Leukemia, Lymphocytic, Chronic, B-Cell
Conditions
Keywords
Chronic Lymphocytic Leukemia, CLL
Brief summary
In research studies, lenalidomide (also called Revlimid) has shown some response in chronic lymphocytic leukemia (CLL); however, responses are usually partial responses that occur after several months of taking the study drug. It is thought that by adding the drug plerixafor (also called Mozobil) responses may be improved and/or occur sooner. The main purpose of this study is to determine the dose of plerixafor that is safe to use in combination with lenalidomide. The study will also look at the response rates of the combination of lenalidomide and plerixafor and the effect the study drugs have on CLL cells.
Detailed description
The combination of lenalidomide and plerixafor will be evaluated in this single institution, open label clinical study of subjects with relapsed chronic lymphocytic leukemia (CLL). The overall design of the phase 1 study includes up to three treatment stages. Each subject will receive lenalidomide 5mg by mouth daily beginning on cycle 1 day 1. If tolerated, the dose will be increased by 2.5mg every 7 days to a maximum dose of 10mg by mouth daily (Stage 1). Once the subject is stably maintained on a daily dose of lenalidomide of 10mg daily and the white blood cell (WBC) count is \<100.0 x 109 / L, and has been taking lenalidomide for at least 28 days, plerixafor will be added (Stage 2). In the dose escalation phase, 4 different doses of plerixafor in combination with lenalidomide will be studied in cohorts of 3 to 6 subjects each, following a standard 3 + 3 format: * Cohort 1: plerixafor 0.24 mg/kg subcutaneous (SC) daily thrice weekly (Mon, Wed, Fri) * Cohort 2: plerixafor 0.32 mg/kg SC daily thrice weekly (Mon, Wed, Fri) * Cohort 3: plerixafor 0.42 mg/kg SC daily thrice weekly (Mon, Wed, Fri) * Cohort 4: plerixafor 0.54 mg/kg SC daily thrice weekly (Mon, Wed, Fri) Plerixafor will be administered for 3 weeks of each cycle (days 1, 3, 5, 8, 10, 12, 15, 17, and 19) followed by a 1 week rest period. Lenalidomide dosing will be continuous. An interim assessment of response will be performed after 4 cycles of combination therapy: * Subjects achieving a complete response (CR) by National Cancer Institute (NCI)-96 criteria will continue lenalidomide monotherapy (plerixafor is discontinued) until disease progression. * Subjects achieving a partial response (PR) will continue both lenalidomide and plerixafor. Additionally, rituximab 375mg/m2 will be added on day 1 of each subsequent cycle beginning with cycle 5, day 1 of combination therapy. (Stage 3). Treatment with the combination of lenalidomide and plerixafor will continue for a maximum of 12 cycles of combination therapy. Subjects may receive up to 8 doses of rituximab concurrent with lenalidomide and plerixafor on day 1 of each cycle. Subjects will then continue single agent lenalidomide until disease progression. * Subjects with stable disease may continue lenalidomide and plerixafor at the discretion of the investigator and the subject. Rituximab 375 mg/m2 will be added on day 1 of each subsequent cycle. Treatment, dose, schedule, and duration are the same as for subjects achieving a PR.
Interventions
DRUGLenalidomide + Plerixafor (+ Rituximab)
1. Lenalidomide 5mg by mouth (PO) daily beginning cycle 1 day 1. 2. Stage 1: increase by 2.5mg every 7 days to a maximum dose of 10mg. 3. Stage 2: plerixafor will be added after 28 days of 10mg dose maintenance and white blood cell count (WBC) \<100.0 x 109 / L. 4. Dose cohorts of escalating subcutaneous (SC) thrice weekly plerixafor with continuous 10mg lenalidomide: * Cohort 1: 0.24 mg/kg * Cohort 2: 0.32 mg/kg * Cohort 3: 0.42 mg/kg * Cohort 4: 0.54 mg/kg 5. Stage 3: Rituximab 375mg/m2 will be added on day 1 of cycles 5-12, day 1 of combination therapy for subjects with PR. 6. Subjects will then continue single agent lenalidomide until disease progression.
Sponsors
Celgene Corporation
Genzyme, a Sanofi Company
David Rizzieri, MD
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
* Histologically confirmed diagnosis of chronic lymphocytic leukemia (CLL) or Small lymphocytic lymphoma (SLL) as established by the National Cancer Institute (NCI) Working Group Response Criteria (NCI 96 Criteria). * Received one or more prior therapies for CLL. * Subjects must have symptomatic disease requiring therapy as defined by the protocol. * \>/= 4 weeks from prior cancer therapy. * Eastern Cooperative Oncology Group (ECOG) performance status of \</= 2. * All study subjects must be registered into the mandatory RevAssist® program, and be willing and able to comply with the requirements of RevAssist®.
Exclusion criteria
* Prolymphocytic leukemia (PLL). * Richter's (large cell) transformation. * Prior allogeneic transplant within 12 months or prior allogeneic transplant \> 12 months currently receiving immunosuppressants. * Active autoimmune hemolytic anemia. * Central nervous system (CNS) involvement. * Chronic enteral corticosteroids \> 10mg prednisone or equivalent. * Evidence of laboratory tumor lysis syndrome (TLS) by Cairo-Bishop Definition of Tumor Lysis Syndrome * Use of any other experimental drug or therapy within 28 days of baseline * Major surgery within 28 days of baseline. * Known hypersensitivity to thalidomide. * The development of erythema nodosum if characterized by a desquamating rash while taking thalidomide or similar drugs. * Any prior use of lenalidomide. * Known seropositive for or active viral infection with human immunodeficiency virus (HIV), hepatitis B virus (HBV) or hepatitis C virus (HCV).
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Maximum Tolerated Dose | 4-16 months |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Response (Complete Response/Partial Response) | at the end of 4 months of combination treatment and at 2 months after completion of therapy | NCI 96 Response Criteria CR (Complete Response): Lymphadenopathy = none \> 1.5cm Hepatomegaly = none Splenomegaly = none Blood lymphocytes = \<4000 per microliter Marrow = normocellular, \<30% lymphocytes, no B-lymphoid nodules. Platelet count = \>100,000 per microliter Hemoglobin = \>11.0 grams per deciliter Neutrophils = \>1500 per microliter PR (Partial Response): Lymphadenopathy = Decrease \>/= 50% Hepatomegaly = Decrease \>/= 50% Splenomegaly = Decrease \>/= 50% Blood lymphocytes = Decrease \>/= 50% from baseline Marrow = 50% reduction in marrow infiltrate or B-lymphoid nodules. Platelet count = \>100,000 per microliter or increase \>/= 50% over baseline Hemoglobin = \>11.0 grams per deciliter or increase \>/= 50% over baseline Neutrophils = \>1500 per microliter or increase \>/= 50% over baseline |
| Progression-free Survival (PFS) | time from day 1 of treatment to disease progression, death, or 2 years, whichever comes first | — |
| Overall Survival (OS) | the time from day 1 of treatment to death or 2 years, whichever comes first | — |
| Reduction in Severity of B Symptoms | at the end of stage 1 (lenalidomide alone), at the end of stage 2 (4 months of combination), and at 2 months post-completion of therapy | Reduction in the severity of the following B symptoms will be assessed: fever ≥ 101F, chills, night sweats, and anorexia with weight loss. |
| Reduction in the Frequency of Blood and Platelet Transfusions | 4 weeks prior to therapy and in the 4 weeks following the completion of therapy | The change in number of transfusions from pre- to post-treatment will be calculated and summarized across all patients by giving the minimum, the 25th, 50th (median) and the 75th percentile and the maximum. |
Countries
United States
Participant flow
Recruitment details
Subjects were recruited from the CLL clinic at Duke Medical Center from January 2012 to December 2013.
Pre-assignment details
21 subjects were consented to this study. Six (6) were screen failures; therefore, only 15 subjects began the treatment regimen which included a lenalidomide run-in phase. Three (3) subjects were unable to complete the run-in phase. Three (3) subjects died prior to completing stage 2, and so were not evaluable for DLT.
Participants by arm
| Arm | Count |
|---|---|
| Lenalidomide + Plerixafor+ Rituximab 1. Lenalidomide 5mg by mouth (PO) daily beginning cycle 1 day 1.
2. Stage 1: increase by 2.5mg every 7 days to a maximum dose of 10mg.
3. Stage 2: plerixafor will be added after 28 days of 10mg dose maintenance and white blood cell count (WBC) \<100.0 x 109 / L.
4. Dose cohorts of escalating subcutaneous (SC) thrice weekly plerixafor with continuous 10mg lenalidomide:
* Cohort 1: 0.24 mg/kg
* Cohort 2: 0.32 mg/kg
5. Stage 3: Rituximab 375mg/m2 will be added on day 1 of cycles 5-12, day 1 of combination therapy for subjects with PR.
6. Subjects will then continue single agent lenalidomide until disease progression. | 15 |
| Total | 15 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Death | 3 |
| Overall Study | Physician Decision | 3 |
Baseline characteristics
| Characteristic | Lenalidomide + Plerixafor+ Rituximab |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 4 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 | 15 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 | 1 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 |
| Region of Enrollment United States | 15 participants |
| Sex: Female, Male Female | 4 Participants |
| Sex: Female, Male Male | 11 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 14 / 15 |
| serious Total, serious adverse events | 14 / 15 |
Outcome results
Primary
Maximum Tolerated Dose
Time frame: 4-16 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Lenalidomide + Plerixafor+ Rituximab | Maximum Tolerated Dose | 0.24 mg/kg |
Secondary
Overall Response (Complete Response/Partial Response)
NCI 96 Response Criteria CR (Complete Response): Lymphadenopathy = none \> 1.5cm Hepatomegaly = none Splenomegaly = none Blood lymphocytes = \<4000 per microliter Marrow = normocellular, \<30% lymphocytes, no B-lymphoid nodules. Platelet count = \>100,000 per microliter Hemoglobin = \>11.0 grams per deciliter Neutrophils = \>1500 per microliter PR (Partial Response): Lymphadenopathy = Decrease \>/= 50% Hepatomegaly = Decrease \>/= 50% Splenomegaly = Decrease \>/= 50% Blood lymphocytes = Decrease \>/= 50% from baseline Marrow = 50% reduction in marrow infiltrate or B-lymphoid nodules. Platelet count = \>100,000 per microliter or increase \>/= 50% over baseline Hemoglobin = \>11.0 grams per deciliter or increase \>/= 50% over baseline Neutrophils = \>1500 per microliter or increase \>/= 50% over baseline
Time frame: at the end of 4 months of combination treatment and at 2 months after completion of therapy
Population: Three (3) subjects were unable to complete the run-in phase. Three (3) subjects died prior to completing stage 2, and three (3) subjects were unable to complete 4 cycles of combination therapy. Therefore, only 6 subjects were analyzed for response.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Lenalidomide + Plerixafor+ Rituximab | Overall Response (Complete Response/Partial Response) | 0 Participants |
Secondary
Overall Survival (OS)
Time frame: the time from day 1 of treatment to death or 2 years, whichever comes first
Population: Subjects who died on study
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Lenalidomide + Plerixafor+ Rituximab | Overall Survival (OS) | 5.5 months | Standard Deviation 10 |
Secondary
Progression-free Survival (PFS)
Time frame: time from day 1 of treatment to disease progression, death, or 2 years, whichever comes first
Population: Subjects who experienced disease progression
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Lenalidomide + Plerixafor+ Rituximab | Progression-free Survival (PFS) | 11 months | Standard Deviation 1 |
Secondary
Reduction in Severity of B Symptoms
Reduction in the severity of the following B symptoms will be assessed: fever ≥ 101F, chills, night sweats, and anorexia with weight loss.
Time frame: at the end of stage 1 (lenalidomide alone), at the end of stage 2 (4 months of combination), and at 2 months post-completion of therapy
Population: Data were not collected and the Outcome will never be analyzed
Secondary
Reduction in the Frequency of Blood and Platelet Transfusions
The change in number of transfusions from pre- to post-treatment will be calculated and summarized across all patients by giving the minimum, the 25th, 50th (median) and the 75th percentile and the maximum.
Time frame: 4 weeks prior to therapy and in the 4 weeks following the completion of therapy
Population: Data were not collected and the Outcome will never be analyzed