EPOCH Chemotherapy and Bortezomib for Associated T-Cell Leukemia Lymphoma

NCT01000285 | Completed Phase 1 Results DMC

• 1 other identifier: 09-1758 / 201108212
• Study Type: interventional
• Target: 18
• Locations: 1 country
• Sites: 6

Brief 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.

Conditions

Leukemia-Lymphoma, Adult T-Cell

Outcome Measures

Primary Outcomes (2)

• Tolerability of Treatment as Measured by Number of Participants With Grade 3 or Higher Adverse Events

  The descriptions and grading scales found in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 3.0 will be utilized for all toxicity reporting.

  Up to 30 days after completion of treatment

• Efficacy of Treatment as Measured by Best Overall Response

  -The response definitions used for this study are the 2007 Cheson criteria.

  Up to 4 years following completion of therapy

Secondary Outcomes (6)

• Time to Progression

  Up to 4 years following completion of therapy

• Effects of on HTLV-1 DNA After Treatment as Measured by Proviral Loads

  6 months

• Relation of NFκB Gene Expression Profile on Response

  6 months

• Effects of HTLV-1 RNA Load After Treatment as Measured by Hbz Messenger RNA

  6 months

• Effects of HTLV-1 Integrase Gene Sequence After Treatment as Measured by Nucleotide Divergence

  6 months

Study Arms (1)

Arm 1

EXPERIMENTAL

Bortezomib 1.0 mg/m2 intravenous (IV) Days 1-4 Etoposide 50 mg/m2/d 96 hour continuous intravenous infusion (CIVI) on Days 1-4 Vincristine 0.4 mg/m2/d 96 hour CIVI on Days 1-4 Doxorubicin 10 mg/m2/d 96 hour CIVI on Days 1-4 Prednisone 60 mg/m2/d PO on Days 1-5 Cyclophosphamide 375 mg/m2 IV on Day 5 Raltegravir 400 mg PO twice per day (BID) every day starting with cycle 2 therapy for the entire duration of the cycle. Cycles will be repeated every 21-28 days for 2 cycles beyond best response, or a maximum of 6 cycles.

Drug: Bortezomib; Drug: Etoposide; Drug: Vincristine; Drug: Doxorubicin; Drug: Prednisone; Drug: Cyclophosphamide; Drug: Raltegravir

Interventions

Bortezomib DRUG

Also known as: Velcade®

Arm 1

Etoposide DRUG

Also known as: Toposar®, VePesid®, Etopophos®

Arm 1

Vincristine DRUG

Also known as: Oncovin ®, Vincasar Pfs ®

Arm 1

Doxorubicin DRUG

Also known as: Adriamycin ®, Rubex ®

Arm 1

Prednisone DRUG

Also known as: Deltasone®, Liquid Pred®, Meticorten®, Orasone®

Arm 1

Cyclophosphamide DRUG

Also known as: Cytoxan ®, Neosar ®

Arm 1

Raltegravir DRUG

Also known as: Isentress®

Arm 1

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.
• Karnofsky Performance Status (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 hepatitis B (HBV) infection are eligible if they are receiving effective anti-HBV therapy.

You may not qualify if:

• 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, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities. Prior to study entry, any electrocardiogram (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.
• x upper limit of normal (ULN) total bilirubin except if is determined to be related to Gilbert's disease or tumor biliary/liver involvement.

Sponsors & Collaborators

• Washington University School of Medicine: lead

Study Sites (6)

University of Miami Hospital/Sylvester

Miami, Florida, 33136, United States

Location

Johns Hopkins University

Baltimore, Maryland, 21231, United States

Location

Washington University School of Medicine

St Louis, Missouri, 63110, United States

Location

Columbia University, College of Physicians and Surgeons

New York, New York, 10032, United States

Location

Memorial Sloan Kettering Cancer Center

New York, New York, 10065, United States

Location

Montefiore Medical Center

The Bronx, New York, 10467, United States

Location

Related Publications (4)

• 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.

  PMID: 19204798 BACKGROUND

• 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. doi: 10.1038/sj.leu.2403400.

  PMID: 15190257 BACKGROUND

• 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. doi: 10.1182/blood-2003-11-3967. Epub 2004 Apr 15.

  PMID: 15090453 BACKGROUND

• 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.

  PMID: 19064971 BACKGROUND

Related Links

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

MeSH Terms

Conditions

Leukemia-Lymphoma, Adult T-Cell

Interventions

Bortezomib; Etoposide; etoposide phosphate; Vincristine; Doxorubicin; Prednisone; Cyclophosphamide; Raltegravir Potassium

Condition Hierarchy (Ancestors)

Leukemia, T-Cell; Leukemia, Lymphoid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases

Intervention Hierarchy (Ancestors)

Boronic Acids; Acids, Noncarboxylic; Acids; Inorganic Chemicals; Boron Compounds; Organic Chemicals; Pyrazines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Podophyllotoxin; Tetrahydronaphthalenes; Naphthalenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Polycyclic Compounds; Glucosides; Glycosides; Carbohydrates; Vinca Alkaloids; Secologanin Tryptamine Alkaloids; Indole Alkaloids; Alkaloids; Indoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Indolizidines; Indolizines; Daunorubicin; Anthracyclines; Naphthacenes; Aminoglycosides; Pregnadienediols; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Phosphoramides; Organophosphorus Compounds; Pyrrolidinones; Pyrrolidines

Results Point of Contact

• Title: Lee Ratner, M.D., Ph.D.
• Organization: Washington University School of Medicine

lratner@dom.wustl.edu

314-362-8836

Study Officials

• Lee Ratner, M.D., Ph.D.

  Washington University School of Medicine

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 19, 2009
• First Posted: October 23, 2009
• Study Start: September 1, 2010
• Primary Completion: May 1, 2014
• Study Completion: April 1, 2016
• Last Updated: March 28, 2017
• Results First Posted: December 13, 2016

Record last verified: 2017-02

Locations

US (6)