Title A Randomized Phase II Study of Azacitidine in Combination with Lenalidomide (NSC-703813) vs. Azacitidine vs. Azacitidine Alone vs. Azacitidine in Combination with Vorinostat (NSC-701852) for Higher-Risk Myelodysplastic Syndromes (MDS) and Chronic Myelomonocytic Leukemia (CMML)'.
IRB SWOG 1117
Hospital Beachwood, Fairview, Hillcrest, Independence, Main Campus, North Coast Cancer, Strongsville, Wooster
Phase Phase 2
Disease Myelodysplastic Syndrome (MDS)
Drug Lenalidomide (Revlimid), Vidaza (Azacitidine), Vorinostat (MK - 0683)
- To test whether the response rate (complete remission, partial remission, or hematologic improvement) of patients with higher-risk myelodysplastic syndromes (MDS) or chronic myelomonocytic leukemia (CMML) who receive either the combination of lenalidomide and azacitidine or the combination of vorinostat and azacitidine is improved compared to patients who receive single-agent azacitidine.
- To estimate relapse-free survival, overall survival and cytogenetic response rate of patients treated on each regimen.
- To estimate the frequency and severity of toxicities of the three regimens in this patient population.
- To investigate in a preliminary manner the frequency of subgroups from prestudy cytogenetic studies and correlate these subgroups with clinical outcomes in this patient population.
- To collect specimens for banking for use in future research studies.
- Patients must have morphologically confirmed diagnosis of myelodysplastic syndrome (MDS) or chronic myelomonocytic leukemia (CMML) based on one of the following: French-American-British (FAB) classifications (27-28):
- Refractory anemia with excess blasts (RAEB - defined as having 5-20% myeloblasts in the bone marrow)
- Chronic Myelomonocytic Leukemia (CMML) with 10-19% myeloblasts in the bone marrow and/or 5-19% blasts in the blood.
World Health Organization (WHO) Classifications (28):
- 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% myeloblasts in the bone marrow and/or 5-19% blasts in the blood)
- Chronic Myelomonocytic Leukemia-1 (CMML-1 defined as having < 10% myeloblasts in the bone marrow and/or < 5% blasts in the blood)
- Chronic Myelomonocytic Leukemia-2 (CMML-2 defined as having 10-19% myeloblasts in the bone marrow and/or 5-19% blasts in the blood.
- International prognostic score (IPSS) of Intermediate 2 (1.5-2.0 points) or High (≥ 2.5 points). A score of Intermediate 1 (0.5-1.0 points) is only allowable in the setting of ≥ 5% myeloblasts. (27,29) (See Section 4.0 for IPSS calculation.)
NOTE: Patients with acute myeloid leukemia (AML) are not eligible.
- Patients must not have received lenalidomide, azacitidine, vorinostat or decitabine as treatment previously. Any hematopoietic growth factors must be stopped for at least 14 days prior to registration. Patients may have received low dose cytarabine for MDS treatment previously, but they must have discontinued its use for at least 28 days prior to registration.
- Patients must not have received radiation therapy, chemotherapy, or cytotoxic therapy to treat conditions other than MDS within 12 months prior to registration, or prior stem cell or bone marrow transplantation at any time.
- Patients must not have undergone prior allogeneic stem cell or bone marrow transplantation at any time. Patients that have undergone an autologous stem cell transplant are eligible.
- Patients must not have used or be using HDAC inhibitor agents for anticancer treatment.
- Patients may not have received agents such as valproic acid for epilepsy within 30 days prior to registration.
- Patients must be ≥ 18 years of age.
- Patients must have Zubrod Performance Status of 0-2 (see Section 10.14).
- Patients must not have any pre-existing neurotoxicity/neuropathy of ≥ Grade 2 according to the NCI Common Toxicity Criteria Version 4.0, or prior ≥ Grade 3 allergic reaction/hypersensitivity or rash to thalidomide, that has not resolved to < Grade 2.
- Patients must not have 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.
- Patients must not have history of thromboembolic event or other condition requiring current use of anticoagulation with coumadin (warfarin) or low molecular-weight heparin.
- Patients must not have known or suspected hypersensitivity to mannitol.
- Patients must receive a 12-lead EKG, chest x-ray, serum creatinine, complete metabolic panel including SGOT or SGPT, electrolytes, and bilirubin testing within 28 days prior to registration in order to establish baseline measurements. Questions regarding patient safety in regards to results of these tests should be directed to the Study Coordinator.
- Females of childbearing potential (FCBP) must have a negative serum or urine pregnancy test with a sensitivity of at least 25 mIU/mL within 10 to 14 days prior to registration. FCBP must agree to have a second pregnancy test within 24 hours prior to starting Cycle 1 if randomized to receive lenalidomide.
- No prior malignancy is allowed except for adequately treated basal (or squamous cell) skin cancer, in situ cervical cancer or other cancer for which the patient has been disease free for five years.
- Cytogenetics requirements:
Further, patients commit to the following if they are randomized to receive lenalidomide: FCBP 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 starting 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. A FCBP is a sexually mature woman who: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months). All patients must be counseled by a trained counselor every 28 days about pregnancy precautions and risks of fetal exposure. (See Appendix 19.2: Lenalidomide Risks of Fetal Exposure, Pregnancy Testing Guidelines and Acceptable Birth Control Methods, and also Appendix 19.3: Lenalidomide Education and Counseling Guidance Document).
NOTE: Patients not randomized to receive lenalidomide will not be required to undergo serial pregnancy testing or lenalidomide counseling after registration.
- SWOG (and other sites not affiliated with CALGB or ECOG): Pretreatment cytogenetics must be performed on all patients. Collection of pretreatment specimens must be completed within 14 days prior to registration to S1117. Specimens must be submitted to the site preferred CLIA-approved cytogenetics laboratory (see Sections 9.0 and 15.2a). Reports of the results must be submitted as described in Section 14.0. Note that cytogenetics are required at other timepoints (see Section 9.0).
- CALGB: CALGB patients must enroll on CALGB 8461, the cytogenetics protocol. CALGB 8461 provides sample procurement and submission instructions to CALGB approved institutional cytogeneticists. Note that cytogenetics are required at other timepoints (see Section 9.0).
- ECOG: Cytogenetic studies are performed locally. Prior to registration on S1117 ECOG patients must be registered on E3903, Ancillary laboratory protocol for collecting diagnostic material on patients considered for ECOG treatment trials for leukemia or related hematologic disorders. Karyotypes and FISH reports must be submitted for central review, via E3903, to the Mayo Clinic Cytogenetics Laboratory in Rochester (Section 15.2c). Note that cytogenetics are required at other timepoints (see Section 9.0).
- SWOG (and other sites not affiliated with CALGB or ECOG): Patients must be offered participation in specimen banking as outlined in Section 15.1a. With patient consent, specimens must be submitted as outlined. See Section 15.1 for additional specimen submission time points.
- CALGB: CALGB patients must be offered participation in CALGB 9665, the CALGB Leukemia Tissue bank protocol. CALGB 9665 provides complete sample procurement and submission instructions. A buccal smear also is required prior to initiation of therapy only. See Section 15.1 for additional specimen submission time points.
- ECOG: Patients must be offered participation in specimen banking as outlined in Section 15.1c. With patient consent, specimens must be submitted to the Leukemia Translational Research Laboratory (LTRL) at Our Lady of Mercy Cancer Center, New York, via E3903, �Ancillary laboratory protocol for collecting diagnostic material on patients considered for ECOG treatment trials for leukemia or related hematologic disorders. See Section 15.1 for additional specimen submission time points.