Clinical trial NCT00006436: EPOCH and Rituximab to Treat Non-Hodgkin's Lymphoma in Patients With HIV Infection
Official title: Short-Course EPOCH - Rituximab in Untreated CD-20+ HIV-Associated Lymphomas
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Lymphoma, AIDS-related
Lymphoma, Large B-Cell, Diffuse
Keywords: AIDS
Malignancy
Antiretroviral
Chemotherapy
Monoclonal
Lead sponsor: National Institutes of Health Clinical Center (CC)
Sponsor class: NIH
First posted: 2000-11-06
Enrollment: 68
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief 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.

Detailed 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.

Eligibility criteria: * 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

Primary outcomes:
measure: Median Progression Free Survival (PFS)
timeFrame: The participants were followed for a median of 15.4 years.
measure: Progression Free Survival at 1 Year
timeFrame: 1 year
Secondary outcomes:
measure: Number of Participants With ≥ Grades 3-5 Non-hematologic Toxicity
timeFrame: Date treatment consent signed to date off study, approximately 209 months and 17 days.
measure: Median Overall Survival
timeFrame: The participants were followed for survival for a median of 15.4 years.
measure: 1 Year Overall Survival
timeFrame: 1 year
measure: Median Duration of Complete Response/Complete Response Unconfirmed
timeFrame: The participants were followed for duration of complete response or complete response unconfirmed for a median of 15.4 years.
measure: Percentage of Participants With CR/CRu Lasting 1 Year
timeFrame: 1 year
measure: Number of Participants With at Least One Hematologic Toxicity Event of Febrile Neutropenia
timeFrame: Date treatment consent signed to date off study, approximately 209 months and 17 days.
measure: Number of Cycles of Hematologic Toxicity
timeFrame: Up to 112 cycles (each cycle is 21 days + 7 days window)
measure: Overall Response
timeFrame: The participants were followed for an average of 6 months to determine response to therapy.
measure: Percentage of Participants With Complete Response
timeFrame: The participants were followed for an average of 6 months to determine response to therapy.
measure: Median Interim Positron Emission Tomography (PET) Positive Progression Free Survival (PFS)
timeFrame: Participants were followed for up to 10.2 years to determine their response on interim PET scans.
measure: 1 Year Interim Positron Emission Tomography (PET) Positive Progression Free Survival (PFS)
timeFrame: 1 year
measure: Recovery of CD4 T Cells (CD4) Counts
timeFrame: From the end of chemotherapy every 3 months for the first 2 years
measure: Recovery of Human Immunodeficiency Virus (HIV) Viral Load
timeFrame: Either following or concurrently with combination chemo and biological therapy, approximately every 6 to 8 weeks after therapy was completed up to 16 months
Other outcomes:
measure: Number of Participants With Serious and/or Non-serious Adverse Events Assessed by the Common Toxicity Criteria (CTC v2.0)
timeFrame: Date treatment consent signed to date off study, approximately 209 months and 17 days.
Locations:
city: Bethesda
country: United States
facility: National Institutes of Health Clinical Center, 9000 Rockville Pike
state: Maryland
Study officials:
affiliation: National Cancer Institute (NCI)
name: Mark J Roschewski, M.D.
role: PRINCIPAL_INVESTIGATOR
References:
citation: Kurtz DM, Scherer F, Jin MC, Soo J, Craig AFM, Esfahani MS, Chabon JJ, Stehr H, Liu CL, Tibshirani R, Maeda LS, Gupta NK, Khodadoust MS, Advani RH, Levy R, Newman AM, Duhrsen U, Huttmann A, Meignan M, Casasnovas RO, Westin JR, Roschewski M, Wilson WH, Gaidano G, Rossi D, Diehn M, Alizadeh AA. Circulating Tumor DNA Measurements As Early Outcome Predictors in Diffuse Large B-Cell Lymphoma. J Clin Oncol. 2018 Oct 1;36(28):2845-2853. doi: 10.1200/JCO.2018.78.5246. Epub 2018 Aug 20.
citation: Dunleavy K, Pittaluga S, Shovlin M, Steinberg SM, Cole D, Grant C, Widemann B, Staudt LM, Jaffe ES, Little RF, Wilson WH. Low-intensity therapy in adults with Burkitt's lymphoma. N Engl J Med. 2013 Nov 14;369(20):1915-25. doi: 10.1056/NEJMoa1308392.