EPOCH Chemotherapy and Bortezomib for Associated T-Cell Leukemia Lymphoma (ATLL)

This study is ongoing, but not recruiting participants.
Sponsor:
Information provided by (Responsible Party):
Washington University School of Medicine
ClinicalTrials.gov Identifier:
NCT01000285
First received: October 19, 2009
Last updated: July 8, 2014
Last verified: July 2014
  Purpose

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.


Condition Intervention Phase
Leukemia-Lymphoma, Adult T-Cell
Drug: Bortezomib
Drug: Etoposide
Drug: Vincristine
Drug: Doxorubicin
Drug: Prednisone
Drug: Cyclophosphamide
Drug: Raltegravir
Phase 1
Phase 2

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

Resource links provided by NLM:


Further study details as provided by Washington University School of Medicine:

Primary Outcome Measures:
  • To determine the tolerability and efficacy of dose adjusted bortezomib-EPOCH (DA B-EPOCH) chemotherapy combined with Raltegravir in ATLL patients [ Time Frame: 6 months ] [ Designated as safety issue: Yes ]
    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.


Secondary Outcome Measures:
  • To determine the duration of response of DA B-EPOCH chemotherapy combined with Raltegravir for HTLV-1 associated leukemia/lymphoma (ATLL [ Time Frame: Up to 4 years following completion of therapy ] [ Designated as safety issue: No ]
  • 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. [ Time Frame: 6 months ] [ Designated as safety issue: No ]
  • To evaluate the relation of NFκB gene expression profile on response to DA B-EPOCH chemotherapy combined with Raltegravir. [ Time Frame: 6 months ] [ Designated as safety issue: No ]

Enrollment: 18
Study Start Date: September 2010
Estimated Study Completion Date: April 2018
Primary Completion Date: May 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Arm 1

Bortezomib 1.0 mg/m2 IV Days 1-4

Etoposide 50 mg/m2/d 96 hour 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 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
Other Name: Velcade®
Drug: Etoposide
Other Name: Toposar®, VePesid®, Etopophos®
Drug: Vincristine
Other Name: Oncovin ®, Vincasar Pfs ®
Drug: Doxorubicin
Other Name: Adriamycin ®, Rubex ®
Drug: Prednisone
Other Name: Deltasone®, Liquid Pred®, Meticorten®, Orasone®
Drug: Cyclophosphamide
Other Name: Cytoxan ®, Neosar ®
Drug: Raltegravir
Other Name: Isentress®

Detailed 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.
  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01000285

Locations
United States, Florida
University of Miami Hospital/Sylvester
Miami, Florida, United States, 33136
United States, Maryland
Johns Hopkins University
Baltimore, Maryland, United States, 21231
United States, Missouri
Washington University School of Medicine
St. Louis, Missouri, United States, 63110
United States, New York
Montefiore Medical Center
Bronx, New York, United States, 10467
Columbia University, College of Physicians and Surgeons
New York, New York, United States, 10032
Memorial Sloan Kettering Cancer Center
New York, New York, United States, 10065
Sponsors and Collaborators
Washington University School of Medicine
Investigators
Principal Investigator: Lee Ratner, M.D., Ph.D. Washington University School of Medicine
  More Information

Additional Information:
Publications:
Responsible Party: Washington University School of Medicine
ClinicalTrials.gov Identifier: NCT01000285     History of Changes
Other Study ID Numbers: 09-1758 / 201108212
Study First Received: October 19, 2009
Last Updated: July 8, 2014
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Leukemia
Leukemia, T-Cell
Leukemia-Lymphoma, Adult T-Cell
Lymphoma
Neoplasms by Histologic Type
Neoplasms
Leukemia, Lymphoid
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Cyclophosphamide
Etoposide phosphate
Bortezomib
Doxorubicin
Etoposide
Prednisone
Vincristine
Integrase Inhibitors
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Pharmacologic Actions
Antirheumatic Agents
Therapeutic Uses
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists

ClinicalTrials.gov processed this record on July 22, 2014