Treatment and Natural History Study of Lymphomatoid Granulomatosis

NCT00001379 | Completed Phase 2 Results FDA Drug

• 2 other identifiers: 94007494-C-0074
• Study Type: interventional
• Target: 94
• Locations: 1 country
• Sites: 1

Brief Summary

This study will evaluate the response and long-term effects of alpha-interferon in patients with lymphomatoid granulomatosis (LYG). The disease causes proliferation of destructive cells involving the lungs, skin, kidneys, and central nervous system. Patients ages 12 and older who have LYG and who are not pregnant, or breast feeding may be eligible for this study. Alpha interferon or chemotherapy, or both, will be used. Alpha interferon is a protein the body naturally produces. If patients have grade 3 disease, they will usually receive etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin (EPOCH)-rituximab (EPOCH-R) chemotherapy (each letter representing a drug). If patients have grade 1 or 2 disease, they will usually receive alpha interferon. If patients have LYG after receiving alpha interferon and/or EPOCH-R, they may receive rituximab alone or with alpha interferon. Rituximab is an antibody, binding to a specific molecule cluster of differentiation 20 (CD20) present on most B-cell lymphomas. Doses of several drugs in EPOCH-R may be increased if patients tolerated them in the previous cycle. If patients respond to EPOCH-R but still have low grade LYG, they may receive alpha interferon. Researchers will also try to obtain a biopsy of patient's lesions, to help in understanding the disease. Patients self-administer alpha interferon by injection under the skin three times weekly. They will visit the clinic every 2 to 12 weeks for follow-up. Patients will receive alpha interferon for 1 year after LYG goes away, depending on response. EPOCH-R has these drugs: rituximab by vein on Day 1; prednisone by mouth on Days 1 to 5; etoposide, doxorubicin, and vincristine as a continuous intravenous infusion on Days 1 to 5; and cyclophosphamide by intravenous injection over 1 hour on Day 5. Each cycle lasts 3 weeks: 5 days of chemotherapy and 16 days of no chemotherapy. Etoposide, doxorubicin, and vincristine are infused through a small pump worn by patients. The drugs are given over 5 days through a central intravenous catheter. There are two cycles of EPOCH-R beyond a maximum response, with six cycles maximum. To reduce harm to bone marrow, patients receive granulocyte colony stimulating factor (G-CSF), self-administered by injection under the skin daily for approximately 10 days between chemotherapy cycles. If at the end of therapy, patients have a complete response, treatment will stop. If there is residual low-grade disease, patients may receive alpha interferon. Alpha interferon can have flu-like side effects of headache, fever, chills, and body aches. EPOCH-R drugs can cause gastrointestinal problems, hair loss, and weakness. Granulocyte colony-stimulating factor (G-CSF) can cause bone pain, body aches, and hair thinning. Chemotherapy can cause some patients to develop leukemia. This study may or may not have a direct benefit for participants. It is not certain whether the new therapy will help decrease tumors. However, knowledge gained may improve the understanding of and treatment for LYG. ...

Conditions

Lymphomatoid Granulomatosis; Granulomatosis, Lymphomatoid; Non-Hodgkins Lymphoma; Lymphoproliferative Disorder

Keywords

Epstein-Barr Virus; Lymphoproliferative Disorder; Viral; Immunosuppression; Lymphoma

Outcome Measures

Primary Outcomes (2)

• Overall Response Rate (ORR)

  Overall response rate will be classified as the following: complete remission (CR), partial remission (PR), disease progression or disease stabilization measured by the Response Criteria. CR is no evidence of active disease on restaging for at least 2 months duration. All lesions must have decreased by \> 75%, be gallium or positron emission tomography (PET) negative (if obtained) and be stable for \> 3 months without new lesions appearing. PR is 50% or greater decrease in the sum of the products of the diameters of all measurable lesions for at least one month. Disease progression is 25% or greater progression in the sum of the products of the diameter of any measurable lesion over one month or the appearance or any new lesion consistent with metastatic disease. Disease stabilization is no change in the sum of the products of the diameters of all measurable lesions over two months and no new lesions consistent with disease.

  From study enrollment and throughout treatment, up to a maximum of 40 months for the 2 interferon groups and 8 months for the 2 EPOCH-R groups.

• Progression Free Survival (PFS)

  PFS is defined as the duration of time from the date of study enrollment until the date of disease relapse, disease progression, death, or last follow-up, whichever occurs first, using the Kaplan-Meier method. Response was assessed by the Lugano Classification Response Criteria for Non-Hodgkin lymphoma (NHL). Disease progression is defined as an increase of ≥ 50% from the product of the perpendicular diameter (PPD) nadir and an increase in longest transverse diameter of a lesion (LDi) or shortest axis perpendicular diameter (SDi) from nadir of \>0.5 cm for lesions \<2 cm or \>1.0 cm for lesions \>2 cm.

  Assessed from date of study enrollment until time of disease relapse, disease progression, death, or last follow-up, whichever comes first, up to a maximum of 27 years for the 2 interferon groups and 20 years for the 2 EPOCH-R groups.

Secondary Outcomes (1)

• Overall Survival (OS)

  Assessed from date of study enrollment until time of death or last follow-up, whichever comes first, up to a maximum of 27 years.

Other Outcomes (1)

• Number of Participants With Serious and/or Non-serious Adverse Events Assessed by the Common Toxicity Criteria (CTC v2.0)

  Adverse Events were monitored/assessed from the first study intervention, Study Day 1 of Cycle 1 through 30 days after the study agent (s) was/were administered, up to a maximum of 49 months.

Study Arms (2)

Arm 1-Interferon

EXPERIMENTAL

Interferon starting at 7.5 million Units subcutaneous (subQ) 3 times a week and increasing on the designated schedule, as tolerated. Patients continue taking interferon for 1 year beyond complete remission (CR). Patients who progress may crossover to receive etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin and rituximab (EPOCH-R).

Biological: Interferon; Procedure: Tumor biopsy; Procedure: Bone marrow biopsy; Biological: Bone marrow aspirate; Procedure: Lumber puncture; Diagnostic Test: CT; Diagnostic Test: Brain MRI; Diagnostic Test: Echocardiogram; Diagnostic Test: FDG-PET

Arm 2-Etoposide, Prednisone, Vincristine, Cyclophosphamide, Doxorubicin & Rituximab (EPOCH-R)

EXPERIMENTAL

Etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin and rituximab (EPOCH-R) every 3 weeks for up to 6 cycles, based on response. Participants who relapse or progress may crossover to receive interferon.

Drug: Rituxan and EPOCH; Procedure: Tumor biopsy; Procedure: Bone marrow biopsy; Biological: Bone marrow aspirate; Procedure: Lumber puncture; Diagnostic Test: CT; Diagnostic Test: Brain MRI; Diagnostic Test: Echocardiogram; Diagnostic Test: FDG-PET

Interventions

Interferon BIOLOGICAL

For lymphomatoid granulomatosis (LYG) Grade 1 and 2: Interferon starting at 7.5 million Units subcutaneous (subQ) 3 times a week and increasing on the following schedule: 10 million U; 15 million U; 20 million U; 25 million U; and increased in 5 million U increments, as tolerated. Patients continue taking interferon for 1 year beyond complete remission (CR).

Also known as: IFN

Arm 1-Interferon

Rituxan and EPOCH DRUG

For lymphomatoid granulomatosis (LYG) Grade 3: EPOCH-R (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, rituximab) every 3 weeks for 6 cycles.

Also known as: Rituximab, etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, rituximab

Arm 2-Etoposide, Prednisone, Vincristine, Cyclophosphamide, Doxorubicin & Rituximab (EPOCH-R)

Tumor biopsy PROCEDURE

Baseline (optional).

Also known as: Tumor bx

Arm 1-Interferon; Arm 2-Etoposide, Prednisone, Vincristine, Cyclophosphamide, Doxorubicin & Rituximab (EPOCH-R)

Bone marrow biopsy PROCEDURE

Baseline.

Also known as: BM biopsy

Arm 1-Interferon; Arm 2-Etoposide, Prednisone, Vincristine, Cyclophosphamide, Doxorubicin & Rituximab (EPOCH-R)

Bone marrow aspirate BIOLOGICAL

Baseline.

Also known as: BM aspirate

Arm 1-Interferon; Arm 2-Etoposide, Prednisone, Vincristine, Cyclophosphamide, Doxorubicin & Rituximab (EPOCH-R)

Lumber puncture PROCEDURE

Baseline.

Also known as: LP

Arm 1-Interferon; Arm 2-Etoposide, Prednisone, Vincristine, Cyclophosphamide, Doxorubicin & Rituximab (EPOCH-R)

CT DIAGNOSTIC_TEST

Arm 1: At baseline, then every 4 weeks until on stable dose of interferon or a maximum of 6 monthly scans, then every 3 months while receiving interferon, and following completion of interferon. In surveillance, every 3 months for 1 year, every 4 months for 1 year, every 6 months for 1 year and yearly thereafter for 2 years. Arm 2: At baseline, following cycle 4, and following cycle 6 of etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab (DA-EPOCH-R). In surveillance, every 3 months for 1 year, every 4 months for 1 year, every 6 months for 1 year and yearly thereafter for 2 years.

Also known as: Computed tomography

Arm 1-Interferon; Arm 2-Etoposide, Prednisone, Vincristine, Cyclophosphamide, Doxorubicin & Rituximab (EPOCH-R)

Brain MRI DIAGNOSTIC_TEST

Arm 1: At baseline, then every 4 weeks until on stable dose of interferon or a maximum of 6 monthly scans, then every 3 months while receiving interferon, and following completion of interferon. In surveillance, every 3 months for 1 year, every 4 months for 1 year, every 6 months for 1 year and yearly thereafter for 2 years (patients with central nervous system (CNS) disease only). Arm 2: At baseline, following cycle 4, and following cycle 6 of etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab (DA-EPOCH-R). In surveillance, every 3 months for 1 year, every 4 months for 1 year, every 6 months for 1 year and yearly thereafter for 2 years (patients with CNS disease only).

Also known as: Brain magnetic resonance imaging

Arm 1-Interferon; Arm 2-Etoposide, Prednisone, Vincristine, Cyclophosphamide, Doxorubicin & Rituximab (EPOCH-R)

Echocardiogram DIAGNOSTIC_TEST

For participants receiving \> 450 mg/m\^2 doxorubicin.

Also known as: Echo

Arm 1-Interferon; Arm 2-Etoposide, Prednisone, Vincristine, Cyclophosphamide, Doxorubicin & Rituximab (EPOCH-R)

FDG-PET DIAGNOSTIC_TEST

Arm 1: Baseline and following completion of interferon. Arm 2: Baseline and following completion of etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab (DA-EPOCH-R).

Also known as: Fluorodeoxyglucose positron emission tomography

Arm 1-Interferon; Arm 2-Etoposide, Prednisone, Vincristine, Cyclophosphamide, Doxorubicin & Rituximab (EPOCH-R)

Eligibility Criteria

• Age: 12 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients must have a tissue-diagnosis of grade 1, 2 and/or 3 lymphomatoid granulomatosis (LYG) (or a diagnosis consistent with LYG) confirmed by the Laboratory of Pathology, National Cancer Institute (NCI). Final histopathologic classification and pathologic grade will be determined by Stephania Pittaluga, medical doctor (M.D.) or her designee.
• Patients with any stage of disease will be eligible.
• Previously untreated and treated patients are eligible.
• Patients aged 12 or older will be eligible.

You may not qualify if:

• Patients with a history of coronary artery disease with angina pectoris, or a history of congestive heart failure will not be eligible to receive. etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin and rituximab (DA-EPOCH-R) chemotherapy.
• Patients with significant renal (serum creatinine (Cr.) greater than 1.5 mg/dl or creatinine clearance less than 40 cc/min) or hepatic (bilirubin greater than 2.5 x upper limit of normal (ULN) dysfunction not due to tumor involvement will not be eligible to receive DA-EPOCH-R chemotherapy.
• Informed consent must be obtained.
• Patients who in the opinion of the principal investigator are poor psychiatric or medical risk are not eligible.
• Patients who received \> 450 mg/m\^2 doxorubicin and have a cardiac ejection fraction on echocardiogram less than or equal to 40% on protocol entry are not eligible to received DA-EPOCH-R.
• Patients with prior hepatitis B exposure may be included in the study provided that they have hepatitis B virus (HBV) deoxyribonucleic acid (DNA) levels below the World Health Organizations cutoff of 100 IU/mL prior to starting therapy.

Sponsors & Collaborators

• National Cancer Institute (NCI): lead

Study Sites (1)

National Institutes of Health Clinical Center

Bethesda, Maryland, 20892, United States

Location

Related Publications (1)

• Melani C, Dowdell K, Pittaluga S, Dunleavy K, Roschewski M, Song JY, Calattini S, Kawada JI, Price DA, Chattopadhyay PK, Roederer M, Lucas AN, Steinberg SM, Jaffe ES, Cohen JI, Wilson WH. Interferon alfa-2b in patients with low-grade lymphomatoid granulomatosis and chemotherapy with DA-EPOCH-R in patients with high-grade lymphomatoid granulomatosis: an open-label, single-centre, phase 2 trial. Lancet Haematol. 2023 May;10(5):e346-e358. doi: 10.1016/S2352-3026(23)00029-7. Epub 2023 Mar 31.

  PMID: 37011643 DERIVED

Related Links

• NIH Clinical Center Detailed Web Page

MeSH Terms

Conditions

Lymphomatoid Granulomatosis; Lymphoma, Non-Hodgkin; Lymphoproliferative Disorders; Epstein-Barr Virus Infections; Lymphoma

Interventions

Interferons; Rituximab; EPOCH protocol; Etoposide; Prednisone; Vincristine; Cyclophosphamide; Doxorubicin; Tomography, X-Ray Computed; Echocardiography; Caves

Condition Hierarchy (Ancestors)

Lymphoma, B-Cell; Neoplasms by Histologic Type; Neoplasms; Precancerous Conditions; Lymphatic Diseases; Hemic and Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Herpesviridae Infections; DNA Virus Infections; Virus Diseases; Infections; Tumor Virus Infections

Intervention Hierarchy (Ancestors)

Cytokines; Intercellular Signaling Peptides and Proteins; Peptides; Amino Acids, Peptides, and Proteins; Proteins; Biological Factors; Antibodies, Monoclonal, Murine-Derived; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Serum Globulins; Globulins; Podophyllotoxin; Tetrahydronaphthalenes; Naphthalenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Polycyclic Compounds; Glucosides; Glycosides; Carbohydrates; Pregnadienediols; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Vinca Alkaloids; Secologanin Tryptamine Alkaloids; Indole Alkaloids; Alkaloids; Heterocyclic Compounds; Indoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Indolizidines; Indolizines; Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Phosphoramides; Organophosphorus Compounds; Daunorubicin; Anthracyclines; Naphthacenes; Aminoglycosides; Image Interpretation, Computer-Assisted; Diagnostic Imaging; Diagnostic Techniques and Procedures; Diagnosis; Radiographic Image Enhancement; Image Enhancement; Photography; Radiography; Tomography, X-Ray; Tomography; Cardiac Imaging Techniques; Ultrasonography; Heart Function Tests; Diagnostic Techniques, Cardiovascular; Geological Phenomena; Physical Phenomena; Environment; Ecological and Environmental Phenomena; Biological Phenomena; Environment and Public Health

Results Point of Contact

• Title: Dr. Christopher J. Melani
• Organization: National Cancer Institute

christopher.melani@nih.gov

240-760-6057

Study Officials

• Christopher J Melani, M.D.

  National Cancer Institute (NCI)

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: NIH
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: November 3, 1999
• First Posted: November 4, 1999
• Study Start: May 5, 1995
• Primary Completion: January 17, 2025
• Study Completion: January 17, 2025
• Last Updated: June 19, 2025
• Results First Posted: June 19, 2025

Record last verified: 2025-06

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF
• Time Frame: Clinical data will be available during the study and indefinitely.
• Access Criteria: Clinical data will be made available via subscription to Biomedical Translational Research Information System (BTRIS) and with the permission of the study principal investigator (PI).

Locations

US (1)