Acute Myeloid Leukemia (AML), Anemia, Leukemia, Myelodysplastic Syndromes (MDS)
Conditions
Brief summary
This is a single-center, single arm, open-label study of oral lenalidomide monotherapy administered to red blood cell (RBC) transfusion dependent adult subjects with Diamond-Blackfan Anemia (DBA). Primary Objective: To evaluate the erythroid response rate as measured by rate of red blood cell transfusion independence \[MDS International Working Group (IWG) 2000 Criteria will be applied\]. Secondary Objective: 1)To evaluate the tolerability and safety profile of lenalidomide in patients with DBA and other inherited marrow failure syndromes 2) To correlate response to lenalidomide with biologic surrogates of DBA including ribosomal protein mutation status, ex vivo erythroid colony growth, and microarray gene expression
Detailed description
This pilot study will utilize an intra-patient dose escalation design. Cycles are 28 days in length. Subjects will receive lenalidomide 2.5 mg weekly during days 1 to 21 of cycle 1 (dose level 1). If patients do not experience any grade \> 3 hematologic or non-hematologic toxicity, the dose will be increased to 2.5 mg twice weekly on days 1 to 21 of cycle 2 (dose level 2). If patients do not experience any grade \> 3 hematologic or non-hematologic toxicity, the dose will be increased to 5 mg twice weekly on days 1 to 21 of cycle 3 (dose level 3). If patients do not experience any grade \>3 hematologic or non-hematologic toxicity, the dose will be increased to 5 mg thrice weekly on days 1 to 21 of cycle 4 (dose level 4). Patients who experience grade \>3 hematologic or non-hematologic toxicity at dose level 1 will be discontinued from study. Patients who experience grade \> 3 hematologic or non-hematologic toxicity at dose level 2, 3, or 4 will have the lenalidomide held and dose reduced according to protocol dose interruption/modification algorithms (section 5.5.3). If at least a minor erythroid response is not achieved at the end of 8 cycles of treatment, patients will be discontinued from study. If a minor or major erythroid response is achieved after completion of 8 cycles of treatment, patients can continue study drug on a maintenance phase until loss of erythroid response (return to baseline hemoglobin or transfusion requirement) or unacceptable toxicity.
Interventions
DRUGLenalidomide
2.5 mg/wk up to 5 mg 3x/wk
Sponsors
Celgene Corporation
Jason Robert Gotlib
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
* Understand and voluntarily sign an informed consent form * Diagnosis of DBA * Age ≥ 18 years at the time of signing the informed consent form. * Able to adhere to the study visit schedule and other protocol requirements. * Red blood cell transfusion-dependent with a requirement of at least one unit of RBCs per month for the 2 months prior to study enrollment (eg, 2 units/8 weeks) * If applicable, ongoing therapy with a stable or decreasing dose of prednisone ≤ 60 mg/d or corticosteroid equivalent, for which there has been no treatment-related improvement in RBC transfusion requirements for at least 2 months prior to study entry * Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2 at study entry. * Laboratory test results within these ranges: * Absolute neutrophil count (ANC) ≥ 1500/uL * Platelet (Plt) count ≥ 100,000/uL * Serum creatinine ≤ 2.0 mg/dL * Direct bilirubin ≤ 1.5 mg/dL * Aspartate aminotransferase (AST) ≤ 2.5 x upper limit of normal (ULN) * Alanine aminotransferase (ALT) ≤ 2.5 x ULN * Disease-free of prior malignancies for ≥ 5 years with exception of currently treated basal cell, squamous cell carcinoma of the skin, or carcinoma in-situ of the cervix or breast * Females of childbearing potential (FCBP) must have a negative serum or urine pregnancy test with a sensitivity of ≥ 50 milli-International Units (MIU)/mL within 10 to 14 days prior to and again within 24 hours of prescribing lenalidomide (prescriptions must be filled within 7 days) and must either commit to continued abstinence from heterosexual intercourse or begin 2 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. FCBP must also agree to ongoing pregnancy testing. Men must agree to use a latex condom during sexual contact with a FCBP even if they have had a successful vasectomy * Able to take aspirin (81 to 325 mg) daily as prophylactic anticoagulation (patients intolerant to aspirin 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 (excluding steroids) specifically used for DBA within 28 days of baseline including metoclopramide, leucine, danazol, or other hormonal therapy * Clinically significant anemia due to factors such as iron, B12, folate deficiencies, autoimmune or hereditary hemolysis, or gastrointestinal bleeding. * 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 * Concurrent use of other anti-cancer agents or treatments * Known positive for HIV or infectious hepatitis, type A, B or C
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Red Blood Cell (RBC) Transfusion Independence | 6 months | Red blood cell (RBC) transfusion independence is reported as the number of subjects who achieve a continuous absence of the intravenous infusion of any RBC transfusion during any consecutive rolling 56 days during the treatment period. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Hemoglobin Concentration | 6 months | The effect on hemoglobin concentration was assessed as the change from baseline, measured in g/dL. |
| Neutrophil Response | 6 months | The effect on neutrophil levels was assessed as the change in neutrophil count from baseline. |
| Red Blood Cell (RBC) Transfusions | 6 months | The effect on red blood cell (RBC) transfusions was assessed as the number of participants that achieved a greater than 50% decrease in RBC transfusion requirements. |
| Duration of Response | 6 months | The response duration was measured from the last of the consecutive 56 days during which the subject was free of red blood cells (RBC) transfusions to the date of the first RBC transfusion after the 56-day RBC-transfusion-free period. |
| Toxicity | 6 months | Toxicity was assessed as the number of adverse events related to lenalidomide. |
| Platelet Response | 6 months | The effect on platelet levels as assessed as the change in platelet count from baseline. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Lenalidomide Subjects will initially receive lenalidomide 2.5 mg, and may escalate up to 2.5 mg/wk up to 5 mg 3x/wk, depending toxicity and response. | 2 |
| Total | 2 |
Baseline characteristics
| Characteristic | Lenalidomide |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 2 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 2 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 | 2 Participants |
| Region of Enrollment United States | 2 participants |
| Sex: Female, Male Female | 1 Participants |
| Sex: Female, Male Male | 1 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 2 / 2 |
| serious Total, serious adverse events | 0 / 2 |
Outcome results
Primary
Red Blood Cell (RBC) Transfusion Independence
Red blood cell (RBC) transfusion independence is reported as the number of subjects who achieve a continuous absence of the intravenous infusion of any RBC transfusion during any consecutive rolling 56 days during the treatment period.
Time frame: 6 months
Population: All treated subjects were analyzed.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Lenalidomide | Red Blood Cell (RBC) Transfusion Independence | 0 participants |
Secondary
Duration of Response
The response duration was measured from the last of the consecutive 56 days during which the subject was free of red blood cells (RBC) transfusions to the date of the first RBC transfusion after the 56-day RBC-transfusion-free period.
Time frame: 6 months
Population: Both participants were assessed and contributed to the analysis, but never demonstrated any therapeutic response.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Lenalidomide | Duration of Response | 0 days |
Secondary
Hemoglobin Concentration
The effect on hemoglobin concentration was assessed as the change from baseline, measured in g/dL.
Time frame: 6 months
Population: Both participants were assessed and contributed to the analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Lenalidomide | Hemoglobin Concentration | 0.4 g/dL |
Secondary
Neutrophil Response
The effect on neutrophil levels was assessed as the change in neutrophil count from baseline.
Time frame: 6 months
Population: Both participants were assessed and contributed to the analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Lenalidomide | Neutrophil Response | 0.50 1000/uL |
Secondary
Platelet Response
The effect on platelet levels as assessed as the change in platelet count from baseline.
Time frame: 6 months
Population: Both participants were assessed and contributed to the analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Lenalidomide | Platelet Response | 25.5 1000/uL |
Secondary
Red Blood Cell (RBC) Transfusions
The effect on red blood cell (RBC) transfusions was assessed as the number of participants that achieved a greater than 50% decrease in RBC transfusion requirements.
Time frame: 6 months
Population: Both participants were assessed and contributed to the analysis.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Lenalidomide | Red Blood Cell (RBC) Transfusions | 0 Participants |
Secondary
Toxicity
Toxicity was assessed as the number of adverse events related to lenalidomide.
Time frame: 6 months
Population: Both participants were assessed and contributed to the analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Lenalidomide | Toxicity | 1 Related Adverse Events |