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A Dose Escalation Study of Ibrutinib With Lenalidomide for Relapsed and Refractory Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

Phase 1
18 Years
Open (Enrolling)
Prolymphocytic Leukemia, Recurrent Small Lymphocytic Lymphoma, Refractory Chronic Lymphocytic Leukemia

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Trial Information

A Dose Escalation Study of Ibrutinib With Lenalidomide for Relapsed and Refractory Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma


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


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

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 and lenalidomide. 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 and lenalidomide orally (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 will
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)

- 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 complete response (CR) or a partial
response (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 may have not received treatment for 28 days before the first day of the
study protocol

- 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

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

- Platelets >= 30,000 cells/uL (30 x 10^9/L)

- 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])
=< 2.0 x ULN

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

- 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; 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; a FCBP is a sexually
mature woman who: 1) has not undergone a hysterectomy or bilateral oophorectomy; or
2) 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); 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 ibrutinib

- Concurrent treatment with other investigational or anti-neoplastic agents

- Need for daily corticosteroids, with the exception of prednisone < 20 mg equivalent
dose daily; must have been discontinued from 7 days prior to first dose of study drug
(topical, inhaled or nasal corticosteroids are permitted)

- Immunotherapy, chemotherapy, 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

- Currently active clinically significant cardiovascular disease such as uncontrolled
arrhythmia, congestive heart failure, any class 3 or 4 cardiac disease as defined by
the New York Heart Association Functional Classification, or history of myocardial
infarction within 6 months prior to first dose with study drug

- 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

- Serologic status reflecting active hepatitis B or C infection; patients that are
hepatitis B core antibody positive but antigen negative will need a negative
polymerase chain reaction (PCR) prior to enrollment

- Active infection at initiation of study

- Major surgery within 10 days of the first day of study drug dosing, and minor surgery
within 7 days of the first day of study drug dosing

- Unable to swallow capsules or disease significantly affecting gastrointestinal
function and/or inhibiting small intestine absorption such as; malabsorption
syndrome, resection of the small bowel, or poorly controlled inflammatory bowel
disease affecting the small intestine

- 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

- Any medications that are strong inhibitors or inducers of cytochrome P450, family 3,
subfamily A, polypeptide 4 (CYP3A4)/cytochrome P450, family 3, subfamily A,
polypeptide 5 (CYP3A5) (e.g., itraconazole, ketoconazole, clarithromycin, ritonavir,
phenytoin, phenobarbital, and rifampicin) should be changed; patients who cannot
change these medications must be excluded

- Use of concomitant antiplatelet agents (except low-dose aspirin) or anticoagulation
with warfarin, other vitamin K antagonists, treatment-dose unfractionated or low
molecular weight heparin or other anticoagulants at treatment doses is prohibited, as
is treatment with these agents in the 28 days prior to enrollment

- 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

- 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)

Type of Study:


Study Design:

Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

MTD of lenalidomide when combined with ibrutinib defined as the highest dose in which less than or equal to 1/6 patients have dose limiting toxicity

Outcome Description:

Assessed using National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. All patient safety information collected will be summarized using descriptive statistics (number of non-missing values, mean, median, standard deviation, minimum and maximum) for continuous variables and counts and percentages for categorical variables, where applicable.

Outcome Time Frame:

28 days

Safety Issue:


Principal Investigator

Daniel Pollyea

Investigator Role:

Principal Investigator

Investigator Affiliation:

University of Colorado Cancer Center - Anschutz Cancer Pavilion


United States: Food and Drug Administration

Study ID:




Start Date:

April 2013

Completion Date:

Related Keywords:

  • Prolymphocytic Leukemia
  • Recurrent Small Lymphocytic Lymphoma
  • Refractory Chronic Lymphocytic Leukemia
  • Leukemia
  • Leukemia, Lymphocytic, Chronic, B-Cell
  • Leukemia, Lymphoid
  • Leukemia, Prolymphocytic
  • Lymphoma



University of Colorado Cancer Center - Anschutz Cancer Pavilion Aurora, Colorado  80045