Azacitidine and Lenalidomide for Acute Myeloid Leukemia | NCT01016600

NCT01016600

Protocol Section

Identification Module

Results Section

Participant Flow Module

Annotation Section

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Document Section

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Derived Section

Miscellaneous Info Module

Status Module

Name	Class
Celgene Corporation	INDUSTRY

Description Module

Arms/Interventions Module

Arm Groups

Label	Type	Description	Intervention Names
Cohort 1	Experimental	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	Drug: Lenalidomide Drug: Azacitidine
Cohort 2	Experimental	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	Drug: Lenalidomide Drug: Azacitidine
Cohort 3	Experimental	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	Drug: Lenalidomide Drug: Azacitidine
Phase II	Experimental	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	Drug: Lenalidomide Drug: Azacitidine

Name	Type	Description	Arm Group Labels	Other Names
Lenalidomide	Drug		Cohort 1 Cohort 2 Cohort 3 Phase II	Revlimid

Outcomes Module

Primary Outcomes

Measure	Description	Time Frame
Phase I Only - Maximum Tolerated Dose (MTD) as Measured by Dose-limiting Toxicities (DLTs)	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.	Completion of the phase I portion of study (approximately 1 year and 4 months)
Phase I Only - Maximum Tolerated Dose (MTD)	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.	Completion of the phase I portion of study (approximately 1 year and 4 months)
Phase II Only - Complete Remission Rate (CRm + CRi) in Participants With Untreated AML ≥60 Years of Age	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 Outcomes

Measure	Description	Time Frame
Response Rate (CRm + CRc + CRi + PR)	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	Median number of cycles completed [3 cycles (12 weeks) full range (1 (4 weeks)-17 (68 weeks))]

Eligibility Module

Eligibility Criteria

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.

Name	Affiliation	Role
Ravi Vij, M.D.	Washington University School of Medicine	Principal Investigator

Facility	Status	City	State	ZIP	Country	Contacts
Washington University School of Medicine		St Louis	Missouri	63110	United States

Label	URL
Alvin J. Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine	View source

Arm/Group Information

ID	Title	Description
FG000	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
FG001	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
FG002	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
FG003	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

ID	Title	Description
BG000	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
BG001	Cohort 2

Units	Counts
Participants	BG000

Title	Description	Population Description	Parameter Type	Dispersion Type	Unit of Measure	Calculate Percentage	Denominator Units Selected	Denominators	Classes
Age, Continuous			Median

Outcome Measures Module

Outcome Measures

Type

Title

Description

Population Description

Reporting Status

Anticipated Posting Date

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Time Frame

Units Analyzed

Denominator Units Selected

Arm/Group Information

Denominators

Classes

Analyses

Primary

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

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.

(1) participant in Cohort 1 did not start treatment. The Phase II cohort was not analyzed because this was a Phase I outcome only.

Posted

Number

dose-limiting toxicities

Completion of the phase I portion of study (approximately 1 year and 4 months)

ID	Title	Description

Adverse Events Module

Arm/Groups

ID	Title	Description	Deaths (Affected)	Deaths (At Risk)	Serious Events (Affected)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	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

ID	Term
D007951	Leukemia, Myeloid
D007938	Leukemia
D009370	Neoplasms by Histologic Type
D009369	Neoplasms

ID	Term
D010797	Phthalimides
D010795	Phthalic Acids
D000146	Acids, Carbocyclic
D002264	Carboxylic Acids

OG000	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
OG001	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
OG002	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
OG003	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