Phase I/II Trial of Azacitidine Plus Lenalidomide in the Treatment of Acute Myeloid Leukemia
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 31
- 试验地点
- 1
- 主要终点
- Phase I Only - Maximum Tolerated Dose (MTD) as Measured by Dose-limiting Toxicities (DLTs)
研究概览
简要总结
Determine toxicity and remission rates of treatment with azacitidine and lenalidomide for patients with Acute Myeloid Leukemia
详细描述
Primary:
Phase 1:
To determine the toxicity and feasibility of combining lenalidomide and azacitidine in patients with relapsed/ refractory AML ≥ 18 years or untreated AML ≥60 years.
Phase 2:
To assess the complete remission (CRm plus CRi) rate after lenalidomide + azacitidine therapy in untreated AML ≥60 years.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Newly diagnosed AML age ≥ 60 years, de novo, secondary to prior therapy, or transformed from MDS, as defined by the International Working Group, except acute promyelocytic leukemia (AML M3) will be included for phase 1 and 2 study. Patients must not have abnormalities of inversion 16, t(16,16), del(16q), t(8,21) or t(15,17) as assessed by routine cytogenetics or FISH. Diagnosis of AML by WHO criteria (>20% blasts) is determined by CBC, bone marrow assessment, and immunophenotypic analysis performed within 2 weeks of study enrollment. No previous treatment for AML, however hydroxyurea, steroids, and leukopheresis are allowed.
- •Relapsed AML age ≥18 years, except acute promyelocytic leukemia (AML M3), with CR < 1 years post 1st induction chemotherapy will be included in phase 1 study only.
- •Primary refractory AML age ≥18 years, except acute promyelocytic leukemia (AML M3) post 1st induction chemotherapy will be included in phase 1 study only.
- •Relapsed or refractory AML age ≥18 years, except acute promyelocytic leukemia (AML M3), post 1st salvage chemotherapy/ autologous stem transplantation/ allogeneic stem cell transplantation will be included in phase 1 study only.
- •Understand and voluntarily sign an informed consent form.
- •Able to adhere to the study visit schedule and other protocol requirements.
- •ECOG performance status of ≤ 2 at study entry
- •Life expectancy > 2 months
- •WBC < 10,000 x 10^6/L (WBC counts may not be reduced by hydroxyurea or leukapheresis to achieve a WBC lower than 10,000 x 106 /L).
- •Adequate renal and hepatic function as defined by:
- •Serum creatinine ≤ 1.5X institution ULN
- •Total bilirubin ≤ 2.0 mg/dL ( except Gilbert's syndrome or known hemolysis)
- •AST(SGOT) and ALT (SGPT) ≤ 2.5 x ULN
- •All study participants must be registered into the mandatory Revlimid REMS® program, and be willing and able to comply with the requirements of Revlimid REMS®.
- •Females of 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.
- •Men must agree not to father a child and agree to use a latex condom during sexual contact with females of child bearing potential even if they have had a successful vasectomy. -Disease free of prior malignancies for ≥ 5 years with exception of AML, currently treated basal cell, squamous cell carcinoma of the skin, or carcinoma "in situ" of the cervix or breast.
排除标准
- •Newly diagnosed AML age < 60 years.
- •Newly diagnosed AML ≥ 60 years with favorable risk cytogenetic abnormalities as defined by SWOG criteria that include: inv(16)/t(16;16)/del(16q), t(15;17) with/without secondary aberrations, t(8;21) lacking del(9q) or complex karyotype
- •Prior to enrollment, FISH studies or routine cytogenetics must be completed to rule out these cytogenetic abnormalities.
- •Known CNS leukemia
- •Any serious medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from signing the informed consent form.
- •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 30 days of enrollment.
- •Known hypersensitivity to thalidomide and mannitol.
- •The development of erythema multiforme if characterized by a desquamating rash while taking thalidomide or similar drugs.
- •Any prior use of lenalidomide
- •Any prior use of azacytidine.
- •Concurrent use of other anti-cancer agents or treatments (with the exception of steroids)
- •Known positive for HIV or infectious hepatitis, type A, B or C.
研究组 & 干预措施
Cohort 1
Induction regimen (total 2 cycles)
Lenalidomide 50 mg PO daily days 1-28
Azacitidine 25 mg/m2 IV days 1-5
Maintenance Regimen
Lenalidomide 10 mg PO daily days 1-28
Azacitidine 75 mg/m2 IV days 1-5
干预措施: Lenalidomide (Drug)
Cohort 1
Induction regimen (total 2 cycles)
Lenalidomide 50 mg PO daily days 1-28
Azacitidine 25 mg/m2 IV days 1-5
Maintenance Regimen
Lenalidomide 10 mg PO daily days 1-28
Azacitidine 75 mg/m2 IV days 1-5
干预措施: Azacitidine (Drug)
Cohort 2
Induction regimen (total 2 cycles)
Lenalidomide 50 mg PO daily days 1-28
Azacitidine 50 mg/m2 IV days 1-5
Maintenance Regimen
Lenalidomide 10 mg PO daily days 1-28
Azacitidine 75 mg/m2 IV days 1-5
干预措施: Lenalidomide (Drug)
Cohort 2
Induction regimen (total 2 cycles)
Lenalidomide 50 mg PO daily days 1-28
Azacitidine 50 mg/m2 IV days 1-5
Maintenance Regimen
Lenalidomide 10 mg PO daily days 1-28
Azacitidine 75 mg/m2 IV days 1-5
干预措施: Azacitidine (Drug)
Cohort 3
Induction regimen (total 2 cycles)
Lenalidomide 50 mg PO daily days 1-28
Azacitidine 75 mg/m2 IV days 1-5
Maintenance Regimen
Lenalidomide 10 mg PO daily days 1-28
Azacitidine 75 mg/m2 IV days 1-5
干预措施: Lenalidomide (Drug)
Phase II
Induction regimen (total 2 cycles)
Lenalidomide 50 mg PO daily days 1-28
Azacitidine 75 mg/m2 (dose determined in Phase I) mg/m2 IV days 1-5
Maintenance Regimen
Lenalidomide 10 mg PO daily days 1-28
Azacitidine 75 mg/m2 IV days 1-5
干预措施: Azacitidine (Drug)
Cohort 3
Induction regimen (total 2 cycles)
Lenalidomide 50 mg PO daily days 1-28
Azacitidine 75 mg/m2 IV days 1-5
Maintenance Regimen
Lenalidomide 10 mg PO daily days 1-28
Azacitidine 75 mg/m2 IV days 1-5
干预措施: Azacitidine (Drug)
Phase II
Induction regimen (total 2 cycles)
Lenalidomide 50 mg PO daily days 1-28
Azacitidine 75 mg/m2 (dose determined in Phase I) mg/m2 IV days 1-5
Maintenance Regimen
Lenalidomide 10 mg PO daily days 1-28
Azacitidine 75 mg/m2 IV days 1-5
干预措施: Lenalidomide (Drug)
结局指标
主要结局
Phase I Only - Maximum Tolerated Dose (MTD) as Measured by Dose-limiting Toxicities (DLTs)
时间窗: Completion of the phase I portion of study (approximately 1 year and 4 months)
* The maximum tolerated dose (MTD) is defined as the dose level immediately below the dose level at which 2 patients of a cohort (of 2 to 6 patients) experience dose-limiting toxicity during the first cycle. * Hematologic DLT is as a persistent bone marrow aplasia with ≤ 10 % cellularity, which persists for \> 60 days from the start of a chemotherapy cycle. * Non-hematologic DLT is defined as any Grade 3 or Grade 4 non-hematologic toxicity that occurs during the first cycle with the specific exceptions of nausea, vomiting, anorexia, weight loss, infections or electrolyte abnormalities attributable to any other cause. Grade 3 triglycerides will be considered a DLT only for patients who have Grade 3 in spite of appropriate lipid lowering drug therapy.
Phase I Only - Maximum Tolerated Dose (MTD)
时间窗: Completion of the phase I portion of study (approximately 1 year and 4 months)
* The maximum tolerated dose (MTD) is defined as the dose level immediately below the dose level at which 2 patients of a cohort (of 2 to 6 patients) experience dose-limiting toxicity during the first cycle. * Hematologic DLT is as a persistent bone marrow aplasia with ≤ 10 % cellularity, which persists for \> 60 days from the start of a chemotherapy cycle. * Non-hematologic DLT is defined as any Grade 3 or Grade 4 non-hematologic toxicity that occurs during the first cycle with the specific exceptions of nausea, vomiting, anorexia, weight loss, infections or electrolyte abnormalities attributable to any other cause. Grade 3 triglycerides will be considered a DLT only for patients who have Grade 3 in spite of appropriate lipid lowering drug therapy.
Phase II Only - Complete Remission Rate (CRm + CRi) in Participants With Untreated AML ≥60 Years of Age
时间窗: Completion of treatment (median follow-up was 8 weeks) (range 4-68 weeks)
* Morphologic complete remission (CRm): Defined as morphologic leukemia-free state, including \<5% blasts in BM aspirate with marrow spicules and a count of \> 200 nucleated cells and no blasts with Auer rods, no persistent extramedullary disease, ANC \> 1000/uL, platelet count \> 100,000/uL. Patient must be independent of transfusions for a minimum of 1 week before each marrow assessment. * Morphologic complete remission with incomplete blood count recovery (CRi): Defined as CR with the exception of neutropenia \<1000/uL or thrombocytopenia \<100,000/ul.
次要结局
- Response Rate (CRm + CRc + CRi + PR)(Median number of cycles completed [3 cycles (12 weeks) full range (1 (4 weeks)-17 (68 weeks))])
- Morphologic Leukemia-free State(Median number of cycles completed [3 cycles (12 weeks) full range (1 (4 weeks)-17 (68 weeks))])
- Morphologic Complete Remission Rate (CRm)(Completion of treatment (median follow-up was 8 weeks) (range 4-68 weeks))
- Cytogenetic CR (CRc) Rate(Completion of treatment (median follow-up was 8 weeks) (range 4-68 weeks))
- CR With Incomplete Blood Counts Rate(Completion of treatment (median follow-up was 8 weeks) (range 4-68 weeks))
- Partial Remission Rate (PR)(Completion of treatment (median follow-up was 8 weeks) (range 4-68 weeks))
- Overall Survival(Until death - median follow-up 4.6 months (full range (0.3-31.4 months)))
- Event Free Survival(Until death - median follow-up 4.6 months (full range (0.3-31.4 months)))
- Time to Progression (TTP)(Until progressive disease - median follow-up 4.6 months (full range (0.3-31.4 months)))
- Relapse Free Survival (RFS)(Until death - median follow-up 4.6 months (full range (0.3-31.4 months)))
- Duration of CR for Complete Responders(Completion of treatment (median follow-up was 8 weeks) (range 4-68 weeks))
- Toxicity Profile (Grade 3/4 Toxicities)(30 days after completion of treatment (median follow-up was 12 weeks (range 8-72 weeks)))