Chronic Lymphocytic Leukemia
Conditions
Keywords
advanced or progressive chronic lymphocytic leukemia, Lenalidomide, Fludarabine
Brief summary
This is a phase I - II multicenter, non-comparative, open label study in patients with previously treated CLL aimed at defining the MTD of Lenalidomide given in combination with Fludarabine, Cyclophosphamide and at evaluating the (CR) rate of FC given in combination with the MTD of Lenalidomide (FCL).
Detailed description
OBJECTIVES: Primary * To define the maximum tolerated dose (MTD) of Lenalidomide given in combination with FC.(Phase I) * To evaluate the complete remission (CR) rate of FC given in combination with the MTD of Lenalidomide (FCL). (Phase II) Secondary * To define the toxicity and the infection rate of patients treated with FCL and the median number of delivered courses of FCL, overall response rate and the progression-free survival and the relationship between the response and the baseline biologic factors (IgVH, FISH, ZAP-70, CD38). * To evaluate the overall response rate (complete and partial responses). * To evaluate the progression-free survival. OUTLINE: This is a phase I - II multicenter, non-comparative, open label study in patients with previously treated CLL aimed at defining the MTD of Lenalidomide given in combination with Fludarabine, Cyclophosphamide and at evaluating the (CR) rate of FC given in combination with the MTD of Lenalidomide (FCL). All patients will receive six monthly courses of FCL schedule consisting of three days of Fludarabine and Cyclophosphamide administration (d1-d3) combined with 14 days of Lenalidomide administration (d1-d14). After completion of study treatment, patients are followed periodically for up to 18 months.
Interventions
DRUGCyclophosphamide
All patients will receive six monthly courses of FCL schedule consisting of three days of Fludarabine and Cyclophosphamide administration (d1-d3) combined with 14 days of Lenalidomide administration (d1-d14).
DRUGFludarabine phosphate
All patients will receive six monthly courses of FCL schedule consisting of three days of Fludarabine and Cyclophosphamide administration (d1-d3) combined with 14 days of Lenalidomide administration (d1-d14).
DRUGLenalidomide
All patients will receive six monthly courses of FCL schedule consisting of three days of Fludarabine and Cyclophosphamide administration (d1-d3) combined with 14 days of Lenalidomide administration (d1-d14). In the first phase of the study, the dose of Lenalidomide given with FC will be gradually escalated to reach the MTD. In the second phase of the study, FC will be given in combination with the Lenalidomide escalated to the MTD or the maximum planned dose.
Sponsors
Gruppo Italiano Malattie EMatologiche dell'Adulto
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
* Age \>=18 years. * Able to adhere to the study visit schedule and other protocol requirements. * Patients with advanced stage or progressive CLL (NCI criteria) and relapsed or refractory disease. * No more than 2 previous different treatment lines. * No treatment with Campath-1H in the previous 6 months. * Disease-free of prior malignancies for \>=5 years, with the exception of currently treated basal cell, squamous cell carcinoma of the skin, or carcinoma in situ of the cervix or breast. * All previous cancer therapy, including chemotherapy, immunotherapy and surgery, must have been discontinued at least 4 weeks prior to treatment in this study. * ECOG performance status of \<=2 at study entry. * Laboratory test results within these ranges: * Serum creatinine \<=1.5 mg/dL and creatinine clearance ≥60mL/min * Total bilirubin \<=1.5 mg/dL * AST (SGOT) and ALT (SGPT) \<=1.5 x ULN * Able to take low molecular weight heparin or in alternative, low- fixed-dose warfarin or, in alternative, low-dose aspirin. * Able to understand and voluntarily sign the informed consent form. * Females of childbearing potential (FCBP) must have a negative serum or urine pregnancy test with a sensitivity of at least 25 mIU/mL 10 - 14 days prior to therapy and repeated within 24 hours of starting study. FCBP must agree to use two reliable forms of contraception for at least 28 days before starting study drug; while participating in the study; and for at least 4 weeks after discontinuation from the study. * Females must agree to abstain from breastfeeding during study participation and for at least 28 days after discontinuation from the study. * Males must agree to use a latex condom during sexual contact with females of childbearing potential while participating in the study and for at least 4 weeks following discontinuation. * (Other details regarding pregnancy tests and contraception are reported in the chapter Eligibility Criteria within the study protocol).
Exclusion criteria
* Treatment with Campath-1H during the previous 6 months. * Concurrent use of other anti-cancer agents. * Positive DAT with clinical and laboratory signs of hemolysis, autoimmune thrombocytopenia. * Known positivity for HIV or active infectious hepatitis. * Active bacterial, viral, or fungal infection requiring systemic anti-viral, antibiotic or anti-fungal therapy. * 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. * Prior history or presence of thrombosis, thromboembolism, hearth failure or arrhythmia, neurologic disease and renal insufficiency. * Use of any other experimental drug or therapy within 28 days of baseline. * Known hypersensitivity to thalidomide. * The development of erythema nodosum, desquamating rash while taking thalidomide or similar drugs. * Any prior use of Lenalidomide * Lactose intolerance
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Tolerated Dose of Lenalidomide (Phase I) | The MTD of Lenalinomide will be evaluated during the two courses given with the escalated dose of Lenalinomide defined by the respective dose level. | Maximum tolerated dose of lenalidomide given in combination with fludarabine. |
| Overall Complete Response (CR) Rate (Phase II) | After 6 months from study entry (end of treatment). | Response will be assessed by clinical examination, peripheral blood, bone marrow aspirate and biopsy, radiographic evaluation. Response will be evaluated at three different levels: clinical, cytometric and molecular. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Patients Reaching Disease-free Survival (DSF) Overall | After 6 months from study entry (end of treatment) | Response will be assessed by clinical examination, peripheral blood, bone marrow aspirate and biopsy, radiographic evaluation. Response will be evaluated at three different levels: clinical, cytometric and molecular. |
| Toxicity as Assessed by NCI CTCAE v3.0 | At 24 months from study entry (end of follow-up) | Data from all subjects who receive any study drug will be included in the safety analyses. |
| Number of Patients With Severe Infections | At 24 months from study entry (end of follow-up) | Severe infection requiring more than 2 weeks of antibiotic therapy. |
| Correlation Between Complete Response (CR) and Baseline Biologic Parameters (i.e., IgHV, CD38, Etc.). | After 6 months from study entry (end of treatment). | — |
Countries
Italy
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Phase I-II Lenalidomide The phase I of the study, carried out at a single center (Hematology, Sapienza University of Rome) was focused at defining the MTD of lenalidomide given in combination with the FC regimen according to a 3 + 3 patient design. During the first course of treatment, lenalidomide was given to all patients at the starting dose of 2.5 mg daily (d1-d14). For the subsequent courses, the dose of lenalidomide was progressively escalated at each course, according to a 3 + 3 patient design. In 3 cohorts of 3 patients each, a daily dose of 5, 10, and 15 mg of lenalidomide was tested unless a dose limiting toxicity (DLT) was experienced.
The presence of a persistent and severe hematologic toxicity, grade 2 tumor lysis syndrome (TLS), grade 3 tumor flare reaction (TFR), or other grade 3 toxicities was defined as DLT.
In the second phase of the study, FC was given in combination with lenalidomide escalated from 2.5 mg to reach the MTD or the maximum planned dose of 15 mg. | 40 |
| Total | 40 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Phase I | Dose Limiting Toxicity | 2 |
Baseline characteristics
| Characteristic | Phase I-II Lenalidomide | — |
|---|---|---|
| Age, Continuous | 66 years | — |
| Race and Ethnicity Not Collected | — | — Participants |
| Region of Enrollment Italy | 40 participants | — |
| Sex: Female, Male Female | 10 Participants | — |
| Sex: Female, Male Male | 30 Participants | — |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 14 / 40 |
| other Total, other adverse events | 0 / 40 |
| serious Total, serious adverse events | 8 / 40 |
Outcome results
Primary
Maximum Tolerated Dose of Lenalidomide (Phase I)
Maximum tolerated dose of lenalidomide given in combination with fludarabine.
Time frame: The MTD of Lenalinomide will be evaluated during the two courses given with the escalated dose of Lenalinomide defined by the respective dose level.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Phase I-II Lenalidomide | Maximum Tolerated Dose of Lenalidomide (Phase I) | Dose level 1 - 5 mg | 6 number of patients without DLT |
| Phase I-II Lenalidomide | Maximum Tolerated Dose of Lenalidomide (Phase I) | Dose level 2 - 10 mg | 1 number of patients without DLT |
Primary
Overall Complete Response (CR) Rate (Phase II)
Response will be assessed by clinical examination, peripheral blood, bone marrow aspirate and biopsy, radiographic evaluation. Response will be evaluated at three different levels: clinical, cytometric and molecular.
Time frame: After 6 months from study entry (end of treatment).
Population: 7 patients coming from the phase I + 33 patients enrolled from the phase II. The whole population of phase II part of the trial is composed of a total of 40 patients.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase I-II Lenalidomide | Overall Complete Response (CR) Rate (Phase II) | 22.5 percentage of patients in CR |
Secondary
Correlation Between Complete Response (CR) and Baseline Biologic Parameters (i.e., IgHV, CD38, Etc.).
Time frame: After 6 months from study entry (end of treatment).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Phase I-II Lenalidomide | Correlation Between Complete Response (CR) and Baseline Biologic Parameters (i.e., IgHV, CD38, Etc.). | CR according to IgHV mutated | 28.00 percentage of participants |
| Phase I-II Lenalidomide | Correlation Between Complete Response (CR) and Baseline Biologic Parameters (i.e., IgHV, CD38, Etc.). | CR according to CD19+/CD38+, <30% | 33.33 percentage of participants |
| Phase I-II Lenalidomide | Correlation Between Complete Response (CR) and Baseline Biologic Parameters (i.e., IgHV, CD38, Etc.). | CR according to CD19+/CD38+, >30% | 16.67 percentage of participants |
| Phase I-II Lenalidomide | Correlation Between Complete Response (CR) and Baseline Biologic Parameters (i.e., IgHV, CD38, Etc.). | CR according to deletion 11q and 17p, absent | 31.82 percentage of participants |
Secondary
Number of Patients Reaching Disease-free Survival (DSF) Overall
Response will be assessed by clinical examination, peripheral blood, bone marrow aspirate and biopsy, radiographic evaluation. Response will be evaluated at three different levels: clinical, cytometric and molecular.
Time frame: After 6 months from study entry (end of treatment)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase I-II Lenalidomide | Number of Patients Reaching Disease-free Survival (DSF) Overall | 35.33 percentage of participants on DFS |
Secondary
Number of Patients With Severe Infections
Severe infection requiring more than 2 weeks of antibiotic therapy.
Time frame: At 24 months from study entry (end of follow-up)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase I-II Lenalidomide | Number of Patients With Severe Infections | 2 participants with severe infecitons |
Secondary
Toxicity as Assessed by NCI CTCAE v3.0
Data from all subjects who receive any study drug will be included in the safety analyses.
Time frame: At 24 months from study entry (end of follow-up)
Population: Fourteen (35%) patients have died.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase I-II Lenalidomide | Toxicity as Assessed by NCI CTCAE v3.0 | 14 Participants who died during the study |