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

Study Overview
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Brief Summary
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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
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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.

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

Conditions
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T-Cell Peripheral Lymphoma, Gamma Delta Hepatosplenic T-Cell Lymphoma, Subcutaneous Panniculitis-Like T-Cell Lymphoma, NK T-Cell Lymphoma

Intervention / Treatment
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* Biological: Rituximab
* Drug: Etoposide
* Biological: Siplizumab
* Drug: Prednisone
* Drug: Vincristine
* Drug: Cyclophosphamide
* Drug: Doxorubicin


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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 120 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: siplizumab + EPOCH (combo chemo) + rituximab<br>siplizumab will be given with EPOCH (combo chemo) and rituximab every 21 days | Biological: Rituximab<br>* Rituximab will be given with siplizumab and etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin every 21 days<br>* Other names: Rituxan;Drug: Etoposide<br>* Etoposide will be given with siplizumab and prednisone, vincristine, cyclophosphamide, doxorubicin and rituximab every 21 days<br>* Other names: Toposar;Biological: Siplizumab<br>* Siplizumab will be given with etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin and rituximab every 21 days<br>* Other names: MEDI-507;Drug: Prednisone<br>* Prednisone will be given with siplizumab and etoposide, vincristine, cyclophosphamide, doxorubicin and rituximab every 21 days<br>* Other names: Deltasone;Drug: Vincristine<br>* Vincristine will be given with siplizumab and etoposide, prednisone, cyclophosphamide, doxorubicin and rituximab every 21 days<br>* Other names: Marqibo;Drug: Cyclophosphamide<br>* Cyclophosphamide will be given with siplizumab and etoposide, prednisone, vincristine, doxorubicin and rituximab every 21 days<br>* Other names: Cytoxan;Drug: Doxorubicin<br>* Doxorubicin will be given with siplizumab and etoposide, prednisone, cyclophosphamide and rituximab every 21 days<br>* Other names: Doxil;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Serious and Non-serious Adverse Events | 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. | Date treatment consent signed until 30 days after removal from study treatment or until off study, whichever comes first, approximately 22 weeks. | 
| Maximum Tolerated Dose (MTD) of Siplizumab | 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. | First 30 days after treatment initiation. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With a Response to Therapy | 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. | Response assessments were performed after the fourth and sixth cycle of therapy, at therapy completion, and every 3 months for year 1, four months for year 2, 6 months for years 3-5, and annually thereafter, up to 5 years. | 
| Overall Progression Free Survival (PFS) | 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. | On-study date until date of progression or last follow up, approximately 7 months. | 
| Overall Survival (OS) | 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. | On study date until date of death or last follow up, approximately 12 months. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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CD2 Positive, Toxicity, EBV Lymphoma, Chemotherapy Naive, Maximum Tolerated Dose, Lymphoma, T-Cell Lymphoma, NK T-Cell Lymphoma