Phase 1 Trial of Siplizumab and Dose-Adjusted EPOCH-Rituximab in T- and NK-Cell Lymphomas

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Brief Title

Phase 1 Trial of Siplizumab and Dose-Adjusted EPOCH-Rituximab in T- and NK-Cell Lymphomas

Official Title

Phase 1 Trial of Siplizumab and Dose-Adjusted EPOCH-Rituximab (DA-EPOCH-R) in T and NK-Cell Lymphomas

Brief 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


      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


      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.


      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.


      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.

Study Phase

Phase 1

Study Type


Primary Outcome

Number of Participants With Serious and Non-serious Adverse Events

Secondary Outcome

 Number of Participants With a Response to Therapy


T-Cell Peripheral Lymphoma



Study Arms / Comparison Groups

 siplizumab + EPOCH (combo chemo) + rituximab
Description:  siplizumab will be given with EPOCH (combo chemo) and rituximab every 21 days


* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information

Recruitment Status


Estimated Enrollment


Start Date

January 13, 2009

Completion Date

October 22, 2020

Primary Completion Date

April 1, 2011

Eligibility Criteria


        Cluster of differentiation 2 (CD2)-expressing lymphoid malignancy, confirmed by pathology
        or flow cytometry staff of the Hematopathology Section, Laboratory of Pathology, National
        Cancer Institute (NCI). At least 30% of the malignant cells must be CD2 positive for
        inclusion in this study.

        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

        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


        Patients less than 18 years of age will be excluded because siplizumab has not been given
        to minors in combination with chemotherapy.




18 Years - 120 Years

Accepts Healthy Volunteers



Wyndham H Wilson, M.D., , 

Location Countries

United States

Location Countries

United States

Administrative Informations



Organization ID


Secondary IDs


Responsible Party

Principal Investigator

Study Sponsor

National Cancer Institute (NCI)

Study Sponsor

Wyndham H Wilson, M.D., Principal Investigator, National Cancer Institute (NCI)

Verification Date

October 2021