Chronic Lymphocytic Leukemia
Conditions
Keywords
CLL
Brief summary
The investigators' hypothesis is that treatment of CLL with an alternating daily dosing schedule of thalidomide and lenalidomide may result in better tolerability by decreasing each agent's individual toxicities, while preserving efficacy, and therefore lead to a longer duration of therapy and improved responses. Additionally, the combination of the 2 agents may have additive or synergistic effects therapeutically. In Cycle -1, odd numbered patients will receive oral thalidomide daily days 1-14 followed by no treatment on days 15-28. Even numbered patients will receive oral lenalidomide daily on days 1-14 and then no treatment on days 15-28. Starting with cycle 1, patients will alternate daily thalidomide (every odd day) with daily lenalidomide (every even day) for days 1-28. Rituximab will be given on days 1, 8, 15, and 22 starting with Cycle 1, and then again every 6th cycle thereafter (cycles 7, 13, 19, etc.)
Detailed description
This is an open label, phase II, single arm, and single institution study investigating daily alternating therapy with IMiD™ compounds, thalidomide and lenalidomide, plus rituximab in untreated CLL patients requiring treatment. In order to obtain correlative samples, patients will receive a two week course of single agent thalidomide or lenalidomide before beginning treatment with the combination regimen. Half of the patients (odd numbered subjects) will start with a two week course of single agent thalidomide and the other half of the patients (even numbered subjects) will start with a two week course of single agent lenalidomide. This will allow the study of correlative samples of monotherapy with either IMiD™ agent. In Cycle -1 half of the patients (odd numbered subjects) will receive thalidomide 50mg PO daily on days 1-14, followed by no treatment days 15-28 and the other half of the patients (even numbered subjects) will receive lenalidomide PO daily on days 1-14, followed by no treatment days 15-28. Starting cycle 1: Patients will receive thalidomide 50 mg every other day (every odd day on days 1-28: Days 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25 & 27 of a 28 day cycle) alternating with lenalidomide on alternate every other day, dosed based upon current level with stepwise incremental dosing (every even day on days 1-28: Days 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26 & 28 of a 28 day cycle). The starting dose of lenalidomide will be based on calculated creatinine clearance and the dose of lenalidomide may be escalated as tolerated to maximal dose of 25 mg (see Section 5 for details). Rituximab 375 mg/m2 will be administered on days 1, 8, 15 and 22 starting with Cycle 1 and then again on the same weekly x 4 schedule every 6th cycle thereafter (Cycles 7, 13, 19, etc).
Interventions
DRUGthalidomide
50 mg oral dosing every other day
DRUGlenalidomide
varying oral doses every other day (max 25 mg/day)
BIOLOGICALrituximab
375 mg/m2 intravenously on days 1, 8, 15, and 22 of cycle 1. Then, repeated on days 1, 8, 15, and 22 of every 6th cycle thereafter (Cycle 7, 13, 19, etc.)
Sponsors
Celgene
Weill Medical College of Cornell University
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1\. Confirmed diagnosis of CLL or SLL based upon standard criteria as outlined in the IWCLL Update of the 1996 NCI-Working Group criteria for CLL: a) Presence of one of the following: 1\. more than or equal to 5 x 10\^9 B lymphocytes/L in the peripheral blood for a duration of at least 3 months. Patients with a B lymphocytosis will be characterized as CLL, while those without will be characterized as SLL 2\. the presence of lymphadenopathy resulting from infiltration with lymphocytes with the phenotype of CLL 3\. bone marrow infiltration with lymphocytes with the phenotype of CLL b) Lymphocytes with the morphologic appearance of small, mature appearing lymphocytes, with less or equal to 55 percent prolymphocytes (blood or bone marrow) c) Cellular phenotype characterized by the: 1. co-expression of the CD5, CD20, and CD23 surface antigens 2. clonal kappa or lambda light chain expression 3. dim surface immunoglobulin expression 2\. No prior therapy for CLL, including treatment for autoimmune conditions that have developed since the initial diagnosis of CLL. 3\. Active disease requiring therapy as defined by the IWCLL Update of the 1996 NCIWG guidelines: 1. Evidence of progressive marrow failure as manifested by the development of worsening of anemia and / or thrombocytopenia 2. Massive, progressive, or symptomatic splenomegaly 3. Massive, progressive, or symptomatic lymphadenopathy 4. Progressive lymphocytosis with an increase of more than 50 percent over a 2-month period or a lymphocyte doubling time of less than 6 months. 5. Autoimmune anemia and/or thrombocytopenia poorly responsive to corticosteroids or other standard therapy 6. Presence of disease related symptoms: unintentional weight loss of more than 10 percent within previous six months, significant fatigue, fevers greater than 100.5 F or 38.0 C for 2 or more weeks without evidence of infection, night sweats for more than 1 month without evidence of infection. 4\. Understand and voluntarily sign an informed consent form. 5\. Age at least 18 years at the time of signing the informed consent form. 6\. Able to adhere to the study visit schedule and other protocol requirements. 7\. ECOG performance status of at most 2 at study entry. 8\. Laboratory test results within these ranges: * Absolute neutrophil count at least 1000/mm³ * Platelet count at least 50,000/mm³ * Creatinine clearance of at least 30 mL/min by Cockroft-Gault formula. Patients with a baseline creatinine clearance of greater than 30 and less than 60 mL/min will have a starting dose of lenalidomide 5 mg PO every other day per the defined schedule. Patients with a baseline creatinine clearance of ≥ 60 mL/min will have a starting dose of lenalidomide 5 mg PO daily per the defined schedule. * Total bilirubin at most 1.5 times the ULN, unless abnormality is the result of Gilbert's disease or the result of the CLL. * AST (SGOT) and ALT (SGPT) at most 3 x ULN (or at most 5 x ULN if due to the CLL) 9\. Disease free of prior malignancies for at least 2 years with exception of curatively treated basal cell carcinoma, squamous cell carcinoma of the skin, or carcinoma in situ of the cervix or breast. 10\. All study participants must be registered into the mandatory Revlimid REMS and S.T.E.P.S. ( P-TAP: Protocol Therapy Assistance Program) program(s), and be willing and able to comply with the requirements of Revlimid REMS and S.T.E.P.S. 11\. Females of childbearing potential (FCBP) must have a negative serum or urine pregnancy test with a sensitivity of at least 25 mIU/mL within 10 -14 days prior to and again within 24 hours of starting treatment and again within 24 hours before the first dose of lenalidomide AND thalidomide. FCBP must either commit to continued abstinence from heterosexual intercourse or begin TWO acceptable methods of birth control, one highly effective method and one additional effective method AT THE SAME TIME, at least 28 days before she starts taking lenalidomide and/or thalidomide. Females of reproductive potential must adhere to the scheduled pregnancy testing as required in the Revlimid REMS program . Men must agree to use a latex condom during sexual contact with a FCBP even if they have had a successful vasectomy. All patients must be counseled at a minimum of every 28 days about pregnancy precautions and risks of fetal exposure. 12\. Able to take aspirin 81 or 325 mg daily as prophylactic anticoagulation, unless already on therapeutic anticoagulation. Patients intolerant to ASA may use coumadin or low molecular weight heparin.
Exclusion criteria
1. Any serious medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from providing informed consent. 2. 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. 3. Evidence of laboratory TLS by Cairo-Bishop Definition of Tumor Lysis Syndrome. Subjects may be enrolled upon correction of electrolyte abnormalities. 4. Concurrent use of other anti-cancer agents or treatments. 5. Prior treatment with thalidomide or lenalidomide. 6. Active serious infection not controlled with antibiotics. 7. Autoimmune hemolytic anemia or thrombocytopenia requiring treatment. 8. Known positive for HIV 9. Active infection with hepatitis B, defined by being positive for HepBsAg or Hep B DNA by PCR, or hepatitis C 10. Pre-existing peripheral neuropathy greater than grade 2 11. Pregnant or breast feeding females. (Lactating females must agree not to breast feed while taking lenalidomide and/or thalidomide).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Response Rate as Defined as the Number of Patients Who Experience a Response (Complete or Partial) to Treatment at the Time of Best Response | From date of study drug initiation until date of best response, assessed up to 6 years. | Response will be evaluated in this study using the International Workshop on CLL (IWCLL) update of the 1996 NCI-Working Group criteria for CLL, which includes assessment of the following: clonal lymphocytes in the peripheral blood by flow cytometry, blood tests for neutrophil count, hemoglobin, and platelet count, CT examination for lymphadenopathy, hepatomegaly, splenomegaly, constitutional symptoms, bone marrow assessment via biopsy/aspirate, and evaluation for disease transformation. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression Free Survival | From date of study drug initiation until date of progression or death, whichever occurs first, assessed through study completion up to 100 months. | Measured from time of study drug administration to progression or death, measured in months. |
| Duration of Response | From date of end of treatment to progression or death, whichever occurs first, assessed through study completion up to 100 months. | Measured from end of treatment to progression or death, measured in months. |
| Time to Response | From date of study drug initiation to date of initial response, assessed up to 12 months. | Measured from time of study drug administration to initial response (partial or complete), measured in months. |
| Overall Survival | From date of study drug initiation to date of death, assessed through study completion up to 105 months. | Measured from time of study drug administration to death, measured in months. |
Countries
United States
Participant flow
Recruitment details
Participants were accrued to the study at Weill Cornell Medical College between March 2012 and September 2013.
Pre-assignment details
One participant was deemed ineligible for the study following the completion of the informed consent process.
Participants by arm
| Arm | Count |
|---|---|
| All Subjects In Cycle -1, even numbered patients will receive oral lenalidomide daily on days 1-14 and then no treatment on days 15-28.
In Cycle -1, odd numbered patients will receive oral thalidomide daily days 1-14 followed by no treatment on days 15-28.
Starting with cycle 1, all patients will alternate daily thalidomide (every odd day) with daily lenalidomide (every even day) for days 1-28. Rituximab will be given on days 1, 8, 15, and 22 starting with Cycle 1, and then again every 6th cycle thereafter (cycles 7, 13, 19, etc.)
Thalidomide: 50 mg oral dosing every other day
Lenalidomide: varying oral doses every other day (max 25 mg/day)
Rituximab: 375 mg/m2 intravenously on days 1, 8, 15, and 22 of cycle 1. Then, repeated on days 1, 8, 15, and 22 of every 6th cycle thereafter (Cycle 7, 13, 19, etc.) | 14 |
| Total | 14 |
Baseline characteristics
| Characteristic | All Subjects |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 3 Participants |
| Age, Categorical Between 18 and 65 years | 11 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 14 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 14 Participants |
| Sex: Female, Male Female | 8 Participants |
| Sex: Female, Male Male | 6 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 14 |
| other Total, other adverse events | 14 / 14 |
| serious Total, serious adverse events | 4 / 14 |
Outcome results
Primary
Overall Response Rate as Defined as the Number of Patients Who Experience a Response (Complete or Partial) to Treatment at the Time of Best Response
Response will be evaluated in this study using the International Workshop on CLL (IWCLL) update of the 1996 NCI-Working Group criteria for CLL, which includes assessment of the following: clonal lymphocytes in the peripheral blood by flow cytometry, blood tests for neutrophil count, hemoglobin, and platelet count, CT examination for lymphadenopathy, hepatomegaly, splenomegaly, constitutional symptoms, bone marrow assessment via biopsy/aspirate, and evaluation for disease transformation.
Time frame: From date of study drug initiation until date of best response, assessed up to 6 years.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| All Subjects | Overall Response Rate as Defined as the Number of Patients Who Experience a Response (Complete or Partial) to Treatment at the Time of Best Response | 12 Participants |
95% CI: [73.5, 100]
Secondary
Duration of Response
Measured from end of treatment to progression or death, measured in months.
Time frame: From date of end of treatment to progression or death, whichever occurs first, assessed through study completion up to 100 months.
Population: The one not assessable came off treatment prior to having an assessment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| All Subjects | Duration of Response | 70 months |
Secondary
Overall Survival
Measured from time of study drug administration to death, measured in months.
Time frame: From date of study drug initiation to date of death, assessed through study completion up to 105 months.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| All Subjects | Overall Survival | 97 months |
Secondary
Progression Free Survival
Measured from time of study drug administration to progression or death, measured in months.
Time frame: From date of study drug initiation until date of progression or death, whichever occurs first, assessed through study completion up to 100 months.
Population: The one not assessable came off treatment prior to having an assessment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| All Subjects | Progression Free Survival | 48 months |
Secondary
Time to Response
Measured from time of study drug administration to initial response (partial or complete), measured in months.
Time frame: From date of study drug initiation to date of initial response, assessed up to 12 months.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| All Subjects | Time to Response | 10 months |