A Phase I/II Study of Revlimid (lenalidomide) in Combination with Vidaza (azacitidine) in Patients with Advanced Myelodysplastic Syndrome (MDS)

This single-arm study design has been selected to investigate the safety of combination therapy with Vidaza® (azacitidine) and Revlimid® (lenalidomide) in a population of 18 participants with advanced MDS for the Phase I portion, and 18 participants for the Phase II portion. The multi-center nature of the study should enhance the general applicability of the results. Participants with advanced MDS were chosen because it is expected that the combination of the two drugs will by myelosuppressive, which can be considered a necessary toxicity to effect improvements in PR and CR rates in this advanced population, akin to participants with AML. Finally, the combination was chosen to be studied because currently available therapies in this population, and their effectiveness, are limited, and single-agent Vidaza® (azacitidine), while effective at delaying transformation to AML or death, is not curative.

The doses of Revlimid® (lenalidomide) in this study are similar to those that were demonstrated to have an effect and to be well-tolerated in participants with MDS. Doses for Vidaza® (azacitidine) are similar to those used in the pivotal trial, though for a 5-day treatment period instead of 7 to minimize toxicity for the first 3 blocks of participants, and then at a lower dose over a protracted period of time to explore the safety of a 10-day treatment course.

• Study Design:
  • Case Set
• Study Type:
  • Case Set
• Total number of consented subjects: 50
• Subject Sample Telemetry Report (SSTR)

Inclusion Criteria

A. Be ≥ 18 years of age
B.Have myelodysplastic syndrome of one of the following French-American-British (FAB) classifications:

• Refractory anemia with excess blasts (RAEB - defined as having 5-20% myeloblasts in the bone marrow. However, as the WHO classification system now considers participants with >20% blasts to have AML, participants with exactly 20% blasts will not be included in this study).
• Chronic Myelomonocytic Leukemia (CMML) with 10-19% myeloblasts in the bone marrow and/or 5-19% blasts in the blood.

These FAB classifications correspond to one of the following WHO Classifications, which can also serve as inclusion criteria:

• CMML-2 (Defined as having 10-19% myeloblasts in the bone marrow and/or 5-19% blasts in the blood)
• Refractory anemia with excess blasts-1 (RAEB-1 - defined as having 5-9% myeloblasts in the bone marrow)
• Refractory anemia with excess blasts-2 (RAEB-2 - defined as having 10-19*#37; myeloblasts in the bone marrow and/or 5-19% blasts in the blood)

OR
Have an IPSS score of Intermediate 2 (1.5-2.0 points based on karyotype, cytopenias, and bone marrow blast percentage) or High (≥2.5 points) in the setting of ≥ 5% myeloblasts

C. Have a life expectancy ≥ 3 months
D. Have an Eastern Clinical Oncology Group (ECOG) status of 0, 1, or 2
E. Must not be candidates for bone marrow transplantation for first-line therapy
F. Must not receive another investigational or approved therapy for MDS within 28 days of study enrollment, or growth factors within 14 days of the first day of study drug treatment
G. Must not be using greater than physiologic doses of a corticosteroid agent (dose equivalent to > 10mg/day of prednisone) within 28 days of the first day of treatment
H. 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 starting lenalidomide 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 agree to use a latex condom during sexual contact with a FCBP even if they have had a successful vasectomy. All patients must be counseled at a minimum of every 28 days about pregnancy precautions and risks of fetal exposure.
I. Must be able to give informed consent to participate in the study

Exclusion Criteria

A. Any serious medical condition, laboratory abnormality, or psychiatric illness that, in the view of the treating physician, would place the participant at an unacceptable risk if he or she were to participate in the study or would prevent that person from giving informed consent.
B. Must not have received prior therapy with either Revlimid® (lenalidomide) or azacitidine
C. Pre-existing neurotoxicity/neuropathy of Grade 2 or greater according to the NCI Common Toxicity Criteria Version 3, or prior ≥ grade 3 allergic reaction/hypersensitivity or rash to thalidomide.
D. Pregnant or breastfeeding women.
E. Any of the following laboratory abnormalities:

• Serum creatinine >2.0 mg/dL
• Serum SGOT/AST or SGPT/ALT >2.0 x upper limit of normal (ULN)
• Serum total bilirubin >2 mg/dL
• Platelet count <20,000/mm₃

♦ Study Activated May 15, 2006
♦ Study Final Closed July 12, 2012

• Primary Phenotype: Myelodysplastic Syndromes

• BioProject
• MeSH

• Study Chair
  • Mikkael A. Sekeres, MD, MS. The Cleveland Clinic Foundation, Cleveland, OH, USA.
• Data Management
  • Jeffrey Krischer, PhD. Data Management and Coordinating Center University of South Florida, Tampa, FL, USA.
• Funding Source
  • Celgene. Celgene Corporation, Summit, NJ, USA.