Phase 1 Trial of Siplizumab and Dose-Adjusted EPOCH-Rituximab in T- and NK-Cell Lymphomas
NCT ID: NCT01445535
Last Updated: 2021-11-03
Study Results
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View full resultsBasic Information
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COMPLETED
PHASE1
15 participants
INTERVENTIONAL
2009-01-13
2020-10-22
Brief Summary
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Study volunteers will need to undergo an initial period of evaluation that may take up to 3 weeks and may be done on an outpatient basis. Evaluation may include some or all of the following tests: blood and urine tests, tests of lung and heart function, lumbar punctures to take samples of cerebrospinal fluid, magnetic resonance imaging (MRI) or computerized tomography (CT) scans, full-body positron emission tomography (PET) scans, bone marrow biopsies, and biopsies of suspected tumor areas.
During the study, patients will receive EPOCH-R chemotherapy, which includes the following drugs: etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab. The additional drug, siplizumab, will be given by IV infusion on the first day of treatment over several hours. When the siplizumab intravenous (IV) infusion is complete, the drugs doxorubicin, etoposide, and vincristine will each be given by continuous IV infusion over the next 4 days (that is, continuously for a total of 96 hours). When this infusion is completed, the drugs rituximab and cyclophosphamide will be given by IV infusion over several hours on Day 5. Prednisone will be given by mouth twice each day for 5 days. Patients may be given other drugs to treat the side effects of chemotherapy and to prevent possible infections.
The siplizumab-EPOCH-R therapy will be repeated every 21 days, which is known as a cycle of therapy, for a total of 6 cycles. Following the fourth and sixth treatment cycles (approximately weeks 12 and 18) of siplizumab-EPOCH-R, study researchers will perform blood tests and CT/MRI scans on all patients to assess their response to the treatment.
Detailed Description
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The clinical outcome for patients with T-cell non-Hodgkin's lymphoma is significantly inferior to the outcome of patients with B-cell non-Hodgkin's lymphoma. In most reports less than 20% of patients with T cell lymphoid malignancies remain free of disease at 5 years.
The combination of alemtuzumab and Etoposide, Prednisone, Vincristine, Cyclophosphamide and Doxorubicin (EPOCH) chemotherapy was evaluated in patients with chemotherapy naive aggressive T and natural killer (NK) cell lymphoid malignancy. Dose-limiting bone marrow toxicity prevented escalation of the alemtuzumab dose.
Siplizumab is a humanized monoclonal antibody directed at cluster of differentiation 2 (CD2) that demonstrated activity in the treatment of relapsed/refractory T cell lymphoma, suggesting further development by combining with chemotherapy for untreated patients. Siplizumab caused Epstein-Barr Virus (EBV) lymphoproliferative disease in patients treated with a weekly schedule of administration.
Rituximab prevents the development of EBV lymphoproliferative disease in the allogeneic transplant setting and may be active in preventing EBV-related B cell lymphoma in other settings.
Objectives:
Determine the toxicity and maximum tolerated dose of siplizumab and dose-adjusted EPOCH rituximab chemotherapy in chemotherapy naïve CD2- expressing T and NK lymphoid malignancies.
Eligibility:
CD2-expressing lymphoid malignancy.
Patients with chemotherapy naive aggressive T \& NK lymphomas. Patients with alk-positive anaplastic large cell lymphoma and patients with T-cell precursor disease are not eligible.
Design:
Four dose levels of siplizumab will be evaluated to determine the toxicity profile and in a preliminary fashion, and its activity in combination with dose-adjusted EPOCH with rituximab.
Four dose levels of siplizumab will be explored, in cohorts of three to six patients each. Patients will receive 3.4, 4.8, 8.5, or 15 mg/kg of siplizumab on day 1 of therapy, followed by dose-adjusted EPOCH-rituximab chemotherapy days 1-5 every 3 weeks for a total of 6 cycles.
Conditions
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Keywords
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Study Design
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NA
SEQUENTIAL
TREATMENT
NONE
Study Groups
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siplizumab + EPOCH (combo chemo) + rituximab
siplizumab will be given with EPOCH (combo chemo) and rituximab every 21 days
Rituximab
Rituximab will be given with siplizumab and etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin every 21 days
Etoposide
Etoposide will be given with siplizumab and prednisone, vincristine, cyclophosphamide, doxorubicin and rituximab every 21 days
Siplizumab
Siplizumab will be given with etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin and rituximab every 21 days
Prednisone
Prednisone will be given with siplizumab and etoposide, vincristine, cyclophosphamide, doxorubicin and rituximab every 21 days
Vincristine
Vincristine will be given with siplizumab and etoposide, prednisone, cyclophosphamide, doxorubicin and rituximab every 21 days
Cyclophosphamide
Cyclophosphamide will be given with siplizumab and etoposide, prednisone, vincristine, doxorubicin and rituximab every 21 days
Doxorubicin
Doxorubicin will be given with siplizumab and etoposide, prednisone, cyclophosphamide and rituximab every 21 days
Interventions
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Rituximab
Rituximab will be given with siplizumab and etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin every 21 days
Etoposide
Etoposide will be given with siplizumab and prednisone, vincristine, cyclophosphamide, doxorubicin and rituximab every 21 days
Siplizumab
Siplizumab will be given with etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin and rituximab every 21 days
Prednisone
Prednisone will be given with siplizumab and etoposide, vincristine, cyclophosphamide, doxorubicin and rituximab every 21 days
Vincristine
Vincristine will be given with siplizumab and etoposide, prednisone, cyclophosphamide, doxorubicin and rituximab every 21 days
Cyclophosphamide
Cyclophosphamide will be given with siplizumab and etoposide, prednisone, vincristine, doxorubicin and rituximab every 21 days
Doxorubicin
Doxorubicin will be given with siplizumab and etoposide, prednisone, cyclophosphamide and rituximab every 21 days
Other Intervention Names
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Eligibility Criteria
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Inclusion Criteria
Patients with chemotherapy naive T \& Natural Killer (NK) lymphomas, including but not limited to peripheral T cell lymphoma (nos), gamma-delta hepatosplenic T cell lymphoma, subcutaneous panniculitis-like T cell, NK-T cell lymphoma confirmed by pathology or flow cytometry staff of the Hematopathology Section, Laboratory of Pathology, NCI. Patients with alk-positive anaplastic large cell lymphoma and patients with T-cell precursor disease are not eligible.
Age greater than or equal to 18 years.
Laboratory tests: Creatinine less than or equal to 1.5 mg/dL or creatinine clearance greater than or equal to 60 ml/min; bilirubin less than 2.0 mg/dl unless due to Gilbert's (unconjugated hyperbilirubinemia without other known cause), aspartate aminotransferase (AST) and alanine aminotransferase (ALT) less than or equal to 3 times upper limit of normal (ULN) (AST and ALT less than or equal to 6 times ULN for patients on hyperalimentation for whom these abnormalities are felt to be due to the hyperalimentation) and; 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 respective organ impairment by tumor.
No active symptomatic ischemic heart disease, myocardial infarction or congestive heart failure within the past year.
Patients must not have a marked baseline prolongation of Q wave, T wave (QT/QTc) interval (e.g., demonstration of a corrected QT interval (QTc) interval \>500 milliseconds (ms)).
Human immunodeficiency virus (HIV) negative, because of the unknown effects of combined therapy with chemotherapy and an immunosuppressive agent on HIV progression.
Signed informed consent by the patient or patient's representative.
Willing to use contraception.
Not pregnant or nursing, because of the unknown effects of dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab (DA-EPOCH-R) or siplizumab on the developing fetus and infant.
No serious underlying medical condition or infection that would contraindicate treatment. Patients with central nervous system (CNS) involvement are eligible for treatment on this study.
Exclusion Criteria
18 Years
120 Years
ALL
No
Sponsors
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National Cancer Institute (NCI)
NIH
Responsible Party
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Wyndham Wilson, M.D.
Principal Investigator
Principal Investigators
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Wyndham H Wilson, M.D.
Role: PRINCIPAL_INVESTIGATOR
National Cancer Institute (NCI)
Locations
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National Institutes of Health Clinical Center, 9000 Rockville Pike
Bethesda, Maryland, United States
Countries
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References
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Abruzzo LV, Rosales CM, Medeiros LJ, Vega F, Luthra R, Manning JT, Keating MJ, Jones D. Epstein-Barr virus-positive B-cell lymphoproliferative disorders arising in immunodeficient patients previously treated with fludarabine for low-grade B-cell neoplasms. Am J Surg Pathol. 2002 May;26(5):630-6. doi: 10.1097/00000478-200205000-00009.
Bhargava R, Barbashina V, Filippa DA, Teruya-Feldstein J. Epstein-Barr virus positive large B-cell lymphoma arising in a patient previously treated with Cladribine for hairy cell leukemia. Leuk Lymphoma. 2004 May;45(5):1043-8. doi: 10.1080/10428190310001625890.
Birkeland SA, Hamilton-Dutoit S. Is posttransplant lymphoproliferative disorder (PTLD) caused by any specific immunosuppressive drug or by the transplantation per se? Transplantation. 2003 Sep 27;76(6):984-8. doi: 10.1097/01.TP.0000085602.22498.CF.
Roswarski J, Roschewski M, Lucas A, Melani C, Pittaluga S, Jaffe ES, Steinberg SM, Waldmann TA, Wilson WH. Phase I dose escalation study of the anti-CD2 monoclonal antibody, siplizumab, with DA-EPOCH-R in aggressive peripheral T-cell lymphomas. Leuk Lymphoma. 2018 Jun;59(6):1466-1469. doi: 10.1080/10428194.2017.1387908. Epub 2017 Oct 16. No abstract available.
Provided Documents
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Document Type: Study Protocol and Statistical Analysis Plan
Document Type: Informed Consent Form
Related Links
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NIH Clinical Center Detailed Web Page
Other Identifiers
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09-C-0065
Identifier Type: -
Identifier Source: secondary_id
090065
Identifier Type: -
Identifier Source: org_study_id
NCT00832936
Identifier Type: -
Identifier Source: nct_alias