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.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
72
UCLA Center for Clinical AIDS Research and Education
Los Angeles, California, United States
Johns Hopkins University/Sidney Kimmel Cancer Center
Baltimore, Maryland, United States
Siteman Cancer Center at Washington University
St Louis, Missouri, United States
Memorial Sloan-Kettering Cancer Center
New York, New York, United States
Albert Einstein College of Medicine
The Bronx, New York, United States
Montefiore Medical Center-Einstein Campus
The Bronx, New York, United States
Montefiore Medical Center - Moses Campus
The Bronx, New York, United States
Incidence of toxicities assessed using National Cancer Institute (NCI) CTCAE version 4.0
Time frame: Up to 30 days
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
1-year OS
Probabilities of 1-year OS will be estimated with the Kaplan-Meier method and reported with 95% CI.
Time frame: From start of study treatment to death, assessed at 6 months
1-year PFS
Probabilities of 1-year PFS will be estimated with the Kaplan-Meier method and reported with 95% CI.
Time frame: From start of study treatment to relapse, progression, or death from any cause, whichever occurs first, assessed at 6 months
6-month overall survival (OS)
Probabilities of 6-month OS will be estimated with the Kaplan-Meier method and reported with 95% CI.
Time frame: From start of study treatment to death, assessed at 6 months
6-month progression free survival (PFS)
Probabilities of 6-month PFS will be estimated with the Kaplan-Meier method and reported with 95% CI.
Time frame: From start of study treatment to relapse, progression, or death from any cause, whichever occurs first, assessed at 6 months
Changes in EBV DNA copy numbers in plasma and in PBMCs in relation to ibrutinib therapy
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.
Time frame: Baseline to up to 30 days
Changes in HHV-8 DNA copy numbers in plasma and in PBMCs in relation to ibrutinib therapy
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.
Time frame: Baseline to up to 30 days
Changes in HIV viral load
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.
Time frame: Baseline to up to 30 days
Changes in immunologic parameters
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.
Time frame: Baseline to up to 30 days
Clinical benefit
The proportion of patients achieving clinical benefit and their corresponding 95% CIs will be reported.
Time frame: Up to 30 days
Objective response rate
The proportion of patients achieving objective responses and their corresponding 95% confidence intervals (CIs) will be reported.
Time frame: Up to 30 days
Pharmacokinetic (PK) parameters of ibrutinib in relation to ART-CYP3A4 interactions, including half-life (T1/2), oral clearance (CL/F), and area under the curve (AUC)
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/F, and AUC) will be compared across relevant antiretroviral therapies using non-parametric statistical testing techniques.
Time frame: Course 1, day 8: pre-dose, 0.5, 1, 2, 4, 6, 8, and 24 hours
Plasma concentrations of ibrutinib and its main metabolite
Correlations with toxicity will be explored using non-parametric statistical testing techniques.
Time frame: Up to 30 days
Time to tumor progression
Time to tumor progression will be reported descriptively with medians and ranges.
Time frame: Up to 30 days
Time to tumor response
Time to tumor response will be reported descriptively with medians and ranges.
Time frame: From the first study treatment until documentation of first objective response, assessed up to 30 days
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