Lenalidomide and Eltrombopag in Low and Intermediate Risk MDS

This study is currently recruiting participants. (see Contacts and Locations)
Verified January 2013 by Albert Einstein College of Medicine of Yeshiva University
Sponsor:
Collaborators:
GlaxoSmithKline
Celgene Corporation
Information provided by (Responsible Party):
Amit Verma, Albert Einstein College of Medicine of Yeshiva University
ClinicalTrials.gov Identifier:
NCT01772420
First received: January 15, 2013
Last updated: January 18, 2013
Last verified: January 2013
  Purpose

Combined treatment with eltrombopag (EP) and lenalidomide (CC-5013; REVLIMID) will reduce the incidence of thrombocytopenia due to Lenalidomide and enable patients to tolerate duration of therapy leading to higher rates of response.


Condition Intervention Phase
Myelodysplastic Syndrome
MDS
Anemia
Drug: Lenalidomide
Drug: Eltrombopag
Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: PHASE II STUDY OF LENALIDOMIDE AND ELTROMBOPAG IN PATIENTS WITH SYMPTOMATIC ANEMIA IN LOW OR INTERMEDIATE I MYELODYSPLASTIC SYNDROME (MDS)

Resource links provided by NLM:


Further study details as provided by Albert Einstein College of Medicine of Yeshiva University:

Primary Outcome Measures:
  • Hematologic improvement [ Time Frame: 2 years ] [ Designated as safety issue: No ]
    To evaluate the rate of hematologic improvement of the eltrombopag/lenalidomide combination as defined by the International Working Group (IWG) criteria

  • Safety and Tolerability [ Time Frame: 24 months ] [ Designated as safety issue: Yes ]
    To evaluate the risk of bleeding, thrombotic events, leukemic transformation and any other adverse events of the eltrombopag/lenalidomide combination in patients with low -intermediate risk MDS


Secondary Outcome Measures:
  • Time to attain and duration of hematologic improvement [ Time Frame: 24 months ] [ Designated as safety issue: No ]
    To compare the time and evaluate the duration of hematologic improvement

  • Platelet counts and Bleeding events [ Time Frame: 24 months ] [ Designated as safety issue: Yes ]
    To evaluate the effect of combination treatment on platelet counts, platelet transfusions,and bleeding events.

  • Bone marrow morphologic and cytogenetic response [ Time Frame: 24 months ] [ Designated as safety issue: Yes ]

    To evaluate the frequency of bone marrow response (Complete Response (CR)+ Partial Response (PR) and cytogenetic response.

    To evaluate the relationship between mutations in bone marrow stem cells and response


  • Alterations in hematopoietic stem and progenitor cell [ Time Frame: 24 months ] [ Designated as safety issue: Yes ]
    To evaluate the relationship between various stem and progenitor alterations and response


Estimated Enrollment: 52
Study Start Date: October 2012
Estimated Study Completion Date: October 2016
Estimated Primary Completion Date: October 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Arm A
Patients with platelet counts >=50k at baseline: These patients will start with Lenalidomide at 10mg/d for 3 weeks/month, and will not start eltrombopag until the platelet counts drop below 50k. When it drops 50k Lenalidomide will be stopped and eltrombopag will be started and gradually titrated up to achieve a platelet count above 50k. Once a platelet count above 50k is achieved and maintained for two weeks, eltrombopag will be discontinued and Lenalidomide will be started as a single agent. The same process will be repeated if the platelets again fall below 50k and eltrombopag will be re-initiated at the dose that was last given to the patient. Once the platelets are increased to above 50k and maintained at this level for 2 weeks Lenalidomide will be started again and this time will be given concurrently with eltrombopag.
Drug: Lenalidomide
The lenalidomide starting dose will be based on baseline calculated creatinine clearance
Other Name: Revlimid
Drug: Eltrombopag
Eltrombopag starting dose will be 100mg (50mg for patients with east Asian descent) and dosing will be based on regimen as detailed in protocol.
Experimental: Arm B
These patients will not receive Len initially. Eltrombopag will be started alone and titrated up to achieve a platelet count above 50,000. Once the platelet count above 50,000 is achieved, the same dose of eltrombopag will be continued for an additional two weeks. Once the plt count > 50,000 is maintained for two weeks, the patients will discontinue eltrombopag and follow the treatment algorithm described for patients in arm A.
Drug: Lenalidomide
The lenalidomide starting dose will be based on baseline calculated creatinine clearance
Other Name: Revlimid
Drug: Eltrombopag
Eltrombopag starting dose will be 100mg (50mg for patients with east Asian descent) and dosing will be based on regimen as detailed in protocol.

Detailed Description:

The rationale for this study is that combined treatment with eltrombopag (PROMACTA) and lenalidomide (REVLIMID) will reduce the incidence of lenalidomide induced thrombocytopenia thus enabling patients to tolerate the required duration of lenalidomide therapy leading to higher rates of response to lenalidomide. A major reason why lenalidomide cannot be used for the treatment of MDS is because of the occurrence of thrombocytopenia. The use of eltrombopag will potentially raise platelet counts in these patients and enable a longer exposure to lenalidomide. Secondly, thrombocytopenia in the first 2 months after lenalidomide therapy predicts the subsequent response to lenalidomide treatment in patients with low risk MDS thus raising platelet counts to enable continuation of Lenalidomide therapy is important in these patients. Lastly, an increase in blasts has been a potential concern with the use of thrombopoietin mimetics. Preclinical studies have indicated that eltrombopag is less likely to increase blasts thus making it a possible potential therapeutic candidate in low risk MDS.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Age ≥ 18 years.
  2. Patient must have a documented diagnosis of MDS of at least three months duration (MDS duration ≥ 3 months) according to World Health Organization (WHO) criteria (see Appendix IV) or non-proliferative chronic myelomonocytic leukemia (CMML) (WBC ≤ 12,000/L)).
  3. Patients must have International Prognostic Scoring System (IPSS) categories of Low- or Intermediate-1-risk disease (see Section 6).
  4. Patients must have symptomatic anemia untransfused with hemoglobin ≤ 9.5 g/dL within 8 weeks of registration or with red blood cell (RBC) transfusion-dependence (i.e., ≥ 2 units/month) confirmed for a minimum of 8 weeks before randomization.
  5. Patients must have IPSS score determined by cytogenetic analysis prior to randomization. Patients with cytogenetic failure and ≤ 10% marrow blasts will be eligible.
  6. Patients must be off all disease modifying therapy for MDS for 28 days prior to initiation of study treatment. Patients may receive hydrocortisone prophylactically to prevent transfusion reactions.
  7. Patients must not have documented iron deficiency. All patients must have documented marrow iron stores. If marrow iron stain is not available, the transferrin saturation must be ≥ 20% or a serum ferritin ≥ 100 mg/100 mL or soluble transferring receptor < 5mg/L.
  8. Women must not be pregnant or breastfeeding. Females of childbearing potential should have 2 negative pregnancy tests. The first test should be performed within 10-14 days, and the second test within 24 hours prior to prescribing lenalidomide.
  9. Women of childbearing potential and sexually active males must agree to use 2 methods of an accepted and effective method of contraception and counseled on the potential teratogenic effects of lenalidomide. Effective contraception must be used by patients for at least 4 weeks before beginning lenalidomide therapy, during lenalidomide therapy, during dose interruptions and for 4 weeks following discontinuation of lenalidomide therapy. Reliable contraception is indicated even where there has been a history of infertility, unless due to hysterectomy or because the patient has been postmenopausal naturally for at least 24 consecutive months. Two reliable forms of contraception must be used simultaneously unless continuous abstinence from heterosexual sexual contact is the chosen method. Females of childbearing potential should be referred to a qualified provider of contraceptive methods, if needed. Sexually mature females who have not undergone a hysterectomy or who have not been postmenopausal naturally for at least 24 consecutive months (i.e., who have had menses at some time in the preceding 24 consecutive months) are considered to be females of childbearing potential. It is not known whether CC-5013 (lenalidomide) is present in the semen of patients receiving the drug. Therefore, males receiving CC-5013 (lenalidomide) must always use a latex condom during any sexual contact with females of childbearing potential even if they have undergone a successful vasectomy.
  10. Patients must not have received prior therapy with lenalidomide (for more than 2 months) nor eltrombopag.
  11. Patients must not have uncontrolled hypertension.
  12. Patients must have absolute neutrophil count (ANC) ≥500 cells/L (0.5 x 109/L).
  13. ECOG Performance 0-3 (ECOG).
  14. Prothrombin time (PT/INR) and activated partial thromboplastin time (aPTT) must be within 80 to 120% of the normal range at baseline.
  15. Patient is able to understand protocol requirements.

Exclusion Criteria:

  1. Pre-existing cardiovascular disease (including congestive heart failure, New York Heart Association (NYHA) Grade III/IV), or arrhythmia known to increase the risk of thromboembolic events (e.g. atrial fibrillation), or subjects with a corrected QT interval (QTc) >450 msec.
  2. Patients determined to be at increased risk of arterial or venous thrombosis by the investigator
  3. Bone marrow fibrosis that leads to a dry tap.
  4. Female subjects who are nursing or pregnant (positive serum or urine -human chorionic gonadotropin (-hCG) pregnancy test) at screening or pre-dose on Day 1.
  5. Treatment with an investigational drug within 30 days or 5 half-lives (whichever is longer) preceding the first dose of study medication.
  6. Patients with documented liver cirrhosis
  7. Patients with splenomegaly with a spleen size > 16cm.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01772420

Contacts
Contact: Amit Verma, MD 718-430-8761 amit.verma@einstein.yu.edu
Contact: Tatiana Carrillo 718-405-8545 tcarrill@montefiore.org

Locations
United States, New York
Montefiore Medical Center-Department of Medical Oncology Recruiting
Bronx, New York, United States, 10461
Contact: Tatiana Carrillo    718-405-8545    tcarrill@montefiore.org   
Contact: Dale Wyville, PA    718-405-8547    dwyville@montefiore.org   
Principal Investigator: Amit Verma, MD         
Sponsors and Collaborators
Amit Verma
GlaxoSmithKline
Celgene Corporation
Investigators
Study Chair: Amit Verma, MD Montefiore Medical Center-Weiler Division
  More Information

No publications provided

Responsible Party: Amit Verma, Associate Professor, Albert Einstein College of Medicine of Yeshiva University
ClinicalTrials.gov Identifier: NCT01772420     History of Changes
Other Study ID Numbers: 2012-407, 115479, RV--MDS-PI-0645
Study First Received: January 15, 2013
Last Updated: January 18, 2013
Health Authority: United States: Food and Drug Administration
United States: Data and Safety Monitoring Board
United States: Institutional Review Board

Keywords provided by Albert Einstein College of Medicine of Yeshiva University:
Myelodysplastic Syndrome
MDS
Anemia
Eltrombopag
Lenalidomide
Bone Marrow Diseases
Hematologic Diseases
Precancerous Conditions
Preleukemia

Additional relevant MeSH terms:
Anemia
Myelodysplastic Syndromes
Preleukemia
Syndrome
Hematologic Diseases
Bone Marrow Diseases
Precancerous Conditions
Neoplasms
Disease
Pathologic Processes
Lenalidomide
Thalidomide
Immunologic Factors
Physiological Effects of Drugs
Pharmacologic Actions
Angiogenesis Inhibitors
Angiogenesis Modulating Agents
Growth Substances
Growth Inhibitors
Antineoplastic Agents
Therapeutic Uses
Immunosuppressive Agents
Leprostatic Agents
Anti-Bacterial Agents
Anti-Infective Agents

ClinicalTrials.gov processed this record on September 22, 2014