A Dose Escalation Study of Ibrutinib With Lenalidomide for Relapsed and Refractory Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma
Overview
- Phase
- Phase 1
- Intervention
- Ibrutinib
- Conditions
- Recurrent B-Cell Prolymphocytic Leukemia
- Sponsor
- National Cancer Institute (NCI)
- Enrollment
- 27
- Locations
- 3
- Primary Endpoint
- Maximum tolerated dose of lenalidomide when combined with ibrutinib
- Status
- Completed
- Last Updated
- 3 years ago
Overview
Brief Summary
This phase I trial studies the side effects and best dose of lenalidomide when given together with ibrutinib in treating patients with chronic lymphocytic leukemia or small lymphocytic lymphoma that has returned after a period of improvement (relapsed) or does not respond to treatment (refractory). Biological therapies, such as lenalidomide, may stimulate the immune system in different ways and stop cancer cells from growing. Ibrutinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Giving lenalidomide together with ibrutinib may work better in treating chronic lymphocytic leukemia or small lymphocytic lymphoma.
Detailed Description
PRIMARY OBJECTIVE: 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 cycle of ibrutinib orally (PO) daily on days 1-28. Patients then receive ibrutinib PO and lenalidomide PO daily on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. After 12 cycles, patients who have achieved complete remission (CR)/CR with incomplete marrow recovery (CRi), nodular partial remission (PR), partial remission with persistent lymphocytosis, partial remission, or who have stable disease discontinue lenalidomide and continue ibrutinib. After completion of study treatment, patients are followed up for 90 days.
Investigators
Eligibility Criteria
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
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; these patients should be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events
- •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
Arms & Interventions
Treatment (ibrutinib and lenalidomide)
Patients receive a run-up cycle of ibrutinib PO daily on days 1-28. Patients then receive ibrutinib PO and lenalidomide PO daily on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. After 12 cycles, patients who have achieved CR/CRi, nodular PR, partial remission with persistent lymphocytosis, partial remission, or who have stable disease discontinue lenalidomide and continue ibrutinib.
Intervention: Ibrutinib
Treatment (ibrutinib and lenalidomide)
Patients receive a run-up cycle of ibrutinib PO daily on days 1-28. Patients then receive ibrutinib PO and lenalidomide PO daily on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. After 12 cycles, patients who have achieved CR/CRi, nodular PR, partial remission with persistent lymphocytosis, partial remission, or who have stable disease discontinue lenalidomide and continue ibrutinib.
Intervention: Lenalidomide
Outcomes
Primary Outcomes
Maximum tolerated dose of lenalidomide when combined with ibrutinib
Time Frame: 28 days
Defined as the highest dose in which less than or equal to 1/6 patients have dose limiting toxicity. Assessed using National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0. 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.
Secondary Outcomes
- Response rates(Up to 12 months)
- Remission/response duration(Up to 90 days)