A Pilot Study of Ibrutinib and R-da-EPOCH for Front Line Treatment of AIDS-Related Lymphomas
Overview
- Phase
- Phase 1
- Intervention
- Filgrastim
- Conditions
- AIDS-Related Lymphoma
- Sponsor
- National Cancer Institute (NCI)
- Enrollment
- 46
- Locations
- 30
- Primary Endpoint
- Maximum Tolerated Dose (MTD) of Ibrutinib in Combination With Chemotherapy
- Status
- Active, Not Recruiting
- Last Updated
- 19 days ago
Overview
Brief Summary
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.
Detailed Description
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.
Investigators
Eligibility Criteria
Inclusion Criteria
- •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, for analysis of integral biomarkers. 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. Tissue and diagnostic slides are required to be submitted within 1 month of enrollment
- •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
- •For the dose-finding cohort participants lymphoma must be untreated. For the dose-expansion cohort participants may have either untreated lymphoma or may have received prior therapy
Exclusion Criteria
- •Participants who have had chemotherapy other than R-EPOCH, R-CHOP, or limited therapy, or radiotherapy other than palliative radiation for medical emergencies (like cord compression), within the last 4 weeks
- •For the dose-finding cohort prior cytotoxic chemotherapy or radiotherapy for this lymphoma is exclusionary. For the dose-expansion cohort participants may have received:
- •A maximum of one cycle of combination chemotherapy, including rituximab-containing regimens R-CHOP and R-EPOCH. The start of previous chemotherapy cycle must occur at least 21 days but no more than 28 days prior 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) OR
- •1 prior cycle of limited therapy including cyclophosphamide and/or rituximab and/or glucocorticoids to improve hepatic or renal function impaired due to lymphoma involvement. The start of this therapy may occur up to 28 days prior to beginning treatment under this protocol; cyclophosphamide administration must have been completed at least 14 days prior to initiation of protocol therapy. Such treatment will not count towards the maximum of 6 cycles under this study (i.e., participants will receive 6 cycles on study)
- •For the dose-finding cohort rituximab within 12 months prior to study registration will be exclusionary; only exception will be if rituximab was given for indications other than the treatment of aggressive lymphoma. For the dose-expansion cohort one cycle of rituximab as part of R-CHOP or R-EPOCH or limited therapy may be administered off study prior to enrollment; prior rituximab will also be allowed if rituximab was given for indications other than the treatment of aggressive lymphoma
- •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
Arms & Interventions
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.
Intervention: Filgrastim
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.
Intervention: Ibrutinib
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.
Intervention: Laboratory Biomarker Analysis
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.
Intervention: Prednisone
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.
Intervention: Rituximab
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.
Intervention: Vincristine Sulfate
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.
Intervention: Cyclophosphamide
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.
Intervention: Doxorubicin Hydrochloride
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.
Intervention: Pharmacological Study
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.
Intervention: Pegfilgrastim
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.
Intervention: Etoposide
Outcomes
Primary Outcomes
Maximum Tolerated Dose (MTD) of Ibrutinib in Combination With Chemotherapy
Time Frame: Up to 21 days
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.
Recommended Phase II Dose (RP2D) of Ibrutinib in Combination With Chemotherapy
Time Frame: Up to 21 days
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.
Maximum tolerated dose (MTD) of ibrutinib in combination with chemotherapy
Time Frame: Up to 21 days
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.
Recommended phase II dose (RP2D) of ibrutinib in combination with chemotherapy
Time Frame: Up to 21 days
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.
Secondary Outcomes
- Incidence of Adverse Events Graded Using Common Terminology Criteria for Adverse Events Version 4.0(Up to 5 years)
- Complete Response Rates(Up to 5 years)
- Progression Free Survival (PFS)(1 year)
- Progression Free Survival (PFS)(2 years)
- Overall Survival (OS)(1 year)
- Overall Survival (OS)(2 years)
- Response by Lymphoma Cell-of-origin (COO) Assessment(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(Up to 5 years)
- Average Number of Days Per Cycle Participants Are Able to Stay on Planned Dose of Ibrutinib(Up to 5 years)
- Changes in the Levels of Human Immunodeficiency Virus (HIV)-1 Viral Reservoirs(Baseline up to 5 years)
- Changes in Epstein-Barr Virus (EBV) Viral Loads(Baseline up to 5 years)
- Effect of Treatment on HIV Latency Reservoirs(Up to 5 years)
- Effect of Treatment on B-cell Receptor Signaling Pathway Including BTK Activity(Up to 5 years)
- Effect of Treatment on T-cell Receptor Signaling Via ITK Activity.(Up to 5 years)
- Soluble Cytokine Response to Treatment(Up to 5 years)
- Pharmacokinetics (PK) Parameters Assessment for Ibrutinib, Doxorubicin Hydrochloride, Etoposide, and Vincristine Sulfate(Up to 5 years)
- Survival by Lymphoma Cell-of-origin (COO) Assessment(up to 2 years)
- Effect of treatment on HIV latency reservoirs(Up to 5 years)
- Effect of treatment on B-cell receptor signaling pathway including BTK activity(Up to 5 years)
- Effect of treatment on T-cell receptor signaling via ITK activity.(Up to 5 years)
- Incidence of adverse events graded using Common Terminology Criteria for Adverse Events version 4.0(Up to 5 years)
- Progression free survival (PFS)(2 years)
- Changes in Epstein-Barr virus (EBV) viral loads(Baseline up to 5 years)
- Pharmacokinetics (PK) parameters assessment for ibrutinib, doxorubicin hydrochloride, etoposide, and vincristine sulfate(Up to 5 years)
- Complete response rates(Up to 5 years)
- Lymphoma cell-of-origin (COO) assessment(Up to 5 years)
- Changes in the levels of human immunodeficiency virus (HIV)-1 viral reservoirs(Baseline up to 5 years)
- Overall survival (OS)(2 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(Up to 5 years)
- Average number of days per cycle participants are able to stay on planned dose of ibrutinib(Up to 5 years)
- Soluble cytokine response to treatment(Up to 5 years)