Ibrutinib in Treating Relapsed or Refractory B-Cell Non-Hodgkin Lymphoma in Patients With HIV Infection

This study is not yet open for participant recruitment. (see Contacts and Locations)
Verified April 2014 by National Cancer Institute (NCI)
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:
NCT02109224
First received: April 7, 2014
Last updated: July 18, 2014
Last verified: April 2014

April 7, 2014
July 18, 2014
May 2014
August 2017   (final data collection date for primary outcome measure)
  • Incidence of toxicities assessed using National Cancer Institute (NCI) CTCAE version 4.0 [ Time Frame: Up to 30 days ] [ Designated as safety issue: Yes ]
  • MTD of ibrutinib defined as the dose level in which no more than 1 out of 6 patients experiences a dose limiting toxicity assessed using NCI CTCAE version 4.0 [ Time Frame: 28 days ] [ Designated as safety issue: Yes ]
Same as current
Complete list of historical versions of study NCT02109224 on ClinicalTrials.gov Archive Site
  • Pharmacokinetic (PK) parameters of ibrutinib in relation to ART-CYP3A4 interactions, including half-life (T1/2), clearance (Cl), and area under the curve (AUC) [ Time Frame: Course 1, day 8: pre-dose, 0.5, 1, 2, 4, 6, 8, and 24 hours ] [ Designated as safety issue: No ]
    Relevant individual PK parameters will be estimated using non-compartmental or compartmental PK methods. For each stratum, the PK variables will be tabulated and descriptive statistics (e.g., geometric means and coefficients of variation) calculated for each dose level. Pharmacokinetic parameters (i.e., T1/2, Cl, and AUC) will be compared across relevant antiretroviral therapies using non-parametric statistical testing techniques.
  • Plasma concentrations of ibrutinib and its main metabolite [ Time Frame: Up to 30 days ] [ Designated as safety issue: No ]
    Correlations with toxicity will be explored using non-parametric statistical testing techniques.
  • Objective response rate [ Time Frame: Up to 30 days ] [ Designated as safety issue: No ]
    The proportion of patients achieving objective responses and their corresponding 95% confidence intervals (CIs) will be reported.
  • Clinical benefit [ Time Frame: Up to 30 days ] [ Designated as safety issue: No ]
    The proportion of patients achieving clinical benefit and their corresponding 95% CIs will be reported.
  • Time to tumor response [ Time Frame: From the first study treatment until documentation of first objective response, assessed up to 30 days ] [ Designated as safety issue: No ]
    Time to tumor response will be reported descriptively with medians and ranges.
  • Time to tumor progression [ Time Frame: Up to 30 days ] [ Designated as safety issue: No ]
    Time to tumor progression will be reported descriptively with medians and ranges.
  • 6-month progression free survival (PFS) [ Time Frame: From start of study treatment to relapse, progression, or death from any cause, whichever occurs first, assessed at 6 months ] [ Designated as safety issue: No ]
    Probabilities of 6-month PFS will be estimated with the Kaplan-Meier method and reported with 95% CI.
  • 1-year PFS [ Time Frame: From start of study treatment to relapse, progression, or death from any cause, whichever occurs first, assessed at 6 months ] [ Designated as safety issue: No ]
    Probabilities of 1-year PFS will be estimated with the Kaplan-Meier method and reported with 95% CI.
  • 6-month overall survival (OS) [ Time Frame: From start of study treatment to death, assessed at 6 months ] [ Designated as safety issue: No ]
    Probabilities of 6-month OS will be estimated with the Kaplan-Meier method and reported with 95% CI.
  • 1-year OS [ Time Frame: From start of study treatment to death, assessed at 6 months ] [ Designated as safety issue: No ]
    Probabilities of 1-year OS will be estimated with the Kaplan-Meier method and reported with 95% CI.
  • Changes in HIV viral load [ Time Frame: Baseline to up to 30 days ] [ Designated as safety issue: No ]
    Changes will be analyzed with descriptive statistics. Where there are sufficient data, repeated measures analysis of variance will be used to assess the effect of ibrutinib on these parameters across time. If the data do not meet the assumptions of normality, the data will either be transformed or Friedman's test (i.e. non-parametric analogue to a repeated measures analysis of variance) will be used.
  • Changes in immunologic parameters [ Time Frame: Baseline to up to 30 days ] [ Designated as safety issue: No ]
    Changes will be analyzed with descriptive statistics. Where there are sufficient data, repeated measures analysis of variance will be used to assess the effect of ibrutinib on these parameters across time. If the data do not meet the assumptions of normality, the data will either be transformed or Friedman's test (i.e. non-parametric analogue to a repeated measures analysis of variance) will be used.
  • Changes in EBV DNA copy numbers in plasma and in PBMCs in relation to ibrutinib therapy [ Time Frame: Baseline to up to 30 days ] [ Designated as safety issue: No ]
    Changes will be analyzed with descriptive statistics. Where there are sufficient data, repeated measures analysis of variance will be used to assess the effect of ibrutinib on these parameters across time. If the data do not meet the assumptions of normality, the data will either be transformed or Friedman's test (i.e. non-parametric analogue to a repeated measures analysis of variance) will be used.
  • Changes in HHV-8 DNA copy numbers in plasma and in PBMCs in relation to ibrutinib therapy [ Time Frame: Baseline to up to 30 days ] [ Designated as safety issue: No ]
    Changes will be analyzed with descriptive statistics. Where there are sufficient data, repeated measures analysis of variance will be used to assess the effect of ibrutinib on these parameters across time. If the data do not meet the assumptions of normality, the data will either be transformed or Friedman's test (i.e. non-parametric analogue to a repeated measures analysis of variance) will be used.
Same as current
Not Provided
Not Provided
 
Ibrutinib in Treating Relapsed or Refractory B-Cell Non-Hodgkin Lymphoma in Patients With HIV Infection
Phase I and Pharmacokinetic Study of Ibrutinib in HIV-Infected Patients With Relapsed or Refractory B-Cell Non-Hodgkin Lymphoma

This phase I trial studies the side effects and best dose of ibrutinib in treating B-cell non-Hodgkin lymphoma that has returned or does not respond to treatment in patients with human immunodeficiency virus (HIV) infection. Ibrutinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. It is not yet known whether it is safe for patients with HIV infection to receive ibrutinib while also taking anti-HIV drugs.

PRIMARY OBJECTIVES:

I. To evaluate the safety and tolerability of single-agent ibrutinib in combination with antiretroviral therapy (ART) specifically with respect to ibrutinib metabolism in HIV-infected patients with relapsed or refractory B-cell neoplasms.

II. To determine the maximum tolerated dose (MTD) of ibrutinib in this setting.

SECONDARY OBJECTIVES:

I. To characterize ibrutinib pharmacokinetics in relation to ART-cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4) interactions.

II. To describe toxicity in relation to plasma concentrations of ibrutinib and its main metabolite.

III. To estimate objective response rate, clinical benefit, times to tumor response and progression, and 6-month and 1-year progression-free and overall survival.

IV. To describe changes in HIV viral load, immunologic parameters, and Epstein-Barr virus (EBV) and human herpesvirus 8 (HHV-8) deoxyribonucleic acid (DNA) copy numbers in plasma and in peripheral blood mononuclear cells (PBMC) in relation to ibrutinib therapy.

OUTLINE: This is a dose-escalation study.

Patients receive ibrutinib orally (PO) once daily (QD) on days 1-28. Courses repeat every 28 days for up to 2 years in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 days.

Interventional
Phase 1
Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
  • B-cell Adult Acute Lymphoblastic Leukemia
  • B-cell Chronic Lymphocytic Leukemia
  • Cutaneous B-cell Non-Hodgkin Lymphoma
  • Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue
  • HIV Infection
  • Intraocular Lymphoma
  • Multicentric Castleman Disease
  • Nodal Marginal Zone B-cell Lymphoma
  • Recurrent Adult Acute Lymphoblastic Leukemia
  • Recurrent Adult Burkitt Lymphoma
  • Recurrent Adult Diffuse Large Cell Lymphoma
  • Recurrent Adult Diffuse Mixed Cell Lymphoma
  • Recurrent Adult Diffuse Small Cleaved Cell Lymphoma
  • Recurrent Adult Grade III Lymphomatoid Granulomatosis
  • Recurrent Adult Immunoblastic Large Cell Lymphoma
  • Recurrent Adult Lymphoblastic Lymphoma
  • Recurrent Grade 1 Follicular Lymphoma
  • Recurrent Grade 2 Follicular Lymphoma
  • Recurrent Grade 3 Follicular Lymphoma
  • Recurrent Mantle Cell Lymphoma
  • Recurrent Marginal Zone Lymphoma
  • Recurrent Small Lymphocytic Lymphoma
  • Refractory Chronic Lymphocytic Leukemia
  • Refractory Hairy Cell Leukemia
  • Refractory Multiple Myeloma
  • Small Intestine Lymphoma
  • Splenic Marginal Zone Lymphoma
  • Testicular Lymphoma
  • Waldenström Macroglobulinemia
  • Drug: ibrutinib
    Given PO
    Other Names:
    • Bruton's tyrosine kinase inhibitor PCI-32765
    • BTK inhibitor PCI-32765
    • CRA-032765
    • Imbruvica
    • PCI-32765
  • Other: pharmacological study
    Correlative studies
    Other Name: pharmacological studies
  • Other: laboratory biomarker analysis
    Correlative studies
Experimental: Treatment (ibrutinib)
Patients receive ibrutinib PO QD on days 1-28. Courses repeat every 28 days for up to 2 years in the absence of disease progression or unacceptable toxicity.
Interventions:
  • Drug: ibrutinib
  • Other: pharmacological study
  • Other: laboratory biomarker analysis
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Not yet recruiting
78
Not Provided
August 2017   (final data collection date for primary outcome measure)

Inclusion Criteria:

  • Known HIV infection and histologically confirmed B-cell non-Hodgkin lymphoma or B-cell lymphoproliferative disease as follows, as defined by the World Health Organization classification:

    • Active B-cell non-Hodgkin lymphoma (cluster of differentiation [CD]20 positive or negative), chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL), multiple myeloma or multicentric Castleman's disease that has relapsed, progressed, or been refractory to at least one regimen
  • At least 28 days between enrollment and last cancer therapy; any number of prior cancer therapies is permitted; patients otherwise fit for blood or marrow transplantation (BMT) should receive second-line chemotherapy before considering enrollment
  • Serologic documentation of HIV infection at any time prior to study entry, as evidenced by positive enzyme-linked immunosorbent assay (ELISA), positive Western blot, or any other federally approved licensed HIV test; alternatively, this documentation may include a record that another physician has documented that the participant has HIV infection based on prior ELISA and Western blot, or other approved diagnostic tests
  • Participants must be on a stable antiretroviral regimen per current International Acquired Immunodeficiency Syndrome (AIDS) Society guidelines as follows, with no intention of changing the regimen within 8 weeks after ibrutinib initiation:

    • Choice of regimen: The specific antiretroviral agents are at physician discretion, and the use of investigational agents currently available on an expanded-access basis is allowed; use of experimental antiretroviral agents or those containing zidovudine (including Combivir and Trizivir) is prohibited
    • Stability of regimen: With the exception of patients on zidovudine-based ART, any changes in antiretroviral regimen must be made at least 4 weeks prior to ibrutinib initiation; patients taking zidovudine-based ART must change to a non-zidovudine-based regimen at least 2 weeks prior to ibrutinib initiation; changes to ART therapy during the study may be made if medically necessary (e.g. toxicity, treatment failure)
  • Eastern Cooperative Oncology Group (ECOG) performance status 0, 1 or 2 (Karnofsky >= 60%)
  • Life expectancy >= 2 months
  • Absolute neutrophil count >= 750 cells/uL
  • Absolute CD4 count: no minimum requirement
  • Platelets >= 50,000 cells/uL, or >= 30,000/uL if bone marrow is involved by malignancy
  • Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3.0 x institutional upper limit of normal (ULN), or =< 5.0 x ULN if attributable to malignancy; patients with active or prior hepatitis B or hepatitis C infection are potentially eligible
  • Creatinine clearance: estimated (est.) glomerular filtration rate (GFR) >= 30 mL/min (Cockcroft-Gault)
  • Must in the opinion of the investigator be capable of complying with this protocol
  • Must have completed major surgery > 10 days before initiating treatment, and/or must have completed minor surgery > 7 days before initiating treatment
  • Willingness of sexually active subjects to use adequate contraception; women of child-bearing potential must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation; (should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately); men enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 4 months after completion of ibrutinib
  • Ability to understand and willingness to sign a written informed consent document

Exclusion Criteria:

  • Prior exposure to ibrutinib
  • Receipt of any investigational agents within 28 days before the first dose of ibrutinib
  • Failure to recover to baseline or Common Terminology Criteria for Adverse Events (CTCAE) =< grade 2 from clinically significant toxicities due to prior cancer therapies
  • Active central nervous system involvement by malignancy; central nervous system disease that has been treated into remission is permitted
  • Patients who require concomitant treatment with CYP3A4/cytochrome P450, family 3, subfamily A, polypeptide 5 (CYP3A5) inhibitors or strong CYP3A4/5 inducers OTHER than antiretroviral therapies for HIV

    • 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 product
    • A prednisone equivalent of < 20 mg daily is permitted in patients requiring chronic use; larger doses must be discontinued >= 7 days prior to ibrutinib initiation and are prohibited during study treatment
  • Anticoagulation with warfarin or equivalent vitamin K antagonists within 28 days prior to starting ibrutinib
  • Significant or uncontrolled intercurrent condition including, but not limited to:

    • Infection other than HIV, hepatitis B, or hepatitis C that is symptomatic or requires systemic treatment
    • Opportunistic infection within 60 days prior to enrollment
    • Significant active cardiac morbidity such as class 3 or 4 cardiac disease as defined by the New York Heart Association Functional Classification, unstable angina pectoris, or uncontrolled arrhythmia; or myocardial infection =< 6 months before enrollment
    • Psychiatric illness that would limit compliance
    • Stroke or intracranial hemorrhage =< 6 months prior to enrollment
    • History of class B or class C cirrhosis, per the modified Child-Pugh classification
  • Inability to swallow capsules whole, or disease significantly affecting gastrointestinal function and/or inhibiting small intestine absorption, such as malabsorption syndrome, small bowel resection, or poorly controlled inflammatory bowel disease affecting the small intestine
  • History of allergic reactions attributed to compounds of similar chemical or biologic composition to ibrutinib
  • Pregnancy or breastfeeding; pregnant women are excluded; breastfeeding must be discontinued
Both
18 Years and older
No
United States
 
NCT02109224
NCI-2014-00707, NCI-2014-00707, AMC-091, AMC-091, U01CA121947
Not Provided
National Cancer Institute (NCI)
National Cancer Institute (NCI)
Not Provided
Principal Investigator: Yvette Kasamon AIDS Associated Malignancies Clinical Trials Consortium
National Cancer Institute (NCI)
April 2014

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP