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

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ClinicalTrials.gov Identifier: NCT00910858
Recruitment Status : Completed
First Posted : June 1, 2009
Results First Posted : September 30, 2013
Last Update Posted : September 30, 2013
Sponsor:
Information provided by (Responsible Party):
Celgene ( Celgene Corporation )

Tracking Information
First Submitted Date  ICMJE May 28, 2009
First Posted Date  ICMJE June 1, 2009
Results First Submitted Date  ICMJE July 31, 2013
Results First Posted Date  ICMJE September 30, 2013
Last Update Posted Date September 30, 2013
Study Start Date  ICMJE January 2005
Actual Primary Completion Date April 2006   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: July 31, 2013)
  • PK Phase: Area-under-the Concentration-time Curve (AUC0-24) for Lenalidomide [ 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. ]
    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 [ 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. ]
    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.
Original Primary Outcome Measures  ICMJE
 (submitted: May 29, 2009)
Single-dose Area-under-the concentration-time curve (AUC0-24) for lenalidomide (its R and S- enantiomers and the enantiomers combined) (Day -7) Single-dose AUC0-5 for lenalidomide (its R- and S- enantiomers and the enantiomers combined) (Day 14)
Change History Complete list of historical versions of study NCT00910858 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: July 31, 2013)
  • PK Phase: Maximum Plasma Concentration of Lenalidomide (Cmax) [ 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. ]
    The maximum observed plasma concentration (Cmax) of lenalidomide (its R- and S- enantiomers and the enantiomers combined) after a single dose on day -7.
  • Monotherapy Phase: Maximum Plasma Concentration of Lenalidomide (Cmax) [ 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. ]
    The Maximum observed plasma concentration (Cmax) of lenalidomide (its R- and S- enantiomers and the enantiomers combined) after multiple dosing for 14 days.
  • PK Phase: Terminal Half-life (t1/2) [ 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. ]
    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).
  • PK Phase: Percent of Administered Lenalidomide Excreted Over 24 Hours After a Single, Oral Dose [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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.
  • Percentage of Participants With a Erythroid Response Across All Phases [ Time Frame: 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).
  • Percentage of Participants Overall With Erythroid Response by Baseline Erythropoietin Level [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: Pre-Study and Week 16 ]
    Due to the low number of bone marrow samples collected this analysis was not performed.
Original Secondary Outcome Measures  ICMJE
 (submitted: May 29, 2009)
  • Maximum plasma concentration (Cmax)
  • Elimination half-life (t1/2)
  • Amount of lenalidomide excreted into urine after a single, oral dose (Day -7 dose)
  • Amount of lenalidomide excreted into urine from 0-5 hours post Day 14 dose.
  • Frequency of and interval to development of grade 4 neutropenia or thrombocytopenia
  • Erythroid response
  • Serum EPO concentration Pre-Study, Weeks 8 and 16
  • Bone marrow cellularity and change from baseline with grade-4 myelosuppression.
  • MIL number and cytolytic activity (Pre-Study and Week 16)
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE A Pharmacokinetic And Pharmacodynamic Study Of Oral Lenalidomide (Revlimid) In Subjects With Low- Or Intermediate-1-Risk Myelodysplastic Syndromes
Official Title  ICMJE A Pharmacokinetic And Pharmacodynamic Study Of Oral Lenalidomide (Revlimid) In Subjects With Low- Or Intermediate-1-Risk Myelodysplastic Syndromes
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).
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Low- or Intermediate-1-risk Myelodysplastic Syndrome (MDS)
Intervention  ICMJE
  • Drug: Lenalidomide
    Lenalidomide 5-mg capsules for oral administration
    Other Name: Revlimid
  • Drug: Recombinant human erythropoietin
    Recombinant human erythropoietin (rhu-EPO) subcutaneous injection of 40,000 units.
Study Arms  ICMJE
  • Experimental: 10 mg Lenalidomide

    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.

    Interventions:
    • Drug: Lenalidomide
    • Drug: Recombinant human erythropoietin
  • Experimental: 15 mg Lenalidomide Non-del 5q
    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.
    Interventions:
    • Drug: Lenalidomide
    • Drug: Recombinant human erythropoietin
Publications * Komrokji RS, Lancet JE, Swern AS, Chen N, Paleveda J, Lush R, Saba HI, List AF. Combined treatment with lenalidomide and epoetin alfa in lower-risk patients with myelodysplastic syndrome. Blood. 2012 Oct 25;120(17):3419-24. doi: 10.1182/blood-2012-03-415661. Epub 2012 Aug 30.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: May 29, 2009)
40
Original Actual Enrollment  ICMJE Same as current
Actual Study Completion Date  ICMJE May 2009
Actual Primary Completion Date April 2006   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT00910858
Other Study ID Numbers  ICMJE CC-5013-PK-002
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Celgene ( Celgene Corporation )
Study Sponsor  ICMJE Celgene Corporation
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Robert Knight, MD Celgene Corporation
PRS Account Celgene
Verification Date July 2013

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP