Lenalidomide and Ibrutinib in Treating Patients With Relapsed or Refractory B-Cell Non-Hodgkin Lymphoma
This phase I trial studies the side effects and best dose of lenalidomide and ibrutinib in treating patients with relapsed or refractory B-cell non-Hodgkin lymphoma. 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 with ibrutinib may be an effective treatment for non-Hodgkin lymphoma.
Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue
Nodal Marginal Zone B-cell Lymphoma
Recurrent Adult Diffuse Large Cell Lymphoma
Recurrent Grade 1 Follicular Lymphoma
Recurrent Grade 2 Follicular Lymphoma
Recurrent Grade 3 Follicular Lymphoma
Recurrent Mantle Cell Lymphoma
Recurrent Marginal Zone Lymphoma
Splenic Marginal Zone Lymphoma
Other: pharmacological study
Other: laboratory biomarker analysis
|Study Design:||Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||A Phase I Study of Ibrutinib (PCI-32765) in Combination With Lenalidomide in Relapsed and Refractory B-Cell Non-Hodgkin's Lymphoma|
- MTD, defined as the highest safely tolerated dose where at most one patient experiences DLT with the next higher dose having at least 2 patients who experience DLT [ Time Frame: 28 days ] [ Designated as safety issue: Yes ]
- Incidence of toxicity according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4 criteria [ Time Frame: Up to 1 year ] [ Designated as safety issue: Yes ]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.
- Number of patients responding to treatment [ Time Frame: Up to 1 year ] [ Designated as safety issue: No ]Responses will be summarized with simple descriptive statistics, delineating complete responses from lesser responses and stable disease or progressive disease according to the International Harmonization Project Lymphoma Response Criteria and the Response Criteria for Waldenstrom's Macroglobulinemia.
- Degree of response [ Time Frame: Up to 1 year ] [ Designated as safety issue: No ]Responses will be summarized with simple descriptive statistics, delineating complete responses from lesser responses and stable disease or progressive disease according to the International Harmonization Project Lymphoma Response Criteria and the Response Criteria for Waldenstrom's Macroglobulinemia.
- Duration of overall response [ Time Frame: 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 1 year ] [ Designated as safety issue: No ]Summarized with simple descriptive statistics.
- Duration of stable disease [ Time Frame: From the start of the treatment until the criteria for progression are met, assessed up to 1 year ] [ Designated as safety issue: No ]Summarized with simple descriptive statistics.
- PFS [ Time Frame: Duration of time from the start of treatment to the time of measured progression or death, assessed up to 2 years ] [ Designated as safety issue: No ]Summarized with simple descriptive statistics.
- Pharmacokinetic interactions between lenalidomide and ibrutinib [ Time Frame: Baseline and on days 1, 2, and 22 of course 1 ] [ Designated as safety issue: No ]Confidence intervals will be presented as the primary method of analysis.
- Single gene polymorphisms, such as those in genes coding for relevant drug metabolizing enzymes, receptors and transporters [ Time Frame: Baseline and on day 1 of course 1 ] [ Designated as safety issue: No ]Pharmacogenetic analyses will be conducted to identify single gene polymorphisms and their effects on drug response. Confidence intervals will be presented as the primary method of analysis.
- Ki67 staining [ Time Frame: Baseline ] [ Designated as safety issue: No ]Potential relationships with response will be explored using graphical analyses and quantitative summaries. Confidence intervals will be presented as the primary method of analysis.
- Pharmacodynamic markers including TH1 and TH2 cytokines, ex vivo NK cell cytotoxicity, serum microRNAs, plasma metabolites, and levels of Bruton's tyrosine kinase occupancy and other selected kinases [ Time Frame: Baseline, on days 1 and 8 of course 1, and day 1 of courses 2 and 3 ] [ Designated as safety issue: No ]Standard paired statistical tests, parametric and nonparametric, will be used to compare baseline with treatment values, and repeated measures analysis of variance will be used to analyze data collected serially over time, recognizing the inherent limitations due to the sample size. Hence, graphical analyses will also be used, including box plots and individual time plots to help identify potential patterns, provide important insights into mechanism, and gather essential preliminary data.
|Study Start Date:||September 2013|
|Estimated Primary Completion Date:||October 2014 (Final data collection date for primary outcome measure)|
Experimental: Treatment (lenalidomide, ibrutinib)
Patients receive lenalidomide PO on days 1-21 and ibrutinib PO on days 1-28 (days 2-28 of course 1). Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Other Names:Drug: lenalidomide
Other Names:Other: pharmacological study
Other Name: pharmacological studiesOther: laboratory biomarker analysis
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.
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 course 1). Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up for 4 weeks and then every 6 months thereafter.
|United States, Illinois|
|University of Chicago Comprehensive Cancer Center||Recruiting|
|Chicago, Illinois, United States, 60637-1470|
|Contact: Sonali M. Smith 773-834-2895 email@example.com|
|Principal Investigator: Sonali M. Smith|
|United States, Ohio|
|Ohio State University Medical Center||Recruiting|
|Columbus, Ohio, United States, 43210|
|Contact: Beth A. Christian 614-293-7807 Beth.Christian@osumc.edu|
|Principal Investigator: Beth A. Christian|
|University Health Network-Princess Margaret Hospital||Recruiting|
|Toronto, Ontario, Canada, M5G 2M9|
|Contact: John Kuruvilla 416-946-2821 firstname.lastname@example.org|
|Principal Investigator: John Kuruvilla|
|Principal Investigator:||Beth Christian||Ohio State University|