Ibrutinib, Rituximab, Etoposide, Prednisone, Vincristine Sulfate, Cyclophosphamide, and Doxorubicin Hydrochloride in Treating Patients With HIV-Positive Stage II-IV Diffuse Large B-Cell Lymphomas
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|ClinicalTrials.gov Identifier: NCT03220022|
Recruitment Status : Recruiting
First Posted : July 18, 2017
Last Update Posted : January 22, 2020
|Condition or disease||Intervention/treatment||Phase|
|AIDS-Related Lymphoma Ann Arbor Stage II Diffuse Large B-Cell Lymphoma Ann Arbor Stage III Diffuse Large B-Cell Lymphoma Ann Arbor Stage IV Diffuse Large B-Cell Lymphoma||Drug: Cyclophosphamide Drug: Doxorubicin Hydrochloride Drug: Etoposide Biological: Filgrastim Drug: Ibrutinib Other: Laboratory Biomarker Analysis Biological: Pegfilgrastim Other: Pharmacological Study Drug: Prednisone Biological: Rituximab Drug: Vincristine Sulfate||Phase 1|
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||54 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|Official Title:||Phase I and Dose-Expansion Study of Ibrutinib and R-da-EPOCH for Front Line Treatment of AIDS-Related Lymphomas|
|Actual Study Start Date :||November 3, 2017|
|Estimated Primary Completion Date :||September 18, 2020|
|Estimated Study Completion Date :||September 18, 2020|
Experimental: Treatment (R-da-EPOCH)
Patients receive rituximab 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 PO daily on days 1-5, cyclophosphamide IV over 1 hour on day 5, and ibrutinib PO 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 SC from 1 calendar day up to 48 hours or filgrastim SC beginning on day 6 for up to 10 days until ANC is satisfactory.
Drug: Doxorubicin Hydrochloride
Other: Laboratory Biomarker Analysis
Other: Pharmacological Study
Drug: Vincristine Sulfate
- Maximum tolerated dose (MTD) of ibrutinib in combination with chemotherapy [ Time Frame: Up to 21 days ]There will be no formal statistical testing for the dose-finding portion of the study.
- Recommended phase II dose (RP2D) of ibrutinib in combination with chemotherapy [ Time Frame: Up to 21 days ]There will be no formal statistical testing for the dose-finding portion of the study.
- Incidence of adverse events graded using Common Terminology Criteria for Adverse Events version 4.0 [ Time Frame: Up to 5 years ]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.
- Complete response rates [ Time Frame: Up to 5 years ]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).
- Progression free survival (PFS) [ Time Frame: 1 year ]PFS will be estimated using Kaplan Meier method, as well as, their corresponding 95% confidence intervals.
- Progression free survival (PFS) [ Time Frame: 2 years ]PFS will be estimated using Kaplan Meier method, as well as, their corresponding 95% confidence intervals.
- Overall survival (OS) [ Time Frame: 1 year ]OS will be estimated using Kaplan Meier method, as well as, their corresponding 95% confidence intervals.
- Overall survival (OS) [ Time Frame: 2 years ]OS will be estimated using Kaplan Meier method, as well as, their corresponding 95% confidence intervals.
- Lymphoma cell-of-origin (COO) assessment [ Time Frame: Up to 5 years ]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.
- 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 [ Time Frame: Up to 5 years ]Hematologic toxicities will be calculated.
- Average number of days per cycle participants are able to stay on planned dose of ibrutinib [ Time Frame: Up to 5 years ]Average number of days will be calculated.
- Changes in the levels of human immunodeficiency virus (HIV)-1 viral reservoirs [ Time Frame: Baseline up to 5 years ]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.
- Changes in Epstein-Barr virus (EBV) viral loads [ Time Frame: Baseline up to 5 years ]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.
- Effect of treatment on HIV latency reservoirs [ Time Frame: Up to 5 years ]Will be correlated with degree of ITK inhibition and Pearson or Spearman correlation coefficients will be used, as appropriate.
- Effect of treatment on B-cell receptor signaling pathway including BTK activity [ Time Frame: Up to 5 years ]Descriptive statistics will be used.
- Effect of treatment on T-cell receptor signaling via ITK activity. [ Time Frame: Up to 5 years ]Descriptive statistics will be used.
- Soluble cytokine response to treatment [ Time Frame: Up to 5 years ]Descriptive statistics will be used.
- Pharmacokinetics (PK) parameters assessment for ibrutinib, doxorubicin hydrochloride, etoposide, and vincristine sulfate [ Time Frame: Up to 5 years ]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.
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03220022
|United States, California|
|UC San Diego Moores Cancer Center||Recruiting|
|La Jolla, California, United States, 92093|
|Contact: Ida C. Wong-Sefidan 858-552-8585 ext 7106 email@example.com|
|Principal Investigator: Ida C. Wong-Sefidan|
|UCLA / Jonsson Comprehensive Cancer Center||Recruiting|
|Los Angeles, California, United States, 90095|
|Contact: Ronald T. Mitsuyasu 310-825-6689 firstname.lastname@example.org|
|Principal Investigator: Ronald T. Mitsuyasu|
|UCSF Medical Center-Parnassus||Recruiting|
|San Francisco, California, United States, 94143|
|Contact: Lawrence D. Kaplan 415-353-2661 LKaplan@ucsf.edu|
|Principal Investigator: Lawrence D. Kaplan|
|United States, Florida|
|University of Miami Miller School of Medicine-Sylvester Cancer Center||Recruiting|
|Miami, Florida, United States, 33136|
|Contact: Juan C. Ramos 305-243-1326 email@example.com|
|Principal Investigator: Juan C. Ramos|
|United States, Illinois|
|John H Stroger Jr Hospital of Cook County||Recruiting|
|Chicago, Illinois, United States, 60612|
|Contact: Paul G. Rubinstein 312-864-7277 firstname.lastname@example.org|
|Principal Investigator: Paul G. Rubinstein|
|United States, Maryland|
|Johns Hopkins University/Sidney Kimmel Cancer Center||Recruiting|
|Baltimore, Maryland, United States, 21287|
|Contact: Richard F. Ambinder 410-955-8839 email@example.com|
|Principal Investigator: Richard F. Ambinder|
|United States, Massachusetts|
|Boston Medical Center||Recruiting|
|Boston, Massachusetts, United States, 02118|
|Contact: Karen Quillen 617-638-7828 Karen.Quillen@bmc.org|
|Principal Investigator: Karen Quillen|
|United States, Missouri|
|Washington University School of Medicine||Recruiting|
|Saint Louis, Missouri, United States, 63110|
|Contact: Lee Ratner 314-747-7405 firstname.lastname@example.org|
|Principal Investigator: Lee Ratner|
|United States, New York|
|Montefiore Medical Center - Moses Campus||Recruiting|
|Bronx, New York, United States, 10467|
|Contact: Murali Janakiram 718-920-4826 email@example.com|
|Principal Investigator: Murali Janakiram|
|Memorial Sloan Kettering Cancer Center||Recruiting|
|New York, New York, United States, 10065|
|Contact: Ariela Noy 212-639-7423 firstname.lastname@example.org|
|Principal Investigator: Ariela Noy|
|United States, North Carolina|
|UNC Lineberger Comprehensive Cancer Center||Recruiting|
|Chapel Hill, North Carolina, United States, 27599|
|Contact: Christopher E. Dittus 919-962-8565 email@example.com|
|Principal Investigator: Christopher E. Dittus|
|United States, Ohio|
|Ohio State University Comprehensive Cancer Center||Recruiting|
|Columbus, Ohio, United States, 43210|
|Contact: Robert A. Baiocchi 614-293-3196 Robert.Baiocchi@osumc.edu|
|Principal Investigator: Robert A. Baiocchi|
|United States, Pennsylvania|
|Philadelphia, Pennsylvania, United States, 19107|
|Contact: Douglas F. Beach 215-829-6307 firstname.lastname@example.org|
|Principal Investigator: Douglas F. Beach|
|Fox Chase Cancer Center||Recruiting|
|Philadelphia, Pennsylvania, United States, 19111|
|Contact: Carlyn Rose Tan 215-214-3119 Carlynrose.email@example.com|
|Principal Investigator: Carlyn Rose Tan|
|United States, Washington|
|Virginia Mason Medical Center||Recruiting|
|Seattle, Washington, United States, 98101|
|Contact: David M. Aboulafia 206-223-6193 firstname.lastname@example.org|
|Principal Investigator: David M. Aboulafia|
|Harborview Medical Center||Withdrawn|
|Seattle, Washington, United States, 98104|
|Principal Investigator:||Ida C Wong-Sefidan||AIDS Malignancy Consortium|