Follicular Lymphoma, Marginal Zone Lymphoma
Conditions
Keywords
relapsed, refractory, lymphoma, follicular, marginal zone
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.
Interventions
DRUGazacitidine
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.
DRUGlenalidomide
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.
Sponsors
Celgene
Duke University
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Response Predicted by Molecular Signatures Compared to True Response | approximately one year | 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 | Response will be assessed after at least 4 months on first study drug. | 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
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Grade 3 and 4 Toxicities | While taking the study drug and 30 days after the last dose | 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 |
Other
| Measure | Time frame |
|---|---|
| Serum Markers Measured on the First Day of Cycle 1 and on the First Day of Cycle 3 | Within 4 months of taking single agent and 6 months of taking the combination |
Countries
United States
Participant flow
Recruitment details
Patients were recruited from June 2010 through January 2012 from the Duke Cancer Institute.
Pre-assignment details
The first 3 patients started on 1a and the next 3 patients started in 1b and the next 3 were in 1a and so on. Eleven subjects consented to the study, 1 patient elected other treatment options prior to assignment and 1 other patient converted to Diffuse Large B-Cell Lymphoma, which made them ineligible.
Participants by arm
| Arm | Count |
|---|---|
| 1a-Azacitidine Followed by Lenalidomide Subjects will take azacitidine for 4-6 cycles (first drug) followed by a 1-6 week washout period. Subjects with a complete remission (CR) may receive up to 6 cycles of first drug and will not receive the next until disease progression.
Subjects with less than a CR after 4 cycles of azacitidine (first drug) will proceed to receive lenalidomide (second drug) for 4-6 cycles.
Subjects with a CR after lenalidomide may receive up to 6 cycles of lenalidomide and will not start on the combination drug until disease progression.
The combination therapy (azacitidine and lenalidomide) will be given in 28-day cycles for up to 13 cycles in subjects who have stable disease or better. | 6 |
| 1b-Lenalidomide Followed by Azacitidine Subjects will take lenalidomide for 4-6 cycles (first drug) followed by a 1-6 week washout period. Subjects with a complete remission (CR) may receive up to 6 cycles of first drug and will not receive the next until disease progression.
Subjects with less than a CR after 4 cycles of lenalidomide (first drug) will proceed to receive azacitidine (second drug) for 4-6 cycles.
Subjects with a CR after azacitidine may receive up to 6 cycles of azacitidine and will not start on the combination drug until disease progression.
The combination therapy (azacitidine and lenalidomide) will be given in 28-day cycles for up to 13 cycles in subjects who have stable disease or better. | 3 |
| Total | 9 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Combination | Disease Progression | 2 | 0 |
| Combination | Physician Decision | 0 | 1 |
| First Drug | Death | 1 | 0 |
| First Drug | Disease Progression | 0 | 2 |
Baseline characteristics
| Characteristic | 1a-Azacitidine Followed by Lenalidomide | 1b-Lenalidomide Followed by Azacitidine | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 3 Participants | 1 Participants | 4 Participants |
| Age, Categorical Between 18 and 65 years | 3 Participants | 2 Participants | 5 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 6 Participants | 3 Participants | 9 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 6 Participants | 3 Participants | 9 Participants |
| Region of Enrollment United States | 6 participants | 3 participants | 9 participants |
| Sex: Female, Male Female | 4 Participants | 1 Participants | 5 Participants |
| Sex: Female, Male Male | 2 Participants | 2 Participants | 4 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 6 / 6 | 3 / 3 |
| serious Total, serious adverse events | 2 / 6 | 2 / 3 |
Outcome results
Primary
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.
Time frame: Response will be assessed after at least 4 months on first study drug.
Population: Everyone who started the first drug regimen
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 1a-Azacitidine Followed by Lenalidomide | Overall Response | 1 participants |
| 1b-Lenalidomide Followed by Azacitidine | Overall Response | 0 participants |
Primary
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.
Time frame: Response will be assessed after at least 4 months on second drug.
Population: Everyone who started the second drug regimen
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 1a-Azacitidine Followed by Lenalidomide | Overall Response | 2 participants |
| 1b-Lenalidomide Followed by Azacitidine | Overall Response | 0 participants |
Primary
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.
Time frame: Response will be assessed after at least 6 months on combination drug.
Population: Only subjects that completed combination drug will be included in analysis.
Primary
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).
Time frame: approximately one year
Population: The number of participants who were evaluated for a response were analyzed to see if the prediction of response vs. no response through gene expression matched the true response.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| 1a-Azacitidine Followed by Lenalidomide | Response Predicted by Molecular Signatures Compared to True Response | Predicted: Response; Actual: Response | 1 participants |
| 1a-Azacitidine Followed by Lenalidomide | Response Predicted by Molecular Signatures Compared to True Response | Predicted: No Response; Actual: No Response | 2 participants |
| 1a-Azacitidine Followed by Lenalidomide | Response Predicted by Molecular Signatures Compared to True Response | Predicted: Response; Actual: No Response | 3 participants |
| 1b-Lenalidomide Followed by Azacitidine | Response Predicted by Molecular Signatures Compared to True Response | Predicted: Response; Actual: Response | 0 participants |
| 1b-Lenalidomide Followed by Azacitidine | Response Predicted by Molecular Signatures Compared to True Response | Predicted: No Response; Actual: No Response | 3 participants |
| 1b-Lenalidomide Followed by Azacitidine | Response Predicted by Molecular Signatures Compared to True Response | Predicted: Response; Actual: No Response | 0 participants |
Secondary
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
Time frame: While taking the study drug and 30 days after the last dose
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| 1a-Azacitidine Followed by Lenalidomide | Number of Participants With Grade 3 and 4 Toxicities | Grade 3 | 5 participants |
| 1a-Azacitidine Followed by Lenalidomide | Number of Participants With Grade 3 and 4 Toxicities | Grade 4 | 1 participants |
| 1b-Lenalidomide Followed by Azacitidine | Number of Participants With Grade 3 and 4 Toxicities | Grade 3 | 3 participants |
| 1b-Lenalidomide Followed by Azacitidine | Number of Participants With Grade 3 and 4 Toxicities | Grade 4 | 1 participants |
Other Pre-specified
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