A Phase I Study of Ibrutinib (PCI-32765) in Combination With Lenalidomide in Relapsed and Refractory B-Cell Non-Hodgkin's Lymphoma
Overview
- Phase
- Phase 1
- Intervention
- Biospecimen Collection
- Conditions
- Recurrent Diffuse Large B-Cell Lymphoma
- Sponsor
- National Cancer Institute (NCI)
- Enrollment
- 39
- Locations
- 3
- Primary Endpoint
- Maximum tolerated dose (MTD)
- Status
- Active, not recruiting
- Last Updated
- 5 months ago
Overview
Brief Summary
This phase I trial studies the side effects and best dose of lenalidomide and ibrutinib in treating patients with B-cell non-Hodgkin lymphoma that has returned (relapsed) or not responded to treatment (refractory). Lenalidomide helps shrink or slow the growth of non-Hodgkin lymphoma. Ibrutinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Giving lenalidomide with ibrutinib may work better in treating non-Hodgkin lymphoma than giving either drug alone.
Detailed Description
PRIMARY OBJECTIVES: I. To determine the dose limiting toxicity (DLT) and maximum tolerated dose (MTD) of the combination of lenalidomide and ibrutinib in patients with relapsed and refractory B-cell non-Hodgkin's lymphoma (NHL). II. To define the qualitative and quantitative toxicities of the combination of lenalidomide and ibrutinib. SECONDARY OBJECTIVES: I. To describe the overall objective response rate to the combination of lenalidomide and ibrutinib in patients with relapsed or refractory B-cell NHL. II. To describe the response duration and two-year progression free survival (PFS) in patients with B-cell NHL receiving lenalidomide and ibrutinib. III. To characterize the pharmacokinetics of the combination of lenalidomide and ibrutinib in patients with relapsed or refractory B-cell NHL. IV. To identify associations of genetic polymorphisms in drug metabolizing enzymes, transporters or target genes with pharmacokinetics, pharmacodynamics, and clinical outcomes. V. To monitor the effects of combined therapy with ibrutinib and lenalidomide on B- T-, and natural killer (NK)-cell subsets by flow cytometry and quantitative immunoglobulin levels. VI. To explore the effects of the combination of ibrutinib and lenalidomide on pharmacodynamic markers including T helper cell, type 1 (TH1) and T helper cell, type 2 (TH2) cytokines, ex vivo NK cell cytotoxicity, serum micro ribonucleic acids (RNAs), plasma metabolites, and levels of Bruton's tyrosine kinase occupancy and other selected kinases. VII. To explore the relationship between pretreatment pathologic prognostic features and overall objective response. OUTLINE: This is a dose-escalation study. Patients receive lenalidomide orally (PO) on days 1-21 and ibrutinib PO on days 1-28 (days 2-28 of cycle 1). Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo blood sample collection and CT or PET/CT throughout the study. Patients may undergo bone marrow biopsy and aspiration and MRI as clinically indicated. After completion of study treatment, patients are followed up for 4 weeks and then every 6 months thereafter.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Histologically confirmed B-cell non-Hodgkin's lymphoma (NHL) of any of the following subtypes recognized by the World Health Organization (WHO) classification: diffuse large B-cell lymphoma, mantle cell lymphoma, marginal zone lymphoma, lymphoplasmacytic lymphoma, or follicular lymphoma; patients with evidence of histological transformation to diffuse large B-cell lymphoma from indolent NHL are eligible
- •Patients must have received at least one prior therapy; prior autologous stem cell transplant is permitted; patients with diffuse large B-cell lymphoma who have not received high-dose therapy (HDT)/autologous stem cell transplant (ASCT) must be ineligible for HDT/ASCT; prior allogeneic stem cell transplant is not permitted; prior ibrutinib is not permitted
- •Age \>= 18 years. Because no dosing or adverse event data are currently available on the use of ibrutinib in combination with lenalidomide in patients \< 18 years of age, children are excluded from this study, but will be eligible for future pediatric trials
- •Eastern Cooperative Oncology Group (ECOG) performance status =\< 2 (Karnofsky \>= 60%)
- •Life expectancy of greater than 12 weeks
- •Patients must have normal organ and marrow function, independent of growth factor or transfusion support; patients should not receive growth factors or transfusions for at least 7 days prior to first dose of study drug, with the exception of pegylated G-CSF (pegfilgrastim) and darbepoeitin which require at least 14 days prior to screening and randomization
- •Absolute neutrophil count \>= 1,000/mcL in the absence of growth factor administration
- •Platelets \>= 50,000/mcL in the absence of transfusion support within 7 days prior to determination of eligibility
- •Total bilirubin =\< 1.5 x upper limit of normal (ULN) unless due to Gilberts disease
- •Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase \[SGOT\])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase \[SGPT\]) =\< 2.5 X institutional upper limit of normal unless due to disease
Exclusion Criteria
- •Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study or those who have not recovered from adverse events due to agents administered more than 4 weeks earlier; steroids used for disease related symptoms should be stopped within 48 hours of protocol therapy; patients who have had prior exposure to a Bruton's tyrosine kinase (BTK) inhibitor; patients who received monoclonal antibody =\< 6 weeks prior to first administration of study treatment
- •Patients who are receiving any other investigational agents
- •Patients with active central nervous system (CNS) involvement with lymphoma 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 allergic reactions attributed to lenalidomide or compounds of similar chemical or biologic composition to lenalidomide including thalidomide
- •Patients receiving any medications or substances that are strong inhibitors or strong inducers of cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4) are ineligible; because the lists of these agents are constantly changing, it is important to regularly consult a frequently-updated list; medical reference texts such as the Physicians' Desk Reference may also provide this information; as part of the enrollment/informed consent procedures, the patient will be counseled on the risk of interactions with other agents, and what to do if new medications need to be prescribed or if the patient is considering a new over-the-counter medicine or herbal product
- •Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, or psychiatric illness/social situations that would limit compliance with study requirements; currently active clinically significant cardiovascular disease such as uncontrolled arrhythmia, congestive heart failure or 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 randomization
- •Recent infections requiring systemic treatment need to have completed therapy \> 14 days before the first dose of study drug
- •Medications with a risk of causing Torsades de Pointes are not permitted; although concomitant treatment with corrected QT (QTc) prolonging agents is not strictly prohibited, these agents should be avoided whenever possible and an alternative non-QTc prolonging drug should be substituted if possible
- •Patients requiring any therapeutic anticoagulation are excluded; patients who have received warfarin or other vitamin K antagonists within 28 days or are taking warfarin or other vitamin K antagonists are not eligible
- •Patients who are within 4 weeks of major surgery or within 2 weeks of minor surgery
Arms & Interventions
Treatment (lenalidomide, ibrutinib)
Patients receive lenalidomide PO on days 1-21 and ibrutinib PO on days 1-28 (days 2-28 of cycle 1). Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo blood sample collection and CT or PET/CT throughout the study. Patients may undergo bone marrow biopsy and aspiration and MRI as clinically indicated.
Intervention: Biospecimen Collection
Treatment (lenalidomide, ibrutinib)
Patients receive lenalidomide PO on days 1-21 and ibrutinib PO on days 1-28 (days 2-28 of cycle 1). Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo blood sample collection and CT or PET/CT throughout the study. Patients may undergo bone marrow biopsy and aspiration and MRI as clinically indicated.
Intervention: Bone Marrow Aspiration
Treatment (lenalidomide, ibrutinib)
Patients receive lenalidomide PO on days 1-21 and ibrutinib PO on days 1-28 (days 2-28 of cycle 1). Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo blood sample collection and CT or PET/CT throughout the study. Patients may undergo bone marrow biopsy and aspiration and MRI as clinically indicated.
Intervention: Bone Marrow Biopsy
Treatment (lenalidomide, ibrutinib)
Patients receive lenalidomide PO on days 1-21 and ibrutinib PO on days 1-28 (days 2-28 of cycle 1). Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo blood sample collection and CT or PET/CT throughout the study. Patients may undergo bone marrow biopsy and aspiration and MRI as clinically indicated.
Intervention: Computed Tomography
Treatment (lenalidomide, ibrutinib)
Patients receive lenalidomide PO on days 1-21 and ibrutinib PO on days 1-28 (days 2-28 of cycle 1). Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo blood sample collection and CT or PET/CT throughout the study. Patients may undergo bone marrow biopsy and aspiration and MRI as clinically indicated.
Intervention: Ibrutinib
Treatment (lenalidomide, ibrutinib)
Patients receive lenalidomide PO on days 1-21 and ibrutinib PO on days 1-28 (days 2-28 of cycle 1). Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo blood sample collection and CT or PET/CT throughout the study. Patients may undergo bone marrow biopsy and aspiration and MRI as clinically indicated.
Intervention: Lenalidomide
Treatment (lenalidomide, ibrutinib)
Patients receive lenalidomide PO on days 1-21 and ibrutinib PO on days 1-28 (days 2-28 of cycle 1). Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo blood sample collection and CT or PET/CT throughout the study. Patients may undergo bone marrow biopsy and aspiration and MRI as clinically indicated.
Intervention: Magnetic Resonance Imaging
Treatment (lenalidomide, ibrutinib)
Patients receive lenalidomide PO on days 1-21 and ibrutinib PO on days 1-28 (days 2-28 of cycle 1). Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo blood sample collection and CT or PET/CT throughout the study. Patients may undergo bone marrow biopsy and aspiration and MRI as clinically indicated.
Intervention: Positron Emission Tomography
Outcomes
Primary Outcomes
Maximum tolerated dose (MTD)
Time Frame: 28 days
Defined as the highest safely tolerated dose where at most one patient experiences dose limiting toxicity (DLT) with the next higher dose having at least 2 patients who experience DLT.
Incidence of toxicity according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0 criteria
Time Frame: Up to 2 years
Worst grade toxicities will be recorded for each patient and summarized using frequency tables. Tolerability of the regimen is assessed by summarizing the number of patients who required dose modifications and/or dose delays. In addition, the proportion of patients who go off treatment due to adverse reactions or even those who refuse further treatment for lesser toxicities that inhibit their willingness to continue participation on the trial will be counted.
Secondary Outcomes
- Number of patients responding to treatment(Up to 2 years)
- Degree of response(Up to 2 years)
- Duration of overall response(From the time measurement criteria are met for complete response or partial response (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented, assessed up to 2 years)
- Duration of stable disease(From the start of the treatment until the criteria for progression are met, assessed up to 2 years)
- Progression free survival (PFS)(Duration of time from the start of treatment to the time of measured progression or death, assessed up to 2 years)