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Epigenetic Modulation in Relapsed/Refractory Follicular Lymphoma and Marginal Zone Lymphoma

Primary Purpose

Follicular Lymphoma, Marginal Zone Lymphoma

Status
Terminated
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
azacitidine
lenalidomide
Sponsored by
Duke University
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Follicular Lymphoma focused on measuring relapsed, refractory, lymphoma, follicular, marginal zone

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  1. Histologically or cytologically confirmed Follicular or Marginal Zone Lymphoma
  2. Refractory disease defined as persistence of evaluable disease after therapy or have relapsed disease to at least one prior treatment regimen
  3. Understand and voluntarily sign an informed consent form
  4. Age > or = to 18 years
  5. Able to adhere to the study requirements

  6. A frozen tumor sample must be available for microarray analysis. This may either be a previously collected sample if it was properly prepared or a new biopsy may be obtained.

    o At least 1 core biopsy specimen using at least a 16 gauge needle, which corresponds to roughly 25 mg of tissue. An equivalent amount of biopsy material from previously performed procedures, as long as it was fresh frozen, can be used. Sample obtained with leukapheresis is acceptable in subjects with a white blood cell count (WBC) of 100,000 or greater.

  7. Eastern Cooperative Oncology Group (ECOG) performance status of < or = to 2
  8. Laboratory test results within ranges specified by the protocol.
  9. Disease free of prior malignancies for > or = to 3 years with exception of currently treated basal cell, squamous cell carcinoma of the skin, or carcinoma "in situ" of the cervix or breast or superficial melanoma only requiring excision or prostate cancer with a prostate specific antigen (PSA) that has not increased for at least 3 months.
  10. All study participants must be willing to be registered into the mandatory RevAssist® program, and comply with the requirements of RevAssist®.
  11. Females of childbearing potential (FCBP) must comply with pregnancy testing requirements. Men and women must use approved birth control methods during the study.
  12. Women of childbearing potential should be advised to avoid becoming pregnant and men should be advised to not father a child while receiving treatment with azacitidine.
  13. If at high risk for thrombotic event (such as on steroids or history of deep vein thrombosis), subjects must be able to take aspirin (81 or 325 mg) daily as prophylactic anticoagulation (patients intolerant to acetylsalicylic acid may use warfarin or low molecular weight heparin)

Exclusion Criteria:

  1. Any serious medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from signing the informed consent form.
  2. Pregnant or breast feeding females. (Lactating females must agree not to breast feed while taking lenalidomide).
  3. Any condition, including the presence of laboratory abnormalities, which places the subject at unacceptable risk if he/she were to participate in the study or confounds the ability to interpret data from the study
  4. Use of any other experimental drug or therapy within 28 days of baseline.
  5. Known hypersensitivity to thalidomide or mannitol.
  6. The development of erythema nodosum if characterized by a desquamating rash while taking thalidomide or similar drugs
  7. Any prior use of lenalidomide or azacitidine
  8. Concurrent use of other anti-cancer agents or treatments
  9. Known positive for HIV or infectious hepatitis, type B or C
  10. No chemotherapy, biologics or immunotherapy within 2 weeks prior to registration as specified in the protocol. Subjects must have recovered from all therapy-related non-hematological toxicities to < grade 1 or to baseline if patient started with > grade 1 toxicity. There is no time limit with regards to radiation prior to registration.
  11. 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.
  12. No prior allogeneic stem cell transplantation unless allogeneic engraftment is <2%
  13. Subjects receiving chronic, systemic treatment with corticosteroids equivalent to >20mg of prednisone per day

Sites / Locations

  • Duke University Medical Center

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Experimental

Arm Label

Azacitidine followed by Lenalidomide

Lenalidomide followed by Azacitidine

Arm Description

Azacitidine 75 mg/m2 subcutaneously (SC) or IV on days 1-5; subjects will begin Part 2 at the azacitidine dose level tolerated in Part 1a. Lenalidomide dose is 15mg po per day on days 1-21; starting dose during Part 2 will depend upon how well the subject tolerated drug during Part 1.

Lenalidomide dose is 15mg po per day on days 1-21; starting dose during Part 2 will depend upon how well the subject tolerated drug during Part 1. Azacitidine 75 mg/m2 subcutaneously (SC) or IV on days 1-5; subjects will begin Part 2 at the azacitidine dose level tolerated in Part 1a.

Outcomes

Primary Outcome Measures

Response Predicted by Molecular Signatures Compared to True Response
The predicted response (response to therapy vs. no response to therapy) using gene sequencing will be compared to the overall "true" response (reported in Primary Outcome 2).
Overall Response
Number of patients with a complete or partial response using Cheson criteria for lymphoma. A complete response is defined as a complete disappearance of all detectable clinical and radiographic evidence of disease and disappearance of all disease-related symptoms if present before therapy. A partial response is defined as a greater than or equal to 50% decrease in the sum of the products of the greatest diameters of 6 largest dominant nodes or nodal masses. No increase in size of nodes, liver or spleen and no new sites of disease. Patients who have been on study drug for at least 2 months will be considered evaluable for response as long as they have had repeat imaging to assess response or clear progression based on physical exam.
Overall Response
Number of patients with a complete or partial response using Cheson criteria for lymphoma. A complete response is defined as a complete disappearance of all detectable clinical and radiographic evidence of disease and disappearance of all disease-related symptoms if present before therapy. A partial response is defined as a greater than or equal to 50% decrease in the sum of the products of the greatest diameters of 6 largest dominant nodes or nodal masses. No increase in size of nodes, liver or spleen and no new sites of disease. Patients who have been on study drug for at least 2 months will be considered evaluable for response as long as they have had repeat imaging to assess response or clear progression based on physical exam.
Overall Response
Number of patients with a complete or partial response using Cheson criteria for lymphoma. A complete response is defined as a complete disappearance of all detectable clinical and radiographic evidence of disease and disappearance of all disease-related symptoms if present before therapy. A partial response is defined as a greater than or equal to 50% decrease in the sum of the products of the greatest diameters of 6 largest dominant nodes or nodal masses. No increase in size of nodes, liver or spleen and no new sites of disease. Patients who have been on study drug for at least 2 months will be considered evaluable for response as long as they have had repeat imaging to assess response or clear progression based on physical exam.

Secondary Outcome Measures

Number of Participants With Grade 3 and 4 Toxicities
Evaluate the safety of lenalidomide, azacitidine and the combination of azacitidine + lenalidomide in patients with lymphoma; grading the adverse events using Common Toxicity Criteria for Adverse Events (CTCAE) version 4.0

Full Information

First Posted
February 11, 2010
Last Updated
August 1, 2016
Sponsor
Duke University
Collaborators
Celgene
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1. Study Identification

Unique Protocol Identification Number
NCT01121757
Brief Title
Epigenetic Modulation in Relapsed/Refractory Follicular Lymphoma and Marginal Zone Lymphoma
Official Title
A Phase 2 Study Evaluating the Efficacy of Epigenetic Modulation in Relapsed/Refractory Follicular Lymphoma and Marginal Zone Lymphoma
Study Type
Interventional

2. Study Status

Record Verification Date
August 2016
Overall Recruitment Status
Terminated
Why Stopped
The study closed temporarily in February 2012 pending analysis of samples collected. In October, 2012, Celgene requested closure of the study.
Study Start Date
April 2010 (undefined)
Primary Completion Date
March 2013 (Actual)
Study Completion Date
January 2016 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Duke University
Collaborators
Celgene

4. Oversight

Data Monitoring Committee
No

5. Study Description

Brief Summary
The purpose of this study is to evaluate the response and safety in subjects receiving the drugs lenalidomide and azacitidine when each drug is given by itself and when the drugs are taken together. This study is open for patients with relapsed or refractory follicular or marginal zone lymphoma.
Detailed Description
This will be a prospective, non-randomized, un-blinded, phase 2 efficacy trial using an Immunomodulatory derivatives of thalidomide (IMiD™)compound and a hypomethylating agent for epigenetic targeted therapies in patients with relapsed/refractory follicular and marginal zone lymphoma. There will be two parts to the trial. Each patient will progress through each part of the study. Part 1: Sequential single agent therapy with azacitidine and lenalidomide. Each agent will be given for four-six 28-day cycles. Subjects with less than a complete response (CR) after 4 cycles of study drug in Part 1a or 1b should proceed to the next study drug(s) after the prescribed washout period. Subjects with a CR may receive up to 6 cycles of study drug and will not receive the next study drug(s) until there is evidence of progressive disease. There will be a 1-6 week 'washout' period between stopping and starting each agent in Part 1, unless rapid progression suggests holding therapy would not be in the patient's best interest. There will be no washout period required between Part 1 and Part 2. Part 2: Combination therapy with azacitidine and lenalidomide given in 28-day cycle for up to 13 cycles in subjects who have stable disease or better.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Follicular Lymphoma, Marginal Zone Lymphoma
Keywords
relapsed, refractory, lymphoma, follicular, marginal zone

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
11 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Azacitidine followed by Lenalidomide
Arm Type
Experimental
Arm Description
Azacitidine 75 mg/m2 subcutaneously (SC) or IV on days 1-5; subjects will begin Part 2 at the azacitidine dose level tolerated in Part 1a. Lenalidomide dose is 15mg po per day on days 1-21; starting dose during Part 2 will depend upon how well the subject tolerated drug during Part 1.
Arm Title
Lenalidomide followed by Azacitidine
Arm Type
Experimental
Arm Description
Lenalidomide dose is 15mg po per day on days 1-21; starting dose during Part 2 will depend upon how well the subject tolerated drug during Part 1. Azacitidine 75 mg/m2 subcutaneously (SC) or IV on days 1-5; subjects will begin Part 2 at the azacitidine dose level tolerated in Part 1a.
Intervention Type
Drug
Intervention Name(s)
azacitidine
Other Intervention Name(s)
Vidaza
Intervention Description
Azacitidine 75 mg/m2 SC or IV on days 1-5; subjects will begin Part 2 at the azacitidine dose level tolerated in Part 1a.
Intervention Type
Drug
Intervention Name(s)
lenalidomide
Other Intervention Name(s)
Revlimid
Intervention Description
Lenalidomide dose is 15mg po per day on days 1-21; starting dose during Part 2 will depend upon how well the subject tolerated drug during Part 1.
Primary Outcome Measure Information:
Title
Response Predicted by Molecular Signatures Compared to True Response
Description
The predicted response (response to therapy vs. no response to therapy) using gene sequencing will be compared to the overall "true" response (reported in Primary Outcome 2).
Time Frame
approximately one year
Title
Overall Response
Description
Number of patients with a complete or partial response using Cheson criteria for lymphoma. A complete response is defined as a complete disappearance of all detectable clinical and radiographic evidence of disease and disappearance of all disease-related symptoms if present before therapy. A partial response is defined as a greater than or equal to 50% decrease in the sum of the products of the greatest diameters of 6 largest dominant nodes or nodal masses. No increase in size of nodes, liver or spleen and no new sites of disease. Patients who have been on study drug for at least 2 months will be considered evaluable for response as long as they have had repeat imaging to assess response or clear progression based on physical exam.
Time Frame
Response will be assessed after at least 4 months on first study drug.
Title
Overall Response
Description
Number of patients with a complete or partial response using Cheson criteria for lymphoma. A complete response is defined as a complete disappearance of all detectable clinical and radiographic evidence of disease and disappearance of all disease-related symptoms if present before therapy. A partial response is defined as a greater than or equal to 50% decrease in the sum of the products of the greatest diameters of 6 largest dominant nodes or nodal masses. No increase in size of nodes, liver or spleen and no new sites of disease. Patients who have been on study drug for at least 2 months will be considered evaluable for response as long as they have had repeat imaging to assess response or clear progression based on physical exam.
Time Frame
Response will be assessed after at least 4 months on second drug.
Title
Overall Response
Description
Number of patients with a complete or partial response using Cheson criteria for lymphoma. A complete response is defined as a complete disappearance of all detectable clinical and radiographic evidence of disease and disappearance of all disease-related symptoms if present before therapy. A partial response is defined as a greater than or equal to 50% decrease in the sum of the products of the greatest diameters of 6 largest dominant nodes or nodal masses. No increase in size of nodes, liver or spleen and no new sites of disease. Patients who have been on study drug for at least 2 months will be considered evaluable for response as long as they have had repeat imaging to assess response or clear progression based on physical exam.
Time Frame
Response will be assessed after at least 6 months on combination drug.
Secondary Outcome Measure Information:
Title
Number of Participants With Grade 3 and 4 Toxicities
Description
Evaluate the safety of lenalidomide, azacitidine and the combination of azacitidine + lenalidomide in patients with lymphoma; grading the adverse events using Common Toxicity Criteria for Adverse Events (CTCAE) version 4.0
Time Frame
While taking the study drug and 30 days after the last dose
Other Pre-specified Outcome Measures:
Title
Serum Markers Measured on the First Day of Cycle 1 and on the First Day of Cycle 3
Time Frame
Within 4 months of taking single agent and 6 months of taking the combination

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Histologically or cytologically confirmed Follicular or Marginal Zone Lymphoma Refractory disease defined as persistence of evaluable disease after therapy or have relapsed disease to at least one prior treatment regimen Understand and voluntarily sign an informed consent form Age > or = to 18 years Able to adhere to the study requirements A frozen tumor sample must be available for microarray analysis. This may either be a previously collected sample if it was properly prepared or a new biopsy may be obtained. o At least 1 core biopsy specimen using at least a 16 gauge needle, which corresponds to roughly 25 mg of tissue. An equivalent amount of biopsy material from previously performed procedures, as long as it was fresh frozen, can be used. Sample obtained with leukapheresis is acceptable in subjects with a white blood cell count (WBC) of 100,000 or greater. Eastern Cooperative Oncology Group (ECOG) performance status of < or = to 2 Laboratory test results within ranges specified by the protocol. Disease free of prior malignancies for > or = to 3 years with exception of currently treated basal cell, squamous cell carcinoma of the skin, or carcinoma "in situ" of the cervix or breast or superficial melanoma only requiring excision or prostate cancer with a prostate specific antigen (PSA) that has not increased for at least 3 months. All study participants must be willing to be registered into the mandatory RevAssist® program, and comply with the requirements of RevAssist®. Females of childbearing potential (FCBP) must comply with pregnancy testing requirements. Men and women must use approved birth control methods during the study. Women of childbearing potential should be advised to avoid becoming pregnant and men should be advised to not father a child while receiving treatment with azacitidine. If at high risk for thrombotic event (such as on steroids or history of deep vein thrombosis), subjects must be able to take aspirin (81 or 325 mg) daily as prophylactic anticoagulation (patients intolerant to acetylsalicylic acid may use warfarin or low molecular weight heparin) Exclusion Criteria: Any serious medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from signing the informed consent form. Pregnant or breast feeding females. (Lactating females must agree not to breast feed while taking lenalidomide). Any condition, including the presence of laboratory abnormalities, which places the subject at unacceptable risk if he/she were to participate in the study or confounds the ability to interpret data from the study Use of any other experimental drug or therapy within 28 days of baseline. Known hypersensitivity to thalidomide or mannitol. The development of erythema nodosum if characterized by a desquamating rash while taking thalidomide or similar drugs Any prior use of lenalidomide or azacitidine Concurrent use of other anti-cancer agents or treatments Known positive for HIV or infectious hepatitis, type B or C No chemotherapy, biologics or immunotherapy within 2 weeks prior to registration as specified in the protocol. Subjects must have recovered from all therapy-related non-hematological toxicities to < grade 1 or to baseline if patient started with > grade 1 toxicity. There is 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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Anne W. Beaven, MD
Organizational Affiliation
Duke University Medical Center Durham, NC USA
Official's Role
Principal Investigator
Facility Information:
Facility Name
Duke University Medical Center
City
Durham
State/Province
North Carolina
ZIP/Postal Code
27710
Country
United States

12. IPD Sharing Statement

Plan to Share IPD
No

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Epigenetic Modulation in Relapsed/Refractory Follicular Lymphoma and Marginal Zone Lymphoma

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