EPOCH and Rituximab to Treat Non-Hodgkin's Lymphoma in Patients With HIV Infection

Lymphoma, Large B-Cell, Diffuse Clinical Trial

Official title:

Short-Course EPOCH - Rituximab in Untreated CD-20+ HIV-Associated Lymphomas

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT00006436
• Other study ID #: 010030
• Secondary ID: 01-C-0030
• Status: Active, not recruiting
• Phase: Phase 2
• Start date: January 29, 2001
• Est. completion date: March 30, 2027

Study information

• Verified date: July 2023
• Source: National Institutes of Health Clinical Center (CC)
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Background:

• Human immunodeficiency virus (HIV)-infected patients have a weakened immune system, and chemotherapy, which is used to treat lymphoma, probably causes further damage to the immune system.

• Limiting the amount of immune damage due to chemotherapy might decrease the number of infections and the risk of developing cancer in the future in HIV-infected patients with non-Hodgkin's lymphoma.

Objectives:

• To determine whether reducing the total amount of chemotherapy using a specific combination of drugs called EPOCH-R (etoposide, doxorubicin, vincristine, cyclophosphamide and rituximab) will rid the body of lymphoma quickly while decreasing the risk of infections and future cancers.

• To determine whether the lymphoma will remain undetectable for at least one year if treatment is stopped one cycle after the patient enters remission.

Eligibility:

-Patients with non-Hodgkin's lymphoma and HIV infection 4 years of age and older who have not been treated previously with rituximab or cytotoxic chemotherapy.

Design:

• Patients receive EPOCH-R in 3-week treatment cycles for at least three and no more than six cycles.

• The lymphoma is evaluated using computed tomography (CT) and positron emission tomography (PET) scans at the end of treatment cycles 2 and 3. A bone marrow biopsy is repeated after cycle 2 if a biopsy was initially positive on screening for participation in the study.

• Anti-HIV therapy is stopped before chemotherapy begins and is restarted when EPOCH-R treatment ends.

• Patients are monitored for treatment response with blood tests and imaging scans at baseline, when treatment ends, 2 months after treatment ends and then every 3 to 6 months for a total of 24 months following chemotherapy.

Description:

Background:

This is a study to investigate in a preliminary fashion the feasibility of short course chemotherapy to participants with HIV-associated non-Hodgkin's lymphoma (HIV-NHL).

This study will investigate if the paradigm for treatment can be successfully changed from a standard of 6 cycles to one cycle beyond complete remission with 6 total allowable cycles.

Objective:

To assess with 90 percent probability that at least 50 percent of participants treated with short-course EPOCH-R (etoposide, doxorubicin, vincristine, cyclophosphamide and rituximab) will be progression free at one year.

Eligibility:

Aggressive B-lymphocyte antigen CD20 (CD20) positive Diffuse large B cell lymphoma (DLBCL).

HIV+ serology.

All stages (I-IV) of disease.

Eastern Cooperative Oncology Group (ECOG) Performance status 0-4.

Non-Hodgkin's Lymphoma (NHL) previously untreated with cytotoxic chemotherapy.

Age greater than or equal to 18 years.

May not be pregnant or nursing.

May not have received previous rituximab.

Design:

Participants will be treated every three weeks with a combination of EPOCH and rituximab for one cycle beyond complete remission (CR)/complete response unconfirmed (CRu) by computed tomography (CT) scan of all detectable tumors for a minimum of three and maximum of six cycles. Following cycle 2, CT, positron emission tomography scans (PET), and bone marrow biopsies (if initially positive) will be performed.

At the conclusion of the study, we will estimate whether the number of cycles can be reduced using the paradigm. If the cumulative number of participants to relapse exceeds 25 percent by 6 months, the study will be closed.

Following the completion of chemotherapy, restaging will be performed 2 months following the end of treatment, then every 3 months for one year, every 6 months for one year, then every 12 months until relapse, death, or loss to follow up.

Antiretroviral therapy (ART) will be given concurrently with treatment regimen.

To study the effects of treatment approach on parameters of HIV disease, measurements of cluster of differentiation 4 (CD4) cells and viral loads will be made at baseline and at the completion of therapy, and then 2 months following the end of treatment, and then every 3-6 months for a total of 24 months following chemotherapy.

Other known NCT identifiers

• NCT00020384

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 68
• Est. completion date: March 30, 2027
• Est. primary completion date: November 30, 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

• INCLUSION CRITERIA:

Aggressive B-lymphocyte antigen CD20 (CD20) positive Diffuse Large B-cell lymphoma confirmed by Laboratory of Pathology, National Cancer Institute (NCI). Note: Participants with aggressive B-cell lymphoma of the plasmablastic lymphoma sub-type who do not have surface CD20 expression, are also eligible.

Human immunodeficiency virus (HIV) + serology.

All stages (I-IV) of disease.

Eastern Cooperative Oncology Group (ECOG) Performance status 0-4

Non-Hodgkin's Lymphoma (NHL) previously untreated with cytotoxic chemotherapy; however, participants may be entered if they have had prior cyclophosphamide for an urgent problem at diagnosis (e.g., epidural cord compression, superior vena cava syndrome) and/or a single dose of intrathecal methotrexate (MTX) at the time of the pre-treatment diagnostic lumbar puncture

Age greater than or equal to 18 years

Laboratory tests (unless impairment due to respective organ involvement by tumor):

• Creatinine less than or equal to 1.5 mg/dl or creatinine clearance greater than or equal to 50 ml/min

• Bilirubin less than 2.0 mg/dl, or total bilirubin less than or equal to 4.5 mg/dl with direct fraction less than or equal to 0.3 mg/dl in participants for whom these abnormalities are felt to be due to protease inhibitor therapy

• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) less than or equal to 3x upper limit of normal (ULN) (AST and ALT less than or equal to 6x ULN for participants on hyperalimentation for whom these abnormalities are felt to be due to the hyperalimentation)

• Absolute neutrophil count (ANC) greater than or equal to 1000/mm(3)

• Platelet greater than or equal to 75,000/mm(3) (unless impairment due to Immune thrombocytopenic purpura (ITP)

Ability of participant to provide informed consent.

EXCLUSION CRITERIA:

Previous rituximab

Pregnancy or nursing.

• Doxorubicin, etoposide, vincristine and cyclophosphamide are teratogenic and may be excreted in milk.

Current clinical heart failure or symptomatic ischemic heart disease.

Serious underlying medical condition or infection other than HIV that would contraindicate subcutaneous (SC)-rituximab, etoposide phosphate, prednisone, vincristine sulfate, cyclophosphamide, and doxorubicin hydrochloride (hydroxydaunorubicin (EPOCH-R).

• Examples include, but are not limited to:

• Severe Acquired immunodeficiency syndrome (AIDS)-related wasting

• Sever intractable diarrhea

• Active inadequately treated opportunistic infection of the central nervous system (CNS)

• Primary CNS lymphoma

Primary CNS lymphoma

Related Conditions & MeSH terms

• Lymphoma
• Lymphoma, AIDS-related
• Lymphoma, Large B-Cell, Diffuse

Intervention

Biological:
• Rituximab
2 doses of rituximab every cycle: first dose on Day 1 and 2nd dose on Day 5
• Filgrastim
Filgrastim day 6 until absolute neutrophil count (ANC) reaches 5000 after the nadir, every cycle

Drug:
• EPOCH
combination chemotheray: EPOCH every 3 weeks for minimum of 3 cycles and max of 6 cycles

Locations

Country	Name	City	State
United States	National Institutes of Health Clinical Center, 9000 Rockville Pike	Bethesda	Maryland

Sponsors (1)

Lead Sponsor	Collaborator
National Cancer Institute (NCI)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Number of Participants With Serious and/or Non-serious Adverse Events Assessed by the Common Toxicity Criteria (CTC v2.0)	Here is the number of participants with serious and/or non-serious adverse events assessed by the Common Toxicity Criteria (CTC v2.0). A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life-threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned.	Date treatment consent signed to date off study, approximately 209 months and 17 days.
Primary	Median Progression Free Survival (PFS)	PFS is the time interval from study entry to documented evidence of disease progression or death due to any cause. Progression is defined according to the Cheson response criteria. Disease progression is defined as increase of 25% or more in the sum of the products of the longest perpendicular diameters of all measured lesions compared to the smallest previous measurements, or the appearance of any new lesion(s). Confidence intervals were made, and a Kaplan-Meier curve of progression free survival was constructed.	The participants were followed for a median of 15.4 years.
Primary	Progression Free Survival at 1 Year	PFS is the time interval from start of treatment to documented evidence of disease progression. Progression is defined according to the Cheson response criteria. Disease progression as indicated by imaging scans at one year following therapy. Disease progression is defined as increase of 25% or more in the sum of the products of the longest perpendicular diameters of all measured lesions compared to the smallest previous measurements, or the appearance of any new lesion(s).	1 year
Secondary	Number of Participants With = Grades 3-5 Non-hematologic Toxicity	Non-hematologic (i.e., not begin in bone marrow or blood) toxicity was assessed by the Common Toxicity Criteria (CTC v2.0). Grade 3 is severe. Grade 4 is life-threatening. Grade 5 is death related to adverse event.	Date treatment consent signed to date off study, approximately 209 months and 17 days.
Secondary	Median Overall Survival	Overall survival is time from treatment start date until date of death or date last known alive.	The participants were followed for survival for a median of 15.4 years.
Secondary	1 Year Overall Survival	Overall survival is time from treatment start date until date of death or date last known alive.	1 year
Secondary	Median Duration of Complete Response/Complete Response Unconfirmed	Complete response (CR) was assessed by the Cheson response criteria. Complete response is disappearance of all signs and symptoms of lymphoma for a period of at least one month. All lymph nodes and nodal masses must have regressed to normal size (1.5 cm in their greatest transverse diameter for nodes > 1.5 cm before therapy).; Complete response unconfirmed (CRu) is when a residual lymph node mass > 1.5 cm in greatest transverse diameter that has regressed by > 75% in sum of the products of the greatest diameters, does not change over the last two treatments, and any biopsies obtained are negative will be considered to be in CR. In organs involved by disease, any residual lesions that have decreased by > 75% in sum of the products of the greatest diameters or are < 1 cm, are consistent with scar, and stable over the last two treatments will be considered to fulfill criteria for CR.	The participants were followed for duration of complete response or complete response unconfirmed for a median of 15.4 years.
Secondary	Percentage of Participants With CR/CRu Lasting 1 Year	Complete response (CR) was assessed by the Cheson response criteria. Complete response is disappearance of all signs and symptoms of lymphoma for a period of at least one month. All lymph nodes and nodal masses must have regressed to normal size (1.5 cm in their greatest transverse diameter for nodes > 1.5 cm before therapy).; Complete response unconfirmed (CRu) is when a residual lymph node mass > 1.5 cm in greatest transverse diameter that has regressed by > 75% in sum of the products of the greatest diameters, does not change over the last two treatments, and any biopsies obtained are negative will be considered to be in CR. In organs involved by disease, any residual lesions that have decreased by > 75% in sum of the products of the greatest diameters or are < 1 cm, are consistent with scar, and stable over the last two treatments will be considered to fulfill criteria for CR.	1 year
Secondary	Number of Participants With at Least One Hematologic Toxicity Event of Febrile Neutropenia	Toxicity was assessed by the Common Toxicity Criteria (CTC v2.0). Febrile neutropenia is defined as a life-threatening complication requiring hospitalization and urgent broad-spectrum antibiotics.	Date treatment consent signed to date off study, approximately 209 months and 17 days.
Secondary	Number of Cycles of Hematologic Toxicity	Cumulative number of cycles of hematologic toxicity. Hematologic (i.e., decrease in bone marrow and blood cells) toxicity was assessed by the Common Toxicity Criteria (CTC v2.0).	Up to 112 cycles (each cycle is 21 days + 7 days window)
Secondary	Overall Response	Overall response was determined by the Cheson Response Criteria. Participants with either a complete response (CR), complete response unconfirmed or partial response were considered responders. Less than a partial response was considered a non-response to therapy (i.e., Stable Disease and/or Progressive Disease). Complete response was defined as the disappearance of all signs and symptoms of lymphoma for a period of at least one month. All lymph nodes and nodal masses must have regressed to normal size. Complete response unconfirmed is a residual lymph node mass > 1.5 cm in greatest transverse diameter that has regressed by > 75% in sum of the products of the greatest diameters, does not change over the last two treatments, and any biopsies obtained are negative will be considered to be in CR. Partial response is defined as a 50% or greater decrease in the sum of the products of the longest perpendicular diameters of all measured lesions lasting for a period of at least one month.	The participants were followed for an average of 6 months to determine response to therapy.
Secondary	Percentage of Participants With Complete Response	Complete response was assessed by the Cheson Response Criteria. Complete response is disappearance of all signs and symptoms of lymphoma for a period of at least one month. All lymph nodes and nodal masses must have regressed to normal size (1.5 cm in their greatest transverse diameter for nodes > 1.5 cm before therapy).	The participants were followed for an average of 6 months to determine response to therapy.
Secondary	Median Interim Positron Emission Tomography (PET) Positive Progression Free Survival (PFS)	PFS is the time interval from start of treatment to documented evidence of disease progression or death from any cause. Disease progression was assessed by positron emission tomography scans after 2 cycles (each cycle is 21 days + 7 days window) of therapy using the Deauville criteria. Deauville score of 4 or 5 is considered positive on interim PET scan while a Deauville score of 1 or 2 or 3 is considered negative. The outcomes of the Deauville score was compared to determine PET positive progression free survival.	Participants were followed for up to 10.2 years to determine their response on interim PET scans.
Secondary	1 Year Interim Positron Emission Tomography (PET) Positive Progression Free Survival (PFS)	1-year PFS is defined as participants who remain free of disease progression or death at one year from study entry. We compared the 1-year PFS of participants with negative results on interim positron emission tomography (PET) scans to those with positive results on interim PET scans.; PFS is defined as the time interval from start of treatment to documented evidence of disease progression or death from any cause. Disease progression was assessed by positron emission tomography scans after 2 cycles of therapy using the Deauville criteria. Deauville score of 4 or 5 is considered positive on interim PET scan while a Deauville score of 1 or 2 or 3 is considered negative. The outcomes of the Deauville score was compared to determine PET positive progression free survival.	1 year
Secondary	Recovery of CD4 T Cells (CD4) Counts	Participants with human immunodeficiency virus (HIV) who undergo chemotherapy may have a delay in the recovery of their normal CD4+ T-cells. This delay could result in an increased risk of infection. Recovery of CD4 cells counts is the time from end of therapy until the time that the CD4 counts first reached above 200 cells/uL.	From the end of chemotherapy every 3 months for the first 2 years
Secondary	Recovery of Human Immunodeficiency Virus (HIV) Viral Load	The HIV viral load is a measure of actively replicating virus in the blood. If no anti-retroviral therapy is given, then reduction of this HIV viral load to manageable levels might risk infection. In our study, the recovery of HIV viral load was measured the time from the initiation of antiretroviral therapy until the viral load was undetectable or < 50 copies.	Either following or concurrently with combination chemo and biological therapy, approximately every 6 to 8 weeks after therapy was completed up to 16 months

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