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A Phase I/II Trial of Very Low to Low-Doses of Continuous Azacitidine in combination with Standard Doses of Lenalidomide and Low-Dose Dexamethasone in Patients with Relapsed or Refractory Multiple Myeloma
- Define the highest tolerated low dose (HTLD and HTLD CKD for GFR > 60 ml/min and 30-59 ml/min, respectively) and safety of azacitidine given at low but increasing doses up to 50mg/m^2 twice a week concurrently with GFR adjusted lenalidomide and low dose dexamethasone in patients with relapsed or refractory multiple myeloma.
- Response according to international response criteria (≥ PR) and clinical benefit response (≥ minor response according to adapted EBMT criteria), see under 7
- Correlate response with plasma activity of the azacitidine inactivating enzyme cytidine deaminase (CDA)
- Progression-free survival and overall survival
- Peripheral blood hematopoietic progenitor (CD34+) yield and time to neutrophil and platelet recovery in patients undergoing autologous stem cell transplantation
- Promoter demethylation and gene reactivation in myeloma cells and hematopoietic progenitors treated at the HTLD/HTLD-CKD level after cycle 1
- Changes in global gene expression in myeloma cells treated at the HTLD/HTLD-CKD after cycle 1
- 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.
- Refractory or relapsed multiple myeloma (see under 5.3.)
- Measurable disease defined as at least one of the following: Serum m-spike ≥ 1g/dL, urine m-spike ≥ 200mg/24hrs, serum free light chains ≥ 100mg/L (provided the kappa/lambda ratio is abnormal), or bone marrow plasma cells ≥ 30%.
- Previous therapy with IMiD compounds (thalidomide, Lenalidomide, Pomalidmid), proteasome inhibitors (bortezomib, carfilzomib), and corticosteroids must be discontinued at least 14 days before entry onto this study.
- Previous cytotoxic chemotherapy (e.g. alkylating chemotherapy, anthracyclines, and vinca alkaloids), radiation therapy, and any experimental therapy within the context of a clinical trial must have been discontinued at least 28 days prior to entry onto this study.
- ECOG performance status of ≤ 2 at study entry (see Appendix II).
- Laboratory test results within these ranges:
- Absolute neutrophil count ≥ 1,500 /mm³
- Platelet count ≥ 75,000/mm³
- Calculated creatinine clearance (Cockroft-Gault) ≥ 30ml/min.
- Total bilirubin ≤ 1.5 x ULN
- Serum glutamic-oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST]) and serum glutamic-pyruvic transaminase (SGPT) (alanine aminotransferase [ALT]) levels ≤ 2 x ULN
- 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 agree to use a latex condom during sexual contact with a FCBP even if they have had a successful vasectomy. See Appendix: Risks of Fetal Exposure, Pregnancy Testing Guidelines and Acceptable Birth Control Methods.
- Able to take aspirin (81 or 325 mg) daily as prophylactic anticoagulation (patients intolerant to ASA may use warfarin or low molecular weight heparin) if no additional risk factor for VTE other than myeloma diagnosis according to IMW guidelines(55) and as specified for this study under Section 184.108.40.206.
- Able to take low molecular weight heparin or warfarin if ≥ 1 additional risk factor for VTE according to IMW guidelines(55) and as specified for this study under Section 220.127.116.11.
- 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 or azacitidine).
- 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 other than carfilzomib and pomalidomide within 28 days of baseline.
- Neuropathy > Grade 2
- Known hypersensitivity to thalidomide, lenalidomide, azacitidine, or mannitol.
- The development of erythema nodosum if characterized by a desquamating rash while taking thalidomide or lenalidomide drugs.
- Concurrent use of other anti-cancer agents or treatment or concurrent radiation to the pelvis. Palliative radiation to areas outside the pelvis is allowed.
- Previous inability to tolerate full-dose lenalidomide, adjusted to creatinine clearance (CrCl) according to Cockroft-Gault at the time of previous lenalidomide treatment (25mg day 1-21 every 28 days if CrCl ≥ 60ml/min, 10mg lenalidomide d1-21 every 28 days if CrCl < 60mL/min but ≥ 30mL/min, lenalidomide 15mg every 48 h d1-21 every 28 days if CrCl < 30mL/min but not requiring dialysis, lenalidomide 5mg daily, day 1-21 every 28 days if CrCl < 30mL/min and requiring dialysis).
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