Leukemia, Myeloid, Acute
Conditions
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.
Interventions
DRUGLenalidomide
DRUGAzacitidine
Sponsors
Celgene Corporation
Washington University School of Medicine
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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 |
| 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 |
| 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. |
| 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. |
Countries
United States
Participant flow
Pre-assignment details
31 participants were enrolled but only 30 participants started treatment and completed treatment.
Participants by arm
| Arm | Count |
|---|---|
| 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 | 9 |
| 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 | 4 |
| 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 | 6 |
| 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 | 12 |
| Total | 31 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Did not start treatment | 1 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Total | Cohort 1 | Cohort 2 | Cohort 3 | Phase II |
|---|---|---|---|---|---|
| Age, Continuous | 72 years | 70 years | 67.5 years | 75.5 years | 72 years |
| Region of Enrollment United States | 31 participants | 9 participants | 4 participants | 6 participants | 12 participants |
| Sex: Female, Male Female | 14 Participants | 6 Participants | 1 Participants | 3 Participants | 4 Participants |
| Sex: Female, Male Male | 17 Participants | 3 Participants | 3 Participants | 3 Participants | 8 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 8 / 8 | 4 / 4 | 6 / 6 | 12 / 12 |
| serious Total, serious adverse events | 8 / 8 | 2 / 4 | 6 / 6 | 12 / 12 |
Outcome results
Primary
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.
Time frame: Completion of treatment (median follow-up was 8 weeks) (range 4-68 weeks)
Population: Participants in Cohort 1, 2, and 3 were not analyzed for this outcome as it is a Phase II outcome measure only. (3) participants in Phase II cohort were not evaluable for response because they did not complete cycle 1.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase II | Phase II Only - Complete Remission Rate (CRm + CRi) in Participants With Untreated AML ≥60 Years of Age | 22 percentage of participants |
Primary
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.
Time frame: Completion of the phase I portion of study (approximately 1 year and 4 months)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort 1 | Phase I Only - Maximum Tolerated Dose (MTD) | 75 mg/m^2 |
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.
Time frame: Completion of the phase I portion of study (approximately 1 year and 4 months)
Population: (1) participant in Cohort 1 did not start treatment. The Phase II cohort was not analyzed because this was a Phase I outcome only.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort 1 | Phase I Only - Maximum Tolerated Dose (MTD) as Measured by Dose-limiting Toxicities (DLTs) | 1 dose-limiting toxicities |
| Cohort 2 | Phase I Only - Maximum Tolerated Dose (MTD) as Measured by Dose-limiting Toxicities (DLTs) | 0 dose-limiting toxicities |
| Cohort 3 | Phase I Only - Maximum Tolerated Dose (MTD) as Measured by Dose-limiting Toxicities (DLTs) | 0 dose-limiting toxicities |
Secondary
CR With Incomplete Blood Counts Rate
Defined as CR with the exception of neutropenia \<1000/uL or thrombocytopenia \<100,000/ul.
Time frame: Completion of treatment (median follow-up was 8 weeks) (range 4-68 weeks)
Population: (3) participants in Cohort 1, (1) participant in Cohort 2, and (3) participants in Phase II did not receive 28 days of lenalidomide and therefore are not evaluable for response.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort 1 | CR With Incomplete Blood Counts Rate | 1 participants |
| Cohort 2 | CR With Incomplete Blood Counts Rate | 1 participants |
| Cohort 3 | CR With Incomplete Blood Counts Rate | 1 participants |
| Phase II | CR With Incomplete Blood Counts Rate | 1 participants |
Secondary
Cytogenetic CR (CRc) Rate
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).
Time frame: Completion of treatment (median follow-up was 8 weeks) (range 4-68 weeks)
Population: (3) participants in Cohort 1, (1) participant in Cohort 2, and (3) participants in Phase II did not receive 28 days of lenalidomide and therefore are not evaluable for response.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort 1 | Cytogenetic CR (CRc) Rate | 1 participants |
| Cohort 2 | Cytogenetic CR (CRc) Rate | 0 participants |
| Cohort 3 | Cytogenetic CR (CRc) Rate | 0 participants |
| Phase II | Cytogenetic CR (CRc) Rate | 0 participants |
Secondary
Duration of CR for Complete Responders
Time frame: Completion of treatment (median follow-up was 8 weeks) (range 4-68 weeks)
Population: (6) participants in Cohort 1, (3) participants in Cohort 2, (4) participants in Cohort 3, and (10) participants in Phase II did not have a complete response and are not evaluable for this outcome.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort 1 | Duration of CR for Complete Responders | 10.9 months |
| Cohort 2 | Duration of CR for Complete Responders | 1.4 months |
| Cohort 3 | Duration of CR for Complete Responders | 4.95 months |
| Phase II | Duration of CR for Complete Responders | 12.15 months |
Secondary
Event Free Survival
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 frame: Until death - median follow-up 4.6 months (full range (0.3-31.4 months))
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort 1 | Event Free Survival | 3.8 months |
| Cohort 2 | Event Free Survival | 3.4 months |
| Cohort 3 | Event Free Survival | 7.8 months |
| Phase II | Event Free Survival | 2.9 months |
Secondary
Morphologic Complete Remission Rate (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. There is no duration requirement for this designation.
Time frame: Completion of treatment (median follow-up was 8 weeks) (range 4-68 weeks)
Population: (3) participants in Cohort 1, (1) participant in Cohort 2, and (3) participants in Phase II did not receive 28 days of lenalidomide and therefore are not evaluable for response.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort 1 | Morphologic Complete Remission Rate (CRm) | 1 participants |
| Cohort 2 | Morphologic Complete Remission Rate (CRm) | 0 participants |
| Cohort 3 | Morphologic Complete Remission Rate (CRm) | 1 participants |
| Phase II | Morphologic Complete Remission Rate (CRm) | 1 participants |
Secondary
Morphologic Leukemia-free State
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.
Time frame: Median number of cycles completed [3 cycles (12 weeks) full range (1 (4 weeks)-17 (68 weeks))]
Population: (3) participants in Cohort 1, (1) participant in Cohort 2, and (3) participants in Phase II did not receive 28 days of lenalidomide and therefore are not evaluable for response.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort 1 | Morphologic Leukemia-free State | 2 participants |
| Cohort 2 | Morphologic Leukemia-free State | 1 participants |
| Cohort 3 | Morphologic Leukemia-free State | 2 participants |
| Phase II | Morphologic Leukemia-free State | 2 participants |
Secondary
Overall Survival
Defined as the date of first dose of study drug to the date of death from any cause.
Time frame: Until death - median follow-up 4.6 months (full range (0.3-31.4 months))
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort 1 | Overall Survival | 4.2 months |
| Cohort 2 | Overall Survival | 4.5 months |
| Cohort 3 | Overall Survival | 8.9 months |
| Phase II | Overall Survival | 4.3 months |
Secondary
Partial Remission Rate (PR)
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.
Time frame: Completion of treatment (median follow-up was 8 weeks) (range 4-68 weeks)
Population: (3) participants in Cohort 1, (1) participant in Cohort 2, and (3) participants in Phase II did not receive 28 days of lenalidomide and therefore are not evaluable for response.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort 1 | Partial Remission Rate (PR) | 2 participants |
| Cohort 2 | Partial Remission Rate (PR) | 0 participants |
| Cohort 3 | Partial Remission Rate (PR) | 2 participants |
| Phase II | Partial Remission Rate (PR) | 5 participants |
Secondary
Relapse Free Survival (RFS)
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.
Time frame: Until death - median follow-up 4.6 months (full range (0.3-31.4 months))
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort 1 | Relapse Free Survival (RFS) | 12.0 months |
| Cohort 2 | Relapse Free Survival (RFS) | 1.4 months |
| Cohort 3 | Relapse Free Survival (RFS) | 4.9 months |
| Phase II | Relapse Free Survival (RFS) | 12.2 months |
Secondary
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
Time frame: Median number of cycles completed [3 cycles (12 weeks) full range (1 (4 weeks)-17 (68 weeks))]
Population: (3) participants in Cohort 1, (1) participant in Cohort 2, and (3) participants in Phase II did not receive 28 days of lenalidomide and therefore are not evaluable for response. (1) participant in Cohort one had both CRm and CRc.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Cohort 1 | Response Rate (CRm + CRc + CRi + PR) | CRm | 1 participants |
| Cohort 1 | Response Rate (CRm + CRc + CRi + PR) | CRc | 1 participants |
| Cohort 1 | Response Rate (CRm + CRc + CRi + PR) | CRi | 1 participants |
| Cohort 1 | Response Rate (CRm + CRc + CRi + PR) | PR | 2 participants |
| Cohort 2 | Response Rate (CRm + CRc + CRi + PR) | CRc | 0 participants |
| Cohort 2 | Response Rate (CRm + CRc + CRi + PR) | CRi | 1 participants |
| Cohort 2 | Response Rate (CRm + CRc + CRi + PR) | PR | 0 participants |
| Cohort 2 | Response Rate (CRm + CRc + CRi + PR) | CRm | 0 participants |
| Cohort 3 | Response Rate (CRm + CRc + CRi + PR) | CRi | 1 participants |
| Cohort 3 | Response Rate (CRm + CRc + CRi + PR) | CRc | 0 participants |
| Cohort 3 | Response Rate (CRm + CRc + CRi + PR) | PR | 2 participants |
| Cohort 3 | Response Rate (CRm + CRc + CRi + PR) | CRm | 1 participants |
| Phase II | Response Rate (CRm + CRc + CRi + PR) | PR | 5 participants |
| Phase II | Response Rate (CRm + CRc + CRi + PR) | CRc | 0 participants |
| Phase II | Response Rate (CRm + CRc + CRi + PR) | CRm | 1 participants |
| Phase II | Response Rate (CRm + CRc + CRi + PR) | CRi | 1 participants |
Secondary
Time to Progression (TTP)
Defined as the interval from the date of the first dose of study drug to the date of progressive disease.
Time frame: Until progressive disease - median follow-up 4.6 months (full range (0.3-31.4 months))
Population: (2) cohort 1 participants were not evaluable for this outcome measure because (1) was removed for DLT \& (1) withdrew from study. (2) phase II participants were not evaluable because both were removed from study in the first cycle for adverse events.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort 1 | Time to Progression (TTP) | 5.7 months |
| Cohort 2 | Time to Progression (TTP) | 3.4 months |
| Cohort 3 | Time to Progression (TTP) | 7.8 months |
| Phase II | Time to Progression (TTP) | 3.7 months |
Secondary
Toxicity Profile (Grade 3/4 Toxicities)
AML ≥18 years or untreated AML ≥60 years
Time frame: 30 days after completion of treatment (median follow-up was 12 weeks (range 8-72 weeks))
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Cohort 1 | Toxicity Profile (Grade 3/4 Toxicities) | Polyarthropathy | 0 participants |
| Cohort 1 | Toxicity Profile (Grade 3/4 Toxicities) | Edema limbs | 0 participants |
| Cohort 1 | Toxicity Profile (Grade 3/4 Toxicities) | Atrial fibrillation | 0 participants |
| Cohort 1 | Toxicity Profile (Grade 3/4 Toxicities) | Catheter related infection | 0 participants |
| Cohort 1 | Toxicity Profile (Grade 3/4 Toxicities) | Bronchial infection | 1 participants |
| Cohort 1 | Toxicity Profile (Grade 3/4 Toxicities) | Alanine aminotransferase increased | 0 participants |
| Cohort 1 | Toxicity Profile (Grade 3/4 Toxicities) | Hypertension | 0 participants |
| Cohort 1 | Toxicity Profile (Grade 3/4 Toxicities) | INR increased | 0 participants |
| Cohort 1 | Toxicity Profile (Grade 3/4 Toxicities) | Otitis mastoditis - worsening | 1 participants |
| Cohort 1 | Toxicity Profile (Grade 3/4 Toxicities) | Hyperglycemia | 0 participants |
| Cohort 1 | Toxicity Profile (Grade 3/4 Toxicities) | Fracture | 0 participants |
| Cohort 1 | Toxicity Profile (Grade 3/4 Toxicities) | Pruritus | 0 participants |
| Cohort 1 | Toxicity Profile (Grade 3/4 Toxicities) | Hematuria | 0 participants |
| Cohort 1 | Toxicity Profile (Grade 3/4 Toxicities) | Bacteremia | 2 participants |
| Cohort 1 | Toxicity Profile (Grade 3/4 Toxicities) | Cough | 0 participants |
| Cohort 1 | Toxicity Profile (Grade 3/4 Toxicities) | Respiratory failure | 0 participants |
| Cohort 1 | Toxicity Profile (Grade 3/4 Toxicities) | Wheezing | 0 participants |
| Cohort 1 | Toxicity Profile (Grade 3/4 Toxicities) | Cardiac arrest | 0 participants |
| Cohort 1 | Toxicity Profile (Grade 3/4 Toxicities) | Hypokalemia | 0 participants |
| Cohort 1 | Toxicity Profile (Grade 3/4 Toxicities) | Perianal hemorrhage | 0 participants |
| Cohort 1 | Toxicity Profile (Grade 3/4 Toxicities) | Lung infection | 3 participants |
| Cohort 1 | Toxicity Profile (Grade 3/4 Toxicities) | Cyst infection | 0 participants |
| Cohort 1 | Toxicity Profile (Grade 3/4 Toxicities) | Hypoalbuminemia | 0 participants |
| Cohort 1 | Toxicity Profile (Grade 3/4 Toxicities) | Incarcerated hernia | 0 participants |
| Cohort 1 | Toxicity Profile (Grade 3/4 Toxicities) | Fall | 0 participants |
| Cohort 1 | Toxicity Profile (Grade 3/4 Toxicities) | Skin infection | 1 participants |
| Cohort 1 | Toxicity Profile (Grade 3/4 Toxicities) | Activated partial thromboplastin time prolonged | 1 participants |
| Cohort 1 | Toxicity Profile (Grade 3/4 Toxicities) | Diarrhea | 1 participants |
| Cohort 1 | Toxicity Profile (Grade 3/4 Toxicities) | Wound infection | 0 participants |
| Cohort 1 | Toxicity Profile (Grade 3/4 Toxicities) | Blood bilirubin increased | 2 participants |
| Cohort 1 | Toxicity Profile (Grade 3/4 Toxicities) | Creatinine increased | 1 participants |
| Cohort 1 | Toxicity Profile (Grade 3/4 Toxicities) | Urinary tract infection | 0 participants |
| Cohort 1 | Toxicity Profile (Grade 3/4 Toxicities) | Neutrophil count decreased | 7 participants |
| Cohort 1 | Toxicity Profile (Grade 3/4 Toxicities) | Neck pain | 0 participants |
| Cohort 1 | Toxicity Profile (Grade 3/4 Toxicities) | Platelet count decreased | 4 participants |
| Cohort 1 | Toxicity Profile (Grade 3/4 Toxicities) | Hyponatremia | 0 participants |
| Cohort 1 | Toxicity Profile (Grade 3/4 Toxicities) | Upper respiratory infection | 0 participants |
| Cohort 1 | Toxicity Profile (Grade 3/4 Toxicities) | White blood cell count decreased | 7 participants |
| Cohort 1 | Toxicity Profile (Grade 3/4 Toxicities) | Nausea | 1 participants |
| Cohort 1 | Toxicity Profile (Grade 3/4 Toxicities) | Lymphocyte count decreased | 5 participants |
| Cohort 1 | Toxicity Profile (Grade 3/4 Toxicities) | Scrotal infection | 0 participants |
| Cohort 1 | Toxicity Profile (Grade 3/4 Toxicities) | Dehydration | 2 participants |
| Cohort 1 | Toxicity Profile (Grade 3/4 Toxicities) | Hypernatremia | 1 participants |
| Cohort 1 | Toxicity Profile (Grade 3/4 Toxicities) | Otitis media | 0 participants |
| Cohort 1 | Toxicity Profile (Grade 3/4 Toxicities) | Hypocalcemia | 1 participants |
| Cohort 1 | Toxicity Profile (Grade 3/4 Toxicities) | Vomiting | 2 participants |
| Cohort 1 | Toxicity Profile (Grade 3/4 Toxicities) | Hypophosphatemia | 4 participants |
| Cohort 1 | Toxicity Profile (Grade 3/4 Toxicities) | Pain | 0 participants |
| Cohort 1 | Toxicity Profile (Grade 3/4 Toxicities) | Back pain | 1 participants |
| Cohort 1 | Toxicity Profile (Grade 3/4 Toxicities) | Febrile neutropenia | 4 participants |
| Cohort 1 | Toxicity Profile (Grade 3/4 Toxicities) | Generalized muscle weakness | 2 participants |
| Cohort 1 | Toxicity Profile (Grade 3/4 Toxicities) | Anorexia | 0 participants |
| Cohort 1 | Toxicity Profile (Grade 3/4 Toxicities) | Lower gastrointestinal hemorrhage | 0 participants |
| Cohort 1 | Toxicity Profile (Grade 3/4 Toxicities) | Pain in extremity | 1 participants |
| Cohort 1 | Toxicity Profile (Grade 3/4 Toxicities) | Dental carries | 1 participants |
| Cohort 1 | Toxicity Profile (Grade 3/4 Toxicities) | Leukemia vasculitis left calf | 1 participants |
| Cohort 1 | Toxicity Profile (Grade 3/4 Toxicities) | Esophagitis | 0 participants |
| Cohort 1 | Toxicity Profile (Grade 3/4 Toxicities) | Acute kidney injury | 1 participants |
| Cohort 1 | Toxicity Profile (Grade 3/4 Toxicities) | Dyspnea | 3 participants |
| Cohort 1 | Toxicity Profile (Grade 3/4 Toxicities) | Dysphagia | 0 participants |
| Cohort 1 | Toxicity Profile (Grade 3/4 Toxicities) | Epistaxis | 1 participants |
| Cohort 1 | Toxicity Profile (Grade 3/4 Toxicities) | Fatigue | 1 participants |
| Cohort 1 | Toxicity Profile (Grade 3/4 Toxicities) | Productive cough | 1 participants |
| Cohort 1 | Toxicity Profile (Grade 3/4 Toxicities) | Supraventricular tachycardia | 0 participants |
| Cohort 1 | Toxicity Profile (Grade 3/4 Toxicities) | Pulmonary edema | 1 participants |
| Cohort 1 | Toxicity Profile (Grade 3/4 Toxicities) | Anemia | 3 participants |
| Cohort 1 | Toxicity Profile (Grade 3/4 Toxicities) | Rash maculo-papular | 1 participants |
| Cohort 1 | Toxicity Profile (Grade 3/4 Toxicities) | Weight loss | 0 participants |
| Cohort 1 | Toxicity Profile (Grade 3/4 Toxicities) | Left ventricular systolic dysfunction | 0 participants |
| Cohort 1 | Toxicity Profile (Grade 3/4 Toxicities) | Skin ulceration | 1 participants |
| Cohort 1 | Toxicity Profile (Grade 3/4 Toxicities) | Sepsis | 1 participants |
| Cohort 1 | Toxicity Profile (Grade 3/4 Toxicities) | Hypotension | 3 participants |
| Cohort 1 | Toxicity Profile (Grade 3/4 Toxicities) | Chest pain cardiac | 0 participants |
| Cohort 1 | Toxicity Profile (Grade 3/4 Toxicities) | Constipation | 0 participants |
| Cohort 1 | Toxicity Profile (Grade 3/4 Toxicities) | Syncope | 0 participants |
| Cohort 1 | Toxicity Profile (Grade 3/4 Toxicities) | Pleuritic pain | 0 participants |
| Cohort 2 | Toxicity Profile (Grade 3/4 Toxicities) | Syncope | 0 participants |
| Cohort 2 | Toxicity Profile (Grade 3/4 Toxicities) | Pleuritic pain | 0 participants |
| Cohort 2 | Toxicity Profile (Grade 3/4 Toxicities) | Leukemia vasculitis left calf | 0 participants |
| Cohort 2 | Toxicity Profile (Grade 3/4 Toxicities) | Atrial fibrillation | 0 participants |
| Cohort 2 | Toxicity Profile (Grade 3/4 Toxicities) | White blood cell count decreased | 1 participants |
| Cohort 2 | Toxicity Profile (Grade 3/4 Toxicities) | Edema limbs | 1 participants |
| Cohort 2 | Toxicity Profile (Grade 3/4 Toxicities) | Fracture | 0 participants |
| Cohort 2 | Toxicity Profile (Grade 3/4 Toxicities) | Dental carries | 0 participants |
| Cohort 2 | Toxicity Profile (Grade 3/4 Toxicities) | Scrotal infection | 0 participants |
| Cohort 2 | Toxicity Profile (Grade 3/4 Toxicities) | Catheter related infection | 1 participants |
| Cohort 2 | Toxicity Profile (Grade 3/4 Toxicities) | Hypotension | 0 participants |
| Cohort 2 | Toxicity Profile (Grade 3/4 Toxicities) | Hypertension | 0 participants |
| Cohort 2 | Toxicity Profile (Grade 3/4 Toxicities) | Lymphocyte count decreased | 1 participants |
| Cohort 2 | Toxicity Profile (Grade 3/4 Toxicities) | Alanine aminotransferase increased | 1 participants |
| Cohort 2 | Toxicity Profile (Grade 3/4 Toxicities) | Bronchial infection | 0 participants |
| Cohort 2 | Toxicity Profile (Grade 3/4 Toxicities) | Nausea | 0 participants |
| Cohort 2 | Toxicity Profile (Grade 3/4 Toxicities) | Pulmonary edema | 0 participants |
| Cohort 2 | Toxicity Profile (Grade 3/4 Toxicities) | INR increased | 1 participants |
| Cohort 2 | Toxicity Profile (Grade 3/4 Toxicities) | Acute kidney injury | 0 participants |
| Cohort 2 | Toxicity Profile (Grade 3/4 Toxicities) | Pruritus | 0 participants |
| Cohort 2 | Toxicity Profile (Grade 3/4 Toxicities) | Dehydration | 0 participants |
| Cohort 2 | Toxicity Profile (Grade 3/4 Toxicities) | Hyperglycemia | 1 participants |
| Cohort 2 | Toxicity Profile (Grade 3/4 Toxicities) | Polyarthropathy | 0 participants |
| Cohort 2 | Toxicity Profile (Grade 3/4 Toxicities) | Otitis media | 0 participants |
| Cohort 2 | Toxicity Profile (Grade 3/4 Toxicities) | Febrile neutropenia | 1 participants |
| Cohort 2 | Toxicity Profile (Grade 3/4 Toxicities) | Hematuria | 1 participants |
| Cohort 2 | Toxicity Profile (Grade 3/4 Toxicities) | Hypernatremia | 0 participants |
| Cohort 2 | Toxicity Profile (Grade 3/4 Toxicities) | Respiratory failure | 0 participants |
| Cohort 2 | Toxicity Profile (Grade 3/4 Toxicities) | Anorexia | 0 participants |
| Cohort 2 | Toxicity Profile (Grade 3/4 Toxicities) | Cough | 1 participants |
| Cohort 2 | Toxicity Profile (Grade 3/4 Toxicities) | Bacteremia | 0 participants |
| Cohort 2 | Toxicity Profile (Grade 3/4 Toxicities) | Dysphagia | 0 participants |
| Cohort 2 | Toxicity Profile (Grade 3/4 Toxicities) | Skin ulceration | 0 participants |
| Cohort 2 | Toxicity Profile (Grade 3/4 Toxicities) | Wheezing | 1 participants |
| Cohort 2 | Toxicity Profile (Grade 3/4 Toxicities) | Otitis mastoditis - worsening | 0 participants |
| Cohort 2 | Toxicity Profile (Grade 3/4 Toxicities) | Hypokalemia | 0 participants |
| Cohort 2 | Toxicity Profile (Grade 3/4 Toxicities) | Hypocalcemia | 0 participants |
| Cohort 2 | Toxicity Profile (Grade 3/4 Toxicities) | Cardiac arrest | 0 participants |
| Cohort 2 | Toxicity Profile (Grade 3/4 Toxicities) | Fall | 0 participants |
| Cohort 2 | Toxicity Profile (Grade 3/4 Toxicities) | Dyspnea | 2 participants |
| Cohort 2 | Toxicity Profile (Grade 3/4 Toxicities) | Pain | 0 participants |
| Cohort 2 | Toxicity Profile (Grade 3/4 Toxicities) | Perianal hemorrhage | 0 participants |
| Cohort 2 | Toxicity Profile (Grade 3/4 Toxicities) | Weight loss | 0 participants |
| Cohort 2 | Toxicity Profile (Grade 3/4 Toxicities) | Hypoalbuminemia | 0 participants |
| Cohort 2 | Toxicity Profile (Grade 3/4 Toxicities) | Hypophosphatemia | 0 participants |
| Cohort 2 | Toxicity Profile (Grade 3/4 Toxicities) | Cyst infection | 0 participants |
| Cohort 2 | Toxicity Profile (Grade 3/4 Toxicities) | Lung infection | 0 participants |
| Cohort 2 | Toxicity Profile (Grade 3/4 Toxicities) | Vomiting | 0 participants |
| Cohort 2 | Toxicity Profile (Grade 3/4 Toxicities) | Left ventricular systolic dysfunction | 0 participants |
| Cohort 2 | Toxicity Profile (Grade 3/4 Toxicities) | Incarcerated hernia | 0 participants |
| Cohort 2 | Toxicity Profile (Grade 3/4 Toxicities) | Anemia | 0 participants |
| Cohort 2 | Toxicity Profile (Grade 3/4 Toxicities) | Sepsis | 0 participants |
| Cohort 2 | Toxicity Profile (Grade 3/4 Toxicities) | Back pain | 0 participants |
| Cohort 2 | Toxicity Profile (Grade 3/4 Toxicities) | Skin infection | 2 participants |
| Cohort 2 | Toxicity Profile (Grade 3/4 Toxicities) | Neck pain | 0 participants |
| Cohort 2 | Toxicity Profile (Grade 3/4 Toxicities) | Wound infection | 0 participants |
| Cohort 2 | Toxicity Profile (Grade 3/4 Toxicities) | Epistaxis | 0 participants |
| Cohort 2 | Toxicity Profile (Grade 3/4 Toxicities) | Activated partial thromboplastin time prolonged | 0 participants |
| Cohort 2 | Toxicity Profile (Grade 3/4 Toxicities) | Lower gastrointestinal hemorrhage | 0 participants |
| Cohort 2 | Toxicity Profile (Grade 3/4 Toxicities) | Rash maculo-papular | 0 participants |
| Cohort 2 | Toxicity Profile (Grade 3/4 Toxicities) | Generalized muscle weakness | 0 participants |
| Cohort 2 | Toxicity Profile (Grade 3/4 Toxicities) | Blood bilirubin increased | 0 participants |
| Cohort 2 | Toxicity Profile (Grade 3/4 Toxicities) | Diarrhea | 0 participants |
| Cohort 2 | Toxicity Profile (Grade 3/4 Toxicities) | Urinary tract infection | 0 participants |
| Cohort 2 | Toxicity Profile (Grade 3/4 Toxicities) | Supraventricular tachycardia | 0 participants |
| Cohort 2 | Toxicity Profile (Grade 3/4 Toxicities) | Creatinine increased | 0 participants |
| Cohort 2 | Toxicity Profile (Grade 3/4 Toxicities) | Hyponatremia | 0 participants |
| Cohort 2 | Toxicity Profile (Grade 3/4 Toxicities) | Chest pain cardiac | 0 participants |
| Cohort 2 | Toxicity Profile (Grade 3/4 Toxicities) | Productive cough | 0 participants |
| Cohort 2 | Toxicity Profile (Grade 3/4 Toxicities) | Neutrophil count decreased | 0 participants |
| Cohort 2 | Toxicity Profile (Grade 3/4 Toxicities) | Pain in extremity | 0 participants |
| Cohort 2 | Toxicity Profile (Grade 3/4 Toxicities) | Upper respiratory infection | 0 participants |
| Cohort 2 | Toxicity Profile (Grade 3/4 Toxicities) | Fatigue | 0 participants |
| Cohort 2 | Toxicity Profile (Grade 3/4 Toxicities) | Platelet count decreased | 2 participants |
| Cohort 2 | Toxicity Profile (Grade 3/4 Toxicities) | Esophagitis | 0 participants |
| Cohort 2 | Toxicity Profile (Grade 3/4 Toxicities) | Constipation | 1 participants |
| Cohort 3 | Toxicity Profile (Grade 3/4 Toxicities) | Platelet count decreased | 3 participants |
| Cohort 3 | Toxicity Profile (Grade 3/4 Toxicities) | Anemia | 0 participants |
| Cohort 3 | Toxicity Profile (Grade 3/4 Toxicities) | Febrile neutropenia | 3 participants |
| Cohort 3 | Toxicity Profile (Grade 3/4 Toxicities) | Otitis mastoditis - worsening | 0 participants |
| Cohort 3 | Toxicity Profile (Grade 3/4 Toxicities) | Diarrhea | 2 participants |
| Cohort 3 | Toxicity Profile (Grade 3/4 Toxicities) | Nausea | 0 participants |
| Cohort 3 | Toxicity Profile (Grade 3/4 Toxicities) | Vomiting | 0 participants |
| Cohort 3 | Toxicity Profile (Grade 3/4 Toxicities) | Dental carries | 0 participants |
| Cohort 3 | Toxicity Profile (Grade 3/4 Toxicities) | Fatigue | 4 participants |
| Cohort 3 | Toxicity Profile (Grade 3/4 Toxicities) | Sepsis | 2 participants |
| Cohort 3 | Toxicity Profile (Grade 3/4 Toxicities) | Bronchial infection | 0 participants |
| Cohort 3 | Toxicity Profile (Grade 3/4 Toxicities) | Bacteremia | 1 participants |
| Cohort 3 | Toxicity Profile (Grade 3/4 Toxicities) | Lung infection | 2 participants |
| Cohort 3 | Toxicity Profile (Grade 3/4 Toxicities) | Skin infection | 2 participants |
| Cohort 3 | Toxicity Profile (Grade 3/4 Toxicities) | Activated partial thromboplastin time prolonged | 0 participants |
| Cohort 3 | Toxicity Profile (Grade 3/4 Toxicities) | Blood bilirubin increased | 2 participants |
| Cohort 3 | Toxicity Profile (Grade 3/4 Toxicities) | Creatinine increased | 1 participants |
| Cohort 3 | Toxicity Profile (Grade 3/4 Toxicities) | Neutrophil count decreased | 2 participants |
| Cohort 3 | Toxicity Profile (Grade 3/4 Toxicities) | White blood cell count decreased | 4 participants |
| Cohort 3 | Toxicity Profile (Grade 3/4 Toxicities) | Lymphocyte count decreased | 1 participants |
| Cohort 3 | Toxicity Profile (Grade 3/4 Toxicities) | Dehydration | 0 participants |
| Cohort 3 | Toxicity Profile (Grade 3/4 Toxicities) | Hypernatremia | 0 participants |
| Cohort 3 | Toxicity Profile (Grade 3/4 Toxicities) | Hypocalcemia | 1 participants |
| Cohort 3 | Toxicity Profile (Grade 3/4 Toxicities) | Hypophosphatemia | 3 participants |
| Cohort 3 | Toxicity Profile (Grade 3/4 Toxicities) | Back pain | 0 participants |
| Cohort 3 | Toxicity Profile (Grade 3/4 Toxicities) | Generalized muscle weakness | 1 participants |
| Cohort 3 | Toxicity Profile (Grade 3/4 Toxicities) | Pain in extremity | 0 participants |
| Cohort 3 | Toxicity Profile (Grade 3/4 Toxicities) | Leukemia vasculitis left calf | 0 participants |
| Cohort 3 | Toxicity Profile (Grade 3/4 Toxicities) | Acute kidney injury | 1 participants |
| Cohort 3 | Toxicity Profile (Grade 3/4 Toxicities) | Dyspnea | 1 participants |
| Cohort 3 | Toxicity Profile (Grade 3/4 Toxicities) | Epistaxis | 0 participants |
| Cohort 3 | Toxicity Profile (Grade 3/4 Toxicities) | Productive cough | 1 participants |
| Cohort 3 | Toxicity Profile (Grade 3/4 Toxicities) | Pulmonary edema | 0 participants |
| Cohort 3 | Toxicity Profile (Grade 3/4 Toxicities) | Rash maculo-papular | 1 participants |
| Cohort 3 | Toxicity Profile (Grade 3/4 Toxicities) | Skin ulceration | 0 participants |
| Cohort 3 | Toxicity Profile (Grade 3/4 Toxicities) | Hypotension | 1 participants |
| Cohort 3 | Toxicity Profile (Grade 3/4 Toxicities) | Constipation | 0 participants |
| Cohort 3 | Toxicity Profile (Grade 3/4 Toxicities) | Edema limbs | 0 participants |
| Cohort 3 | Toxicity Profile (Grade 3/4 Toxicities) | Catheter related infection | 1 participants |
| Cohort 3 | Toxicity Profile (Grade 3/4 Toxicities) | Alanine aminotransferase increased | 0 participants |
| Cohort 3 | Toxicity Profile (Grade 3/4 Toxicities) | INR increased | 0 participants |
| Cohort 3 | Toxicity Profile (Grade 3/4 Toxicities) | Hyperglycemia | 0 participants |
| Cohort 3 | Toxicity Profile (Grade 3/4 Toxicities) | Hematuria | 0 participants |
| Cohort 3 | Toxicity Profile (Grade 3/4 Toxicities) | Cough | 0 participants |
| Cohort 3 | Toxicity Profile (Grade 3/4 Toxicities) | Wheezing | 0 participants |
| Cohort 3 | Toxicity Profile (Grade 3/4 Toxicities) | Cardiac arrest | 1 participants |
| Cohort 3 | Toxicity Profile (Grade 3/4 Toxicities) | Perianal hemorrhage | 1 participants |
| Cohort 3 | Toxicity Profile (Grade 3/4 Toxicities) | Cyst infection | 1 participants |
| Cohort 3 | Toxicity Profile (Grade 3/4 Toxicities) | Incarcerated hernia | 1 participants |
| Cohort 3 | Toxicity Profile (Grade 3/4 Toxicities) | Hypoalbuminemia | 1 participants |
| Cohort 3 | Toxicity Profile (Grade 3/4 Toxicities) | Hypokalemia | 2 participants |
| Cohort 3 | Toxicity Profile (Grade 3/4 Toxicities) | Respiratory failure | 1 participants |
| Cohort 3 | Toxicity Profile (Grade 3/4 Toxicities) | Pruritus | 1 participants |
| Cohort 3 | Toxicity Profile (Grade 3/4 Toxicities) | Hypertension | 1 participants |
| Cohort 3 | Toxicity Profile (Grade 3/4 Toxicities) | Atrial fibrillation | 0 participants |
| Cohort 3 | Toxicity Profile (Grade 3/4 Toxicities) | Chest pain cardiac | 0 participants |
| Cohort 3 | Toxicity Profile (Grade 3/4 Toxicities) | Left ventricular systolic dysfunction | 0 participants |
| Cohort 3 | Toxicity Profile (Grade 3/4 Toxicities) | Supraventricular tachycardia | 0 participants |
| Cohort 3 | Toxicity Profile (Grade 3/4 Toxicities) | Dysphagia | 0 participants |
| Cohort 3 | Toxicity Profile (Grade 3/4 Toxicities) | Esophagitis | 0 participants |
| Cohort 3 | Toxicity Profile (Grade 3/4 Toxicities) | Lower gastrointestinal hemorrhage | 0 participants |
| Cohort 3 | Toxicity Profile (Grade 3/4 Toxicities) | Pain | 0 participants |
| Cohort 3 | Toxicity Profile (Grade 3/4 Toxicities) | Otitis media | 0 participants |
| Cohort 3 | Toxicity Profile (Grade 3/4 Toxicities) | Scrotal infection | 0 participants |
| Cohort 3 | Toxicity Profile (Grade 3/4 Toxicities) | Upper respiratory infection | 0 participants |
| Cohort 3 | Toxicity Profile (Grade 3/4 Toxicities) | Urinary tract infection | 0 participants |
| Cohort 3 | Toxicity Profile (Grade 3/4 Toxicities) | Wound infection | 0 participants |
| Cohort 3 | Toxicity Profile (Grade 3/4 Toxicities) | Fall | 0 participants |
| Cohort 3 | Toxicity Profile (Grade 3/4 Toxicities) | Fracture | 0 participants |
| Cohort 3 | Toxicity Profile (Grade 3/4 Toxicities) | Weight loss | 0 participants |
| Cohort 3 | Toxicity Profile (Grade 3/4 Toxicities) | Anorexia | 0 participants |
| Cohort 3 | Toxicity Profile (Grade 3/4 Toxicities) | Hyponatremia | 0 participants |
| Cohort 3 | Toxicity Profile (Grade 3/4 Toxicities) | Neck pain | 0 participants |
| Cohort 3 | Toxicity Profile (Grade 3/4 Toxicities) | Syncope | 0 participants |
| Cohort 3 | Toxicity Profile (Grade 3/4 Toxicities) | Polyarthropathy | 0 participants |
| Cohort 3 | Toxicity Profile (Grade 3/4 Toxicities) | Pleuritic pain | 0 participants |
| Phase II | Toxicity Profile (Grade 3/4 Toxicities) | Pleuritic pain | 2 participants |
| Phase II | Toxicity Profile (Grade 3/4 Toxicities) | Polyarthropathy | 1 participants |
| Phase II | Toxicity Profile (Grade 3/4 Toxicities) | Syncope | 2 participants |
| Phase II | Toxicity Profile (Grade 3/4 Toxicities) | Atrial fibrillation | 1 participants |
| Phase II | Toxicity Profile (Grade 3/4 Toxicities) | Hypotension | 1 participants |
| Phase II | Toxicity Profile (Grade 3/4 Toxicities) | Skin ulceration | 0 participants |
| Phase II | Toxicity Profile (Grade 3/4 Toxicities) | Otitis mastoditis - worsening | 0 participants |
| Phase II | Toxicity Profile (Grade 3/4 Toxicities) | Chest pain cardiac | 1 participants |
| Phase II | Toxicity Profile (Grade 3/4 Toxicities) | Rash maculo-papular | 1 participants |
| Phase II | Toxicity Profile (Grade 3/4 Toxicities) | Pulmonary edema | 0 participants |
| Phase II | Toxicity Profile (Grade 3/4 Toxicities) | Fracture | 1 participants |
| Phase II | Toxicity Profile (Grade 3/4 Toxicities) | Left ventricular systolic dysfunction | 1 participants |
| Phase II | Toxicity Profile (Grade 3/4 Toxicities) | Productive cough | 0 participants |
| Phase II | Toxicity Profile (Grade 3/4 Toxicities) | Epistaxis | 0 participants |
| Phase II | Toxicity Profile (Grade 3/4 Toxicities) | Fatigue | 4 participants |
| Phase II | Toxicity Profile (Grade 3/4 Toxicities) | Supraventricular tachycardia | 1 participants |
| Phase II | Toxicity Profile (Grade 3/4 Toxicities) | Dyspnea | 2 participants |
| Phase II | Toxicity Profile (Grade 3/4 Toxicities) | Acute kidney injury | 0 participants |
| Phase II | Toxicity Profile (Grade 3/4 Toxicities) | Dental carries | 0 participants |
| Phase II | Toxicity Profile (Grade 3/4 Toxicities) | Dysphagia | 1 participants |
| Phase II | Toxicity Profile (Grade 3/4 Toxicities) | Leukemia vasculitis left calf | 0 participants |
| Phase II | Toxicity Profile (Grade 3/4 Toxicities) | Pain in extremity | 1 participants |
| Phase II | Toxicity Profile (Grade 3/4 Toxicities) | Anemia | 4 participants |
| Phase II | Toxicity Profile (Grade 3/4 Toxicities) | Esophagitis | 1 participants |
| Phase II | Toxicity Profile (Grade 3/4 Toxicities) | Generalized muscle weakness | 2 participants |
| Phase II | Toxicity Profile (Grade 3/4 Toxicities) | Back pain | 0 participants |
| Phase II | Toxicity Profile (Grade 3/4 Toxicities) | Weight loss | 1 participants |
| Phase II | Toxicity Profile (Grade 3/4 Toxicities) | Lower gastrointestinal hemorrhage | 1 participants |
| Phase II | Toxicity Profile (Grade 3/4 Toxicities) | Hypophosphatemia | 6 participants |
| Phase II | Toxicity Profile (Grade 3/4 Toxicities) | Hypocalcemia | 0 participants |
| Phase II | Toxicity Profile (Grade 3/4 Toxicities) | Vomiting | 2 participants |
| Phase II | Toxicity Profile (Grade 3/4 Toxicities) | Pain | 1 participants |
| Phase II | Toxicity Profile (Grade 3/4 Toxicities) | Hypernatremia | 0 participants |
| Phase II | Toxicity Profile (Grade 3/4 Toxicities) | Dehydration | 3 participants |
| Phase II | Toxicity Profile (Grade 3/4 Toxicities) | Nausea | 1 participants |
| Phase II | Toxicity Profile (Grade 3/4 Toxicities) | Otitis media | 1 participants |
| Phase II | Toxicity Profile (Grade 3/4 Toxicities) | Lymphocyte count decreased | 2 participants |
| Phase II | Toxicity Profile (Grade 3/4 Toxicities) | White blood cell count decreased | 10 participants |
| Phase II | Toxicity Profile (Grade 3/4 Toxicities) | Neck pain | 1 participants |
| Phase II | Toxicity Profile (Grade 3/4 Toxicities) | Scrotal infection | 1 participants |
| Phase II | Toxicity Profile (Grade 3/4 Toxicities) | Platelet count decreased | 6 participants |
| Phase II | Toxicity Profile (Grade 3/4 Toxicities) | Neutrophil count decreased | 2 participants |
| Phase II | Toxicity Profile (Grade 3/4 Toxicities) | Anorexia | 1 participants |
| Phase II | Toxicity Profile (Grade 3/4 Toxicities) | Upper respiratory infection | 1 participants |
| Phase II | Toxicity Profile (Grade 3/4 Toxicities) | Creatinine increased | 0 participants |
| Phase II | Toxicity Profile (Grade 3/4 Toxicities) | Blood bilirubin increased | 3 participants |
| Phase II | Toxicity Profile (Grade 3/4 Toxicities) | Febrile neutropenia | 8 participants |
| Phase II | Toxicity Profile (Grade 3/4 Toxicities) | Urinary tract infection | 1 participants |
| Phase II | Toxicity Profile (Grade 3/4 Toxicities) | Activated partial thromboplastin time prolonged | 0 participants |
| Phase II | Toxicity Profile (Grade 3/4 Toxicities) | Skin infection | 2 participants |
| Phase II | Toxicity Profile (Grade 3/4 Toxicities) | Hyponatremia | 3 participants |
| Phase II | Toxicity Profile (Grade 3/4 Toxicities) | Wound infection | 1 participants |
| Phase II | Toxicity Profile (Grade 3/4 Toxicities) | Incarcerated hernia | 0 participants |
| Phase II | Toxicity Profile (Grade 3/4 Toxicities) | Cyst infection | 0 participants |
| Phase II | Toxicity Profile (Grade 3/4 Toxicities) | Perianal hemorrhage | 0 participants |
| Phase II | Toxicity Profile (Grade 3/4 Toxicities) | Lung infection | 9 participants |
| Phase II | Toxicity Profile (Grade 3/4 Toxicities) | Hypoalbuminemia | 1 participants |
| Phase II | Toxicity Profile (Grade 3/4 Toxicities) | Cardiac arrest | 0 participants |
| Phase II | Toxicity Profile (Grade 3/4 Toxicities) | Wheezing | 0 participants |
| Phase II | Toxicity Profile (Grade 3/4 Toxicities) | Bacteremia | 0 participants |
| Phase II | Toxicity Profile (Grade 3/4 Toxicities) | Hypokalemia | 3 participants |
| Phase II | Toxicity Profile (Grade 3/4 Toxicities) | Cough | 0 participants |
| Phase II | Toxicity Profile (Grade 3/4 Toxicities) | Hematuria | 1 participants |
| Phase II | Toxicity Profile (Grade 3/4 Toxicities) | Diarrhea | 0 participants |
| Phase II | Toxicity Profile (Grade 3/4 Toxicities) | Respiratory failure | 1 participants |
| Phase II | Toxicity Profile (Grade 3/4 Toxicities) | Hyperglycemia | 5 participants |
| Phase II | Toxicity Profile (Grade 3/4 Toxicities) | INR increased | 0 participants |
| Phase II | Toxicity Profile (Grade 3/4 Toxicities) | Fall | 1 participants |
| Phase II | Toxicity Profile (Grade 3/4 Toxicities) | Pruritus | 0 participants |
| Phase II | Toxicity Profile (Grade 3/4 Toxicities) | Alanine aminotransferase increased | 1 participants |
| Phase II | Toxicity Profile (Grade 3/4 Toxicities) | Catheter related infection | 1 participants |
| Phase II | Toxicity Profile (Grade 3/4 Toxicities) | Bronchial infection | 0 participants |
| Phase II | Toxicity Profile (Grade 3/4 Toxicities) | Hypertension | 0 participants |
| Phase II | Toxicity Profile (Grade 3/4 Toxicities) | Edema limbs | 1 participants |
| Phase II | Toxicity Profile (Grade 3/4 Toxicities) | Constipation | 0 participants |
| Phase II | Toxicity Profile (Grade 3/4 Toxicities) | Sepsis | 1 participants |