Phase 1 Trial of Siplizumab and Dose-Adjusted EPOCH-Rituximab in T- and NK-Cell Lymphomas
Condition: T-Cell Peripheral Lymphoma; Gamma Delta Hepatosplenic T-Cell Lymphoma; Subcutaneous Panniculitis-Like T-Cell Lymphoma; NK T-Cell Lymphoma
MeSH terms: Lymphoma; Lymphoma, T-Cell; Lymphoma, T-Cell, Peripheral; Panniculitis
Study type: Interventional
Phase: Phase 1

Summary: 
      Studies conducted at the National Cancer Institute suggest that certain chemotherapy drugs
      may be more effective if given by continuous infusion into the vein rather than by the
      standard method of rapid intravenous injection. One such combination of six chemotherapy
      drugs, known as Etoposide, Prednisone, Vincristine, Cyclophosphamide, Doxorubicin, Rituximab
      (EPOCH-R), has had a high degree of effectiveness in people with certain kinds of cancer.
      Recent evidence also indicates that the effects of chemotherapy may be improved by combining
      the treatment with monoclonal antibodies, which are purified proteins that are specially made
      to attach to foreign substances such as cancer cells. This protocol is specifically for
      adults with the types of cancer known as T-cell and Naturel Killer (NK)-cell lymphomas, who
      have never received chemotherapy previously. The additional monoclonal antibody in the study,
      called siplizumab, has been manufactured to attach to the cluster of differentiation 2 (CD2)
      protein contained in these types of tumors.

      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: 
      Background:

      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.
    

Intervention name(s): Rituximab; Etoposide; Siplizumab; Prednisone; Vincristine; Cyclophosphamide; Doxorubicin
Intervention type(s): Biological; Drug; Biological; Drug; Drug; Drug; Drug
Intervention description(s): Rituximab will be given with siplizumab and etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin every 21 days; Etoposide will be given with siplizumab and prednisone, vincristine, cyclophosphamide, doxorubicin and rituximab every 21 days; Siplizumab will be given with etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin and rituximab every 21 days; Prednisone will be given with siplizumab and etoposide, vincristine, cyclophosphamide, doxorubicin and rituximab every 21 days; Vincristine will be given with siplizumab and etoposide, prednisone, cyclophosphamide, doxorubicin and rituximab every 21 days; Cyclophosphamide will be given with siplizumab and etoposide, prednisone, vincristine, doxorubicin and rituximab every 21 days; Doxorubicin will be given with siplizumab and etoposide, prednisone, cyclophosphamide and rituximab every 21 days
Other intervention name(s): Rituxan; Toposar; MEDI-507; Deltasone; Marqibo; Cytoxan; Doxil
Intervention MeSH terms: Prednisone; Cyclophosphamide; Rituximab; Doxorubicin; Etoposide; Vincristine
Intervention model: Sequential Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: CD2 Positive; Toxicity; EBV Lymphoma; Chemotherapy Naive; Maximum Tolerated Dose; Lymphoma; T-Cell Lymphoma; NK T-Cell Lymphoma