A Pharmacokinetic And Pharmacodynamic Study Of Oral Lenalidomide (Revlimid) In Subjects With Low- Or Intermediate-1-Risk Myelodysplastic Syndromes

Study Overview
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Brief Summary
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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).

Official Title
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A Pharmacokinetic And Pharmacodynamic Study Of Oral Lenalidomide (Revlimid) In Subjects With Low- Or Intermediate-1-Risk Myelodysplastic Syndromes

Conditions
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Low- or Intermediate-1-risk Myelodysplastic Syndrome (MDS)

Intervention / Treatment
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* Drug: Lenalidomide
* Drug: Recombinant human erythropoietin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Must understand and voluntarily sign an informed consent form. Age ≥18 years at the time of signing the informed consent form. Must be able to adhere to the study visit schedule and other protocol requirements. 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). Must be able to provide adequate bone marrow (BM) aspirate and biopsy specimens for histopathological analysis and standard cytogenetic analysis during the screening procedure. 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). 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). Eastern Cooperative Oncology Group (ECOG) performance status score of 0, 1, or 2. 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: Pregnant or lactating females. Prior therapy with lenalidomide. Proliferative white blood cell (WBC) ≥12,000/µL) chronic myelomonocytic leukemia (CMML). MDS secondary to treatment with radiotherapy, chemotherapy, and/or immunotherapy for malignant or autoimmune diseases. 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) Prior ≥grade-2 National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) allergic reaction to thalidomide. Prior desquamating (blistering) rash while taking thalidomide. Patients with ≥grade-2 neuropathy. Clinically significant anemia due to factors such as iron, B12 or folate deficiencies, autoimmune or hereditary hemolysis or gastrointestinal bleeding. 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. 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. 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. Known human immunodeficiency virus (HIV-1) positivity.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 10 mg Lenalidomide<br>Participants in the Pharmacokinetic Phase received a single 10 mg oral dose of lenalidomide on Day -7. 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. During the Combined Treatment Phase participants who were erythroid nonresponders and erythroid responders who had developed an erythroid relapse continued treatment with 10 mg lenalidomide 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. | Drug: Lenalidomide<br>* Lenalidomide 5-mg capsules for oral administration<br>* Other names: Revlimid;Drug: Recombinant human erythropoietin<br>* Recombinant human erythropoietin (rhu-EPO) subcutaneous injection of 40,000 units.<br>|
| Experimental: 15 mg Lenalidomide Non-del 5q<br>Following the enrollment of the first 25 patients into the Monotherapy Phase, a second group of 15 patients with low- or intermediate-1-risk MDS not associated with a del 5q (non-del 5q) cytogenetic abnormality were enrolled to receive 15 mg of lenalidomide once daily. Erythroid responders could continue lenalidomide monotherapy in the absence of limiting toxicity, disease progression, or erythroid failure. During the Combined Treatment Phase participants who were erythroid nonresponders and erythroid responders who had developed an erythroid relapse continued treatment with 15 mg lenalidomide 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. | Drug: Lenalidomide<br>* Lenalidomide 5-mg capsules for oral administration<br>* Other names: Revlimid;Drug: Recombinant human erythropoietin<br>* Recombinant human erythropoietin (rhu-EPO) subcutaneous injection of 40,000 units.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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. | 
| 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. | 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. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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. | 
| 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. | 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. | 
| 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). | 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. | 
| 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. | On Day -7 at predose and over the intervals of 0-5, 5-8, 8-12, and 12-24 hours postdose. | 
| 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. | On Day 14, at predose and over the interval of 0-5 hours postdose. | 
| 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. | From the date of first dose until 30 days after the last dose (up to 1218 days) | 
| 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). | Assessed every 28 days until study discontinuation (up to 1218 days). | 
| 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. | Assessed every 28 days until study discontinuation (up to 1218 days) | 
| 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. | Baseline and Week 16 | 
| Marrow-infiltrating Lymphocyte (MIL) Number and Cytolytic Activity | Due to the low number of bone marrow samples collected this analysis was not performed. | Pre-Study and Week 16 |