Low- or Intermediate-1-risk Myelodysplastic Syndrome (MDS)
Conditions
Brief summary
The purpose of this study is to assess pharmacokinetic and pharmacodynamic characteristics of oral lenalidomide monotherapy administered to patients with Low- or Intermediate-1-risk Myelodysplastic Syndrome (MDS).
Interventions
DRUGLenalidomide
Lenalidomide 5-mg capsules for oral administration
DRUGRecombinant human erythropoietin
Recombinant human erythropoietin (rhu-EPO) subcutaneous injection of 40,000 units.
Sponsors
Celgene Corporation
Study design
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Must understand and voluntarily sign an informed consent form. 2. Age ≥18 years at the time of signing the informed consent form. 3. Must be able to adhere to the study visit schedule and other protocol requirements. 4. Documented diagnosis of MDS that meets International Prognostic Scoring System (IPSS) criteria for Low- to Intermediate-1-risk disease. •Must have a diagnosis of low- or intermediate- risk MDS without a del 5q chromosomal abnormality (patients taking 15 mg starting dose only). 5. Must be able to provide adequate bone marrow (BM) aspirate and biopsy specimens for histopathological analysis and standard cytogenetic analysis during the screening procedure. 6. Red blood cell (RBC) transfusion-dependent anemia defined as having received ≥4 transfusions of RBCs within 56 days of randomization or symptomatic anemia (hemoglobin \< 9.0 g/dl). 7. Failed prior treatment with recombinant human erythropoietin (rhu-EPO) (≥ 30,000 U/week x 6) or serum erythropoietin (EPO) concentration ≥500 mU/ml (hemoglobin \< 9.0 g/dl). 8. Eastern Cooperative Oncology Group (ECOG) performance status score of 0, 1, or 2. 9. Females of childbearing potential (FCBP) must agree to use two reliable forms of contraception simultaneously or to practice complete abstinence from heterosexual intercourse 1) for at least 28 days before starting study drug; 2) while participating in the study; and 3) for at least 28 days after discontinuation from the study. The two methods of reliable contraception must include one highly effective method (i.e. intrauterine device \[IUD\], hormonal \[birth control pills, injections, or implants\], tubal ligation, partner's vasectomy) and one additional effective (barrier) method (i.e. latex condom, diaphragm, cervical cap). FCBP must be referred to a qualified provider of contraceptive methods, if needed.
Exclusion criteria
1. Pregnant or lactating females. 2. Prior therapy with lenalidomide. 3. Proliferative white blood cell (WBC) ≥12,000/µL) chronic myelomonocytic leukemia (CMML). 4. MDS secondary to treatment with radiotherapy, chemotherapy, and/or immunotherapy for malignant or autoimmune diseases. 5. Any of the following lab abnormalities: * Absolute neutrophil count (ANC) \<500 cells/µL (0.5 x 10\^9/L) * Platelet count \<50,000/µL (50 x 10\^9/L) * Serum creatinine \> upper limit of normal (ULN) * Serum glutamic oxaloacetic transaminase/aspartate transaminase (SGOT/AST) or serum glutamic pyruvic transaminase/alanine transaminase (SGPT/ALT) \>2.0 x ULN * Serum total bilirubin \>2.0 mg/dL (34 µmol/L) 6. Prior ≥grade-2 National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) allergic reaction to thalidomide. 7. Prior desquamating (blistering) rash while taking thalidomide. 8. Patients with ≥grade-2 neuropathy. 9. Clinically significant anemia due to factors such as iron, B12 or folate deficiencies, autoimmune or hereditary hemolysis or gastrointestinal bleeding. 10. Use of cytotoxic chemotherapeutic agents, erythropoietin, or experimental agents (agents that are not commercially available) for the treatment of MDS within 28 days of the first day of study drug treatment. 11. Prior history of malignancy other than MDS (except basal cell or squamous cell carcinoma or carcinoma in situ of the cervix or breast) unless the subject has been free of disease for ≥3 years. 12. Any serious medical condition or psychiatric illness that will prevent the patient from signing the informed consent form or will place the subject at unacceptable risk if he/she participates in the study. 13. Known human immunodeficiency virus (HIV-1) positivity.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| PK Phase: Area-under-the Concentration-time Curve (AUC0-24) for Lenalidomide | On Day -7 blood samples were taken at predose (0 hour), 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, and 24 hours post-dose. | Area under the plasma concentration-time curve from Time 0 to 24 hours post-dose for lenalidomide after a single dose, calculated using the log-linear trapezoidal method. |
| Monotherapy Phase: Area-under-the Concentration-time Curve (AUC0-5) for Lenalidomide | On Day 14 blood samples were taken at predose (0 hour), 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, and 5 hours postdose. | Area under the plasma concentration-time curve from Time 0 to 5 hours postdose for lenalidomide (its R- and S- enantiomers and the enantiomers combined) after multiple dosing for 14 days, calculated using the log-linear trapezoidal method. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| PK Phase: Maximum Plasma Concentration of Lenalidomide (Cmax) | On Day -7 blood samples were taken at predose (0 hour), 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, and 24 hours postdose. | The maximum observed plasma concentration (Cmax) of lenalidomide (its R- and S- enantiomers and the enantiomers combined) after a single dose on day -7. |
| PK Phase: Percent of Administered Lenalidomide Excreted Over 24 Hours After a Single, Oral Dose | On Day -7 at predose and over the intervals of 0-5, 5-8, 8-12, and 12-24 hours postdose. | Percent of the administered dose of lenalidomide excreted unchanged in urine over 24 hours postdose after a single dose on Day -7, calculated as: (amount excreted unchanged in urine over 24 hours postdose / Dose) \* 100. The dose was 10 mg for total lenalidomide and 5 mg for the enantiomers. |
| Monotherapy Phase: Percent of Lenalidomide Excreted Over 5 Hours Post Day 14 Dose | On Day 14, at predose and over the interval of 0-5 hours postdose. | Percent of the administered lenalidomide dose excreted unchanged in urine over 5 hours postdose after multiple dosing for 14 days, calculated as: (amount excreted unchanged in urine over the first 5 hours postdose / Dose) \* 100. The dose was 10 mg for total lenalidomide and 5 mg for the enantiomers. |
| Time to Grade 4 Neutropenia or Thrombocytopenia | From the date of first dose until 30 days after the last dose (up to 1218 days) | Time to the first event of grade 4 neutropenia or thrombocytopenia, graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 3.0, was calculated as date of first event - date of first dose + 1. |
| Monotherapy Phase: Maximum Plasma Concentration of Lenalidomide (Cmax) | On Day 14 blood samples were taken at predose (0 hour), 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, and 5 hours postdose. | The Maximum observed plasma concentration (Cmax) of lenalidomide (its R- and S- enantiomers and the enantiomers combined) after multiple dosing for 14 days. |
| Percentage of Participants Overall With Erythroid Response by Baseline Erythropoietin Level | Assessed every 28 days until study discontinuation (up to 1218 days) | To evaluate the predictive value of pretreatment serum erythropoietin (EPO) concentration for erythroid response to lenalidomide, the percentage of erythroid responders versus non-responders were stratified by Baseline EPO levels (≤ 500 mIU/mL versus \> 500 mIU/mL). Response includes participants with either a major or minor response. |
| Change From Baseline in Bone Marrow Cellularity and Correlation With Grade 4 Myelosuppression | Baseline and Week 16 | Bone marrow cellularity is the volume ratio of hematopoietic stem cells and adipocytes (fat cells). Due to the small number of bone marrow samples, this analysis was not performed. |
| Marrow-infiltrating Lymphocyte (MIL) Number and Cytolytic Activity | Pre-Study and Week 16 | Due to the low number of bone marrow samples collected this analysis was not performed. |
| Percentage of Participants With a Erythroid Response Across All Phases | Assessed every 28 days until study discontinuation (up to 1218 days). | Erythroid response was categorized as either a major response or a minor response. A major response was defined as red blood cell (RBC) transfusion independence during any consecutive 56-day period and an increase in hemoglobin of at least 1.5 g/dL. A minor response was defined as a ≥ 50% or ≥ 4 unit decrease in RBC transfusions from pretreatment requirements (the number of RBC transfusions required over an 8-week period before the start of study drug treatment). |
| PK Phase: Terminal Half-life (t1/2) | On Day -7 blood samples were taken at predose (0 hour), 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, and 24 hours postdose. | The apparent terminal half-life is the time required for plasma concentration to decrease by 50% after pseudo-equilibrium of distribution has been reached, and calculated as the natural logarithm of 2 (0.693) / Apparent terminal rate constant (λz). |
Countries
United States
Participant flow
Recruitment details
A total of 40 participants were enrolled at 1 site in this study, with 12 participants enrolled in the Pharmacokinetic (PK) Phase of the study, 39 participants enrolled in the Monotherapy Phase of the study, and 23 participants enrolled in the Combined Treatment Phase of the study.
Pre-assignment details
The Monotherapy Phase included an initial group of 24 patients (11 from the PK Phase and 13 newly enrolled) who participated in the multiple-dose PK assessment and a second group of 15 patients (15 mg Non-del 5q) for whom no PK samples were taken. Erythroid nonresponders or responders who relapsed could participate in the Combined Treatment Phase.
Participants by arm
| Arm | Count |
|---|---|
| 10 mg Non-del 5q Participants with low- or intermediate-1-risk myelodysplastic syndromes (MDS) not associated with a deletion 5q (del 5q) cytogenetic abnormality received a single 10 mg oral dose of lenalidomide on Day -7 in the Pharmacokinetic Phase.
During the Monotherapy Phase participants received 10 mg oral lenalidomide once daily. Erythroid responders could continue lenalidomide monotherapy in the absence of limiting toxicity, disease progression, or erythroid failure.
After the completion of 16 weeks of lenalidomide monotherapy, in the Combined Treatment Phase participants who were erythroid nonresponders and erythroid responders who had developed an erythroid relapse continued treatment with 10 mg lenalidomide daily in conjunction with recombinant human erythropoietin (rhu EPO) 40,000 units administered weekly by subcutaneous injection for 8 weeks. Responding patients could continue combined treatment. | 17 |
| 15 mg Non-del 5q Participants with low- or intermediate-1-risk MDS not associated with a deletion 5q (del 5q) cytogenetic abnormality were enrolled directly into the Monotherapy Phase and received 15 mg oral lenalidomide once daily. Erythroid responders could continue lenalidomide monotherapy in the absence of limiting toxicity, disease progression, or erythroid failure.
After the completion of 16 weeks of lenalidomide monotherapy, in the Combined Treatment Phase participants who were erythroid nonresponders and erythroid responders who had developed an erythroid relapse continued treatment with 15 mg lenalidomide daily in conjunction with recombinant human erythropoietin (rhu EPO) 40,000 units administered weekly by subcutaneous injection for 8 weeks. Responding patients could continue combined treatment. | 15 |
| 10 mg Del 5q Participants with a deletion 5q (del 5q) cytogenetic abnormality received a single 10 mg oral dose of lenalidomide on Day -7 in the Pharmacokinetic Phase.
During the Monotherapy Phase participants received 10 mg oral lenalidomide once daily. Erythroid responders could continue lenalidomide monotherapy in the absence of limiting toxicity, disease progression, or erythroid failure.
After the completion of 16 weeks of lenalidomide monotherapy, in the Combined Treatment Phase participants who were erythroid nonresponders and erythroid responders who had developed an erythroid relapse continued treatment with 10 mg of lenalidomide daily in conjunction with recombinant human erythropoietin (rhu EPO) 40,000 units administered weekly by subcutaneous injection for 8 weeks. Responding patients could continue combined treatment. | 7 |
| Total | 39 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Combined Treatment Phase | Lack of therapeutic effect | 8 | 6 | 3 |
| Combined Treatment Phase | Other | 0 | 2 | 1 |
| Combined Treatment Phase | Protocol Violation | 1 | 0 | 0 |
| Combined Treatment Phase | Withdrawal by Subject | 0 | 2 | 0 |
| Monotherapy Phase | Adverse Event | 3 | 2 | 0 |
| Monotherapy Phase | Lack of therapeutic effect | 9 | 6 | 4 |
| Monotherapy Phase | Other | 3 | 4 | 2 |
| Monotherapy Phase | Protocol Violation | 1 | 0 | 0 |
| Monotherapy Phase | Withdrawal by Subject | 1 | 3 | 1 |
| Pharmacokinetic Phase | Adverse Event | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | 10 mg Non-del 5q | Total | 10 mg Del 5q | 15 mg Non-del 5q |
|---|---|---|---|---|
| Age Continuous | 67.8 years STANDARD_DEVIATION 10.96 | 70.8 years STANDARD_DEVIATION 9.07 | 72.6 years STANDARD_DEVIATION 7.39 | 73.4 years STANDARD_DEVIATION 6.51 |
| Duration of MDS | 2.8 years STANDARD_DEVIATION 2.28 | 3.0 years STANDARD_DEVIATION 2.81 | 4.2 years STANDARD_DEVIATION 4.74 | 2.6 years STANDARD_DEVIATION 2.22 |
| Eastern Cooperative Oncology Group (ECOG) Performance Status 0 | 2 participants | 7 participants | 1 participants | 4 participants |
| Eastern Cooperative Oncology Group (ECOG) Performance Status 1 | 14 participants | 31 participants | 6 participants | 11 participants |
| Eastern Cooperative Oncology Group (ECOG) Performance Status 2 | 1 participants | 1 participants | 0 participants | 0 participants |
| French-American-British (FAB) classification of MDS Other | 3 participants | 4 participants | 1 participants | 0 participants |
| French-American-British (FAB) classification of MDS Refractory anemia (RA) | 6 participants | 15 participants | 2 participants | 7 participants |
| French-American-British (FAB) classification of MDS Refractory anemia with excess blasts -1 (RAEB-1) | 0 participants | 1 participants | 0 participants | 1 participants |
| French-American-British (FAB) classification of MDS Refractory anemia with excess blasts (RAEB) | 3 participants | 8 participants | 4 participants | 1 participants |
| French-American-British (FAB) classification of MDS Refractory anemia with ringed sideroblasts (RARS) | 5 participants | 11 participants | 0 participants | 6 participants |
| International Prognostic Scoring System (IPSS) Score Intermediate-1 (0.5-1.0) | 9 participants | 21 participants | 5 participants | 7 participants |
| International Prognostic Scoring System (IPSS) Score Low risk (0) | 8 participants | 18 participants | 2 participants | 8 participants |
| Race/Ethnicity, Customized Hispanic | 1 participants | 2 participants | 0 participants | 1 participants |
| Race/Ethnicity, Customized Other | 1 participants | 2 participants | 0 participants | 1 participants |
| Race/Ethnicity, Customized White | 17 participants | 37 participants | 7 participants | 13 participants |
| Serum erythropoietin level < 500 mIU/mL | 9 participants | 15 participants | 2 participants | 4 participants |
| Serum erythropoietin level ≥ 500 mIU/mL | 7 participants | 14 participants | 5 participants | 2 participants |
| Serum erythropoietin level Missing | 1 participants | 10 participants | 0 participants | 9 participants |
| Sex: Female, Male Female | 3 Participants | 11 Participants | 4 Participants | 4 Participants |
| Sex: Female, Male Male | 14 Participants | 28 Participants | 3 Participants | 11 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 24 / 24 | 15 / 15 |
| serious Total, serious adverse events | 10 / 24 | 5 / 15 |
Outcome results
Primary
Monotherapy Phase: Area-under-the Concentration-time Curve (AUC0-5) for Lenalidomide
Area under the plasma concentration-time curve from Time 0 to 5 hours postdose for lenalidomide (its R- and S- enantiomers and the enantiomers combined) after multiple dosing for 14 days, calculated using the log-linear trapezoidal method.
Time frame: On Day 14 blood samples were taken at predose (0 hour), 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, and 5 hours postdose.
Population: Monotherapy Phase pharmacokinetic population
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| 10 mg Lenalidomide | Monotherapy Phase: Area-under-the Concentration-time Curve (AUC0-5) for Lenalidomide | Total Lenalidomide | 563 ng*h/mL | Geometric Coefficient of Variation 32.5 |
| 10 mg Lenalidomide | Monotherapy Phase: Area-under-the Concentration-time Curve (AUC0-5) for Lenalidomide | S-Lenalidomide | 315 ng*h/mL | Geometric Coefficient of Variation 34.2 |
| 10 mg Lenalidomide | Monotherapy Phase: Area-under-the Concentration-time Curve (AUC0-5) for Lenalidomide | R-Lenalidomide | 248 ng*h/mL | Geometric Coefficient of Variation 30.6 |
Primary
PK Phase: Area-under-the Concentration-time Curve (AUC0-24) for Lenalidomide
Area under the plasma concentration-time curve from Time 0 to 24 hours post-dose for lenalidomide after a single dose, calculated using the log-linear trapezoidal method.
Time frame: On Day -7 blood samples were taken at predose (0 hour), 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, and 24 hours post-dose.
Population: All Pharmacokinetic Phase participants.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| 10 mg Lenalidomide | PK Phase: Area-under-the Concentration-time Curve (AUC0-24) for Lenalidomide | 817 ng*h/mL | Geometric Coefficient of Variation 30.5 |
Secondary
Change From Baseline in Bone Marrow Cellularity and Correlation With Grade 4 Myelosuppression
Bone marrow cellularity is the volume ratio of hematopoietic stem cells and adipocytes (fat cells). Due to the small number of bone marrow samples, this analysis was not performed.
Time frame: Baseline and Week 16
Population: Unable to obtain sufficient bone marrow samples to perform analyses.
Secondary
Marrow-infiltrating Lymphocyte (MIL) Number and Cytolytic Activity
Due to the low number of bone marrow samples collected this analysis was not performed.
Time frame: Pre-Study and Week 16
Population: Unable to obtain sufficient bone marrow samples to perform analyses
Secondary
Monotherapy Phase: Maximum Plasma Concentration of Lenalidomide (Cmax)
The Maximum observed plasma concentration (Cmax) of lenalidomide (its R- and S- enantiomers and the enantiomers combined) after multiple dosing for 14 days.
Time frame: On Day 14 blood samples were taken at predose (0 hour), 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, and 5 hours postdose.
Population: Monotherapy Phase pharmacokinetic population.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| 10 mg Lenalidomide | Monotherapy Phase: Maximum Plasma Concentration of Lenalidomide (Cmax) | Total Lenalidomide | 185 ng/mL | Geometric Coefficient of Variation 38.7 |
| 10 mg Lenalidomide | Monotherapy Phase: Maximum Plasma Concentration of Lenalidomide (Cmax) | S-Lenalidomide | 104 ng/mL | Geometric Coefficient of Variation 39 |
| 10 mg Lenalidomide | Monotherapy Phase: Maximum Plasma Concentration of Lenalidomide (Cmax) | R-Lenalidomide | 80.7 ng/mL | Geometric Coefficient of Variation 38.8 |
Secondary
Monotherapy Phase: Percent of Lenalidomide Excreted Over 5 Hours Post Day 14 Dose
Percent of the administered lenalidomide dose excreted unchanged in urine over 5 hours postdose after multiple dosing for 14 days, calculated as: (amount excreted unchanged in urine over the first 5 hours postdose / Dose) \* 100. The dose was 10 mg for total lenalidomide and 5 mg for the enantiomers.
Time frame: On Day 14, at predose and over the interval of 0-5 hours postdose.
Population: Monotherapy Phase Pharmacokinetic Population.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| 10 mg Lenalidomide | Monotherapy Phase: Percent of Lenalidomide Excreted Over 5 Hours Post Day 14 Dose | Total Lenalidomide | 34.0 percent of administered dose | Geometric Coefficient of Variation 60.3 |
| 10 mg Lenalidomide | Monotherapy Phase: Percent of Lenalidomide Excreted Over 5 Hours Post Day 14 Dose | S-Lenalidomide | 35.4 percent of administered dose | Geometric Coefficient of Variation 59 |
| 10 mg Lenalidomide | Monotherapy Phase: Percent of Lenalidomide Excreted Over 5 Hours Post Day 14 Dose | R-Lenalidomide | 32.5 percent of administered dose | Geometric Coefficient of Variation 62 |
Secondary
Percentage of Participants Overall With Erythroid Response by Baseline Erythropoietin Level
To evaluate the predictive value of pretreatment serum erythropoietin (EPO) concentration for erythroid response to lenalidomide, the percentage of erythroid responders versus non-responders were stratified by Baseline EPO levels (≤ 500 mIU/mL versus \> 500 mIU/mL). Response includes participants with either a major or minor response.
Time frame: Assessed every 28 days until study discontinuation (up to 1218 days)
Population: Safety population.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| 10 mg Lenalidomide | Percentage of Participants Overall With Erythroid Response by Baseline Erythropoietin Level | Baseline EPO ≤ 500 mIU/mL | 62.5 percentage of participants |
| 10 mg Lenalidomide | Percentage of Participants Overall With Erythroid Response by Baseline Erythropoietin Level | Baseline EPO > 500 mIU/mL | 37.5 percentage of participants |
| Del 5q | Percentage of Participants Overall With Erythroid Response by Baseline Erythropoietin Level | Baseline EPO > 500 mIU/mL | 39.1 percentage of participants |
| Del 5q | Percentage of Participants Overall With Erythroid Response by Baseline Erythropoietin Level | Baseline EPO ≤ 500 mIU/mL | 47.8 percentage of participants |
| 10 mg Del 5q | Percentage of Participants Overall With Erythroid Response by Baseline Erythropoietin Level | Baseline EPO ≤ 500 mIU/mL | 53.8 percentage of participants |
| 10 mg Del 5q | Percentage of Participants Overall With Erythroid Response by Baseline Erythropoietin Level | Baseline EPO > 500 mIU/mL | 38.5 percentage of participants |
Secondary
Percentage of Participants With a Erythroid Response Across All Phases
Erythroid response was categorized as either a major response or a minor response. A major response was defined as red blood cell (RBC) transfusion independence during any consecutive 56-day period and an increase in hemoglobin of at least 1.5 g/dL. A minor response was defined as a ≥ 50% or ≥ 4 unit decrease in RBC transfusions from pretreatment requirements (the number of RBC transfusions required over an 8-week period before the start of study drug treatment).
Time frame: Assessed every 28 days until study discontinuation (up to 1218 days).
Population: Safety population, which comprised all enrolled patients who took at least 1 dose of study drug during the Monotherapy Phase or the Combined Treatment Phase.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| 10 mg Lenalidomide | Percentage of Participants With a Erythroid Response Across All Phases | Minor response | 5.9 percentage of participants |
| 10 mg Lenalidomide | Percentage of Participants With a Erythroid Response Across All Phases | Major response | 17.6 percentage of participants |
| Del 5q | Percentage of Participants With a Erythroid Response Across All Phases | Minor response | 0 percentage of participants |
| Del 5q | Percentage of Participants With a Erythroid Response Across All Phases | Major response | 40.0 percentage of participants |
| 10 mg Del 5q | Percentage of Participants With a Erythroid Response Across All Phases | Major response | 85.7 percentage of participants |
| 10 mg Del 5q | Percentage of Participants With a Erythroid Response Across All Phases | Minor response | 0 percentage of participants |
Secondary
PK Phase: Maximum Plasma Concentration of Lenalidomide (Cmax)
The maximum observed plasma concentration (Cmax) of lenalidomide (its R- and S- enantiomers and the enantiomers combined) after a single dose on day -7.
Time frame: On Day -7 blood samples were taken at predose (0 hour), 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, and 24 hours postdose.
Population: All Pharmacokinetic Phase participants
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| 10 mg Lenalidomide | PK Phase: Maximum Plasma Concentration of Lenalidomide (Cmax) | Total Lenalidomide | 179 ng/mL | Geometric Coefficient of Variation 33.6 |
| 10 mg Lenalidomide | PK Phase: Maximum Plasma Concentration of Lenalidomide (Cmax) | S-Lenalidomide | 101 ng/mL | Geometric Coefficient of Variation 34.9 |
| 10 mg Lenalidomide | PK Phase: Maximum Plasma Concentration of Lenalidomide (Cmax) | R-Lenalidomide | 78.3 ng/mL | Geometric Coefficient of Variation 32.7 |
Secondary
PK Phase: Percent of Administered Lenalidomide Excreted Over 24 Hours After a Single, Oral Dose
Percent of the administered dose of lenalidomide excreted unchanged in urine over 24 hours postdose after a single dose on Day -7, calculated as: (amount excreted unchanged in urine over 24 hours postdose / Dose) \* 100. The dose was 10 mg for total lenalidomide and 5 mg for the enantiomers.
Time frame: On Day -7 at predose and over the intervals of 0-5, 5-8, 8-12, and 12-24 hours postdose.
Population: PK Phase participants for whom data was available.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| 10 mg Lenalidomide | PK Phase: Percent of Administered Lenalidomide Excreted Over 24 Hours After a Single, Oral Dose | Total Lenalidomide | 65.1 percent of administered dose | Geometric Coefficient of Variation 13.5 |
| 10 mg Lenalidomide | PK Phase: Percent of Administered Lenalidomide Excreted Over 24 Hours After a Single, Oral Dose | S-Lenalidomide | 67.9 percent of administered dose | Geometric Coefficient of Variation 13.9 |
| 10 mg Lenalidomide | PK Phase: Percent of Administered Lenalidomide Excreted Over 24 Hours After a Single, Oral Dose | R-Lenalidomide | 62.2 percent of administered dose | Geometric Coefficient of Variation 14 |
Secondary
PK Phase: Terminal Half-life (t1/2)
The apparent terminal half-life is the time required for plasma concentration to decrease by 50% after pseudo-equilibrium of distribution has been reached, and calculated as the natural logarithm of 2 (0.693) / Apparent terminal rate constant (λz).
Time frame: On Day -7 blood samples were taken at predose (0 hour), 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, and 24 hours postdose.
Population: Pharmacokinetic Phase participants.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| 10 mg Lenalidomide | PK Phase: Terminal Half-life (t1/2) | Total Lenalidomide | 3.72 hours | Geometric Coefficient of Variation 19.5 |
| 10 mg Lenalidomide | PK Phase: Terminal Half-life (t1/2) | R-Lenalidomide | 3.58 hours | Geometric Coefficient of Variation 21.4 |
| 10 mg Lenalidomide | PK Phase: Terminal Half-life (t1/2) | S-Lenalidomide | 4.14 hours | Geometric Coefficient of Variation 29 |
Secondary
Time to Grade 4 Neutropenia or Thrombocytopenia
Time to the first event of grade 4 neutropenia or thrombocytopenia, graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 3.0, was calculated as date of first event - date of first dose + 1.
Time frame: From the date of first dose until 30 days after the last dose (up to 1218 days)
Population: Safety population, which comprised all enrolled patients who took at least 1 dose of study drug during the Monotherapy Phase or the Combined Treatment Phase.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| 10 mg Lenalidomide | Time to Grade 4 Neutropenia or Thrombocytopenia | Grade 4 Neutropenia | 69.0 days |
| 10 mg Lenalidomide | Time to Grade 4 Neutropenia or Thrombocytopenia | Grade 4 Thrombocytopenia | 53.0 days |
| Del 5q | Time to Grade 4 Neutropenia or Thrombocytopenia | Grade 4 Neutropenia | 28.0 days |
| Del 5q | Time to Grade 4 Neutropenia or Thrombocytopenia | Grade 4 Thrombocytopenia | 29.0 days |