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

Adult T Cell Leukemia Clinical Trial

Official title:

Phase II Study of Therapy With IMTOX-25 in Adults With Refractory/Relapsed Cd25 Positive Adult T Cell Leukemia/Lymphoma

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT01378871
• Other study ID #: 2009-530
• Status: Terminated
• Phase: Phase 2
• Start date: September 2010
• Est. completion date: January 2013

Study information

• Verified date: May 2023
• Source: Albert Einstein College of Medicine
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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).

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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 1
• Est. completion date: January 2013
• Est. primary completion date: January 2013
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Adult T Cell Leukemia
• Adult T Cell Lymphoma
• Leukemia
• Leukemia, T-Cell
• Leukemia-Lymphoma, Adult T-Cell
• Lymphoma

Intervention

Drug:
• IMTOX-25
This agent is supplied as a sterile solution at 0.5 mg/ml. Thus a vial with 5 mL contains 2.5 mg IMTOX-25 IMTOX-25 is an immunotoxin. It is an antibody that is bound to a piece of the poison ricin. This antibody have been shown to bind to leukemia cells and kill them because of the ricin. 15 mg/m²/cycle IV. The calculated total dose for the cycle will be divided by four and given on Days 1, 3, 5 and 7.

Locations

Country	Name	City	State
United States	Albert Einstein Cancer Center	Bronx	New York
United States	Albert Einstein Cancer Center at Albert Einstein College of Medicine	Bronx	New York
United States	Albert Einstein Clinical Cancer Center	Bronx	New York
United States	Albert Einstein Comprehensive Cancer Center	Bronx	New York
United States	Montefiore Medical Center	Bronx	New York
United States	Montefiore Medical Center	Bronx	New York
United States	Montefiore Medical Center-	Bronx	New York

Sponsors (1)

Lead Sponsor	Collaborator
Amit Verma

Country where clinical trial is conducted

United States, 

References & Publications (12)

Amrolia PJ, Mucioli-Casadei G, Huls H, Heslop HE, Schindler J, Veys P, Vitetta ES, Brenner MK. Add-back of allodepleted donor T cells to improve immune reconstitution after haplo-identical stem cell transplantation. Cytotherapy. 2005;7(2):116-25. doi: 10.1080/14653240510018181. — View Citation

Barth S, Schnell R, Diehl V, Engert A. Development of immunotoxins for potential clinical use in Hodgkin's disease. Ann Oncol. 1996;7 Suppl 4:135-41. doi: 10.1093/annonc/7.suppl_4.s135. — View Citation

Engert A, Diehl V, Schnell R, Radszuhn A, Hatwig MT, Drillich S, Schon G, Bohlen H, Tesch H, Hansmann ML, Barth S, Schindler J, Ghetie V, Uhr J, Vitetta E. A phase-I study of an anti-CD25 ricin A-chain immunotoxin (RFT5-SMPT-dgA) in patients with refractory Hodgkin's lymphoma. Blood. 1997 Jan 15;89(2):403-10. — View Citation

Ghetie V, Ghetie MA, Uhr JW, Vitetta ES. Large scale preparation of immunotoxins constructed with the Fab' fragment of IgG1 murine monoclonal antibodies and chemically deglycosylated ricin A chain. J Immunol Methods. 1988 Sep 13;112(2):267-77. doi: 10.1016/0022-1759(88)90367-5. — View Citation

Gill PS, Harrington W Jr, Kaplan MH, Ribeiro RC, Bennett JM, Liebman HA, Bernstein-Singer M, Espina BM, Cabral L, Allen S, et al. Treatment of adult T-cell leukemia-lymphoma with a combination of interferon alfa and zidovudine. N Engl J Med. 1995 Jun 29;332(26):1744-8. doi: 10.1056/NEJM199506293322603. — View Citation

Martin PJ, Pei J, Gooley T, Anasetti C, Appelbaum FR, Deeg J, Hansen JA, Nash RA, Petersdorf EW, Storb R, Ghetie V, Schindler J, Vitetta ES. Evaluation of a CD25-specific immunotoxin for prevention of graft-versus-host disease after unrelated marrow transplantation. Biol Blood Marrow Transplant. 2004 Aug;10(8):552-60. doi: 10.1016/j.bbmt.2004.04.002. — View Citation

Schnell R, Vitetta E, Schindler J, Borchmann P, Barth S, Ghetie V, Hell K, Drillich S, Diehl V, Engert A. Treatment of refractory Hodgkin's lymphoma patients with an anti-CD25 ricin A-chain immunotoxin. Leukemia. 2000 Jan;14(1):129-35. doi: 10.1038/sj.leu.2401626. — View Citation

Taylor GP, Matsuoka M. Natural history of adult T-cell leukemia/lymphoma and approaches to therapy. Oncogene. 2005 Sep 5;24(39):6047-57. doi: 10.1038/sj.onc.1208979. — View Citation

Thrush GR, Lark LR, Clinchy BC, Vitetta ES. Immunotoxins: an update. Annu Rev Immunol. 1996;14:49-71. doi: 10.1146/annurev.immunol.14.1.49. — View Citation

Waldmann TA, Goldman CK, Bongiovanni KF, Sharrow SO, Davey MP, Cease KB, Greenberg SJ, Longo DL. Therapy of patients with human T-cell lymphotrophic virus I-induced adult T-cell leukemia with anti-Tac, a monoclonal antibody to the receptor for interleukin-2. Blood. 1988 Nov;72(5):1805-16. — View Citation

Waldmann TA, White JD, Goldman CK, Top L, Grant A, Bamford R, Roessler E, Horak ID, Zaknoen S, Kasten-Sportes C, et al. The interleukin-2 receptor: a target for monoclonal antibody treatment of human T-cell lymphotrophic virus I-induced adult T-cell leukemia. Blood. 1993 Sep 15;82(6):1701-12. — View Citation

Winkler U, Gottstein C, Schon G, Kapp U, Wolf J, Hansmann ML, Bohlen H, Thorpe P, Diehl V, Engert A. Successful treatment of disseminated human Hodgkin's disease in SCID mice with deglycosylated ricin A-chain immunotoxins. Blood. 1994 Jan 15;83(2):466-75. — View Citation

* Note: There are 12 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Overall Response of Imtox-25	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	28 days
Secondary	Toxicity and Affect of Treatment	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	28 days +