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

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

Siplizumab

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

Wyndham H Wilson, M.D.

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.

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.

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

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

DLTs for siplizumab was defined as infusional grade 3 non-hematologic toxicity lasting longer than 6 hours after the infusion, any grade 4 non-hematologic toxicity, or the development of an EBV-related lymphoproliferative disorder (LPD). Expected toxicities of dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin and rituximab (EPOCH-R) and grade 3 laboratory AEs were not considered to be DLTs.

Here is the count of participants with serious and non-serious adverse events assessed by the Common Terminology Criteria for Adverse Events (CTCAE v3.0). A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life-threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned.

A classic 3+3 dose-escalation design was used to assess the MTD of siplizumab in combination with dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin and rituximab (EPOCH-R). If 2 of 6 patients experienced a dose-limiting toxicity (DLT) at a particular dose level, the MTD has been exceeded. The preceding dose level will be the MTD, provided 6 patients have been entered at this level and no more than one has experienced a DLT. DLTs for siplizumab was defined as infusional grade 3 non-hematologic toxicity lasting longer than 6 hours after the infusion, any grade 4 non-hematologic toxicity, or the development of an Epstein Barr Virus (EBV)-related lymphoproliferative disorder (LPD). Expected toxicities of dose-adjusted EPOCH-R and grade 3 laboratory adverse events (AEs) were not considered to be DLTs.

Response was assessed by the International Workshop to Standardize Response Criteria for Non-Hodgkin's Lymphoma. Complete Remission was defined as the disappearance of all detectable clinical and radiographic evidence of disease, disappearance of all disease related symptoms if present before therapy, and normalization of those biochemical abnormalities (for example lactate dehydrogenase (LDH)) definitely assignable to the lymphoma. Complete response unconfirmed was defined as a residual node greater than 1.5 cm, with a decrease by greater than 75 percent in the sum of the products of the perpendicular diameters (SPD) of all measured lymph nodes. Partial Response was defined as a ≥ 50% decreased in SPD of 6 largest dominant nodes or nodal masses. Relapsed disease was defined as the appearance of any new lesion or increase by ≥50% in the size of the previously identified sites. Progressive disease was defined as a ≥50% increase from nadir in the SPD.

Progression was assessed by the International Workshop to Standardize Response Criteria for Non-Hodgkin's Lymphoma. Progression is defined as ≥50% increase from nadir in the sum of the products of the perpendicular diameters (SPD) of any previously identified abnormal nodes for Partial Response's or non-responders. Progression-free survival (PFS) was determined from the on-study date until date of progression or last follow-up. The probability of PFS as a function of time was estimated by the Kaplan-Meier method.

Overall survival was determined from the on-study date until date of progression or last follow up. The probability of OS as a function of time was estimated by the Kaplan-Meier method.

National Cancer Institute (NCI)

Principal Investigator

3.4 mg/kg siplizumab was given on day 1 of each cycle followed by etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin and rituximab (EPOCH) (combo chemo) on days 1-5 for 21 days.

Cohort 1 - 3.4 mg/kg

4.8 mg/kg siplizumab was given on day 1 of each cycle followed by etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin and rituximab (EPOCH) (combo chemo) on days 1-5 for 21 days.

Cohort 2 - 4.8 mg/kg

8.5 mg/kg siplizumab was given on day 1 of each cycle followed by etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin and rituximab (EPOCH) (combo chemo) on days 1-5 for 21 days.

Cohort 3 - 8.5 mg/kg

15 mg/kg siplizumab was given on day 1 of each cycle followed by etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin and rituximab (EPOCH) (combo chemo) on days 1-5 for 21 days.

Cohort 4 - 15 mg/kg

Total

Age, Categorical

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

United States

Region of Enrollment

PTCL, NOS

EATL

CGDTCL

ATL: Adult T-cell leukemia/lymphoma; PTCL: peripheral T-cell lymphoma not-otherwise specified; EATL: enteropathy-associated T-cell lymphoma; CGDTCL: cutaneous gamma/delta T-cell lymphoma.

Disease Status

Dr. Wyndham Wilson

Number of Participants With Serious and Non-serious Adverse Events

All participants who received 3.4 mg/kg, 4.8 mg/kg, 8.5 mg/kg and 15 mg/kg siplizumab given on day 1 of each cycle followed by etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin and rituximab (EPOCH) (combo chemo) on days 1-5 for 21 days.

All Participants

Maximum Tolerated Dose (MTD) of Siplizumab

Complete Remission

Complete Response Unconfirmed

Partial Response

Relapsed Disease

Progressive Disease

Stable Disease

Not Evaluable

Number of Participants With a Response to Therapy

Data collected from participants receiving different dose levels were combined and analyzed as a single Arm/Group as pre-specified in the study protocol.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Phase 1 Trial of Siplizumab and Dose-Adjusted EPOCH-Rituximab in T- and NK-Cell Lymphomas	NCT01445535	T-Cell Peripher... Gamma Delta Hep... Subcutaneous Pa... NK T-Cell Lymph...	Rituximab Etoposide Siplizumab Prednisone Vincristine Cyclophosphamid... Doxorubicin	18 Years - 120 Years	National Institutes of Health Clinical Center (CC)
Phase 1 Trial of Siplizumab and Dose-Adjusted EPOCH-Rituximab in T- and NK-Cell Lymphomas	NCT01445535	T-Cell Peripher... Gamma Delta Hep... Subcutaneous Pa... NK T-Cell Lymph...	Rituximab Etoposide Siplizumab Prednisone Vincristine Cyclophosphamid... Doxorubicin	18 Years - 120 Years	National Institutes of Health Clinical Center (CC)

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