Now Available for Public Comment: Notice of Proposed Rulemaking (NPRM) for FDAAA 801 and NIH Draft Reporting Policy for NIH-Funded Trials

The Addition of Temozolomide to Conditioning for Autologous Transplantation in Relapsed & Refractory Central Nervous System (CNS) Lymphoma (DRBEAT)

This study is currently recruiting participants. (see Contacts and Locations)
Verified November 2014 by Cedars-Sinai Medical Center
Sponsor:
Information provided by (Responsible Party):
Michael Lill, Cedars-Sinai Medical Center
ClinicalTrials.gov Identifier:
NCT01235793
First received: November 5, 2010
Last updated: November 12, 2014
Last verified: November 2014
  Purpose

Currently there is no standard of care for relapsed or refractory primary central nervous system (CNS) lymphoma. After high-dose methotrexate or radiation therapy, the best approach to relapsed disease is undefined. Common practice is the regimen RBEAM as a conditioning regimen in this patient population prior to transplantation. The RBEAM regimen includes R (rituximab), B (BCNU), E (etoposide), A (Ara-C (cytarabine)) and M (melphalan). In addition, dexamethasone is included in the regimen although not noted in the RBEAM mnemonic. However, the melphalan used in this combination is not thought to have much CNS penetration. Therefore, temozolomide, an alkylating agent known to penetrate the CNS and approved by the FDA for brain tumors will be used and evaluated in this study instead of melphalan.

The aim of this study is to determine an effective and safe dose of temozolomide orally administered to patients with relapsed primary CNS lymphoma over the 5 days preceding autologous stem-cell transplantation. The hope is that the conditioning regimen DRBEAT [D (dexamethasone) (R (rituximab), B (BCNU), E (etoposide), A (Ara-C (cytarabine)) and T (temozolomide)] will significantly improve the survival of patients with relapsed CNS lymphoma.


Condition Intervention Phase
B-Cell Lymphoma Originating in the CNS
Drug: Temozolomide
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: A Phase 2a Study of the Addition of Temozolomide to a Standard Conditioning Regimen for Autologous Stem Cell Transplantation in Relapsed and Refractory Central Nervous System (CNS) Lymphoma

Resource links provided by NLM:


Further study details as provided by Cedars-Sinai Medical Center:

Primary Outcome Measures:
  • Efficacy of the DRBEAT Regimen [ Time Frame: One Year ] [ Designated as safety issue: Yes ]

    Efficacy of the DRBEAT Regimen will be assessed by analysis of

    1. one-year progression-free survival (PFS), defined as the time interval from maximal response from therapy to tumor regrowth, progression, or death,

      and

    2. Overall survival, defined as the time interval between the date of transplant and the date of death from any cause.

  • Safest dose of temozolomide for the DRBEAT Regimen [ Time Frame: One year ] [ Designated as safety issue: Yes ]
    Safety will be assessed using a dose escalation design for temozolomide's use to determine the target dose and also to evaluate any and all acute treatment related toxicities. During the course of patient follow up and therapy, toxicities will be evaluated, particularly as the investigators will be determining the target dose of temozolomide. One of the major criteria for dose limiting toxicity for the study will be any Grade 3 or 4 nonhematologic toxicity from a list of commonly expected toxicities associated with autologous transplantation and temozolomide.


Estimated Enrollment: 20
Study Start Date: September 2010
Estimated Study Completion Date: December 2018
Estimated Primary Completion Date: December 2017 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: DRBEAT Regimen Drug: Temozolomide
The DRBEAT regimen will be similar to RBEAM. Rituximab and Carmustine will be given Day -6. Etoposide and Cytarabine will be given on Days -5 to -2. Temozolomide will be given via divided doses over five days starting on Day -5 to Day -1. A dose escalation design, known as EWOC (Escalation with overdose control) will be used to determine the target dose of temozolomide for this study. The starting dose given over five days will begin at 250mg/m2 (cumulative total dose of 1250 mg/m2), as previous data indicates this to be a safe dose. Based on the reported Dose Limiting toxicities from the previous patients, the EWOC statistical modeling will be performed to determine the next dose level.

  Eligibility

Ages Eligible for Study:   18 Years to 75 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Patients ≥ 18 years of age and ≤ 75 years of age
  2. Patients must have Central Nervous System (CNS) involvement with a mature B-cell non-Hodgkin's Lymphoma, (WHO criteria)
  3. Patients must meet one of the below criteria:

    • Patients who have achieved a complete response (CR) or partial response (PR) after initial therapy for Central Nervous System (CNS) B-cell lymphoma, OR
    • Patients with relapsed or progressed disease following therapy for CNS B-cell lymphoma who has achieved a subsequent CR or PR following salvage chemotherapy, OR
    • Patients who are initially refractory to therapy for CNS B-cell lymphoma but who have achieved a CR or PR following a salvage chemotherapy regimen, OR
    • Patients who have developed CNS relapse from systemic B-cell Non-Hodgkin's lymphoma, and have evidence of chemotherapy sensitive lymphoma.
  4. Patients fit for autologous stem cell transplantation
  5. Patients able to understand and willing to sign a written informed consent document

Exclusion Criteria:

  1. Patients with primary CNS B-cell lymphoma in remission status post primary, initial therapy
  2. Patients initially enrolled at relapse but who were not responsive to induction therapy will not be continued on the study
  3. Patients whose life expectancy is severely limited by diseases other than malignancy
  4. Karnofsky Performance Score <60
  5. Patients who are pregnant or breastfeeding
  6. Patients who are HIV seropositive
  7. Patients who have an uncontrolled infection (presumed or documented) with progression after appropriate therapy for greater than one month
  8. Patients with symptomatic coronary artery disease, uncontrolled congestive heart failure. Left Ventricular Ejection Fraction is not required to be measured, however if it is measured, patient is excluded if ejection fraction is <30%
  9. Patients requiring supplementary continuous oxygen.
  10. Patients with clinical or laboratory evidence of liver disease will be evaluated for the cause of liver disease, its clinical severity in terms of liver function and histology, and for the degree of portal hypertension. Patients with any of the following liver function abnormalities will be excluded

    1. Fulminant liver failure
    2. Cirrhosis with evidence of portal hypertension or bridging fibrosis
    3. Alcoholic hepatitis
    4. Esophageal varices
    5. A history of bleeding esophageal varices
    6. Hepatic encephalopathy
    7. Uncorrectable hepatic synthetic dysfunction evidenced by prolongation of the prothrombin time
    8. Ascites related to portal hypertension
    9. Chronic viral hepatitis with total serum bilirubin >3 mg/dL ____mg/dL
    10. Symptomatic biliary disease
  11. Patients with non-B-cell lymphomas or brain tumors that are not lymphomas are Excluded from the study. Non-B-cell lymphomas include: any T-cell lymphoma, natural killer (NK)-cell lymphomas, and Hodgkin lymphomas
  12. Patients for whom an insufficient number of stem cells (<2 X 106/kg) have been collected
  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: NCT01235793

Contacts
Contact: Almar Guevarra, RN (310) 423-1365 Almar.Guevarra@cshs.org
Contact: Dominique Durant (310) 248-8542 Dominique.Durant@cshs.org

Locations
United States, California
Cedars Sinai Medical Center Recruiting
Los Angeles, California, United States, 90048
Contact: Almar Guevarra, RN    310-423-1365    Almar.Guevarra@cshs.org   
Contact: Dominique Durant    (310) 248-8542    Dominique.Durant@cshs.org   
Sub-Investigator: Maria Delioukina, MD         
Sub-Investigator: Jethro Hu, MD         
Sub-Investigator: Stephen Lim, MD         
Sub-Investigator: Surasak Phuphanich, MD         
Sub-Investigator: Jeremy Rudnick, MD         
Sub-Investigator: Dimitrios Tzachanis, MD         
Principal Investigator: Michael Lill, MD         
Sponsors and Collaborators
Cedars-Sinai Medical Center
Investigators
Principal Investigator: Michael Lill, MD Cedars-Sinai Medical Center
Principal Investigator: Jeremy Rudnick, MD Cedars-Sinai Medical Center
  More Information

Publications:
Skeel R. Antioneoplastic Drugs and Biologic Response Modifiers: Classification, Use, and Toxicity of Clinically Useful Agents. Pp64-66 in Handbook of Cancer Chemotherapy, 5th edition 1999, Editor Skeel R
Issa S, Hwang J, Karch J, et al. Treatment of primary CNS lymphoma with induction high-dose methotrexate, temozolomide, rituximab followed by consolidation cytarabine/etoposide: A pilot study with biomarker analysis. Journal of Clinical Oncology, 2006 ASCO Annual Meeting Proceedings Part I. Vol 24, No. 18S (June 20 Supplement), 2006: 7595
Handbook of statistics in clinical oncology By John Crowley, Donna Pauler Ankerst Pahse 1 Trials Page 8 Edition 2, 2005
Zacks s, Rogatko A, Babb J. Optimal Bayesian-feasible dose escalation for cancer phase I trials. Statistics & Probability Letters, 1998, vol. 38, issue 3, pages 215-220
S.R. Plotkin, R.H. Betensky and F.H. Hochberg et al., Treatment of relapsed PCNSL with high-dose methotrexate, Clin. Cancer Res. 10 (2004), pp. 5643-5646
AU Reni M; Zaja F; Mason W; Perry J; Mazza E; Spina M; Bordonaro R; Ilariucci F; Faedi M; Corazzelli G; Manno P; Franceschi E; Pace A; Candela M; Abbadessa A; Stelitano C; Latte G; Ferreri AJ Temozolomide as salvage treatment in primary brain lymphomas SO Br J Cancer. 2007 Mar 26;96(6):864-7

Responsible Party: Michael Lill, Director, Blood and Marrow Transplant Program, Cedars-Sinai Medical Center
ClinicalTrials.gov Identifier: NCT01235793     History of Changes
Other Study ID Numbers: Pro00019873
Study First Received: November 5, 2010
Last Updated: November 12, 2014
Health Authority: United States: Food and Drug Administration
United States: Institutional Review Board

Keywords provided by Cedars-Sinai Medical Center:
Relapsed
Refractory
Primary Central Nervous System B-cell Lymphoma
Autologous Stem Cell Transplant
Temozolomide
B-Cell Lymphoma
RBEAM
Conditioning Regimen

Additional relevant MeSH terms:
Lymphoma
Lymphoma, B-Cell
Immune System Diseases
Immunoproliferative Disorders
Lymphatic Diseases
Lymphoma, Non-Hodgkin
Lymphoproliferative Disorders
Neoplasms
Neoplasms by Histologic Type
Dacarbazine
Temozolomide
Alkylating Agents
Antineoplastic Agents
Antineoplastic Agents, Alkylating
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Therapeutic Uses

ClinicalTrials.gov processed this record on November 23, 2014