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Lenalidomide and Ibrutinib in Treating Patients With Relapsed or Refractory B-cell Non-Hodgkin Lymphoma

This study is ongoing, but not recruiting participants.
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:
NCT01955499
First received: September 27, 2013
Last updated: January 31, 2017
Last verified: January 2017
  Purpose
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 or not responded to treatment. 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 work better in treating non-Hodgkin lymphoma.

Condition Intervention Phase
Recurrent Diffuse Large B-Cell Lymphoma
Recurrent Follicular Lymphoma
Recurrent Lymphoplasmacytic Lymphoma
Recurrent Mantle Cell Lymphoma
Recurrent Marginal Zone Lymphoma
Refractory Diffuse Large B-Cell Lymphoma
Refractory Follicular Lymphoma
Refractory Lymphoplasmacytic Lymphoma
Refractory Mantle Cell Lymphoma
Drug: Ibrutinib
Other: Laboratory Biomarker Analysis
Drug: Lenalidomide
Other: Pharmacological Study
Phase 1

Study Type: Interventional
Study Design: Intervention Model: Single Group Assignment
Masking: No masking
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

Resource links provided by NLM:


Further study details as provided by National Cancer Institute (NCI):

Primary Outcome Measures:
  • Incidence of toxicity according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4 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.

  • 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 ]

Secondary Outcome Measures:
  • Degree of response [ Time Frame: Up to 2 years ]
    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 2 years ]
    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 2 years ]
    Summarized with simple descriptive statistics.

  • Number of patients responding to treatment [ Time Frame: Up to 2 years ]
    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.

  • PFS [ Time Frame: Duration of time from the start of treatment to the time of measured progression or death, assessed up to 2 years ]
    Summarized with simple descriptive statistics.


Other Outcome Measures:
  • Change in 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 ]
    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.

  • Changes in B- T-, and NK- cell subsets [ Time Frame: Baseline and on day 1 of courses 1, 3, 6, and 12 ]
    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.

  • Changes in quantitative immunoglobulin levels [ Time Frame: Baseline and on day 1 of courses 1, 3, 6, and 12 ]
    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.

  • Ki67 staining [ Time Frame: Baseline ]
    Potential relationships with response will be explored using graphical analyses and quantitative summaries. Confidence intervals will be presented as the primary method of analysis.

  • Pharmacokinetic interactions between lenalidomide and ibrutinib [ Time Frame: Baseline and on days 1, 2, and 22 of course 1 ]
    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 ]
    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.


Estimated Enrollment: 34
Study Start Date: September 2013
Estimated Primary Completion Date: December 2019 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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.
Drug: Ibrutinib
Given PO
Other Names:
  • BTK Inhibitor PCI-32765
  • CRA-032765
  • Imbruvica
  • PCI-32765
Other: Laboratory Biomarker Analysis
Correlative studies
Drug: Lenalidomide
Given PO
Other Names:
  • CC-5013
  • CC5013
  • CDC 501
  • Revlimid
Other: Pharmacological Study
Correlative studies

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 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.

  Eligibility

Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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
  • Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)
  • Life expectancy of greater than 12 weeks
  • 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
  • Creatinine =< 2.0 mg/dL OR creatinine clearance >= 50 mL/min as determined by the Cockcroft-Gault equation or a 24 hour urine collection
  • Non-pregnant and non-nursing; females of childbearing potential (FCBP) must have a negative serum or urine pregnancy test with a sensitivity of at least 25 mIU/mL within 10-14 days prior to and again within 24 hours of starting cycle 1 of lenalidomide; further, they 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
  • Patients with human immunodeficiency virus (HIV) infection are eligible provided they meet the following criteria: no evidence of co-infection with hepatitis B or C, cluster of differentiation (CD)4 count >= 400 cells/mm^3, no resistant viral strains, on highly active antiretroviral treatment (HAART) therapy with a viral load < 50 RNA copies/ml, and no history of acquired immunodeficiency syndrome (AIDS)-defining conditions
  • Ability to understand and the willingness to sign a written informed consent document
  • Curative therapy must have been exhausted or not feasible to administer; patients with diffuse large B-cell lymphoma, germinal center subtype should only enroll on the study if there are no other potentially effective therapeutic options

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 are receiving any other investigational agents
  • Patients with active central nervous system (CNS) involvement with lymphoma should be excluded from this clinical trial
  • 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 4/5 (CYP3A4/5) are ineligible
  • 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 within 28 days or are taking warfarin are not eligible
  • Patients who are within 4 weeks of major surgery or within 2 weeks of minor surgery
  • Concurrent systemic immunosuppressant therapy other than corticosteroids (e.g. cyclosporine A, tacrolimus, etc) within 28 days of the first dose of study drug
  • 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 4), grade 1 =< 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
  • Patients requiring daily corticosteroids at a prednisone equivalent of >= 20 mg daily should not be enrolled
  • 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
  • Serologic status reflecting active hepatitis B or C infection; patients that are positive for 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)
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01955499

Locations
United States, Illinois
University of Chicago Comprehensive Cancer Center
Chicago, Illinois, United States, 60637
United States, Ohio
Ohio State University Comprehensive Cancer Center
Columbus, Ohio, United States, 43210
Canada, Ontario
University Health Network-Princess Margaret Hospital
Toronto, Ontario, Canada, M5G 2M9
Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
Principal Investigator: Beth Christian Ohio State University Comprehensive Cancer Center
  More Information

Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT01955499     History of Changes
Other Study ID Numbers: NCI-2013-01810
NCI-2013-01810 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
OSU 13022
9426 ( Other Identifier: Ohio State University Comprehensive Cancer Center )
9426 ( Other Identifier: CTEP )
P30CA016058 ( US NIH Grant/Contract Award Number )
U01CA132123 ( US NIH Grant/Contract Award Number )
U01CA076576 ( US NIH Grant/Contract Award Number )
UM1CA186644 ( US NIH Grant/Contract Award Number )
UM1CA186705 ( US NIH Grant/Contract Award Number )
UM1CA186712 ( US NIH Grant/Contract Award Number )
Study First Received: September 27, 2013
Last Updated: January 31, 2017

Additional relevant MeSH terms:
Lymphoma
Lymphoma, Follicular
Lymphoma, Non-Hodgkin
Lymphoma, B-Cell
Lymphoma, Mantle-Cell
Lymphoma, B-Cell, Marginal Zone
Lymphoma, Large B-Cell, Diffuse
Waldenstrom Macroglobulinemia
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Neoplasms, Plasma Cell
Hemostatic Disorders
Vascular Diseases
Cardiovascular Diseases
Paraproteinemias
Blood Protein Disorders
Hematologic Diseases
Hemorrhagic Disorders
Lenalidomide
Thalidomide
Immunologic Factors
Physiological Effects of Drugs
Angiogenesis Inhibitors
Angiogenesis Modulating Agents
Growth Substances
Growth Inhibitors

ClinicalTrials.gov processed this record on March 24, 2017