Azacitidine and Lenalidomide for Acute Myeloid Leukemia

Phase 1

Completed

Conditions: Leukemia, Myeloid, Acute

Interventions: Drug: Lenalidomide
Drug: Azacitidine

Registration Number: NCT01016600

Lead Sponsor: Washington University School of Medicine

Brief Summary: Determine toxicity and remission rates of treatment with azacitidine and lenalidomide for patients with Acute Myeloid Leukemia

Detailed Description: 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.

Secondary:

1. To assess the response rate (RR), morphologic leukemia-free state, morphologic complete remission rate (CRm), cytogenetic CR (CRc) rate, CR with incomplete blood counts 14 rate, and partial remission 15 rate (PR).

2. To assess overall survival (OS) and event free survival (EFS).

3. To assess time to progression (TTP) in untreated AML ≥60 years.

4. To assess relapse free survival (RFS) and duration of CR for complete responders.

5. To determine the incidence and severity of other toxicities of lenalidomide in combination with azacitidine.

6. Assay the expression levels of cytokines/chemokines in the bone marrow plasma, expression of chemokine receptors/ligands on leukemic blasts important for the AML microenvironment and study the direct cytotoxic effects of lenalidomide, azacitidine and combination of both drugs on cryopreserved AML blast cells.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 31

Inclusion Criteria

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.

Exclusion Criteria

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 17. 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.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Cohort 2	Azacitidine	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
Cohort 3	Lenalidomide	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
Cohort 3	Azacitidine	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
Phase II	Lenalidomide	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
Cohort 1	Azacitidine	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
Cohort 2	Lenalidomide	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
Cohort 1	Lenalidomide	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
Phase II	Azacitidine	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

Primary Outcome Measures

Name	Time	Method
Phase I Only - Maximum Tolerated Dose (MTD) as Measured by Dose-limiting Toxicities (DLTs)	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)	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	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.

Secondary Outcome Measures

Name	Time	Method
Response Rate (CRm + CRc + CRi + PR)	Median number of cycles completed [3 cycles (12 weeks) full range (1 (4 weeks)-17 (68 weeks))]	* Response rate (CRm + CRc + CRi + PR) * CRm = morphologic complete remission * CRc = cytogenetic complete remission * CRi = morphologic complete remission with incomplete blood count recovery * PR = partial remission
Morphologic Leukemia-free State	Median number of cycles completed [3 cycles (12 weeks) full range (1 (4 weeks)-17 (68 weeks))]	Defined as \< 5% blasts on the BM aspirate with spicules and a count of \>200 nucleated cells and no blasts with Auer rods, and no persistent extramedullary disease.
Morphologic Complete Remission Rate (CRm)	Completion of treatment (median follow-up was 8 weeks) (range 4-68 weeks)	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. There is no duration requirement for this designation.
Cytogenetic CR (CRc) Rate	Completion of treatment (median follow-up was 8 weeks) (range 4-68 weeks)	Only patients with an identified cytogenetic abnormality may receive this designation. Defines as a morphologic complete remission plus reversion to a normal karyotype (no clonal abnormalities detected in a minimum of 20 mitotic cells).
CR With Incomplete Blood Counts Rate	Completion of treatment (median follow-up was 8 weeks) (range 4-68 weeks)	Defined as CR with the exception of neutropenia \<1000/uL or thrombocytopenia \<100,000/ul.
Partial Remission Rate (PR)	Completion of treatment (median follow-up was 8 weeks) (range 4-68 weeks)	Requires that the criteria for complete remission be met with the following exceptions: decrease of \>50% in the percentage of blasts to 5-25% in the BM aspirate. A value of \< 5% blasts in BM with Auer rods is also considered a partial remission.
Overall Survival	Until death - median follow-up 4.6 months (full range (0.3-31.4 months))	Defined as the date of first dose of study drug to the date of death from any cause.
Event Free Survival	Until death - median follow-up 4.6 months (full range (0.3-31.4 months))	Defined as the interval from the date of first dose of study drug to date of treatment failure, recurrence, or death due to any cause.
Time to Progression (TTP)	Until progressive disease - median follow-up 4.6 months (full range (0.3-31.4 months))	Defined as the interval from the date of the first dose of study drug to the date of progressive disease.
Relapse Free Survival (RFS)	Until death - median follow-up 4.6 months (full range (0.3-31.4 months))	This is determined only for patients achieving a complete remission. Defined as the interval from the date of first documentation of a leukemia free state to date of recurrence or death due to any cause.
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))	AML ≥18 years or untreated AML ≥60 years