EPOCH Chemotherapy and Bortezomib for Associated T-Cell Leukemia Lymphoma

Leukemia-Lymphoma, Adult T-Cell Clinical Trial

— ATLL  

Official title:

Phase I/II Trial of Dose-Adjusted EPOCH Chemotherapy With Bortezomib Combined With Integrase Inhibitor Therapy for HTLV-1 Associated T-Cell Leukemia Lymphoma

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT01000285
• Other study ID #: 09-1758 / 201108212
• Status: Active, not recruiting
• Phase: Phase 1/Phase 2
• First received: October 19, 2009
• Last updated: July 8, 2014
• Start date: September 2010
• Est. completion date: April 2018

Study information

• Verified date: July 2014
• Source: Washington University School of Medicine
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial Summary

The rationale of the current study is to explore the use of combination chemotherapy together with antiretroviral agents in order to determine the efficacy and toxicity of this approach, while also examining markers of virus replication and expression, and tumor cell proliferation to gain understanding of the biological basis of this malignancy and to identify predictors of response.

Description:

Primary Endpoint:

• To determine the tolerability and efficacy (response rate) of dose adjusted bortezomib-EPOCH (DA B-EPOCH) chemotherapy combined with Raltegravir in patients with HTLV-1 associated leukemia/lymphoma (ATLL).

Secondary Endpoints:

• To evaluate the effects of DA B-EPOCH chemotherapy combined with Raltegravir on HTLV-1 DNA and RNA load, HTLV-1 integrase gene sequence, and HTLV-1 integration sites. To determine if relapsed or progressive disease is a result of renewed virus replication.

• To evaluate the relation of NFκB gene expression profile on response to DA B-EPOCH chemotherapy combined with Raltegravir.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 18
• Est. completion date: April 2018
• Est. primary completion date: May 2014
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Histologically or cytologically documented ATLL. Patients with previously untreated or treated ATLL are eligible.

• Tumors must be CD3 positive (>50% cells express CD3).

• Documented HTLV-1 infection: documentation may be serologic assay (ELISA, Western blot) Confirmation of HTLV-1 rather than HTLV-2 by differential Western blot (e.g. Genelabs Diagnostics HTLV Blot 2.4) or PCR is desirable but his result is not required prior to trial enrollment.

• Measurable disease must be present. These nodes or masses should be selected according to all of the following: they should be clearly measurable in at least two perpendicular dimensions; if possible they should be from disparate regions of the body; and they should include mediastinal and retroperitoneal areas of disease whenever these sites are involved.For patients with acute (leukemic) form of ATLL, measureable disease can be derived from CD4+ lymphocyte flow data on the peripheral blood and/or bone marrow.

• All stages are eligible.

• Adequate hematologic function within 14 days before enrollment: ANC>1000 cells/mm3, platelet count>75,000 cells/mm3 unless cytopenias are secondary to ATLL. All patients must be off hematologic growth factors for at least 24 hrs.

• Adequate hepatic function, transaminase <3 times the upper limit of normal unless due to to Gilbert's disease or hepatic involvement by tumor; total bilirubin =1.5 times the upper limit of normal

• Creatinine<2.0 unless due to lymphoma.

• KPS at least 50

• Age at least 18. -Voluntary written informed consent before performance of any study- related procedure not part of normal medical care, with the understanding that consent may be withdrawn by the subject at any time without prejudice to future medical care.

• Female patients of child bearing potential must have a negative pregnancy test within 72 hrs of initiation of therapy. Female patients are either post-menopausal or surgically sterilized or willing to use two acceptable methods of birth control (i.e., a hormonal contraceptive, intra-uterine device, diaphragm with spermicide, condom with spermicide, or abstinence) during the study. Male patients must agree to use two acceptable methods for contraception for the duration of the study. Women must avoid pregnancy and men avoid fathering children while in the study.

• HIV positive patients are eligible if they are receiving at least two other active anti-HIV therapies other than zidovudine or atazanavir.

• Patients with active HBV infection are eligible if they are receiving effective anti-HBV therapy.

• Inclusion of Women and Minorities: Both men and women and members of all races and ethnic groups are eligible for this trial.

Exclusion Criteria:

• Acute active infection requiring acute therapy. Chronic therapy with potentially myelosuppressive agents is allowed provided that entry hematologic criteria are met.

• Diagnosed or treated for another malignancy within 3 years of enrollment, with the exception of complete resection of basal cell carcinoma or squamous cell carcinoma of the skin, an in situ malignancy, or low-risk prostate cancer after curative therapy.

• Women who are pregnant or breastfeeding. Confirmation that the subject is not pregnant must be established by a negative serum B-human chorionic gonadotropin (B-hCG) pregnancy test result obtained during screening. Pregnancy testing is not required for post-menopausal or surgically sterilized women.

• Patient has =Grade 2 peripheral neuropathy

• Myocardial infarction within 6 months prior to enrollment or has New York Heart Association (NYHA) Class III or IV heart failure (see Appendix VI), uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities. Prior to study entry, any ECG abnormality at Screening has to be documented by the investigator as not medically relevant.

• Patient has hypersensitivity to bortezomib, boron or mannitol.

• Patient has received other investigational drugs with 14 days before enrollment

• Serious medical or psychiatric illness likely to interfere with participation in this clinical study.

• 1.5x ULN total bilirubin except if is determined to be related to Gilbert's disease or tumor biliary/liver involvement.

Study Design

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

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

Intervention

Drug:
• Bortezomib

• Etoposide

• Vincristine

• Doxorubicin

• Prednisone

• Cyclophosphamide

• Raltegravir

Locations

Country	Name	City	State
United States	Johns Hopkins University	Baltimore	Maryland
United States	Montefiore Medical Center	Bronx	New York
United States	University of Miami Hospital/Sylvester	Miami	Florida
United States	Columbia University, College of Physicians and Surgeons	New York	New York
United States	Memorial Sloan Kettering Cancer Center	New York	New York
United States	Washington University School of Medicine	St. Louis	Missouri

Sponsors (1)

Lead Sponsor	Collaborator
Washington University School of Medicine

Country where clinical trial is conducted

United States, 

References & Publications (4)

Mitra-Kaushik S, Harding JC, Hess JL, Ratner L. Effects of the proteasome inhibitor PS-341 on tumor growth in HTLV-1 Tax transgenic mice and Tax tumor transplants. Blood. 2004 Aug 1;104(3):802-9. Epub 2004 Apr 15. — View Citation

Ratner L, Harrington W, Feng X, Grant C, Jacobson S, Noy A, Sparano J, Lee J, Ambinder R, Campbell N, Lairmore M; AIDS Malignancy Consortium. Human T cell leukemia virus reactivation with progression of adult T-cell leukemia-lymphoma. PLoS One. 2009;4(2):e4420. doi: 10.1371/journal.pone.0004420. Epub 2009 Feb 10. — View Citation

Satou Y, Nosaka K, Koya Y, Yasunaga JI, Toyokuni S, Matsuoka M. Proteasome inhibitor, bortezomib, potently inhibits the growth of adult T-cell leukemia cells both in vivo and in vitro. Leukemia. 2004 Aug;18(8):1357-63. — View Citation

Tsukasaki K, Hermine O, Bazarbachi A, Ratner L, Ramos JC, Harrington W Jr, O'Mahony D, Janik JE, Bittencourt AL, Taylor GP, Yamaguchi K, Utsunomiya A, Tobinai K, Watanabe T. Definition, prognostic factors, treatment, and response criteria of adult T-cell leukemia-lymphoma: a proposal from an international consensus meeting. J Clin Oncol. 2009 Jan 20;27(3):453-9. doi: 10.1200/JCO.2008.18.2428. Epub 2008 Dec 8. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	To determine the tolerability and efficacy of dose adjusted bortezomib-EPOCH (DA B-EPOCH) chemotherapy combined with Raltegravir in ATLL patients	A sequential probability ratio test will be used to monitor the frequency of patients who fail to complete 2 cycles of chemo-antiviral therapy due to toxicity.	6 months	Yes
Secondary	To determine the duration of response of DA B-EPOCH chemotherapy combined with Raltegravir for HTLV-1 associated leukemia/lymphoma (ATLL		Up to 4 years following completion of therapy	No
Secondary	To evaluate the effects of DA B-EPOCH chemo combined with Raltegravir on HTLV-1 DNA and RNA load, HTLV-1 integrase gene sequence, and HTLV-1 integration sites. To determine if relapsed or progressive disease is a result of renewed virus replication.		6 months	No
Secondary	To evaluate the relation of NF?B gene expression profile on response to DA B-EPOCH chemotherapy combined with Raltegravir.		6 months	No

External Links

•   Alvin J. Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine