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 : February 8, 2023
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|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 30, 2023|
|Estimated Study Completion Date :||September 30, 2023|
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.
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|Ages Eligible for Study:||18 Years and older (Adult, Older Adult)|
|Sexes Eligible for Study:||All|
|Accepts Healthy Volunteers:||No|
- Participants must have histologically (via at least a core or ideally, incisional or excisional biopsy) documented CD20 positive or negative diffuse large B-cell lymphoma (DLBCL)
- Tissue available from the diagnostic biopsy in the form of blocks, tissue cores, or slides available for submission to central pathology is required for all participants enrolled to this study; formalin-fixed paraffin-embedded tissue from diagnostic tissue is acceptable and recommended; submission of the institutional diagnostic slides is also preferred for all participants enrolled in the study
- Stage II-IV disease; participant will need measurable disease by computed tomography (CT) or positron emission tomography (PET) scans if enrolled in the dose-expansion cohort
HIV positive; documentation of HIV-1 infection by means of any one of the following:
- Documentation of HIV diagnosis in the medical record by a licensed health care provider;
- Documentation of receipt of ART (at least three different medications) by a licensed health care provider (documentation may be a record of an antiretroviral therapy (ART) prescription in the participant's medical record, a written prescription in the name of the participant for ART, or pill bottles for ART with a label showing the participant's name);
- HIV-1 ribonucleic acid (RNA) detection by a licensed HIV-1 RNA assay demonstrating > 1000 RNA copies/mL;
- Any licensed HIV screening antibody and/or HIV antibody/antigen combination assay confirmed by a second licensed HIV assay such as a HIV-1 western blot confirmation or HIV rapid multispot antibody differentiation assay
- NOTE: a "licensed" assay refers to a United States (U.S.) Food and Drug Administration (FDA)-approved assay, which is required for all investigational food drug (IND) studies
- Only participants whose lymphoma is untreated are allowed for the dose-finding portion; for the dose expansion cohort both untreated and participants who have received a maximum of one cycle of combination chemotherapy, including rituximab-containing regimens R-cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, prednisone (CHOP) and R-EPOCH, prior are eligible; the start of previous chemotherapy cycle must occur at least 21 days prior and 28 days maximum to beginning treatment under this protocol, and such cycle will count towards the maximum of 6 cycles under this study (i.e. cycle off study will count as cycle 1)
- Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 50%)
- CD4 count >= 100 in the dose-finding cohort; once the dose-finding cohort is complete and if safety is established, participants with any CD4 count, including CD4 count < 100, will be allowed in the dose-escalation phase
- Absolute neutrophil count: >= 1,000/mm^3, unless decreased due to bone marrow involvement with lymphoma
- Platelets: >= 75,000/mm^3, unless decreased due to bone marrow involvement with lymphoma
- Total bilirubin: =< 1.5 institutional upper limit of normal (ULN); if potential due to lymphoma, the first cycle may be given without ibrutinib and if transaminitis and bilirubinemia improves to meet parameters, participant mat be enrolled on the clinical trial
- Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]): < 2 institutional ULN; if potentially due to lymphoma, the first cycle will be given without ibrutinib and if transaminitis and bilirubinemia improves to meet parameters, participant may be enrolled on trial
- Creatinine levels within normal institutional limits; or, creatinine clearance >= 60 mL/min/1.73 m^2 for participants with creatinine levels above institutional normal; unless decreased due to renal involvement by lymphoma
- Participants must not be on medications, including antiretroviral (ARV) regimens such as cobicistat, indinavir, or ritonavir, or agents with moderate or strong CYP3A4 inhibition; if on a moderate or strong CYP3A4 inhibitor regimen prior to study enrollment, participants must be switched to a qualifying regimen with the last dose of the strong CYP3A4 inhibitor taken at least one week before administration of ibrutinib
- Willingness of sexually active participants to use adequate contraception; both men and women of child-bearing potential treated or enrolled on this study must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) before study entry, for the duration of study participation, 90 days after completion of ibrutinib, and 12 months after the last dose of rituximab, whichever comes last; men who only have sex with other men do not need to use contraception specifically for this study (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)
- All participants will be required to be screened for hepatitis B; all participants who present with acute hepatitis B or show normal transaminases and are hepatitis B surface antigen (HBsAg) positive (+) and IgM+ for hepatitis core antigen will not be eligible for trial enrollment; per Infectious Diseases Society of America (IDSA) and Assistance for AIDS Specific Drugs (AASD) guidelines, those participants that show no immunity, defined by the lack of hepatitis B surface antibody, and show evidence of chronic infection (i.e. hepatitis B [HB]sAg+, HBcore+, hepatitis B surface antibody [HBsAB] negative [-]) will be required to be on anti-hepatitis B therapy, during the study, in order to be eligible; the exact hepatitis B therapy will be at the discretion of the infection disease specialist or investigator; if infected with hepatitis B, participants will be permitted to enroll in the study provided liver function tests meet criteria listed above, there is no evidence of cirrhosis AND participants will be required to be on anti-hepatitis B therapy
- All participants will be required to be screened for hepatitis C; if hepatitis C antibody positive, with or without a positive hepatitis C RNA level, participants will be permitted to enroll in the study provided liver function tests meet criteria listed, and have no evidence of cirrhosis; participants diagnosed with hepatitis C less than 6 months from trial enrollment will be considered to have acute hepatitis C, and will be excluded from study UNLESS hepatitis C viral load is undetectable
- Adequate cardiac function defined as an ejection fraction on echocardiogram (ECHO) or multi-gated acquisition (MUGA) that is at or above the institutional normal limits
- Participants must be able to swallow oral pills
- Ability to understand and willing to sign a written informed consent document
- Participants who have had chemotherapy other than R-EPOCH or R-CHOP, or radiotherapy other than palliative radiation for medical emergencies (like cord compression), within the last 4 weeks
- Prior cytotoxic chemotherapy or radiotherapy for this lymphoma
- Rituximab within 12 months prior to study registration; only exception will be if rituximab was given for indications other than the treatment of aggressive lymphoma, or for one prior cycle of treatment
- Participants who are receiving any other investigational agents
- Participants who have previously received ibrutinib for another indication
- Expected survival < 2 months
- Participants with a history of an opportunistic fungal infection or active fungal infection requiring, or at high risk of requiring, prophylactic or treatment with fluconazole, voriconazole or posaconazole
- Participants with known brain metastases from solid tumors should be excluded from this clinical trial
- Presence of second active tumor, other than non-melanoma skin cancer, carcinoma in situ of the cervix, or Kaposi's sarcoma (KS) that requires systemic therapy
- In the dose-finding portion of the study, participants with known or suspected parenchymal brain, spinal cord, leptomeningeal disease prior to study enrollment will be excluded; in the dose-expansion portion of the study, known or suspected parenchymal brain or spinal cord disease, and/or suspected or symptomatic leptomeningeal disease prior to study enrollment will be excluded; asymptomatic leptomeningeal disease only will be allowed in the dose-expansion cohort
- History of allergic reactions attributed to compounds of similar chemical or biologic composition to ibrutinib or other agents used in study
- Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
- Pregnancy or breastfeeding; a pregnancy test must be performed within 7 days prior to ibrutinib initiation in women of childbearing potential; pregnant women; breastfeeding must be discontinued because of unknown but potential risks in the nursing infant
- Unable to comply with the requirements of the protocol, or unable to provide adequate informed consent in the opinion of the principal investigator
- Serious, ongoing, non-malignant disease or infection, which in the opinion of the investigator and/or the sponsor would compromise other protocol objectives; participants with active opportunistic infections are ineligible
- Major surgery, other than diagnostic surgery, occurring 4 weeks prior to study entry; splenectomy will not be considered an exclusionary major surgery
- History of cutaneous or mucocutaneous reactions, or diseases in the past, due to any cause, severe enough to cause hospitalization or an inability to eat or drink for > 2 days; this exclusion relates to the long-term possibility of severe cutaneous or mucocutaneous reactions to rituximab that might occur at increased frequency in participants who have had severe skin disease or reactions in the past
- Myocardial infarction (MI) within 6 months prior to study entry, New York Heart Association (NYHA) class II or greater heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, clinically significant pericardial disease, or electrocardiographic evidence of acute ischemic or active conduction system abnormalities
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
|Principal Investigator:||Ida C Wong-Sefidan||AIDS Malignancy Consortium|
|Responsible Party:||National Cancer Institute (NCI)|
|Other Study ID Numbers:||
NCI-2017-01240 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
AMC-101 ( Other Identifier: AIDS Malignancy Consortium )
AMC-101 ( Other Identifier: CTEP )
UM1CA121947 ( U.S. NIH Grant/Contract )
|First Posted:||July 18, 2017 Key Record Dates|
|Last Update Posted:||February 8, 2023|
|Last Verified:||October 2022|
|Studies a U.S. FDA-regulated Drug Product:||Yes|
|Studies a U.S. FDA-regulated Device Product:||No|
Lymphoma, Large B-Cell, Diffuse
Neoplasms by Histologic Type
Immune System Diseases
Antineoplastic Agents, Immunological
Physiological Effects of Drugs