Back to resultsPhase 1 Trial of Siplizumab and Dose-Adjusted EPOCH-Rituximab in T- and NK-Cell Lymphomas
Primary Purpose
T-Cell Peripheral Lymphoma, Gamma Delta Hepatosplenic T-Cell Lymphoma, Subcutaneous Panniculitis-Like T-Cell Lymphoma
Status
Completed
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
Rituximab
Etoposide
Siplizumab
Prednisone
Vincristine
Cyclophosphamide
Doxorubicin
Sponsored by
About this trial
This is an interventional treatment trial for T-Cell Peripheral Lymphoma focused on measuring CD2 Positive, Toxicity, EBV Lymphoma, Chemotherapy Naive, Maximum Tolerated Dose, Lymphoma, T-Cell Lymphoma, NK T-Cell Lymphoma
Eligibility Criteria
- 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.
Sites / Locations
- National Institutes of Health Clinical Center, 9000 Rockville Pike
Arms of the Study
Arm 1
Arm Type
Experimental
Arm Label
siplizumab + EPOCH (combo chemo) + rituximab
Arm Description
siplizumab will be given with EPOCH (combo chemo) and rituximab every 21 days
Outcomes
Primary Outcome Measures
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.
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.
Secondary Outcome Measures
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.
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.
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.
Full Information
NCT ID
NCT01445535
First Posted
September 30, 2011
Last Updated
October 28, 2021
Sponsor
National Cancer Institute (NCI)
1. Study Identification
Unique Protocol Identification Number
NCT01445535
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
Study Type
Interventional
2. Study Status
Record Verification Date
October 2021
Overall Recruitment Status
Completed
Study Start Date
January 13, 2009 (Actual)
Primary Completion Date
April 1, 2011 (Actual)
Study Completion Date
October 22, 2020 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
National Cancer Institute (NCI)
4. Oversight
Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No
5. Study Description
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
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
T-Cell Peripheral Lymphoma, Gamma Delta Hepatosplenic T-Cell Lymphoma, Subcutaneous Panniculitis-Like T-Cell Lymphoma, NK T-Cell Lymphoma
Keywords
CD2 Positive, Toxicity, EBV Lymphoma, Chemotherapy Naive, Maximum Tolerated Dose, Lymphoma, T-Cell Lymphoma, NK T-Cell Lymphoma
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Sequential Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
15 (Actual)
8. Arms, Groups, and Interventions
Arm Title
siplizumab + EPOCH (combo chemo) + rituximab
Arm Type
Experimental
Arm Description
siplizumab will be given with EPOCH (combo chemo) and rituximab every 21 days
Intervention Type
Biological
Intervention Name(s)
Rituximab
Other Intervention Name(s)
Rituxan
Intervention Description
Rituximab will be given with siplizumab and etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin every 21 days
Intervention Type
Drug
Intervention Name(s)
Etoposide
Other Intervention Name(s)
Toposar
Intervention Description
Etoposide will be given with siplizumab and prednisone, vincristine, cyclophosphamide, doxorubicin and rituximab every 21 days
Intervention Type
Biological
Intervention Name(s)
Siplizumab
Other Intervention Name(s)
MEDI-507
Intervention Description
Siplizumab will be given with etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin and rituximab every 21 days
Intervention Type
Drug
Intervention Name(s)
Prednisone
Other Intervention Name(s)
Deltasone
Intervention Description
Prednisone will be given with siplizumab and etoposide, vincristine, cyclophosphamide, doxorubicin and rituximab every 21 days
Intervention Type
Drug
Intervention Name(s)
Vincristine
Other Intervention Name(s)
Marqibo
Intervention Description
Vincristine will be given with siplizumab and etoposide, prednisone, cyclophosphamide, doxorubicin and rituximab every 21 days
Intervention Type
Drug
Intervention Name(s)
Cyclophosphamide
Other Intervention Name(s)
Cytoxan
Intervention Description
Cyclophosphamide will be given with siplizumab and etoposide, prednisone, vincristine, doxorubicin and rituximab every 21 days
Intervention Type
Drug
Intervention Name(s)
Doxorubicin
Other Intervention Name(s)
Doxil
Intervention Description
Doxorubicin will be given with siplizumab and etoposide, prednisone, cyclophosphamide and rituximab every 21 days
Primary Outcome Measure Information:
Title
Number of Participants With Serious and Non-serious Adverse Events
Description
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.
Time Frame
Date treatment consent signed until 30 days after removal from study treatment or until off study, whichever comes first, approximately 22 weeks.
Title
Maximum Tolerated Dose (MTD) of Siplizumab
Description
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.
Time Frame
First 30 days after treatment initiation.
Secondary Outcome Measure Information:
Title
Number of Participants With a Response to Therapy
Description
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.
Time Frame
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.
Title
Overall Progression Free Survival (PFS)
Description
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.
Time Frame
On-study date until date of progression or last follow up, approximately 7 months.
Title
Overall Survival (OS)
Description
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.
Time Frame
On study date until date of death or last follow up, approximately 12 months.
Other Pre-specified Outcome Measures:
Title
Number of Dose-Limiting Toxicities (DLT)
Description
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.
Time Frame
First 30 days after treatment initiation.
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
120 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Wyndham H Wilson, M.D.
Organizational Affiliation
National Cancer Institute (NCI)
Official's Role
Principal Investigator
Facility Information:
Facility Name
National Institutes of Health Clinical Center, 9000 Rockville Pike
City
Bethesda
State/Province
Maryland
ZIP/Postal Code
20892
Country
United States
12. IPD Sharing Statement
Plan to Share IPD
No
Citations:
PubMed Identifier
11979093
Citation
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.
Results Reference
background
PubMed Identifier
15291365
Citation
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.
Results Reference
background
PubMed Identifier
14508366
Citation
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.
Results Reference
background
PubMed Identifier
29032710
Citation
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.
Results Reference
result
Links:
URL
https://clinicalstudies.info.nih.gov/cgi/detail.cgi?B_2009-C-0065.html
Description
NIH Clinical Center Detailed Web Page
Learn more about this trial
Phase 1 Trial of Siplizumab and Dose-Adjusted EPOCH-Rituximab in T- and NK-Cell Lymphomas
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