A Phase II Study Of Imtox-25 In Adults With Refractory/Relapsed Cd25 Positive Adult T Cell Leukemia/Lymphoma

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]-Ą-methyl-Ą-(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.

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.