Lenalidomide and Ibrutinib in Treating Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma

PRIMARY OBJECTIVES:

I. To define the safety, tolerability and maximum tolerated dose (MTD) of lenalidomide when
used in combination with ibrutinib in adults with relapsed or refractory chronic lymphocytic
leukemia (CLL)/small lymphocytic lymphoma (SLL).

SECONDARY OBJECTIVES:

I. To determine the response rate and response duration in relapsed and refractory CLL/SLL
patients with ibrutinib and lenalidomide.

II. To characterize the plasma pharmacokinetic (PK) interaction between ibrutinib and
lenalidomide.

III. To explore whether pharmacogenetic studies can predict response, resistance or toxicity
to ibrutinib and lenalidomide.

IV. To explore the ability of ibrutinib to occupy its targets (Bruton's tyrosine kinase [BTK]
in B-cells and interleukin-2 inducible kinase [ITK] in T-cells), and whether
co-administration with lenalidomide influences this binding.

V. To explore the early and late immunologic consequences of combining ibrutinib with
lenalidomide in relapsed and refractory CLL.

VI. To explore the impact of ibrutinib and lenalidomide on ras homolog family member H (RhoH)
expression and whether baseline RhoH expression predicts outcomes with this regimen.

VII. To explore mechanisms of resistance to ibrutinib. VIII. To explore the influence of
traditional and new CLL/SLL clinical and laboratory prognostic factors on response to
ibrutinib and lenalidomide.

OUTLINE: This is a dose-escalation study of lenalidomide.

Patients receive a run-up course of ibrutinib orally (PO) daily on days 1-28. Patients then
receive ibrutinib PO and lenalidomide PO daily on days 1-28. Courses repeat every 28 days in
the absence of disease progression or unacceptable toxicity. After 12 courses, patients who
have achieved complete remission (CR)/CR with incomplete marrow recovery (CRi), nodular
partial remission (PR), partial remission or who have stable disease discontinue lenalidomide
and continue ibrutinib.

After completion of study treatment, patients are followed up for 90 days.

Inclusion Criteria:

- Patients must have a diagnosis of CLL/SLL or B-cell prolymphocytic leukemia, as
defined by the World Health Organization (WHO)

- During dose escalation, patients must have received at least one prior therapy, need
additional cytoreduction, and meet criteria for relapsed or refractory disease;
relapsed disease is defined as a patient who previously achieved a CR or a PR, but
after a period of six or more months demonstrates evidence of disease progression;
refractory disease is defined as progression within six months of the last
anti-leukemic therapy, or any response less than a CR or PR; patients who are
previously untreated, and do not wish to receive chemotherapy or immunotherapy, are
eligible for the dose expansion portion of the study

- Patients may have not received treatment for 28 days before the first day of the study
protocol (dose escalation only)

- Estimated life expectancy greater than two months

- Eastern Cooperative Oncology Group (ECOG) performance status 0-2

- Ability to understand and willingness to sign a written informed consent document

- Patients must have acceptable organ and marrow function, which should be present
independent of growth factor or transfusion support for at least 7 days prior to first
dose of study drug, with the exception of pegylated G-CSF (pegfilgrastim) and
darbopoeitin which require a 14-day period between dosing and first dose of study drug

- Absolute neutrophil count (ANC) >= 750 cells/uL (0.75 x 10^9/L)

- Platelets >= 50,000 cells/uL (50 x 10^9/L)

- Hemoglobin > 8 mg/dL

- Total bilirubin =< 1.5 x upper limit of normal (ULN) unless Gilbert's syndrome or
disease infiltration of the liver is present

- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase
[SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
=< 3.0 x ULN

- Creatinine < 2.0 x ULN or creatinine clearance (estimated [est.] glomerular filtration
rate [GFR] [Cockcroft-Gault]) >= 30 mL/min

- Prothrombin time (PT)/international normalized ratio (INR) < 1.5 x ULN and partial
thromboplastin time (PTT)/activated partial thromboplastin time (aPTT) < 1.5 x ULN

- Females of childbearing potential (FCBP) must have a negative pregnancy test
(sensitivity of at least 25 mIU/mL) performed once before ibrutinib and a total of two
negative tests before initiating lenalidomide; a FCBP is a sexually mature woman who:
1) has achieved menarche at some point; 2) has not undergone a hysterectomy or
bilateral oophorectomy; or 3) has not been naturally postmenopausal for at least 24
consecutive months (i.e., has had menses at any time in the preceding 24 consecutive
months); the pre- ibrutinib pregnancy test will be initiated at enrollment; the first
pre-lenalidomide test will be performed within 10-14 days of starting lenalidomide
(cycle 0, day 15), and the second pre- lenalidomide test (3rd total test) will be
within 24 hours of the first dose of lenalidomide; the patient may not receive
lenalidomide until the study doctor has verified that the results of these pregnancy
tests are negative; pregnancy tests (if applicable) are then to be conducted weekly
during the first month, and monthly thereafter in women with a regular menstrual
cycle, as well as at study discontinuation, and at day 28 following study
discontinuation; if menstrual cycles are irregular, pregnancy testing will be
conducted weekly for the first month, and then every 14 days while on the study, at
study discontinuation, and at days 14 and 28 following study drug discontinuation;
pregnancy testing and counseling are to be performed if a patient misses her period or
if there is any abnormality in menstrual bleeding; should a woman become pregnant or
suspect she is pregnant while she is participating in this study, she should inform
her treating physician immediately; further, FCBP 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; FCBP must also agree to ongoing
pregnancy testing; men must agree to use a latex condom during sexual contact with a
FCBP, even if they have had a successful vasectomy; male and female patients, must
agree to use highly effective methods of birth control (e.g. condoms, implants,
injectables, combined oral contraceptives, some intrauterine devices [IUDs], complete
sexual abstinence, or sterilized partner) during the period of therapy and for 90 days
after the last dose of study drug; all patients must be counseled by a trained
counselor every 28 days about pregnancy precautions and risks of fetal exposure

Exclusion Criteria:

- Prior therapy with Bruton's tyrosine kinase (BTK) inhibitor

- Concurrent treatment with other investigational or anti-neoplastic agents

- Patients requiring daily corticosteroids at a prednisone equivalent of > 20 mg daily
should not be enrolled; if corticosteroids can be discontinued (or reduced to < 20 mg
per day of prednisone or equivalent), the discontinuation or dose reduction should be
done at least 7 days prior to first dose

- Chemotherapy =< 21 days prior to first administration of study treatment and/or
monoclonal antibody =< 6 weeks prior to first administration of study treatment;
immunotherapy, radiotherapy or experimental therapy within 28 days of first day of
study drug dosing, or within six weeks of first day of study drug dosing in the event
that nitrosoureas or mitomycin were used; concurrent systemic immunosuppressant
therapy other than corticosteroids (e.g. cyclosporine A, tacrolimus, etc) must be
discontinued within 28 days of the first dose of study drug

- Currently active clinically significant cardiovascular disease such as uncontrolled
arrhythmia, congestive heart failure, or any class 3 or 4 congestive heart failure as
defined by the New York Heart Association Functional Classification, or history of
myocardial infarction, unstable angina or acute coronary syndrome within 6 months
prior to on-study registration

- Uncontrolled psychiatric illness that would limit compliance with study requirements

- Central nervous system disease involvement

- History of prior malignancy, with the exception of the following:

- Malignancy treated with curative intent and with no evidence of active disease
present for more than 3 years prior to screening, and felt to be at low risk for
recurrence by treating physician

- Adequately treated non-melanomatous skin cancer or lentigo maligna melanoma
without current evidence of disease

- Adequately treated cervical carcinoma in situ without current evidence of disease

- Serologic status reflecting active hepatitis B or C infection; patients that are
hepatitis B core antibody, hepatitis B surface antigen (HBsAg) or hepatitis C antibody
must have a negative polymerase chain reaction (PCR) prior to enrollment; PCR positive
patients will be excluded

- Active infection at initiation of study; recent infections requiring systemic
treatment need to have completed therapy > 14 days before the first dose of study drug

- Major surgery within 4 weeks or minor surgery within 7 days of the first day of study
drug dosing

- Unable to swallow capsules or disease significantly affecting gastrointestinal
function or resection of the stomach or small bowel, or symptomatic inflammatory bowel
disease or ulcerative colitis or partial or complete bowel obstruction

- Prior allogeneic stem cell transplantation

- Active, uncontrolled autoimmune hemolytic anemia or idiopathic thrombocytopenic
purpura (ITP)

- Presence of transfusion-dependent thrombocytopenia or a history of bleeding disorders
or clinical conditions (e.g. gastrointestinal [GI] bleeding or constitutional
disorders) that may increase risk of life-threatening bleeding when thrombocytopenic

- History of stroke or intracranial hemorrhage within 6 months prior to enrollment

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to ibrutinib or lenalidomide

- Patients who received a strong cytochrome P450 (CYP) 3A inhibitor within 7 days prior
to the first dose of ibrutinib or patients who require continuous treatment with a
strong CYP3A inhibitor

- Requires or is receiving anticoagulation with warfarin or equivalent vitamin K
antagonists (e.g.: phenprocoumon) within 28 days of the first dose of study drug

- Pregnant women are excluded from this study; breastfeeding should be discontinued if
the mother is treated with either agent, and for 30 days after discontinuation of
therapy

- Current life-threatening illness, medical condition, or organ system dysfunction
which, in the investigator's opinion, could compromise the patient's safety, or put
the study at risk

- Human immunodeficiency virus (HIV)-positive patients with cluster of differentiation 4
(CD4) counts less than the lower limit of institutional normal

- HIV-positive patients requiring antivirals which are cytochrome P450 (CYP) interactive
with the investigational agents (CYP3A4/5 strong inducers and inhibitors)

- Other laboratory abnormalities that, in the opinion of the investigator, would
compromise the patient's safety or interfere with data interpretation

- Vaccinated with live, attenuated vaccines within 4 weeks of first dose of study drug

- Unresolved toxicities from prior anti-cancer therapy, defined as having not resolved
to Common Terminology Criteria for Adverse Event (CTCAE, version 5), grade =< 1, or to
the levels dictated in the inclusion/exclusion criteria with the exception of alopecia

- Known bleeding disorders (e.g., von Willebrand's disease) or hemophilia

- Unwilling or unable to participate in all required study evaluations and procedures

- Currently active, clinically significant hepatic impairment (>= moderate hepatic
impairment according to the National Cancer Institute (NCI)/Child Pugh classification)