Epigenetic Modulation in Relapsed/Refractory Diffuse Large B-Cell Lymphoma (DLBCL)

This study is currently recruiting participants.
Verified February 2012 by Duke University

First Received on September 15, 2009.  
Last Updated on February 17, 2012  
History of Changes
This Clinical Trial Sponsored By: Duke University
Collaborator: Novartis
Information provided by (Responsible Party): Duke University
ClinicalTrials.gov Identifier: NCT00978432
 

Purpose for Clinical Trial

The purpose of this study is evaluate the response, safety and tolerability in subjects receiving the investigational drugs (RAD001 and LBH589), when each investigational drug is given by itself and when they are taken together.

Condition Study Intervention Clinical Trial Phase
Diffuse Large B-cell Lymphoma Drug: RAD001
Drug: LBH589
Drug: RAD001 and LBH589 as a doublet
Phase 2

Study Type: Study Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Study Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase 2 Study to Evaluate the Efficacy of Epigenetic Modulation in Relapsed/Refractory Diffuse Large B-Cell Lymphoma (DLBCL)

Resource links provided by NLM:

MedlinePlus related topics:
Lymphoma
Drug Information available for:
Sirolimus
Everolimus
Temsirolimus

U.S. FDA Resources

Further study details as provided by Duke University:

Primary Outcome Measures For Clinical Trial:

  • Overall response rate (complete plus partial response) to single agents RAD001 and LBH589 and to the doublet (RAD001 and LBH589 combined). [ Time Frame: within 4 months of taking single agent and 6 months of taking the doublet. ] [ Designated as safety issue: No ]

Secondary Outcome Measures For Clinical Trial:

  • Evaluate adverse events associated with single agent LBH589 and RAD001 and the doublet. [ Time Frame: For duration of taking any study drug and for 30 days after completing all study drugs. ] [ Designated as safety issue: Yes ]

Estimated Enrollment: 75
Study Start Date: February 2012
Estimated Study Completion Date: June 2015
Estimated Primary Completion Date: June 2013 (Final data collection date for primary outcome measure)
Study Intervention Details:

    Drug: RAD001

    10 mg/day for Part 1 of the trial
    Other Name: RAD001 (everolimus)

    Drug: LBH589

    40 mg on Monday, Wednesday and Friday weekly for Part 1 of the trial
    Other Name: LBH589 (panobinostat)

    Drug: RAD001 and LBH589 as a doublet

    RAD001 10 mg on Monday/Wednesday/Friday during Part 2 LBH589 20 mg during Part 2

Detailed Description:

This will be a prospective, non-randomized, un-blinded phase 2 efficacy trial using an mTOR inhibitor and a histone deacetylase (HDAC) inhibitor for epigenetic targeted therapies. There will be two parts to the trial.

Part 1: Sequential single agent therapy with RAD001 and LBH589 (Part 1 a & 1b). Each agent will be given for up to six 28-day cycles. There will be a 1-6 week ‘washout’ period between stopping and starting each agent, unless rapid progression suggests holding therapy would not be in the patient’s best interest.

There will be no washout period between Part 1 and Part 2. Part 2 will follow a standard 3+3 dose escalation design to determine dose limiting toxicities.

Treatment will be administered on an outpatient basis. Patients will be followed for up to 2 years after completion of therapy or until progression of disease or death. Patients removed from study for unacceptable adverse events will be followed until resolution or stabilization of the adverse event and will continue to be followed for 2 years or until progression of disease or death.

  Eligibility

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

Inclusion Criteria:

  1. Histologically or cytologically confirmed diffuse large B cell non-Hodgkin lymphoma (DLBCL) that is de novo or transformed. Based on the revised 2008 WHO criteria subjects with DLBCL-like lymphomas will also be allowed including the list below, although this list is not all-inclusive.

    • DLBCL
    • EBV+ DLBCL in elderly,
    • DLBCL associated with chronic inflammation,
    • Primary cutaneous DLBCL, leg type,
    • B cell lymphoma unclassifiable with features intermediate between DLBCL and Burkitt lymphoma,
    • B cell lymphoma unclassifiable with features intermediate between large B cell lymphoma and classical Hodgkin lymphoma,
    • ALK+ large B cell lymphoma,
    • T cell histiocyte rich large B cell lymphoma
    • Primary mediastinal B cell lymphoma
    • Follicular grade 3 B cell lymphoma
  2. Refractory or relapsed disease to at least one prior treatment regimen, which should include autologous stem cell transplant unless the patient refused or was ineligible for transplant for any reason.
  3. Age > 18 years old
  4. ECOG performance status of <2.
  5. Measurable or evaluable disease based on physical exam and/or radiographs or bone marrow involvement
  6. Have a frozen tumor sample available for microarray analysis. May either be a previously collected sample if properly prepared or a new biopsy may be obtained.
  7. At least 3-4 core biopsy specimens using at least a 18 gauge needle. An equivalent amount of biopsy material from previously performed procedures, as long as it was fresh frozen, can be used in lieu of freshly obtained tissue. FNA is not acceptable for this initial specimen. Leukapheresis sample may be obtained instead of core biopsy for patients with leukocytosis.
  8. Laboratory Values as per protocol.

Exclusion Criteria:

  1. Laboratory Values

    • Grade 3 hyperlipidemia (Serum cholesterol >400mg/dl or serum triglycerides >5 x ULN) despite optimal supportive medical therapy
    • Serum Glucose > 250mg/dl on at least two checks on two separate days despite optimal medical management
    • Patients with diabetes may be enrolled on the trial as long as their sugars are adequately controlled
  2. No limit to the number of prior chemotherapy regimens, however:

    • No prior exposure to RAD001 or LBH589 or to any drugs that mainly target mTOR (everolimus, sirolimus, temsirolimus etc) or HDAC (vorinostat)

      • Valproic acid is a mild HDAC inhibitor so patients may not receive valproic acid at any time during the study or for the 5 days preceding starting the first study drug.
    • No chemotherapy, biologics or immunotherapy within 2 weeks prior to registration (6 weeks if last received BCNU or mitomycin C). Subjects must have recovered from all therapy-related non-hematological toxicities to < grade 1 or to baseline if patient started with > grade 1 toxicity.
    • No time limit with regards to radiation prior to registration.
    • No radioimmunotherapy within 2 months prior to registration. Subjects must have recovered from all therapy-related toxicities to < grade 1 or to baseline if patient started with > grade 1 toxicity.
    • No prior allogeneic stem cell transplantation unless allogeneic engraftment is <2%.
    • Subjects receiving chronic, systemic treatment with corticosteroids equivalent to >20mg of prednisone per day.

      • Subjects receiving replacement for adrenal insufficiency will be al

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