline sequence)

- None of the following:

- Progressive splenomegaly and/or lymphadenopathy identified by physical
examination or radiographic studies

- Progressive lymphocytosis with total WBC ≥ 300,000/µL

- Anemia (< 11 g/dL) or thrombocytopenia (< 100,000/μL) due to bone marrow
involvement

- Progressive lymphocytosis with an increase of > 50% over a 2-month period or an
anticipated doubling time of < 6 months

- Patients must discontinue treatment with H2-blockers (cimetidine, ranitidine, etc.)
prior to beginning protocol therapy

- Estimated life expectancy of greater than 24 months

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

- Total bilirubin ≤ 1.5 times upper limit of normal (ULN) (unless secondary to Gilbert
disease)

- AST/ALT ≤ 2.5 times ULN

- Creatinine normal or creatinine clearance ≥ 60 mL/min

- ANC ≥ 1,500/μL

- Platelet count ≥ 100,000/μL

- Able to swallow capsules without difficulty

- No history of malabsorption syndrome; disease significantly affecting
gastrointestinal function; resection of the stomach or small bowel; ulcerative
colitis; symptomatic inflammatory bowel disease; or partial or complete bowel
obstruction

- Negative serum or urine pregnancy test

- Fertile patients must either commit to continued abstinence from heterosexual
intercourse or begin TWO acceptable methods of birth control: one highly effective
method and one additional effective method AT THE SAME TIME, at least 28 days before
starting lenalidomide; men must agree to use a latex condom during sexual contact
with a female, even if they have had a successful vasectomy

- No presence of unintentional weight loss > 10% over the preceding 6 months

- No NCI CTCAE grade 2 or 3 fatigue

- No fever > 100.5° or night sweats for > 2 weeks without evidence of infection

- No patients with a recent history (within 6 months of study entry) of deep vein
thrombosis/pulmonary embolism (DVT/PE)

- Patients with a distant history (greater than 6 months before study entry) of
venous thromboembolic disease are eligible, but should receive prophylactic
aspirin or low-molecular weight heparin

- No history of allergic reactions attributable to compounds of similar chemical or
biologic composition to thalidomide, lenalidomide, or any component of PCV7 or PCV13,
including the diphtheria toxoid

- No prior malignancy, except for adequately treated basal cell or squamous cell skin
cancer, in situ cervical cancer, or other cancer from which the subject is considered
by his or her physician to have a 2-year survival expectation

- No uncontrolled intercurrent illness including, but not limited to: ongoing or active
infection; symptomatic congestive heart failure; unstable angina pectoris; cardiac
arrhythmia; or psychiatric illness/social situations that would limit compliance with
study requirements

- HIV-positive patients with CD4 cell count ≥ 200/mm³ and viral load < 50 /mm³ will be
eligible if they otherwise meet required hematologic parameters and are not receiving
an antiviral agent with known or potential interaction with lenalidomide

- No patients who have developed erythema nodosum characterized by a desquamating rash
while taking thalidomide or similar drugs in the past

- No prior therapy for chronic lymphocytic leukemia or small lymphocytic lymphoma
(CLL/SLL), including chemotherapy, radiotherapy, and/or immunotherapy

- No corticosteroid use will be permitted within two weeks prior to study, except for
maintenance therapy for a non-malignant disease

- Maintenance therapy dose may not exceed 20 mg/day prednisone or equivalent

- No other concurrent investigational agents

- HIV-positive patients on combination antiretroviral therapy will be eligible if they
otherwise meet required hematologic parameters and are not receiving an antiviral
agent with known or potential interaction with lenalidomide

- No patients who have been treated for autoimmune hemolytic anemia or autoimmune
thrombocytopenia within the last 6 months or are direct antiglobulin test/Coomb's
test or indirect antiglobulin test positive at the time of screening

Type of Study:

Interventional

Study Design:

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Proportion of patients who achieve an antibody response

Outcome Description:

Defined as achieving at least a four-fold increase in post-vaccination serotype-specific IgG titers or serotype-specific IgG concentrations of >= 0.35 ug/mL for 6 of 7 serotypes measured by a standard ELISA assay.

Outcome Time Frame:

Up to 1 month

Safety Issue:

No

Principal Investigator

Jeffrey Jones

Investigator Role:

Principal Investigator

Investigator Affiliation:

Ohio State University

Authority:

United States: Food and Drug Administration

Study ID:

NCI-2011-02584

NCT ID:

NCT01351896

Start Date:

September 2011

Completion Date:

Related Keywords:

  • B-cell Chronic Lymphocytic Leukemia
  • Bacterial Infection
  • Contiguous Stage II Small Lymphocytic Lymphoma
  • Noncontiguous Stage II Small Lymphocytic Lymphoma
  • Stage 0 Chronic Lymphocytic Leukemia
  • Stage I Chronic Lymphocytic Leukemia
  • Stage I Small Lymphocytic Lymphoma
  • Stage II Chronic Lymphocytic Leukemia
  • Stage II Small Lymphocytic Lymphoma
  • Bacterial Infections
  • Leukemia
  • Leukemia, Lymphocytic, Chronic, B-Cell
  • Leukemia, Lymphoid
  • Lymphoma

Name

Location

Ohio State University Medical CenterColumbus, Ohio  43210