Brief Summary
This clinical trial will be a multicenter phase II fixed-dose trial in which a minimum of 10 patients with immunophenotypically confirmed ATL with at least 50% of the blasts expressing CD25 as measured by flow cytometry at relapse, will receive Imtox-25. Patients are eligible for repeat courses of treatment every two weeks if they do not experience a dose limiting toxicity (DLT) as defined in Section 5.2 and do not have a HAMA/HARA level \> 1 μg/ml. The treatment will be administered in the in-patient setting. If no response is observed among the initial 9 patients, the study would be terminated early and declared negative; if at least one response is observed, accrual would continue to a total of 17 evaluable patients (total study size=19 to account for 10% of the patients being unevaluable for any reason).
Brief Title
A Phase II Study Of Imtox-25 In Adults With Refractory/Relapsed Cd25 Positive Adult T Cell Leukemia/Lymphoma
Detailed Description
Adult T Cell Leukemia/Lymphoma (ATL) is a lymphoproliferative disease associated with HTLV-1 infection, characterized by circulating malignant cells expressing the IL-2 receptor (CD25). Prognosis for patients with ATL remains poor despite advances in chemotherapy, with survival in leukemic patients ranging from six months to less than one year. Novel agents that are potent and specific for the tumor cells are urgently needed to improve overall survival and decrease toxicity in this dismal disease. One therapeutic approach would be to use immunotoxins (ITs). ITs utilize a potent toxin linked to a targeting moiety designed to maximize drug delivery to the tumor cells, thus avoiding the nonspecific toxicity of conventional chemotherapeutic agents. Imtox-25 is constructed using the RFT5 murine monoclonal antibody (Mab) coupled to deglycosylated ricin-A chain (dgA) via the heterobifunctional, thiol-containing crosslinker, 4\[(succinimidyloxy) carbonyl\]-ƒÑ-methyl-ƒÑ-(2 pyridyldithio) toluene (SMPT). Phase I and II clinical studies with Imtox-25 (RFT5.dGA) have been shown safety and efficacy in adult patients with Hodgkin¡¦s disease and a recommended Phase II dose has been established.. In vitro experiments using ATL cell lines and in vivo studies in a murine xenograft model have demonstrated significant activity of Imtox-25 in this disease. Based on these results, the investigators propose to conduct a phase II trial utilizing Imtox-25 in adults with relapsed or refractory ATL.
Categories
Completion Date
Completion Date Type
Actual
Conditions
Adult T Cell Leukemia
Adult T Cell Lymphoma
Eligibility Criteria
Inclusion Criteria:
* Age \> 17 years inclusive at the time of original diagnosis of HTLV-1 associated ATL.
* Histologic verification of ATL and HTLV-1 sero-positivity at diagnosis and either evidence of relapse/refractory disease based on a Bone Marrow/Peripheral Blood examination or evidence by flow cytometry.
* Disease refractory to conventional CHOP based therapy or transplantation or deemed ineligible for salvage by transplantation.
* Presence of CD25 on at least 50% of the lymphoblasts obtained via BMA or peripheral blood as determined by flow cytometry.
* ECOG performance status 2.
* Life expectancy of \> 2 months.
* Patients must have recovered from effects of prior therapy. At least 2 weeks should have elapsed since the last dose of chemotherapy (4 weeks in the case of nitrosourea-containing therapy). Steroids are considered as chemotherapy. However, if the patient has recovered from the side effects of prior therapy and has had a \> 50% rise in peripheral blast count, they are immediately eligible. The 50% rise in peripheral blast count must be calculated as follows. The sample for the baseline peripheral blast count must have been taken at least 24 hours after the end of chemotherapy. The sample for the peripheral blast count that is increased by 50% of the baseline peripheral blast count may be taken at any subsequent time. A second peripheral blast count confirming the 50% rise is recommended.
* No hematopoietic limitations as patients with relapsed leukemia routinely have pancytopenia and ITs have not demonstrated hematopoietic toxicity.
* Adequate renal function defined as a serum creatinine 1.5 x normal range.
* Adequate liver function defined as a total bilirubin 1.5 x normal range and SGOT (AST) or SGPT (ALT) 1.5 x normal range.
* Adequate cardiac function defined as a shortening fraction of 27% by echocardiogram, or ejection fraction of 35-40% by MUGA scan.
* Adequate pulmonary function defined as no evidence of dyspnea at rest.
* Normal neurological exam.
* Patient and/or legal guardian must sign a written informed consent.
* All institutional, FDA, and NCI requirements for human studies must be met.
Exclusion Criteria:
* Presence of leukemic or infectious pulmonary parenchymal disease or presence of a pulmonary effusion by chest x-ray.
* Presence of CNS involvement with leukemia.
* History of documented seizure disorder or abnormal neurological examination.
* Human anti-mouse (HAMA) levels of \< 1 μg/ml.
* Age \> 17 years inclusive at the time of original diagnosis of HTLV-1 associated ATL.
* Histologic verification of ATL and HTLV-1 sero-positivity at diagnosis and either evidence of relapse/refractory disease based on a Bone Marrow/Peripheral Blood examination or evidence by flow cytometry.
* Disease refractory to conventional CHOP based therapy or transplantation or deemed ineligible for salvage by transplantation.
* Presence of CD25 on at least 50% of the lymphoblasts obtained via BMA or peripheral blood as determined by flow cytometry.
* ECOG performance status 2.
* Life expectancy of \> 2 months.
* Patients must have recovered from effects of prior therapy. At least 2 weeks should have elapsed since the last dose of chemotherapy (4 weeks in the case of nitrosourea-containing therapy). Steroids are considered as chemotherapy. However, if the patient has recovered from the side effects of prior therapy and has had a \> 50% rise in peripheral blast count, they are immediately eligible. The 50% rise in peripheral blast count must be calculated as follows. The sample for the baseline peripheral blast count must have been taken at least 24 hours after the end of chemotherapy. The sample for the peripheral blast count that is increased by 50% of the baseline peripheral blast count may be taken at any subsequent time. A second peripheral blast count confirming the 50% rise is recommended.
* No hematopoietic limitations as patients with relapsed leukemia routinely have pancytopenia and ITs have not demonstrated hematopoietic toxicity.
* Adequate renal function defined as a serum creatinine 1.5 x normal range.
* Adequate liver function defined as a total bilirubin 1.5 x normal range and SGOT (AST) or SGPT (ALT) 1.5 x normal range.
* Adequate cardiac function defined as a shortening fraction of 27% by echocardiogram, or ejection fraction of 35-40% by MUGA scan.
* Adequate pulmonary function defined as no evidence of dyspnea at rest.
* Normal neurological exam.
* Patient and/or legal guardian must sign a written informed consent.
* All institutional, FDA, and NCI requirements for human studies must be met.
Exclusion Criteria:
* Presence of leukemic or infectious pulmonary parenchymal disease or presence of a pulmonary effusion by chest x-ray.
* Presence of CNS involvement with leukemia.
* History of documented seizure disorder or abnormal neurological examination.
* Human anti-mouse (HAMA) levels of \< 1 μg/ml.
Inclusion Criteria
Inclusion Criteria:
* Age \> 17 years inclusive at the time of original diagnosis of HTLV-1 associated ATL.
* Histologic verification of ATL and HTLV-1 sero-positivity at diagnosis and either evidence of relapse/refractory disease based on a Bone Marrow/Peripheral Blood examination or evidence by flow cytometry.
* Disease refractory to conventional CHOP based therapy or transplantation or deemed ineligible for salvage by transplantation.
* Presence of CD25 on at least 50% of the lymphoblasts obtained via BMA or peripheral blood as determined by flow cytometry.
* ECOG performance status 2.
* Life expectancy of \> 2 months.
* Patients must have recovered from effects of prior therapy. At least 2 weeks should have elapsed since the last dose of chemotherapy (4 weeks in the case of nitrosourea-containing therapy). Steroids are considered as chemotherapy. However, if the patient has recovered from the side effects of prior therapy and has had a \> 50% rise in peripheral blast count, they are immediately eligible. The 50% rise in peripheral blast count must be calculated as follows. The sample for the baseline peripheral blast count must have been taken at least 24 hours after the end of chemotherapy. The sample for the peripheral blast count that is increased by 50% of the baseline peripheral blast count may be taken at any subsequent time. A second peripheral blast count confirming the 50% rise is recommended.
* No hematopoietic limitations as patients with relapsed leukemia routinely have pancytopenia and ITs have not demonstrated hematopoietic toxicity.
* Adequate renal function defined as a serum creatinine 1.5 x normal range.
* Adequate liver function defined as a total bilirubin 1.5 x normal range and SGOT (AST) or SGPT (ALT) 1.5 x normal range.
* Adequate cardiac function defined as a shortening fraction of 27% by echocardiogram, or ejection fraction of 35-40% by MUGA scan.
* Adequate pulmonary function defined as no evidence of dyspnea at rest.
* Normal neurological exam.
* Patient and/or legal guardian must sign a written informed consent.
* All institutional, FDA, and NCI requirements for human studies must be met.
* Age \> 17 years inclusive at the time of original diagnosis of HTLV-1 associated ATL.
* Histologic verification of ATL and HTLV-1 sero-positivity at diagnosis and either evidence of relapse/refractory disease based on a Bone Marrow/Peripheral Blood examination or evidence by flow cytometry.
* Disease refractory to conventional CHOP based therapy or transplantation or deemed ineligible for salvage by transplantation.
* Presence of CD25 on at least 50% of the lymphoblasts obtained via BMA or peripheral blood as determined by flow cytometry.
* ECOG performance status 2.
* Life expectancy of \> 2 months.
* Patients must have recovered from effects of prior therapy. At least 2 weeks should have elapsed since the last dose of chemotherapy (4 weeks in the case of nitrosourea-containing therapy). Steroids are considered as chemotherapy. However, if the patient has recovered from the side effects of prior therapy and has had a \> 50% rise in peripheral blast count, they are immediately eligible. The 50% rise in peripheral blast count must be calculated as follows. The sample for the baseline peripheral blast count must have been taken at least 24 hours after the end of chemotherapy. The sample for the peripheral blast count that is increased by 50% of the baseline peripheral blast count may be taken at any subsequent time. A second peripheral blast count confirming the 50% rise is recommended.
* No hematopoietic limitations as patients with relapsed leukemia routinely have pancytopenia and ITs have not demonstrated hematopoietic toxicity.
* Adequate renal function defined as a serum creatinine 1.5 x normal range.
* Adequate liver function defined as a total bilirubin 1.5 x normal range and SGOT (AST) or SGPT (ALT) 1.5 x normal range.
* Adequate cardiac function defined as a shortening fraction of 27% by echocardiogram, or ejection fraction of 35-40% by MUGA scan.
* Adequate pulmonary function defined as no evidence of dyspnea at rest.
* Normal neurological exam.
* Patient and/or legal guardian must sign a written informed consent.
* All institutional, FDA, and NCI requirements for human studies must be met.
Gender
All
Gender Based
false
Keywords
T Cell
T-Cell
Leukemia
Lymphoma
Leukemia/Lymphoma
ATL
Healthy Volunteers
No
Last Update Post Date
Last Update Post Date Type
Actual
Last Update Submit Date
Minimum Age
18 Years
NCT Id
NCT01378871
Org Class
Other
Org Full Name
Albert Einstein College of Medicine
Org Study Id
2009-530
Overall Status
Terminated
Phases
Phase 2
Primary Completion Date
Primary Completion Date Type
Actual
Official Title
Phase II Study of Therapy With IMTOX-25 in Adults With Refractory/Relapsed Cd25 Positive Adult T Cell Leukemia/Lymphoma
Primary Outcomes
Outcome Description
To determine any anti-tumor activity of Imtox-25 in relapsed/refractory ATL patients within the confines of a Phase II study as defined by overall response
Outcome Measure
Overall Response of Imtox-25
Outcome Time Frame
28 days
Secondary Outcomes
Outcome Description
To determine the toxicity of Imtox-25 in ATL patients To measure levels of human anti-mouse (HAMA) and human anti-dgA (HARA) antibodies.
To determine whether the expression of the CD25 cell surface antigens is affected by treatment with Imtox-25 using flow cytometric analysis of lymphoblasts in peripheral blood and bone marrow
To determine whether the expression of the CD25 cell surface antigens is affected by treatment with Imtox-25 using flow cytometric analysis of lymphoblasts in peripheral blood and bone marrow
Outcome Time Frame
28 days +
Outcome Measure
Toxicity and Affect of Treatment
Start Date
Status Verified Date
First Post Date
First Post Date Type
Estimated
First Submit Date
First Submit QC Date
Std Ages
Adult
Older Adult
Maximum Age Number (converted to Years and rounded down)
999
Minimum Age Number (converted to Years and rounded down)
18
Investigators
Investigator Type
Principal Investigator
Investigator Name
Samir Parekh
Investigator Email
Investigator Phone