Clinical trial NCT00910858: A Pharmacokinetic And Pharmacodynamic Study Of Oral Lenalidomide (Revlimid) In Subjects With Low- Or Intermediate-1-Risk Myelodysplastic Syndromes
Official title: A Pharmacokinetic And Pharmacodynamic Study Of Oral Lenalidomide (Revlimid) In Subjects With Low- Or Intermediate-1-Risk Myelodysplastic Syndromes
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Low- or Intermediate-1-risk Myelodysplastic Syndrome (MDS)
Lead sponsor: Celgene
Sponsor class: INDUSTRY
First posted: 2009-06-01
Enrollment: 40
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Intervention model: PARALLEL
Primary purpose: TREATMENT

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).


Eligibility criteria: 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.

Primary outcomes:
measure: PK Phase: Area-under-the Concentration-time Curve (AUC0-24) for Lenalidomide
timeFrame: 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.
measure: Monotherapy Phase: Area-under-the Concentration-time Curve (AUC0-5) for Lenalidomide
timeFrame: 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 outcomes:
measure: PK Phase: Maximum Plasma Concentration of Lenalidomide (Cmax)
timeFrame: 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.
measure: Monotherapy Phase: Maximum Plasma Concentration of Lenalidomide (Cmax)
timeFrame: 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.
measure: PK Phase: Terminal Half-life (t1/2)
timeFrame: 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.
measure: PK Phase: Percent of Administered Lenalidomide Excreted Over 24 Hours After a Single, Oral Dose
timeFrame: On Day -7 at predose and over the intervals of 0-5, 5-8, 8-12, and 12-24 hours postdose.
measure: Monotherapy Phase: Percent of Lenalidomide Excreted Over 5 Hours Post Day 14 Dose
timeFrame: On Day 14, at predose and over the interval of 0-5 hours postdose.
measure: Time to Grade 4 Neutropenia or Thrombocytopenia
timeFrame: From the date of first dose until 30 days after the last dose (up to 1218 days)
measure: Percentage of Participants With a Erythroid Response Across All Phases
timeFrame: Assessed every 28 days until study discontinuation (up to 1218 days).
measure: Percentage of Participants Overall With Erythroid Response by Baseline Erythropoietin Level
timeFrame: Assessed every 28 days until study discontinuation (up to 1218 days)
measure: Change From Baseline in Bone Marrow Cellularity and Correlation With Grade 4 Myelosuppression
timeFrame: Baseline and Week 16
measure: Marrow-infiltrating Lymphocyte (MIL) Number and Cytolytic Activity
timeFrame: Pre-Study and Week 16
Other outcomes:
Locations:
city: Tampa
country: United States
facility: H. Lee Moffitt Cancer Center and Research Institute
state: Florida
Study officials:
affiliation: Celgene Corporation
name: Robert Knight, MD
role: STUDY_DIRECTOR
References:
citation: 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.