Efficacy and Safety of Lenalidomide in Combination With Cyclosporine A in Patients With Myelodysplastic Syndromes

• Sponsor: Weill Medical College of Cornell University (Other)
• Overall Status: Terminated
• CT.gov ID: NCT00840827
• Collaborator: Celgene (Industry)
• Enrollment: 6
• Location: 1
• Arm: 1
• Duration (Months): 24
• Patients Per Site Per Month: 0.3

Study Details

Study Description

Brief Summary

Lenalidomide has shown significant efficacy in the treatment of anemia associated with both 5q- and non 5q- MDS patients. The mechanism(s) of action of lenalidomide in MDS is still to be determined, but given the differences in response rates seen, it is probable that the mechanism is different for patients with 5q- disease compared to non 5q- patients. T-cell mediated activation of intramedullary apoptosis in patients with early MDS leading to impaired hematopoiesis has been well described. Immunomodulation with agents such as ATG, cyclosporine and thalidomide have demonstrated clear activity in some patients with MDS. Lenalidomide, among its many effects, is a potent immunomodulator, which may contribute to its ability to improve red blood cell counts in patients with MDS. It is possible that this effect could be augmented with the addition of cyclosporine A (CSA), in a similar manner to CSA effects in patients with other bone marrow failure syndromes such as aplastic anemia.

Subjects will be treated with lenalidomide 10 mg PO daily days 1-28 of a 28-day cycle. Cyclosporine A will be started on day 1 of cycle 2 (day 29) at a dose of 5 mg/kg per day given orally in 2 divided doses. Cyclosporine A levels will be assessed weekly and doses will be adjusted to maintain a serum trough level between 100-450 mg/ml. Patients will continue on therapy for minimum of 16 weeks unless toxicity occurs which precludes continuation on therapy, disease progression and/or patient withdrawal of consent. Patients not achieving response after completing 16 weeks of therapy will discontinue treatment. Patients achieving response will continue therapy until disease progression, unacceptable toxicity or loss of response.

Condition or Disease	Intervention/Treatment	Phase
Myelodysplastic Syndrome	Drug: lenalidomide; Drug: cyclosporine A	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 6 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Single-Arm, Open-Label Study of the Efficacy and Safety of Lenalidomide in Combination With Cyclosporine A in Patients With Red Blood Cell Transfusion-Dependent Myelodysplastic Syndromes
• Study Start Date: Dec 1, 2008
• Actual Primary Completion Date: Dec 1, 2010
• Actual Study Completion Date: Dec 1, 2010

Arms and Interventions

Arm	Intervention/Treatment
Experimental: all patients Lenalidomide 10mg po daily/ CSA 250mg orally twice daily	Drug: lenalidomide; Lenalidomide 10mg po daily; Other Names: revlimid ; Drug: cyclosporine A; CSA 250mg orally twice daily; Other Names: Sandimmune

Outcome Measures

Primary Outcome Measures

1. Efficacy of Lenalidomide in Combination With Cyclosporine A (CSA) to Achieve Red Cell Transfusion Independence in Subjects With Low- or Intermediate-1 Risk IPSS MDS Without a Del (5q31-33) Cytogenetic Abnormality. [16 weeks]

   Efficacy of lenalidomide + CSA will be evaluated as a function of red blood cell transfusion needs improvement (≥ 50% decrease in RBC transfusion requirements after 16 weeks of study treatment).

2. Efficacy of Lenalidomide in Combination With Cyclosporine A (CSA) to Achieve Red Cell Transfusion Independence in Subjects With Low- or Intermediate-1 Risk IPSS MDS Without a Del (5q31-33) Cytogenetic Abnormality. [12 months]

   Efficacy of lenalidomide + CSA will be evaluated as a function of red blood cell transfusion independence.

3. Efficacy of Lenalidomide in Combination With Cyclosporine A (CSA) to Achieve Red Cell Transfusion Independence in Subjects With Low- or Intermediate-1 Risk IPSS MDS Without a Del (5q31-33) Cytogenetic Abnormality by Hemoglobin Change. [Baseline and 12 months]

   Efficacy of lenalidomide + CSA will be evaluated as a function of change of hemoglobin concentration from baseline to 12 months.

Secondary Outcome Measures

1. Safety of Lenalidomide in Combination With CSA in Subjects With Low- or Intermediate-1 Risk MDS Without a Del (5q31-33) Cytogenetic Abnormality by Type of Adverse Events. [12 months]

   Safety will be evaluated by type of adverse events to lenalidomide in combination with CSA

2. Tolerability of Lenalidomide in Combination With CSA in Subjects With Low- or Intermediate-1 Risk MDS Without a Del (5q31-33) Cytogenetic Abnormality by Frequency of Adverse Events. [12 months]

   Tolerability will be evaluated by the frequency of adverse events to lenalidomide in combination with CSA

3. Tolerability of Lenalidomide in Combination With CSA in Subjects With Low- or Intermediate-1 Risk MDS Without a Del (5q31-33) Cytogenetic Abnormality by Severity of Adverse Events. [12 months]

   Tolerability will be evaluated by the severity of adverse events to lenalidomide in combination with CSA

4. Tolerability of Lenalidomide in Combination With CSA in Subjects With Low- or Intermediate-1 Risk MDS Without a Del (5q31-33) Cytogenetic Abnormality by the Relatedness of Adverse Events. [12 months]

   Tolerability will be evaluated by the relatedness of adverse events to lenalidomide in combination with CSA

5. Safety of Lenalidomide in Combination With CSA in Subjects With Low- or Intermediate-1 Risk MDS Without a Del (5q31-33) Cytogenetic Abnormality by Frequency of Adverse Events. [12 months]

   Safety will be evaluated by frequency of each type of adverse event to lenalidomide in combination with CSA

6. Safety of Lenalidomide in Combination With CSA in Subjects With Low- or Intermediate-1 Risk MDS Without a Del (5q31-33) Cytogenetic Abnormality by Relatedness of Adverse Events to the Combination of Treatments. [12 months]

   Safety will be evaluated by the relatedness of each type of adverse event to lenalidomide in combination with CSA

7. Safety of Lenalidomide in Combination With CSA in Subjects With Low- or Intermediate-1 Risk MDS Without a Del (5q31-33) Cytogenetic Abnormality by Severity of Adverse Events. [12 months]

   Safety will be evaluated by the severity of each type of adverse event to lenalidomide in combination with CSA

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Understand and voluntarily sign an informed consent form.

• Age ≥ 18 years at the time of signing the informed consent form.

• Able to adhere to the study visit schedule and other protocol requirements.

• Diagnosis of low or intermediate-1 risk IPSS (MDS without an abnormality of chromosome 5 involving a deletion between bands q31 and q33. Red blood cell (RBC) transfusion-dependent anemia as having received ≥ 2 units of RBCs within 8 weeks on the first day of study treatment.

• ECOG performance status of ≤ 2 at study entry

• Laboratory test results within the following ranges:

• Absolute neutrophil count (ANC) >500 x 109/L

• Platelet count ≥ 50 x 109/L

• Serum creatinine ≤ 2.0 mg/dL

• Total bilirubin ≤ 1.5 mg/dL

• AST (SGOT) and ALT (SGPT) ≤ 2 x ULN

• Disease free of prior malignancies for ≥ 5 years with exception of currently treated basal cell, squamous cell carcinoma of the skin, or carcinoma "insitu" of the cervix or breast.

• All study participants must be registered into the mandatory RevAssist® program, and be willing and able to comply with the requirements of RevAssist®.

• Females of childbearing potential (FCBP) must have a negative serum or urine pregnancy test with a sensitivity of at least 50 mIU/mL within 10 - 14 days prior to and again within 24 hours of prescribing lenalidomide (prescriptions must be filled within 7 days) and must either commit to continued abstinence from heterosexual intercourse or begin TWO acceptable methods of birth control, one highly effective method and one additional effective method AT THE SAME TIME, at least 28 days before she starts taking lenalidomide. FCBP must also agree to ongoing pregnancy testing. Men must also agree to use a latex condom during sexual contact with a FCBP even if they have had a successful vasectomy.

• Able to take asprin (81 or 325 mg) daily as a prophylactic anticoagulation (patients intolerant to ASA may use warfarin or low molecular weight heparin).

Exclusion Criteria:

• Any serious medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from signing the informed consent form.

• Pregnant or breast feeding females. (Lactating females must agree not to breast feed while taking lenalidomide).

• Any condition, including the presence of laboratory abnormalities, which places the subject at unacceptable risk if he/she were to participate in the study or confounds the ability to interpret data from the study.

• Use of any other experimental drug or therapy within 28 days of baseline.

• Known hypersensitivity to thalidomide. Prior ≥ grade 3 NCI CTCAE (Version 3.0) allergic reaction/hypersensitivity.

• The development of erythema nodosum if characterized by a desquamating rash while taking thalidomide or similar drugs.

• Any prior use of lenalidomide.

• Concurrent use of other anti-cancer agents or treatments.

• Known positive for HIV or infectious hepatitis, type A, B, or C.

• Inability to aspirate bone marrow (dry tap).

• Proliferative (WBC ≥ 12,000/ul) CMML

• An abnormality of chromosome 5 involving a deletion between bands q31 and q 33.

• Any of the following lab abnormalities:

• Absolute neutrophil count (ANC) <500 cells/mm3 (0.5 x 109/L)

• Platelet count ≤ 50,000/mm3 (50 x 109/L)

• Serum creatinine ≥ 2.5 mg/dL (221µmol/L)

• Serum SGOT/AST or SGPT/ALT ≥ 2.0 x upper limit of normal (ULN)

• Serum direct bilirubin ≥ 2.0 mg/dL (34µmol/L)

• Clinically significant anemia due to factors such as iron, B12 or folate deficiencies, autoimmune or hereditary hemolysis or gastrointestinal bleeding (if a marrow aspirate is not evaluable for storage iron, transferring saturation must be ≥ 20% and serum ferritin not less than 50ng/mL).

• Use of hematopoietic growth factors within 7 days of the first day of study drug treatment.

• Chronic use (≥2 weeks) of greater than physiologic doses of a corticosteroid agent (dose equivalent to ≥ 10mg/day of prednisone) within 28 days of the first study drug treatment.

• Use of experimental or standard drug (i.e chemotherapeutic, immunosuppressive, cytoprotective agents) for the treatment of MDS within 28 days of the first day of study drug

• Prior history of malignancy other than MDS except basal cell or squamous cell carcinoma in situ of the cervix or breast, unless the patient has been free of disease for ≥ 5 year.

• Myocardial infarction within 6 months prior to enrollment, or NYHA (New York Hospital Association) Class III or IV heart failure disease. History of active angina, congestive heart disease, uncontrolled angina, severe uncontrolled ventricular arrhythmias, electrocardiographic evidence of uncontrolled ischemia and/or active conduction system abnormalities, or myocardial infarction within 6 months prior to enrollment, acute ischemia, or active conduction system abnormalities.

• Active viral or bacterial infections or any coexisting medical problem that would significantly increase the risks of this treatment program.

• History of thromboembolic event within the past 6 months prior to enrollment.

• Patients who have a hypersensitivity to Sandimmune® (cyclosporine).

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Weill Cornell Medical College	New York	New York	United States	10021

Sponsors and Collaborators

• Weill Medical College of Cornell University
• Celgene

Investigators

• Principal Investigator: Eric Feldman, MD, Weill Medical College of Cornell University

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Weill Medical College of Cornell University
• ClinicalTrials.gov Identifier: NCT00840827
• Other Study ID Numbers: 0810010063
• First Posted: Feb 10, 2009
• Last Update Posted: Nov 19, 2019
• Last Verified: Nov 1, 2019

• Keywords provided by Weill Medical College of Cornell University: stage (IPSS low and INT-1); RBC transfusion-dependent; non-del 5q MDS
• Additional relevant MeSH terms: Preleukemia; Myelodysplastic Syndromes; Syndrome; Cyclosporine; Lenalidomide; Cyclosporins

Study Results

Participant Flow

Arm/Group Title	All Patients
Arm/Group Description	Lenalidomide 10mg po daily/ CSA 250mg orally twice daily lenalidomide: Lenalidomide 10mg po daily cyclosporine A: CSA 250mg orally twice daily
Period Title: Overall Study
STARTED	6
COMPLETED	0
NOT COMPLETED	6

Baseline Characteristics

Arm/Group Title	All Patients
Arm/Group Description	Lenalidomide 10mg po daily/ CSA 250mg orally twice daily lenalidomide: Lenalidomide 10mg po daily cyclosporine A: CSA 250mg orally twice daily
Overall Participants	6
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	2 33.3%
>=65 years	4 66.7%
Sex: Female, Male (Count of Participants)
Female	2 33.3%
Male	4 66.7%

Outcome Measures

1. Primary Outcome

Title	Efficacy of Lenalidomide in Combination With Cyclosporine A (CSA) to Achieve Red Cell Transfusion Independence in Subjects With Low- or Intermediate-1 Risk IPSS MDS Without a Del (5q31-33) Cytogenetic Abnormality.
Description	Efficacy of lenalidomide + CSA will be evaluated as a function of red blood cell transfusion needs improvement (≥ 50% decrease in RBC transfusion requirements after 16 weeks of study treatment).
Time Frame	16 weeks

Outcome Measure Data

Analysis Population Description

6 patients were enrolled, the target enrollment was not met. Study was terminated by the PI and no statistical analysis was performed. None of the patients completed the 16 weeks of study treatment, therefore red blood cell transfusion could not be evaluated.

Arm/Group Title	All Patients
Arm/Group Description	Lenalidomide 10mg po daily/ CSA 250mg orally twice daily lenalidomide: Lenalidomide 10mg po daily cyclosporine A: CSA 250mg orally twice daily
Measure Participants	0

2. Secondary Outcome

Title	Safety of Lenalidomide in Combination With CSA in Subjects With Low- or Intermediate-1 Risk MDS Without a Del (5q31-33) Cytogenetic Abnormality by Type of Adverse Events.
Description	Safety will be evaluated by type of adverse events to lenalidomide in combination with CSA
Time Frame	12 months

Outcome Measure Data

Analysis Population Description

6 patients were enrolled, the target enrollment was not met. Study was terminated by the PI and no statistical analysis was performed. None of the patients completed the 12 months of study treatment, therefore the type of adverse events to lenalidomide in combination with CSA, could not be evaluated.

Arm/Group Title	All Patients
Arm/Group Description	Lenalidomide 10mg po daily/ CSA 250mg orally twice daily lenalidomide: Lenalidomide 10mg po daily cyclosporine A: CSA 250mg orally twice daily
Measure Participants	0

3. Secondary Outcome

Title	Tolerability of Lenalidomide in Combination With CSA in Subjects With Low- or Intermediate-1 Risk MDS Without a Del (5q31-33) Cytogenetic Abnormality by Frequency of Adverse Events.
Description	Tolerability will be evaluated by the frequency of adverse events to lenalidomide in combination with CSA
Time Frame	12 months

Outcome Measure Data

Analysis Population Description

6 patients were enrolled, the target enrollment was never met. Study was terminated by the PI and no statistical analysis was performed. None of the patients completed the 12 months of study treatment, therefore tolerability could not be evaluated.

Arm/Group Title	All Patients
Arm/Group Description	Lenalidomide 10mg po daily/ CSA 250mg orally twice daily lenalidomide: Lenalidomide 10mg po daily cyclosporine A: CSA 250mg orally twice daily
Measure Participants	0

4. Primary Outcome

Title	Efficacy of Lenalidomide in Combination With Cyclosporine A (CSA) to Achieve Red Cell Transfusion Independence in Subjects With Low- or Intermediate-1 Risk IPSS MDS Without a Del (5q31-33) Cytogenetic Abnormality.
Description	Efficacy of lenalidomide + CSA will be evaluated as a function of red blood cell transfusion independence.
Time Frame	12 months

Outcome Measure Data

Analysis Population Description

6 patients were enrolled, the target enrollment was not met. Study was terminated by the PI and no statistical analysis was performed. None of the patients completed the 12 months of study treatment, therefore red blood cell transfusion independence could not be evaluated.

Arm/Group Title	All Patients
Arm/Group Description	Lenalidomide 10mg po daily/ CSA 250mg orally twice daily lenalidomide: Lenalidomide 10mg po daily cyclosporine A: CSA 250mg orally twice daily
Measure Participants	0

5. Primary Outcome

Title	Efficacy of Lenalidomide in Combination With Cyclosporine A (CSA) to Achieve Red Cell Transfusion Independence in Subjects With Low- or Intermediate-1 Risk IPSS MDS Without a Del (5q31-33) Cytogenetic Abnormality by Hemoglobin Change.
Description	Efficacy of lenalidomide + CSA will be evaluated as a function of change of hemoglobin concentration from baseline to 12 months.
Time Frame	Baseline and 12 months

Outcome Measure Data

Analysis Population Description

6 patients were enrolled, the target enrollment was not met. Study was terminated by the PI and no statistical analysis was performed. None of the patients completed the 12 months of study treatment, therefore the change of hemoglobin concentration from baseline to 12 weeks could not be evaluated.

Arm/Group Title	All Patients
Arm/Group Description	Lenalidomide 10mg po daily/ CSA 250mg orally twice daily lenalidomide: Lenalidomide 10mg po daily cyclosporine A: CSA 250mg orally twice daily
Measure Participants	0

6. Secondary Outcome

Title	Tolerability of Lenalidomide in Combination With CSA in Subjects With Low- or Intermediate-1 Risk MDS Without a Del (5q31-33) Cytogenetic Abnormality by Severity of Adverse Events.
Description	Tolerability will be evaluated by the severity of adverse events to lenalidomide in combination with CSA
Time Frame	12 months

Outcome Measure Data

Analysis Population Description

6 patients were enrolled, the target enrollment was never met. Study was terminated by the PI and no statistical analysis was performed. None of the patients completed the 12 months of study treatment, therefore tolerability could not be evaluated.

Arm/Group Title	All Patients
Arm/Group Description	Lenalidomide 10mg po daily/ CSA 250mg orally twice daily lenalidomide: Lenalidomide 10mg po daily cyclosporine A: CSA 250mg orally twice daily
Measure Participants	0

7. Secondary Outcome

Title	Tolerability of Lenalidomide in Combination With CSA in Subjects With Low- or Intermediate-1 Risk MDS Without a Del (5q31-33) Cytogenetic Abnormality by the Relatedness of Adverse Events.
Description	Tolerability will be evaluated by the relatedness of adverse events to lenalidomide in combination with CSA
Time Frame	12 months

Outcome Measure Data

Analysis Population Description

6 patients were enrolled, the target enrollment was never met. Study was terminated by the PI and no statistical analysis was performed. None of the patients completed the 12 months of study treatment, therefore tolerability could not be evaluated.

Arm/Group Title	All Patients
Arm/Group Description	Lenalidomide 10mg po daily/ CSA 250mg orally twice daily lenalidomide: Lenalidomide 10mg po daily cyclosporine A: CSA 250mg orally twice daily
Measure Participants	0

8. Secondary Outcome

Title	Safety of Lenalidomide in Combination With CSA in Subjects With Low- or Intermediate-1 Risk MDS Without a Del (5q31-33) Cytogenetic Abnormality by Frequency of Adverse Events.
Description	Safety will be evaluated by frequency of each type of adverse event to lenalidomide in combination with CSA
Time Frame	12 months

Outcome Measure Data

Analysis Population Description

6 patients were enrolled, the target enrollment was never met. Study was terminated by the PI and no statistical analysis was performed. None of the patients completed the 12 months of study treatment, therefore safety could not be evaluated.

Arm/Group Title	All Patients
Arm/Group Description	Lenalidomide 10mg po daily/ CSA 250mg orally twice daily lenalidomide: Lenalidomide 10mg po daily cyclosporine A: CSA 250mg orally twice daily
Measure Participants	0

9. Secondary Outcome

Title	Safety of Lenalidomide in Combination With CSA in Subjects With Low- or Intermediate-1 Risk MDS Without a Del (5q31-33) Cytogenetic Abnormality by Relatedness of Adverse Events to the Combination of Treatments.
Description	Safety will be evaluated by the relatedness of each type of adverse event to lenalidomide in combination with CSA
Time Frame	12 months

Outcome Measure Data

Analysis Population Description

6 patients were enrolled, the target enrollment was never met. Study was terminated by the PI and no statistical analysis was performed. None of the patients completed the 12 months of study treatment, therefore safety could not be evaluated.

Arm/Group Title	All Patients
Arm/Group Description	Lenalidomide 10mg po daily/ CSA 250mg orally twice daily lenalidomide: Lenalidomide 10mg po daily cyclosporine A: CSA 250mg orally twice daily
Measure Participants	0

10. Secondary Outcome

Title	Safety of Lenalidomide in Combination With CSA in Subjects With Low- or Intermediate-1 Risk MDS Without a Del (5q31-33) Cytogenetic Abnormality by Severity of Adverse Events.
Description	Safety will be evaluated by the severity of each type of adverse event to lenalidomide in combination with CSA
Time Frame	12 months

Outcome Measure Data

Analysis Population Description

6 patients were enrolled, the target enrollment was never met. Study was terminated by the PI and no statistical analysis was performed. None of the patients completed the 12 months of study treatment, therefore safety could not be evaluated.

Arm/Group Title	All Patients
Arm/Group Description	Lenalidomide 10mg po daily/ CSA 250mg orally twice daily lenalidomide: Lenalidomide 10mg po daily cyclosporine A: CSA 250mg orally twice daily
Measure Participants	0

Adverse Events

Time Frame	AEs were collected from the 8th day of the study drug administration till discontinuation of study drug. An additional safety assessment was done 30 days (+/- 2 days) following the last dose of study drug.
Arm/Group Title	All Patients
Arm/Group Description	Lenalidomide 10mg po daily/ CSA 250mg orally twice daily lenalidomide: Lenalidomide 10mg po daily cyclosporine A: CSA 250mg orally twice daily
All Cause Mortality
	All Patients
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	All Patients
	Affected / at Risk (%)	# Events
Total	4/6 (66.7%)
Blood and lymphatic system disorders
Thrombocytopenia	1/6 (16.7%)
Cytopenia	1/6 (16.7%)
Cardiac disorders
Myocardial Infarction	1/6 (16.7%)
Respiratory, thoracic and mediastinal disorders
Pneumonia	1/6 (16.7%)
Other (Not Including Serious) Adverse Events
	All Patients
	Affected / at Risk (%)	# Events
Total	6/6 (100%)
Blood and lymphatic system disorders
Anemia	4/6 (66.7%)
Eye disorders
Decreased Vision	1/6 (16.7%)
Gastrointestinal disorders
Constipation	1/6 (16.7%)
GERD	1/6 (16.7%)
Intermittent Diarrhea	1/6 (16.7%)
General disorders
Fatigue	3/6 (50%)
Nausea	1/6 (16.7%)
Lip tingling	1/6 (16.7%)
Musculoskeletal and connective tissue disorders
Leg Cramps	1/6 (16.7%)
Skin and subcutaneous tissue disorders
Skin rash	1/6 (16.7%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.