This phase I trial studies the side effect and best dose of ibrutinib in combination with rituximab, etoposide, prednisone, vincristine sulfate, cyclophosphamide, and doxorubicin hydrochloride in treating patients with human immunodeficiency virus (HIV)-positive stage II-IV diffuse large B-cell lymphomas. Ibrutinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Monoclonal antibodies, such as rituximab, may interfere with the ability of cancer cells to grow and spread. Drugs used in chemotherapy, such as etoposide, prednisone, vincristine sulfate, cyclophosphamide, and doxorubicin hydrochloride, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving ibrutinib and etoposide, prednisone, vincristine sulfate, cyclophosphamide, and doxorubicin hydrochloride may work better in treating patients with HIV-positive diffuse large B-cell lymphomas.
PRIMARY OBJECTIVES: I. To assess the safety and tolerability of ibrutinib and rituximab (R)-dose adjusted (da)-etoposide, prednisone, vincristine sulfate, cyclophosphamide, and doxorubicin hydrochloride (EPOCH) in participants with acquired immunodeficiency syndrome (AIDS)-related lymphomas (ARL). SECONDARY OBJECTIVES: I. To evaluate the complete response (CR) rates of ARL to ibrutinib and R-da-EPOCH. II. To measure the 1-year and 2-year overall and progression-free survival of participants with ARL treated with combination ibrutinib and R-da-EPOCH, including preliminary comparison of non-germinal center B-cell (GCB) with historical controls treated with R-da-EPOCH. III. To categorize and compare the cell-of-origin by gene expression profiling (GEP) gene expression-based classification (GCB, activated B-cell-like, unclassifiable) to immunohistochemistry (IHC) classification (GCB, non-GCB), estimate the discordant classification, and correlate each biological classification (IHC and GEP) with treatment response rates and survival. IV. To calculate the percentage of participants who receive two or more cycles of R-da-EPOCH, and are able to continue on a minimum dose level of cyclophosphamide of -1 and above after dose adjustments for hematologic toxicities. V. To determine the average number of days per cycle participants are able to stay on planned dose of ibrutinib at the recommended phase II dose (RP2D). VI. To assess the effect of ibrutinib and R-da-EPOCH on levels of circulating tumor deoxyribonucleic acid (DNA). VII. To assess the effect and degree of ibrutinib and R-da-EPOCH on T-cell receptor signaling via ITK inhibition. VIII. To assess the effect of ibrutinib and R-da-EPOCH on B-cell receptor signaling pathway including BTK activity in ARL. IX. To evaluate the soluble cytokine response to ibrutinib and R-da-EPOCH. X. To characterize the pharmacokinetics of doxorubicin, etoposide, and vincristine in the presence of ibrutinib, and vice versa, and assess the clinical relevance of any drug-drug interaction and correlate with pharmacodynamics outcomes. OUTLINE: This is a dose escalation study of ibrutinib. Patients receive rituximab intravenously (IV) on day 1 (for CD20 positive patients only), etoposide IV over 96 hours on days 1-4, doxorubicin hydrochloride IV over 96 hours on days 1-4, vincristine sulfate IV over 96 hours on days 1-4, prednisone orally (PO) daily on days 1-5, cyclophosphamide IV over 1 hour on day 5, and ibrutinib PO once daily (QD) on days 1-21. Treatment repeats every 21 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. Patients also receive pegfilgrastim subcutaneously (SC) from 1 calendar day up to 48 hours or filgrastim SC beginning on day 6 for up to 10 days until absolute neutrophil count (ANC) is satisfactory. After completion of study treatment, patients are followed up every 3 months for 2 years, and then every 6 months for up to 5 years.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
46
Given IV
Given IV
Given IV
Given SC
Given PO
Correlative studies
Given SC
Correlative studies
Given PO
Given IV
Given IV
UC San Diego Moores Cancer Center
La Jolla, California, United States
UCSF Medical Center-Parnassus
San Francisco, California, United States
University of Miami Miller School of Medicine-Sylvester Cancer Center
Miami, Florida, United States
Memorial Hospital West
Pembroke Pines, Florida, United States
John H Stroger Jr Hospital of Cook County
Chicago, Illinois, United States
University of Illinois College of Medicine - Chicago
Chicago, Illinois, United States
Johns Hopkins University/Sidney Kimmel Cancer Center
Baltimore, Maryland, United States
Boston Medical Center
Boston, Massachusetts, United States
Siteman Cancer Center at Washington University
St Louis, Missouri, United States
Washington University School of Medicine
St Louis, Missouri, United States
...and 9 more locations
Maximum tolerated dose (MTD) of ibrutinib in combination with chemotherapy
Will be descriptive and will be reported in tabular format with the appropriate summary statistics (count and percentage). In the dose-finding portion, the number of dose limiting toxicities (DLTs) identified among the DLT-evaluable subjects will be listed and summarized by dose level. The safety variables will be listed and summarized for (1) subjects in the dose-finding portion, (2) subjects in the dose expansion cohort (DEC), and (3) all subjects in the study.
Time frame: Up to 21 days
Recommended phase II dose (RP2D) of ibrutinib in combination with chemotherapy
Will be descriptive and will be reported in tabular format with the appropriate summary statistics (count and percentage). In the dose-finding portion, the number of DLTs identified among the DLT-evaluable subjects will be listed and summarized by dose level. The safety variables will be listed and summarized for (1) subjects in the dose-finding portion, (2) subjects in the DEC, and (3) all subjects in the study.
Time frame: Up to 21 days
Incidence of adverse events graded using Common Terminology Criteria for Adverse Events version 4.0
Toxicity data will be presented by type and severity for each dose cohort. Incidence of toxicity related dose reductions and treatment discontinuations will be summarized for each dose group.
Time frame: Up to 5 years
Complete response rates
The complete response rates and their corresponding 95% confidence intervals will be calculated for participants with AIDS-related lymphomas (ARL) treated with combination ibrutinib and rituximab (R)-dose adjusted (da)-etoposide, prednisone, vincristine sulfate, cyclophosphamide and doxorubicin hydrochloride (EPOCH).
Time frame: Up to 5 years
Progression free survival (PFS)
PFS will be estimated using Kaplan Meier method, as well as, their corresponding 95% confidence intervals.
Time frame: 1 year
Progression free survival (PFS)
PFS will be estimated using Kaplan Meier method, as well as, their corresponding 95% confidence intervals.
Time frame: 2 years
Overall survival (OS)
OS will be estimated using Kaplan Meier method, as well as, their corresponding 95% confidence intervals.
Time frame: 1 year
Overall survival (OS)
OS will be estimated using Kaplan Meier method, as well as, their corresponding 95% confidence intervals.
Time frame: 2 years
Lymphoma cell-of-origin (COO) assessment
Will be determined by gene expression profiling (GEP) (germinal center B-cell \[GCB\], activated B-cell \[ABC\], unclassifiable) and immunohistochemistry \[IHC\] (GCB, non-GCB). The concordances and discordances between classifications will be estimated with binomial proportions and their 95% corresponding confidence intervals. The response rates and survival as categorized by GEP or IHC will be compared, to see which analysis of COO best correlates with treatment response. Chi-square tests will be used to test the associations between 1) GEP (GCB, ABC, unclassifiable) with response rates and 2) IHC (GCB, non-GCB) with responses rate. The Kaplan Meier method will be used to calculate estimates of OS and PFS within GEP (GCB, ABC, unclassifiable) and within IHC (GCB, non-GCB), as well as their 95% confidence intervals. The log-rank test will be used to test differences with respect to OS and PFS within GEP and within IHC.
Time frame: Up to 5 years
Percentage of participants who receive two or more cycles of combination chemotherapy, and are able to continue on a minimum dose level of cyclophosphamide of -1 and above after dose adjustments
Hematologic toxicities will be calculated.
Time frame: Up to 5 years
Average number of days per cycle participants are able to stay on planned dose of ibrutinib
Average number of days will be calculated.
Time frame: Up to 5 years
Changes in the levels of human immunodeficiency virus (HIV)-1 viral reservoirs
Descriptive statistics will be used to evaluate the changes and will be compared with treatment completion. If there are sufficient data, the binomial test of proportions will be used to test if the long term viral reservoir is either undetectable or below baseline in at least half of the participants.
Time frame: Baseline up to 5 years
Changes in Epstein-Barr virus (EBV) viral loads
Descriptive statistics will be used to evaluate the changes and compared with treatment completion. If there are sufficient data, the binomial test of proportions will be used to test if the long term viral reservoir is either undetectable or below baseline in at least half of the participants.
Time frame: Baseline up to 5 years
Effect of treatment on HIV latency reservoirs
Will be correlated with degree of ITK inhibition and Pearson or Spearman correlation coefficients will be used, as appropriate.
Time frame: Up to 5 years
Effect of treatment on B-cell receptor signaling pathway including BTK activity
Descriptive statistics will be used.
Time frame: Up to 5 years
Effect of treatment on T-cell receptor signaling via ITK activity.
Descriptive statistics will be used.
Time frame: Up to 5 years
Soluble cytokine response to treatment
Descriptive statistics will be used.
Time frame: Up to 5 years
Pharmacokinetics (PK) parameters assessment for ibrutinib, doxorubicin hydrochloride, etoposide, and vincristine sulfate
Relevant individual PK parameters will be estimated using non-compartmental or compartmental PK methods with the software WinNonlin. The PK variables will be tabulated and descriptive statistics (e.g., geometric means and coefficients of variation) and compared across dose levels (if applicable) using nonparametric statistical testing techniques. PK parameters (i.e., steady state concentration \[Css\], clearance \[Cl\], and area under the curve \[AUC\]) will be correlated with pharmacodynamics effects using nonparametric statistical testing techniques.
Time frame: Up to 5 years
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