Leukemia, Myeloid, Acute
Conditions
Keywords
stem cell mobilization, chemosensitization, CXCR4, SDF-1, CXCL-12
Brief summary
This study is designed to test the combination of Plerixafor with G-CSF for chemosensitization in patients with relapsed or refractory AML.
Detailed description
In this study, we are seeking to target the leukemia microenvironment to overcome disease resistance. We hypothesize that by disrupting the interaction of leukemic blasts with the bone marrow microenvironment, we may sensitize leukemic blasts to the effects of cytotoxic chemotherapy. In this study, we seek to maximize blockage of the SDF-1/CXCR4 axis through the following: 1. Addition of G-CSF, which down regulates SDF-1 expression and acts synergistically with plerixafor in stem cell mobilization 2. Intravenous instead of subcutaneous dosing of plerixafor to improve kinetics of administration. 3. Dose escalation of plerixafor and twice daily dosing to maintain maximum CXCR4 blockade.
Interventions
DRUGG-CSF
DRUGPlerixafor
DRUGMitoxantrone
DRUGEtoposide
DRUGCytarabine
Sponsors
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 70 Years
Healthy volunteers
No
Inclusion criteria
1. Acute myeloid leukemia diagnosed by WHO criteria with one of the following: * Primary refractory disease following no more than 2 cycles of induction chemotherapy * First relapse with no prior unsuccessful salvage chemotherapy 2. Age between 18 and 70 years old 3. ECOG performance status ≤ 3 4. Adequate organ function defined as: * Calculated creatinine clearance ≥ 50 ml/min * AST, ALT, total bilirubin ≤ 2 x ULN except when in the opinion of treating physician is due to direct involvement of leukemia (eg. hepatic infiltration or biliary obstruction due to leukemia) * Left ventricular ejection fraction of ≥ 40% by MUGA scan or echocardiogram 5. Are surgically or biologically sterile or willing to practice acceptable birth control, as follows: * Females of child bearing potential must agree to abstain from sexual activity or to use a medically approved contraceptive measure/regimen during and for 3 months after the treatment period. Women of child bearing potential must have a negative serum or urine pregnancy test at the time of enrollment. Acceptable methods of birth control include oral contraceptive, intrauterine device (IUD), transdermal/implanted or injected contraceptives and abstinence. * Males must agree to abstain from sexual activity or agree to utilize a medically approved contraception method during and for 3 months after the treatment period 6. Able to provide signed informed consent prior to registration on study
Exclusion criteria
1. Acute promyelocytic leukemia (AML with t(15;17)(q22;q11) and variants) 2. Peripheral blood blast count ≥ 20 x 103 /mm3 3. Active CNS involvement with leukemia 4. Previous treatment with MEC or other regimen containing both mitoxantrone and etoposide 5. Pregnant or nursing 6. Received any other investigational agent or cytotoxic chemotherapy (excluding hydroxyurea) within the preceding 2 weeks 7. Received colony stimulating factors filgrastim or sargramostim within 1 week or pegfilgrastim within 2 weeks of study 8. Severe concurrent illness that would limit compliance with study requirements
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Phase I: Maximum Tolerated Dose of Plerixafor Plus G-CSF When Combined With MEC | Completion of Phase I enrollment (17 months) | — |
| Phase II: Complete Response Rate (CR+CRi) | 45 days | * Morphologic complete remission (CR): 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 \> 1,000/mm3, platelet count \> 100,000/mm3. * Morphologic complete remission with incomplete blood count recovery (CRi): Defined as CR with the exception of neutropenia \<1,000/mm3 or thrombocytopenia \<100,000/mm3. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to Hematologic Recovery as Measured by Time to Neutrophil Recovery | Up to 62 days after treatment | -Neutrophil recovery is defined as absolute neutrophil count (ANC) \>= 500/mm\^3 |
| Characterize the Mobilization of Leukemic Cells With Plerixafor Plus G-CSF as Measured by Fold Change in White Blood Cells | 6 hours after plerixafor | — |
| Characterize the Mobilization of Leukemic Cells With Plerixafor Plus G-CSF as Measured by Fold Change in AML Blast Count | 6 hours after plerixafor | — |
| Characterize the Effects of Plerixafor Plus G-CSF on Fold Change in CXCR4 Clone 1D9 Relative Mean Fluorescent Intensity | 6 hours after plerixafor | — |
| Time to Hematologic Recovery as Measured by Time to Platelet Recovery | Up to 62 days after treatment | -Platelet recovery is defined as platelets \>= 50,000/mm\^3 |
| Time to Progression | 2 years | Recurrence / morphologic relapse: Defined as reappearance of blasts in the blood or the finding of \> 5% blasts in the BM, not attributable to any other cause. New dysplastic changes are considered a relapse. If there are no blasts in the peripheral blood and 5-19% blasts in the BM, the BM biopsy and aspirate should be repeated in \> 1 week to confirm relapse. |
| Time to Treatment Failure | 8 days | — |
| Overall Survival | Median follow-up was 34.6 months | Overall survival: Defined as the date of first dose of study drug to the date of death from any cause. |
| Characterize the Effects of Plerixafor Plus G-CSF on Fold Change in CXCR4 Clone 12G5 Relative Mean Fluorescent Intensity | 6 hours after plerixafor | — |
| Phase I and Phase II: Safety and Tolerability of Regimen as Measured by Grade and Frequency of Adverse Events Exceeding 10% in Total Frequency | 30 days following end of treatment | — |
Countries
United States
Participant flow
Recruitment details
The study opened to participant enrollment on 02/04/2011 and closed to participant enrollment on 08/19/2013.
Participants by arm
| Arm | Count |
|---|---|
| Dose Level 1 * G-CSF 10 mcg/kg SQ on Days 1-8
* Plerixafor 240 mcg/kg/d IV qd
* Mitoxantrone 8 mg/m2/day IV once over 30 minutes daily on days 4-8
* Etoposide 100 mg/m2/day IV once over 60 minutes daily on days 4-8
* Cytarabine 1000 mg/m2/day IV once over 60 minutes daily on days 4-8 | 3 |
| Dose Level 2 * G-CSF 10 mcg/kg SQ on Days 1-8
* Plerixafor 320 mcg/kg/d IV qd
* Mitoxantrone 8 mg/m2/day IV once over 30 minutes daily on days 4-8
* Etoposide 100 mg/m2/day IV once over 60 minutes daily on days 4-8
* Cytarabine 1000 mg/m2/day IV once over 60 minutes daily on days 4-8 | 3 |
| Dose Level 3 * G-CSF 10 mcg/kg SQ on Days 1-8
* Plerixafor 420 mcg/kg/d IV qd
* Mitoxantrone 8 mg/m2/day IV once over 30 minutes daily on days 4-8
* Etoposide 100 mg/m2/day IV once over 60 minutes daily on days 4-8
* Cytarabine 1000 mg/m2/day IV once over 60 minutes daily on days 4-8 | 3 |
| Dose Level 4 * G-CSF 10 mcg/kg SQ on Days 1-8
* Plerixafor 560 mcg/kg/d IV qd
* Mitoxantrone 8 mg/m2/day IV once over 30 minutes daily on days 4-8
* Etoposide 100 mg/m2/day IV once over 60 minutes daily on days 4-8
* Cytarabine 1000 mg/m2/day IV once over 60 minutes daily on days 4-8 | 6 |
| Dose Level 5 (Includes MTD-Phase II) * G-CSF 10 mcg/kg SQ on Days 1-8
* Plerixafor 750 mcg/kg/d IV qd
* Mitoxantrone 8 mg/m2/day IV once over 30 minutes daily on days 4-8
* Etoposide 100 mg/m2/day IV once over 60 minutes daily on days 4-8
* Cytarabine 1000 mg/m2/day IV once over 60 minutes daily on days 4-8 | 20 |
| Total | 35 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Overall Study | Found to be not eligible | 0 | 0 | 0 | 1 | 1 | 1 |
| Overall Study | Physician Decision | 0 | 0 | 0 | 0 | 0 | 1 |
Baseline characteristics
| Characteristic | Dose Level 1 | Dose Level 2 | Dose Level 3 | Dose Level 4 | Dose Level 5 (Includes MTD-Phase II) | Total |
|---|---|---|---|---|---|---|
| Age, Continuous | 63 years | 47 years | 64 years | 54 years | 56 years | 56 years |
| Region of Enrollment United States | 3 participants | 3 participants | 3 participants | 6 participants | 20 participants | 35 participants |
| Sex: Female, Male Female | 2 Participants | 2 Participants | 1 Participants | 4 Participants | 8 Participants | 17 Participants |
| Sex: Female, Male Male | 1 Participants | 1 Participants | 2 Participants | 2 Participants | 12 Participants | 18 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 3 / 3 | 3 / 3 | 3 / 3 | 6 / 6 | 6 / 6 | 14 / 14 |
| serious Total, serious adverse events | 0 / 3 | 2 / 3 | 0 / 3 | 2 / 6 | 2 / 6 | 2 / 14 |
Outcome results
Primary
Phase II: Complete Response Rate (CR+CRi)
* Morphologic complete remission (CR): 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 \> 1,000/mm3, platelet count \> 100,000/mm3. * Morphologic complete remission with incomplete blood count recovery (CRi): Defined as CR with the exception of neutropenia \<1,000/mm3 or thrombocytopenia \<100,000/mm3.
Time frame: 45 days
Population: Only patients enrolled in Phase 2 portion were analyzed for this outcome measure.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase I (Includes Levels 1-5) | Phase II: Complete Response Rate (CR+CRi) | 30 percentage of participants |
Primary
Phase I: Maximum Tolerated Dose of Plerixafor Plus G-CSF When Combined With MEC
Time frame: Completion of Phase I enrollment (17 months)
Population: Number of participants analyzed is the number of participants enrolled in the Phase I portion of the study.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase I (Includes Levels 1-5) | Phase I: Maximum Tolerated Dose of Plerixafor Plus G-CSF When Combined With MEC | 750 mcg/kg/day |
Secondary
Characterize the Effects of Plerixafor Plus G-CSF on Fold Change in CXCR4 Clone 12G5 Relative Mean Fluorescent Intensity
Time frame: 6 hours after plerixafor
Population: 29 patients were evaluable for this outcome measure (3 patients were never treated due to being ineligible and 1 patient never treated due to physician decision). The remaining 6 patients did not have usable peripheral blood samples for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Phase I (Includes Levels 1-5) | Characterize the Effects of Plerixafor Plus G-CSF on Fold Change in CXCR4 Clone 12G5 Relative Mean Fluorescent Intensity | 0.9 fold change in CXCR4 clone 1D9 | Standard Deviation 0.9 |
Secondary
Characterize the Effects of Plerixafor Plus G-CSF on Fold Change in CXCR4 Clone 1D9 Relative Mean Fluorescent Intensity
Time frame: 6 hours after plerixafor
Population: 29 patients were evaluable for this outcome measure (3 patients were never treated due to being ineligible and 1 patient never treated due to physician decision). The remaining 6 patients did not have usable peripheral blood samples for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Phase I (Includes Levels 1-5) | Characterize the Effects of Plerixafor Plus G-CSF on Fold Change in CXCR4 Clone 1D9 Relative Mean Fluorescent Intensity | 8.0 fold change in CXCR4 clone 1D9 | Standard Deviation 13.2 |
Secondary
Characterize the Mobilization of Leukemic Cells With Plerixafor Plus G-CSF as Measured by Fold Change in AML Blast Count
Time frame: 6 hours after plerixafor
Population: 31 patients were evaluable for this outcome measure (3 patients were never treated due to being ineligible and 1 patient never treated due to physician decision). The remaining 4 patients did not have usable peripheral blood samples for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Phase I (Includes Levels 1-5) | Characterize the Mobilization of Leukemic Cells With Plerixafor Plus G-CSF as Measured by Fold Change in AML Blast Count | 9.4 fold change in AML blast count | Standard Deviation 11.6 |
Secondary
Characterize the Mobilization of Leukemic Cells With Plerixafor Plus G-CSF as Measured by Fold Change in White Blood Cells
Time frame: 6 hours after plerixafor
Population: 31 patients were evaluable for this outcome measure (3 patients were never treated due to being ineligible and 1 patient never treated due to physician decision). The remaining 4 patients did not have usable peripheral blood samples for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Phase I (Includes Levels 1-5) | Characterize the Mobilization of Leukemic Cells With Plerixafor Plus G-CSF as Measured by Fold Change in White Blood Cells | 4.6 fold change in white blood cells | Standard Deviation 3.6 |
Secondary
Overall Survival
Overall survival: Defined as the date of first dose of study drug to the date of death from any cause.
Time frame: Median follow-up was 34.6 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase I (Includes Levels 1-5) | Overall Survival | 227 days |
Secondary
Phase I and Phase II: Safety and Tolerability of Regimen as Measured by Grade and Frequency of Adverse Events Exceeding 10% in Total Frequency
Time frame: 30 days following end of treatment
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Phase I (Includes Levels 1-5) | Phase I and Phase II: Safety and Tolerability of Regimen as Measured by Grade and Frequency of Adverse Events Exceeding 10% in Total Frequency | Anorexia | 4 number of events |
| Phase I (Includes Levels 1-5) | Phase I and Phase II: Safety and Tolerability of Regimen as Measured by Grade and Frequency of Adverse Events Exceeding 10% in Total Frequency | Activated partial thromboplastin time prolonged | 5 number of events |
| Phase I (Includes Levels 1-5) | Phase I and Phase II: Safety and Tolerability of Regimen as Measured by Grade and Frequency of Adverse Events Exceeding 10% in Total Frequency | Dyspnea | 3 number of events |
| Phase I (Includes Levels 1-5) | Phase I and Phase II: Safety and Tolerability of Regimen as Measured by Grade and Frequency of Adverse Events Exceeding 10% in Total Frequency | White blood cell count decreased | 0 number of events |
| Phase I (Includes Levels 1-5) | Phase I and Phase II: Safety and Tolerability of Regimen as Measured by Grade and Frequency of Adverse Events Exceeding 10% in Total Frequency | Alanine aminotransferase increased | 3 number of events |
| Phase I (Includes Levels 1-5) | Phase I and Phase II: Safety and Tolerability of Regimen as Measured by Grade and Frequency of Adverse Events Exceeding 10% in Total Frequency | Diarrhea | 7 number of events |
| Phase I (Includes Levels 1-5) | Phase I and Phase II: Safety and Tolerability of Regimen as Measured by Grade and Frequency of Adverse Events Exceeding 10% in Total Frequency | Platelet count decreased | 0 number of events |
| Phase I (Includes Levels 1-5) | Phase I and Phase II: Safety and Tolerability of Regimen as Measured by Grade and Frequency of Adverse Events Exceeding 10% in Total Frequency | Alkaline phosphatase increased | 3 number of events |
| Phase I (Includes Levels 1-5) | Phase I and Phase II: Safety and Tolerability of Regimen as Measured by Grade and Frequency of Adverse Events Exceeding 10% in Total Frequency | Neutrophil count decreased | 0 number of events |
| Phase I (Includes Levels 1-5) | Phase I and Phase II: Safety and Tolerability of Regimen as Measured by Grade and Frequency of Adverse Events Exceeding 10% in Total Frequency | Aspartate aminotransferase increased | 4 number of events |
| Phase I (Includes Levels 1-5) | Phase I and Phase II: Safety and Tolerability of Regimen as Measured by Grade and Frequency of Adverse Events Exceeding 10% in Total Frequency | Febrile neutropenia | 0 number of events |
| Phase I (Includes Levels 1-5) | Phase I and Phase II: Safety and Tolerability of Regimen as Measured by Grade and Frequency of Adverse Events Exceeding 10% in Total Frequency | INR increased | 7 number of events |
| Phase I (Includes Levels 1-5) | Phase I and Phase II: Safety and Tolerability of Regimen as Measured by Grade and Frequency of Adverse Events Exceeding 10% in Total Frequency | Blood bilirubin increased | 2 number of events |
| Phase I (Includes Levels 1-5) | Phase I and Phase II: Safety and Tolerability of Regimen as Measured by Grade and Frequency of Adverse Events Exceeding 10% in Total Frequency | Cough | 3 number of events |
| Phase I (Includes Levels 1-5) | Phase I and Phase II: Safety and Tolerability of Regimen as Measured by Grade and Frequency of Adverse Events Exceeding 10% in Total Frequency | Gastroesophageal reflux disease | 1 number of events |
| Phase I (Includes Levels 1-5) | Phase I and Phase II: Safety and Tolerability of Regimen as Measured by Grade and Frequency of Adverse Events Exceeding 10% in Total Frequency | Anemia | 0 number of events |
| Phase I (Includes Levels 1-5) | Phase I and Phase II: Safety and Tolerability of Regimen as Measured by Grade and Frequency of Adverse Events Exceeding 10% in Total Frequency | Mucositis oral | 2 number of events |
| Phase I (Includes Levels 1-5) | Phase I and Phase II: Safety and Tolerability of Regimen as Measured by Grade and Frequency of Adverse Events Exceeding 10% in Total Frequency | Proteinuria | 3 number of events |
| Phase I (Includes Levels 1-5) | Phase I and Phase II: Safety and Tolerability of Regimen as Measured by Grade and Frequency of Adverse Events Exceeding 10% in Total Frequency | Nausea | 21 number of events |
| Phase I (Includes Levels 1-5) | Phase I and Phase II: Safety and Tolerability of Regimen as Measured by Grade and Frequency of Adverse Events Exceeding 10% in Total Frequency | Insomnia | 5 number of events |
| Phase I (Includes Levels 1-5) | Phase I and Phase II: Safety and Tolerability of Regimen as Measured by Grade and Frequency of Adverse Events Exceeding 10% in Total Frequency | Vomiting | 12 number of events |
| Phase I (Includes Levels 1-5) | Phase I and Phase II: Safety and Tolerability of Regimen as Measured by Grade and Frequency of Adverse Events Exceeding 10% in Total Frequency | Rash maculo-papular | 3 number of events |
| Phase I (Includes Levels 1-5) | Phase I and Phase II: Safety and Tolerability of Regimen as Measured by Grade and Frequency of Adverse Events Exceeding 10% in Total Frequency | Paresthesia | 4 number of events |
| Phase I (Includes Levels 1-5) | Phase I and Phase II: Safety and Tolerability of Regimen as Measured by Grade and Frequency of Adverse Events Exceeding 10% in Total Frequency | Chills | 5 number of events |
| Phase I (Includes Levels 1-5) | Phase I and Phase II: Safety and Tolerability of Regimen as Measured by Grade and Frequency of Adverse Events Exceeding 10% in Total Frequency | Abdominal pain | 6 number of events |
| Phase I (Includes Levels 1-5) | Phase I and Phase II: Safety and Tolerability of Regimen as Measured by Grade and Frequency of Adverse Events Exceeding 10% in Total Frequency | Headache | 7 number of events |
| Phase I (Includes Levels 1-5) | Phase I and Phase II: Safety and Tolerability of Regimen as Measured by Grade and Frequency of Adverse Events Exceeding 10% in Total Frequency | Edema-limbs | 5 number of events |
| Phase I (Includes Levels 1-5) | Phase I and Phase II: Safety and Tolerability of Regimen as Measured by Grade and Frequency of Adverse Events Exceeding 10% in Total Frequency | Dizziness | 4 number of events |
| Phase I (Includes Levels 1-5) | Phase I and Phase II: Safety and Tolerability of Regimen as Measured by Grade and Frequency of Adverse Events Exceeding 10% in Total Frequency | Fatigue | 9 number of events |
| Phase I (Includes Levels 1-5) | Phase I and Phase II: Safety and Tolerability of Regimen as Measured by Grade and Frequency of Adverse Events Exceeding 10% in Total Frequency | Bone pain | 4 number of events |
| Phase I (Includes Levels 1-5) | Phase I and Phase II: Safety and Tolerability of Regimen as Measured by Grade and Frequency of Adverse Events Exceeding 10% in Total Frequency | Fever | 6 number of events |
| Phase I (Includes Levels 1-5) | Phase I and Phase II: Safety and Tolerability of Regimen as Measured by Grade and Frequency of Adverse Events Exceeding 10% in Total Frequency | Hyponatremia | 4 number of events |
| Phase I (Includes Levels 1-5) | Phase I and Phase II: Safety and Tolerability of Regimen as Measured by Grade and Frequency of Adverse Events Exceeding 10% in Total Frequency | Non-cardiac chest pain | 1 number of events |
| Phase I (Includes Levels 1-5) | Phase I and Phase II: Safety and Tolerability of Regimen as Measured by Grade and Frequency of Adverse Events Exceeding 10% in Total Frequency | Pneumonitis | 1 number of events |
| Phase I (Includes Levels 1-5) | Phase I and Phase II: Safety and Tolerability of Regimen as Measured by Grade and Frequency of Adverse Events Exceeding 10% in Total Frequency | Hypomagnesemia | 7 number of events |
| Phase I (Includes Levels 1-5) | Phase I and Phase II: Safety and Tolerability of Regimen as Measured by Grade and Frequency of Adverse Events Exceeding 10% in Total Frequency | Pain | 2 number of events |
| Phase I (Includes Levels 1-5) | Phase I and Phase II: Safety and Tolerability of Regimen as Measured by Grade and Frequency of Adverse Events Exceeding 10% in Total Frequency | Constipation | 5 number of events |
| Phase I (Includes Levels 1-5) | Phase I and Phase II: Safety and Tolerability of Regimen as Measured by Grade and Frequency of Adverse Events Exceeding 10% in Total Frequency | Hypokalemia | 5 number of events |
| Phase I (Includes Levels 1-5) | Phase I and Phase II: Safety and Tolerability of Regimen as Measured by Grade and Frequency of Adverse Events Exceeding 10% in Total Frequency | Bacteremia | 0 number of events |
| Phase I (Includes Levels 1-5) | Phase I and Phase II: Safety and Tolerability of Regimen as Measured by Grade and Frequency of Adverse Events Exceeding 10% in Total Frequency | Hypocalcemia | 2 number of events |
| Phase I (Includes Levels 1-5) | Phase I and Phase II: Safety and Tolerability of Regimen as Measured by Grade and Frequency of Adverse Events Exceeding 10% in Total Frequency | Lung infection | 0 number of events |
| Phase I (Includes Levels 1-5) | Phase I and Phase II: Safety and Tolerability of Regimen as Measured by Grade and Frequency of Adverse Events Exceeding 10% in Total Frequency | Hypotension | 4 number of events |
| Phase I (Includes Levels 1-5) | Phase I and Phase II: Safety and Tolerability of Regimen as Measured by Grade and Frequency of Adverse Events Exceeding 10% in Total Frequency | Hypoalbuminemia | 3 number of events |
| Phase I (Includes Levels 1-5) | Phase I and Phase II: Safety and Tolerability of Regimen as Measured by Grade and Frequency of Adverse Events Exceeding 10% in Total Frequency | Sepsis | 0 number of events |
| Grade 2 | Phase I and Phase II: Safety and Tolerability of Regimen as Measured by Grade and Frequency of Adverse Events Exceeding 10% in Total Frequency | Headache | 6 number of events |
| Grade 2 | Phase I and Phase II: Safety and Tolerability of Regimen as Measured by Grade and Frequency of Adverse Events Exceeding 10% in Total Frequency | White blood cell count decreased | 0 number of events |
| Grade 2 | Phase I and Phase II: Safety and Tolerability of Regimen as Measured by Grade and Frequency of Adverse Events Exceeding 10% in Total Frequency | Constipation | 2 number of events |
| Grade 2 | Phase I and Phase II: Safety and Tolerability of Regimen as Measured by Grade and Frequency of Adverse Events Exceeding 10% in Total Frequency | Activated partial thromboplastin time prolonged | 0 number of events |
| Grade 2 | Phase I and Phase II: Safety and Tolerability of Regimen as Measured by Grade and Frequency of Adverse Events Exceeding 10% in Total Frequency | Chills | 0 number of events |
| Grade 2 | Phase I and Phase II: Safety and Tolerability of Regimen as Measured by Grade and Frequency of Adverse Events Exceeding 10% in Total Frequency | Sepsis | 0 number of events |
| Grade 2 | Phase I and Phase II: Safety and Tolerability of Regimen as Measured by Grade and Frequency of Adverse Events Exceeding 10% in Total Frequency | Platelet count decreased | 0 number of events |
| Grade 2 | Phase I and Phase II: Safety and Tolerability of Regimen as Measured by Grade and Frequency of Adverse Events Exceeding 10% in Total Frequency | Hypokalemia | 2 number of events |
| Grade 2 | Phase I and Phase II: Safety and Tolerability of Regimen as Measured by Grade and Frequency of Adverse Events Exceeding 10% in Total Frequency | Alanine aminotransferase increased | 0 number of events |
| Grade 2 | Phase I and Phase II: Safety and Tolerability of Regimen as Measured by Grade and Frequency of Adverse Events Exceeding 10% in Total Frequency | Dizziness | 1 number of events |
| Grade 2 | Phase I and Phase II: Safety and Tolerability of Regimen as Measured by Grade and Frequency of Adverse Events Exceeding 10% in Total Frequency | Hypoalbuminemia | 6 number of events |
| Grade 2 | Phase I and Phase II: Safety and Tolerability of Regimen as Measured by Grade and Frequency of Adverse Events Exceeding 10% in Total Frequency | Neutrophil count decreased | 0 number of events |
| Grade 2 | Phase I and Phase II: Safety and Tolerability of Regimen as Measured by Grade and Frequency of Adverse Events Exceeding 10% in Total Frequency | Edema-limbs | 1 number of events |
| Grade 2 | Phase I and Phase II: Safety and Tolerability of Regimen as Measured by Grade and Frequency of Adverse Events Exceeding 10% in Total Frequency | Alkaline phosphatase increased | 1 number of events |
| Grade 2 | Phase I and Phase II: Safety and Tolerability of Regimen as Measured by Grade and Frequency of Adverse Events Exceeding 10% in Total Frequency | Diarrhea | 6 number of events |
| Grade 2 | Phase I and Phase II: Safety and Tolerability of Regimen as Measured by Grade and Frequency of Adverse Events Exceeding 10% in Total Frequency | Abdominal pain | 0 number of events |
| Grade 2 | Phase I and Phase II: Safety and Tolerability of Regimen as Measured by Grade and Frequency of Adverse Events Exceeding 10% in Total Frequency | INR increased | 0 number of events |
| Grade 2 | Phase I and Phase II: Safety and Tolerability of Regimen as Measured by Grade and Frequency of Adverse Events Exceeding 10% in Total Frequency | Pain | 2 number of events |
| Grade 2 | Phase I and Phase II: Safety and Tolerability of Regimen as Measured by Grade and Frequency of Adverse Events Exceeding 10% in Total Frequency | Aspartate aminotransferase increased | 0 number of events |
| Grade 2 | Phase I and Phase II: Safety and Tolerability of Regimen as Measured by Grade and Frequency of Adverse Events Exceeding 10% in Total Frequency | Bone pain | 2 number of events |
| Grade 2 | Phase I and Phase II: Safety and Tolerability of Regimen as Measured by Grade and Frequency of Adverse Events Exceeding 10% in Total Frequency | Anorexia | 2 number of events |
| Grade 2 | Phase I and Phase II: Safety and Tolerability of Regimen as Measured by Grade and Frequency of Adverse Events Exceeding 10% in Total Frequency | Blood bilirubin increased | 3 number of events |
| Grade 2 | Phase I and Phase II: Safety and Tolerability of Regimen as Measured by Grade and Frequency of Adverse Events Exceeding 10% in Total Frequency | Fatigue | 2 number of events |
| Grade 2 | Phase I and Phase II: Safety and Tolerability of Regimen as Measured by Grade and Frequency of Adverse Events Exceeding 10% in Total Frequency | Cough | 2 number of events |
| Grade 2 | Phase I and Phase II: Safety and Tolerability of Regimen as Measured by Grade and Frequency of Adverse Events Exceeding 10% in Total Frequency | Hypotension | 4 number of events |
| Grade 2 | Phase I and Phase II: Safety and Tolerability of Regimen as Measured by Grade and Frequency of Adverse Events Exceeding 10% in Total Frequency | Lung infection | 1 number of events |
| Grade 2 | Phase I and Phase II: Safety and Tolerability of Regimen as Measured by Grade and Frequency of Adverse Events Exceeding 10% in Total Frequency | Gastroesophageal reflux disease | 5 number of events |
| Grade 2 | Phase I and Phase II: Safety and Tolerability of Regimen as Measured by Grade and Frequency of Adverse Events Exceeding 10% in Total Frequency | Febrile neutropenia | 0 number of events |
| Grade 2 | Phase I and Phase II: Safety and Tolerability of Regimen as Measured by Grade and Frequency of Adverse Events Exceeding 10% in Total Frequency | Hyponatremia | 0 number of events |
| Grade 2 | Phase I and Phase II: Safety and Tolerability of Regimen as Measured by Grade and Frequency of Adverse Events Exceeding 10% in Total Frequency | Proteinuria | 1 number of events |
| Grade 2 | Phase I and Phase II: Safety and Tolerability of Regimen as Measured by Grade and Frequency of Adverse Events Exceeding 10% in Total Frequency | Hypocalcemia | 11 number of events |
| Grade 2 | Phase I and Phase II: Safety and Tolerability of Regimen as Measured by Grade and Frequency of Adverse Events Exceeding 10% in Total Frequency | Mucositis oral | 3 number of events |
| Grade 2 | Phase I and Phase II: Safety and Tolerability of Regimen as Measured by Grade and Frequency of Adverse Events Exceeding 10% in Total Frequency | Anemia | 4 number of events |
| Grade 2 | Phase I and Phase II: Safety and Tolerability of Regimen as Measured by Grade and Frequency of Adverse Events Exceeding 10% in Total Frequency | Fever | 4 number of events |
| Grade 2 | Phase I and Phase II: Safety and Tolerability of Regimen as Measured by Grade and Frequency of Adverse Events Exceeding 10% in Total Frequency | Insomnia | 2 number of events |
| Grade 2 | Phase I and Phase II: Safety and Tolerability of Regimen as Measured by Grade and Frequency of Adverse Events Exceeding 10% in Total Frequency | Pneumonitis | 3 number of events |
| Grade 2 | Phase I and Phase II: Safety and Tolerability of Regimen as Measured by Grade and Frequency of Adverse Events Exceeding 10% in Total Frequency | Nausea | 3 number of events |
| Grade 2 | Phase I and Phase II: Safety and Tolerability of Regimen as Measured by Grade and Frequency of Adverse Events Exceeding 10% in Total Frequency | Rash maculo-papular | 3 number of events |
| Grade 2 | Phase I and Phase II: Safety and Tolerability of Regimen as Measured by Grade and Frequency of Adverse Events Exceeding 10% in Total Frequency | Dyspnea | 3 number of events |
| Grade 2 | Phase I and Phase II: Safety and Tolerability of Regimen as Measured by Grade and Frequency of Adverse Events Exceeding 10% in Total Frequency | Paresthesia | 1 number of events |
| Grade 2 | Phase I and Phase II: Safety and Tolerability of Regimen as Measured by Grade and Frequency of Adverse Events Exceeding 10% in Total Frequency | Hypomagnesemia | 0 number of events |
| Grade 2 | Phase I and Phase II: Safety and Tolerability of Regimen as Measured by Grade and Frequency of Adverse Events Exceeding 10% in Total Frequency | Vomiting | 0 number of events |
| Grade 2 | Phase I and Phase II: Safety and Tolerability of Regimen as Measured by Grade and Frequency of Adverse Events Exceeding 10% in Total Frequency | Bacteremia | 0 number of events |
| Grade 2 | Phase I and Phase II: Safety and Tolerability of Regimen as Measured by Grade and Frequency of Adverse Events Exceeding 10% in Total Frequency | Non-cardiac chest pain | 2 number of events |
| Grade 3 | Phase I and Phase II: Safety and Tolerability of Regimen as Measured by Grade and Frequency of Adverse Events Exceeding 10% in Total Frequency | Proteinuria | 0 number of events |
| Grade 3 | Phase I and Phase II: Safety and Tolerability of Regimen as Measured by Grade and Frequency of Adverse Events Exceeding 10% in Total Frequency | Anemia | 9 number of events |
| Grade 3 | Phase I and Phase II: Safety and Tolerability of Regimen as Measured by Grade and Frequency of Adverse Events Exceeding 10% in Total Frequency | Febrile neutropenia | 20 number of events |
| Grade 3 | Phase I and Phase II: Safety and Tolerability of Regimen as Measured by Grade and Frequency of Adverse Events Exceeding 10% in Total Frequency | Abdominal pain | 1 number of events |
| Grade 3 | Phase I and Phase II: Safety and Tolerability of Regimen as Measured by Grade and Frequency of Adverse Events Exceeding 10% in Total Frequency | Constipation | 0 number of events |
| Grade 3 | Phase I and Phase II: Safety and Tolerability of Regimen as Measured by Grade and Frequency of Adverse Events Exceeding 10% in Total Frequency | Diarrhea | 0 number of events |
| Grade 3 | Phase I and Phase II: Safety and Tolerability of Regimen as Measured by Grade and Frequency of Adverse Events Exceeding 10% in Total Frequency | Gastroesophageal reflux disease | 0 number of events |
| Grade 3 | Phase I and Phase II: Safety and Tolerability of Regimen as Measured by Grade and Frequency of Adverse Events Exceeding 10% in Total Frequency | Mucositis oral | 1 number of events |
| Grade 3 | Phase I and Phase II: Safety and Tolerability of Regimen as Measured by Grade and Frequency of Adverse Events Exceeding 10% in Total Frequency | Nausea | 0 number of events |
| Grade 3 | Phase I and Phase II: Safety and Tolerability of Regimen as Measured by Grade and Frequency of Adverse Events Exceeding 10% in Total Frequency | Vomiting | 1 number of events |
| Grade 3 | Phase I and Phase II: Safety and Tolerability of Regimen as Measured by Grade and Frequency of Adverse Events Exceeding 10% in Total Frequency | Chills | 0 number of events |
| Grade 3 | Phase I and Phase II: Safety and Tolerability of Regimen as Measured by Grade and Frequency of Adverse Events Exceeding 10% in Total Frequency | Edema-limbs | 0 number of events |
| Grade 3 | Phase I and Phase II: Safety and Tolerability of Regimen as Measured by Grade and Frequency of Adverse Events Exceeding 10% in Total Frequency | Fatigue | 1 number of events |
| Grade 3 | Phase I and Phase II: Safety and Tolerability of Regimen as Measured by Grade and Frequency of Adverse Events Exceeding 10% in Total Frequency | Fever | 0 number of events |
| Grade 3 | Phase I and Phase II: Safety and Tolerability of Regimen as Measured by Grade and Frequency of Adverse Events Exceeding 10% in Total Frequency | Non-cardiac chest pain | 1 number of events |
| Grade 3 | Phase I and Phase II: Safety and Tolerability of Regimen as Measured by Grade and Frequency of Adverse Events Exceeding 10% in Total Frequency | Pain | 0 number of events |
| Grade 3 | Phase I and Phase II: Safety and Tolerability of Regimen as Measured by Grade and Frequency of Adverse Events Exceeding 10% in Total Frequency | Bacteremia | 4 number of events |
| Grade 3 | Phase I and Phase II: Safety and Tolerability of Regimen as Measured by Grade and Frequency of Adverse Events Exceeding 10% in Total Frequency | Lung infection | 5 number of events |
| Grade 3 | Phase I and Phase II: Safety and Tolerability of Regimen as Measured by Grade and Frequency of Adverse Events Exceeding 10% in Total Frequency | Sepsis | 0 number of events |
| Grade 3 | Phase I and Phase II: Safety and Tolerability of Regimen as Measured by Grade and Frequency of Adverse Events Exceeding 10% in Total Frequency | Activated partial thromboplastin time prolonged | 0 number of events |
| Grade 3 | Phase I and Phase II: Safety and Tolerability of Regimen as Measured by Grade and Frequency of Adverse Events Exceeding 10% in Total Frequency | Alanine aminotransferase increased | 1 number of events |
| Grade 3 | Phase I and Phase II: Safety and Tolerability of Regimen as Measured by Grade and Frequency of Adverse Events Exceeding 10% in Total Frequency | Alkaline phosphatase increased | 0 number of events |
| Grade 3 | Phase I and Phase II: Safety and Tolerability of Regimen as Measured by Grade and Frequency of Adverse Events Exceeding 10% in Total Frequency | Aspartate aminotransferase increased | 0 number of events |
| Grade 3 | Phase I and Phase II: Safety and Tolerability of Regimen as Measured by Grade and Frequency of Adverse Events Exceeding 10% in Total Frequency | Blood bilirubin increased | 1 number of events |
| Grade 3 | Phase I and Phase II: Safety and Tolerability of Regimen as Measured by Grade and Frequency of Adverse Events Exceeding 10% in Total Frequency | INR increased | 0 number of events |
| Grade 3 | Phase I and Phase II: Safety and Tolerability of Regimen as Measured by Grade and Frequency of Adverse Events Exceeding 10% in Total Frequency | Neutrophil count decreased | 0 number of events |
| Grade 3 | Phase I and Phase II: Safety and Tolerability of Regimen as Measured by Grade and Frequency of Adverse Events Exceeding 10% in Total Frequency | Platelet count decreased | 0 number of events |
| Grade 3 | Phase I and Phase II: Safety and Tolerability of Regimen as Measured by Grade and Frequency of Adverse Events Exceeding 10% in Total Frequency | White blood cell count decreased | 0 number of events |
| Grade 3 | Phase I and Phase II: Safety and Tolerability of Regimen as Measured by Grade and Frequency of Adverse Events Exceeding 10% in Total Frequency | Anorexia | 0 number of events |
| Grade 3 | Phase I and Phase II: Safety and Tolerability of Regimen as Measured by Grade and Frequency of Adverse Events Exceeding 10% in Total Frequency | Hypoalbuminemia | 0 number of events |
| Grade 3 | Phase I and Phase II: Safety and Tolerability of Regimen as Measured by Grade and Frequency of Adverse Events Exceeding 10% in Total Frequency | Hypocalcemia | 0 number of events |
| Grade 3 | Phase I and Phase II: Safety and Tolerability of Regimen as Measured by Grade and Frequency of Adverse Events Exceeding 10% in Total Frequency | Hypokalemia | 2 number of events |
| Grade 3 | Phase I and Phase II: Safety and Tolerability of Regimen as Measured by Grade and Frequency of Adverse Events Exceeding 10% in Total Frequency | Hypomagnesemia | 0 number of events |
| Grade 3 | Phase I and Phase II: Safety and Tolerability of Regimen as Measured by Grade and Frequency of Adverse Events Exceeding 10% in Total Frequency | Hyponatremia | 1 number of events |
| Grade 3 | Phase I and Phase II: Safety and Tolerability of Regimen as Measured by Grade and Frequency of Adverse Events Exceeding 10% in Total Frequency | Bone pain | 2 number of events |
| Grade 3 | Phase I and Phase II: Safety and Tolerability of Regimen as Measured by Grade and Frequency of Adverse Events Exceeding 10% in Total Frequency | Dizziness | 0 number of events |
| Grade 3 | Phase I and Phase II: Safety and Tolerability of Regimen as Measured by Grade and Frequency of Adverse Events Exceeding 10% in Total Frequency | Headache | 1 number of events |
| Grade 3 | Phase I and Phase II: Safety and Tolerability of Regimen as Measured by Grade and Frequency of Adverse Events Exceeding 10% in Total Frequency | Paresthesia | 0 number of events |
| Grade 3 | Phase I and Phase II: Safety and Tolerability of Regimen as Measured by Grade and Frequency of Adverse Events Exceeding 10% in Total Frequency | Insomnia | 0 number of events |
| Grade 3 | Phase I and Phase II: Safety and Tolerability of Regimen as Measured by Grade and Frequency of Adverse Events Exceeding 10% in Total Frequency | Cough | 0 number of events |
| Grade 3 | Phase I and Phase II: Safety and Tolerability of Regimen as Measured by Grade and Frequency of Adverse Events Exceeding 10% in Total Frequency | Dyspnea | 0 number of events |
| Grade 3 | Phase I and Phase II: Safety and Tolerability of Regimen as Measured by Grade and Frequency of Adverse Events Exceeding 10% in Total Frequency | Pneumonitis | 0 number of events |
| Grade 3 | Phase I and Phase II: Safety and Tolerability of Regimen as Measured by Grade and Frequency of Adverse Events Exceeding 10% in Total Frequency | Rash maculo-papular | 0 number of events |
| Grade 3 | Phase I and Phase II: Safety and Tolerability of Regimen as Measured by Grade and Frequency of Adverse Events Exceeding 10% in Total Frequency | Hypotension | 2 number of events |
| Grade 4 | Phase I and Phase II: Safety and Tolerability of Regimen as Measured by Grade and Frequency of Adverse Events Exceeding 10% in Total Frequency | Non-cardiac chest pain | 0 number of events |
| Grade 4 | Phase I and Phase II: Safety and Tolerability of Regimen as Measured by Grade and Frequency of Adverse Events Exceeding 10% in Total Frequency | Hypotension | 0 number of events |
| Grade 4 | Phase I and Phase II: Safety and Tolerability of Regimen as Measured by Grade and Frequency of Adverse Events Exceeding 10% in Total Frequency | Headache | 0 number of events |
| Grade 4 | Phase I and Phase II: Safety and Tolerability of Regimen as Measured by Grade and Frequency of Adverse Events Exceeding 10% in Total Frequency | Bacteremia | 0 number of events |
| Grade 4 | Phase I and Phase II: Safety and Tolerability of Regimen as Measured by Grade and Frequency of Adverse Events Exceeding 10% in Total Frequency | Vomiting | 0 number of events |
| Grade 4 | Phase I and Phase II: Safety and Tolerability of Regimen as Measured by Grade and Frequency of Adverse Events Exceeding 10% in Total Frequency | Pneumonitis | 0 number of events |
| Grade 4 | Phase I and Phase II: Safety and Tolerability of Regimen as Measured by Grade and Frequency of Adverse Events Exceeding 10% in Total Frequency | Rash maculo-papular | 0 number of events |
| Grade 4 | Phase I and Phase II: Safety and Tolerability of Regimen as Measured by Grade and Frequency of Adverse Events Exceeding 10% in Total Frequency | Paresthesia | 0 number of events |
| Grade 4 | Phase I and Phase II: Safety and Tolerability of Regimen as Measured by Grade and Frequency of Adverse Events Exceeding 10% in Total Frequency | Hypomagnesemia | 0 number of events |
| Grade 4 | Phase I and Phase II: Safety and Tolerability of Regimen as Measured by Grade and Frequency of Adverse Events Exceeding 10% in Total Frequency | Nausea | 0 number of events |
| Grade 4 | Phase I and Phase II: Safety and Tolerability of Regimen as Measured by Grade and Frequency of Adverse Events Exceeding 10% in Total Frequency | Lung infection | 0 number of events |
| Grade 4 | Phase I and Phase II: Safety and Tolerability of Regimen as Measured by Grade and Frequency of Adverse Events Exceeding 10% in Total Frequency | Fever | 0 number of events |
| Grade 4 | Phase I and Phase II: Safety and Tolerability of Regimen as Measured by Grade and Frequency of Adverse Events Exceeding 10% in Total Frequency | Insomnia | 0 number of events |
| Grade 4 | Phase I and Phase II: Safety and Tolerability of Regimen as Measured by Grade and Frequency of Adverse Events Exceeding 10% in Total Frequency | Abdominal pain | 0 number of events |
| Grade 4 | Phase I and Phase II: Safety and Tolerability of Regimen as Measured by Grade and Frequency of Adverse Events Exceeding 10% in Total Frequency | Mucositis oral | 0 number of events |
| Grade 4 | Phase I and Phase II: Safety and Tolerability of Regimen as Measured by Grade and Frequency of Adverse Events Exceeding 10% in Total Frequency | Hypocalcemia | 0 number of events |
| Grade 4 | Phase I and Phase II: Safety and Tolerability of Regimen as Measured by Grade and Frequency of Adverse Events Exceeding 10% in Total Frequency | Gastroesophageal reflux disease | 0 number of events |
| Grade 4 | Phase I and Phase II: Safety and Tolerability of Regimen as Measured by Grade and Frequency of Adverse Events Exceeding 10% in Total Frequency | Proteinuria | 0 number of events |
| Grade 4 | Phase I and Phase II: Safety and Tolerability of Regimen as Measured by Grade and Frequency of Adverse Events Exceeding 10% in Total Frequency | Hyponatremia | 0 number of events |
| Grade 4 | Phase I and Phase II: Safety and Tolerability of Regimen as Measured by Grade and Frequency of Adverse Events Exceeding 10% in Total Frequency | Sepsis | 4 number of events |
| Grade 4 | Phase I and Phase II: Safety and Tolerability of Regimen as Measured by Grade and Frequency of Adverse Events Exceeding 10% in Total Frequency | Diarrhea | 0 number of events |
| Grade 4 | Phase I and Phase II: Safety and Tolerability of Regimen as Measured by Grade and Frequency of Adverse Events Exceeding 10% in Total Frequency | Fatigue | 0 number of events |
| Grade 4 | Phase I and Phase II: Safety and Tolerability of Regimen as Measured by Grade and Frequency of Adverse Events Exceeding 10% in Total Frequency | Cough | 0 number of events |
| Grade 4 | Phase I and Phase II: Safety and Tolerability of Regimen as Measured by Grade and Frequency of Adverse Events Exceeding 10% in Total Frequency | Pain | 0 number of events |
| Grade 4 | Phase I and Phase II: Safety and Tolerability of Regimen as Measured by Grade and Frequency of Adverse Events Exceeding 10% in Total Frequency | Anorexia | 0 number of events |
| Grade 4 | Phase I and Phase II: Safety and Tolerability of Regimen as Measured by Grade and Frequency of Adverse Events Exceeding 10% in Total Frequency | Blood bilirubin increased | 0 number of events |
| Grade 4 | Phase I and Phase II: Safety and Tolerability of Regimen as Measured by Grade and Frequency of Adverse Events Exceeding 10% in Total Frequency | Bone pain | 0 number of events |
| Grade 4 | Phase I and Phase II: Safety and Tolerability of Regimen as Measured by Grade and Frequency of Adverse Events Exceeding 10% in Total Frequency | Aspartate aminotransferase increased | 0 number of events |
| Grade 4 | Phase I and Phase II: Safety and Tolerability of Regimen as Measured by Grade and Frequency of Adverse Events Exceeding 10% in Total Frequency | Hypoalbuminemia | 0 number of events |
| Grade 4 | Phase I and Phase II: Safety and Tolerability of Regimen as Measured by Grade and Frequency of Adverse Events Exceeding 10% in Total Frequency | Edema-limbs | 0 number of events |
| Grade 4 | Phase I and Phase II: Safety and Tolerability of Regimen as Measured by Grade and Frequency of Adverse Events Exceeding 10% in Total Frequency | INR increased | 0 number of events |
| Grade 4 | Phase I and Phase II: Safety and Tolerability of Regimen as Measured by Grade and Frequency of Adverse Events Exceeding 10% in Total Frequency | Hypokalemia | 2 number of events |
| Grade 4 | Phase I and Phase II: Safety and Tolerability of Regimen as Measured by Grade and Frequency of Adverse Events Exceeding 10% in Total Frequency | Alkaline phosphatase increased | 0 number of events |
| Grade 4 | Phase I and Phase II: Safety and Tolerability of Regimen as Measured by Grade and Frequency of Adverse Events Exceeding 10% in Total Frequency | Febrile neutropenia | 0 number of events |
| Grade 4 | Phase I and Phase II: Safety and Tolerability of Regimen as Measured by Grade and Frequency of Adverse Events Exceeding 10% in Total Frequency | Constipation | 0 number of events |
| Grade 4 | Phase I and Phase II: Safety and Tolerability of Regimen as Measured by Grade and Frequency of Adverse Events Exceeding 10% in Total Frequency | Neutrophil count decreased | 7 number of events |
| Grade 4 | Phase I and Phase II: Safety and Tolerability of Regimen as Measured by Grade and Frequency of Adverse Events Exceeding 10% in Total Frequency | Dizziness | 0 number of events |
| Grade 4 | Phase I and Phase II: Safety and Tolerability of Regimen as Measured by Grade and Frequency of Adverse Events Exceeding 10% in Total Frequency | Alanine aminotransferase increased | 0 number of events |
| Grade 4 | Phase I and Phase II: Safety and Tolerability of Regimen as Measured by Grade and Frequency of Adverse Events Exceeding 10% in Total Frequency | White blood cell count decreased | 16 number of events |
| Grade 4 | Phase I and Phase II: Safety and Tolerability of Regimen as Measured by Grade and Frequency of Adverse Events Exceeding 10% in Total Frequency | Anemia | 0 number of events |
| Grade 4 | Phase I and Phase II: Safety and Tolerability of Regimen as Measured by Grade and Frequency of Adverse Events Exceeding 10% in Total Frequency | Platelet count decreased | 15 number of events |
| Grade 4 | Phase I and Phase II: Safety and Tolerability of Regimen as Measured by Grade and Frequency of Adverse Events Exceeding 10% in Total Frequency | Chills | 0 number of events |
| Grade 4 | Phase I and Phase II: Safety and Tolerability of Regimen as Measured by Grade and Frequency of Adverse Events Exceeding 10% in Total Frequency | Activated partial thromboplastin time prolonged | 0 number of events |
| Grade 4 | Phase I and Phase II: Safety and Tolerability of Regimen as Measured by Grade and Frequency of Adverse Events Exceeding 10% in Total Frequency | Dyspnea | 0 number of events |
| Grade 5 | Phase I and Phase II: Safety and Tolerability of Regimen as Measured by Grade and Frequency of Adverse Events Exceeding 10% in Total Frequency | Sepsis | 4 number of events |
| Grade 5 | Phase I and Phase II: Safety and Tolerability of Regimen as Measured by Grade and Frequency of Adverse Events Exceeding 10% in Total Frequency | White blood cell count decreased | 0 number of events |
| Grade 5 | Phase I and Phase II: Safety and Tolerability of Regimen as Measured by Grade and Frequency of Adverse Events Exceeding 10% in Total Frequency | Lung infection | 2 number of events |
| Grade 5 | Phase I and Phase II: Safety and Tolerability of Regimen as Measured by Grade and Frequency of Adverse Events Exceeding 10% in Total Frequency | Dyspnea | 0 number of events |
| Grade 5 | Phase I and Phase II: Safety and Tolerability of Regimen as Measured by Grade and Frequency of Adverse Events Exceeding 10% in Total Frequency | Anorexia | 0 number of events |
| Grade 5 | Phase I and Phase II: Safety and Tolerability of Regimen as Measured by Grade and Frequency of Adverse Events Exceeding 10% in Total Frequency | Bacteremia | 0 number of events |
| Grade 5 | Phase I and Phase II: Safety and Tolerability of Regimen as Measured by Grade and Frequency of Adverse Events Exceeding 10% in Total Frequency | Abdominal pain | 0 number of events |
| Grade 5 | Phase I and Phase II: Safety and Tolerability of Regimen as Measured by Grade and Frequency of Adverse Events Exceeding 10% in Total Frequency | Hypoalbuminemia | 0 number of events |
| Grade 5 | Phase I and Phase II: Safety and Tolerability of Regimen as Measured by Grade and Frequency of Adverse Events Exceeding 10% in Total Frequency | Pain | 0 number of events |
| Grade 5 | Phase I and Phase II: Safety and Tolerability of Regimen as Measured by Grade and Frequency of Adverse Events Exceeding 10% in Total Frequency | Hypocalcemia | 0 number of events |
| Grade 5 | Phase I and Phase II: Safety and Tolerability of Regimen as Measured by Grade and Frequency of Adverse Events Exceeding 10% in Total Frequency | Non-cardiac chest pain | 0 number of events |
| Grade 5 | Phase I and Phase II: Safety and Tolerability of Regimen as Measured by Grade and Frequency of Adverse Events Exceeding 10% in Total Frequency | Hypotension | 0 number of events |
| Grade 5 | Phase I and Phase II: Safety and Tolerability of Regimen as Measured by Grade and Frequency of Adverse Events Exceeding 10% in Total Frequency | Hypokalemia | 0 number of events |
| Grade 5 | Phase I and Phase II: Safety and Tolerability of Regimen as Measured by Grade and Frequency of Adverse Events Exceeding 10% in Total Frequency | Fever | 0 number of events |
| Grade 5 | Phase I and Phase II: Safety and Tolerability of Regimen as Measured by Grade and Frequency of Adverse Events Exceeding 10% in Total Frequency | Hypomagnesemia | 0 number of events |
| Grade 5 | Phase I and Phase II: Safety and Tolerability of Regimen as Measured by Grade and Frequency of Adverse Events Exceeding 10% in Total Frequency | Fatigue | 0 number of events |
| Grade 5 | Phase I and Phase II: Safety and Tolerability of Regimen as Measured by Grade and Frequency of Adverse Events Exceeding 10% in Total Frequency | Pneumonitis | 1 number of events |
| Grade 5 | Phase I and Phase II: Safety and Tolerability of Regimen as Measured by Grade and Frequency of Adverse Events Exceeding 10% in Total Frequency | Hyponatremia | 0 number of events |
| Grade 5 | Phase I and Phase II: Safety and Tolerability of Regimen as Measured by Grade and Frequency of Adverse Events Exceeding 10% in Total Frequency | Edema-limbs | 0 number of events |
| Grade 5 | Phase I and Phase II: Safety and Tolerability of Regimen as Measured by Grade and Frequency of Adverse Events Exceeding 10% in Total Frequency | Febrile neutropenia | 0 number of events |
| Grade 5 | Phase I and Phase II: Safety and Tolerability of Regimen as Measured by Grade and Frequency of Adverse Events Exceeding 10% in Total Frequency | Bone pain | 0 number of events |
| Grade 5 | Phase I and Phase II: Safety and Tolerability of Regimen as Measured by Grade and Frequency of Adverse Events Exceeding 10% in Total Frequency | Chills | 0 number of events |
| Grade 5 | Phase I and Phase II: Safety and Tolerability of Regimen as Measured by Grade and Frequency of Adverse Events Exceeding 10% in Total Frequency | Dizziness | 0 number of events |
| Grade 5 | Phase I and Phase II: Safety and Tolerability of Regimen as Measured by Grade and Frequency of Adverse Events Exceeding 10% in Total Frequency | Vomiting | 0 number of events |
| Grade 5 | Phase I and Phase II: Safety and Tolerability of Regimen as Measured by Grade and Frequency of Adverse Events Exceeding 10% in Total Frequency | Headache | 0 number of events |
| Grade 5 | Phase I and Phase II: Safety and Tolerability of Regimen as Measured by Grade and Frequency of Adverse Events Exceeding 10% in Total Frequency | Nausea | 0 number of events |
| Grade 5 | Phase I and Phase II: Safety and Tolerability of Regimen as Measured by Grade and Frequency of Adverse Events Exceeding 10% in Total Frequency | Paresthesia | 0 number of events |
| Grade 5 | Phase I and Phase II: Safety and Tolerability of Regimen as Measured by Grade and Frequency of Adverse Events Exceeding 10% in Total Frequency | Mucositis oral | 0 number of events |
| Grade 5 | Phase I and Phase II: Safety and Tolerability of Regimen as Measured by Grade and Frequency of Adverse Events Exceeding 10% in Total Frequency | Rash maculo-papular | 0 number of events |
| Grade 5 | Phase I and Phase II: Safety and Tolerability of Regimen as Measured by Grade and Frequency of Adverse Events Exceeding 10% in Total Frequency | Insomnia | 0 number of events |
| Grade 5 | Phase I and Phase II: Safety and Tolerability of Regimen as Measured by Grade and Frequency of Adverse Events Exceeding 10% in Total Frequency | Gastroesophageal reflux disease | 0 number of events |
| Grade 5 | Phase I and Phase II: Safety and Tolerability of Regimen as Measured by Grade and Frequency of Adverse Events Exceeding 10% in Total Frequency | Proteinuria | 0 number of events |
| Grade 5 | Phase I and Phase II: Safety and Tolerability of Regimen as Measured by Grade and Frequency of Adverse Events Exceeding 10% in Total Frequency | Diarrhea | 0 number of events |
| Grade 5 | Phase I and Phase II: Safety and Tolerability of Regimen as Measured by Grade and Frequency of Adverse Events Exceeding 10% in Total Frequency | Anemia | 0 number of events |
| Grade 5 | Phase I and Phase II: Safety and Tolerability of Regimen as Measured by Grade and Frequency of Adverse Events Exceeding 10% in Total Frequency | Aspartate aminotransferase increased | 0 number of events |
| Grade 5 | Phase I and Phase II: Safety and Tolerability of Regimen as Measured by Grade and Frequency of Adverse Events Exceeding 10% in Total Frequency | Cough | 0 number of events |
| Grade 5 | Phase I and Phase II: Safety and Tolerability of Regimen as Measured by Grade and Frequency of Adverse Events Exceeding 10% in Total Frequency | Blood bilirubin increased | 0 number of events |
| Grade 5 | Phase I and Phase II: Safety and Tolerability of Regimen as Measured by Grade and Frequency of Adverse Events Exceeding 10% in Total Frequency | Alkaline phosphatase increased | 0 number of events |
| Grade 5 | Phase I and Phase II: Safety and Tolerability of Regimen as Measured by Grade and Frequency of Adverse Events Exceeding 10% in Total Frequency | Constipation | 0 number of events |
| Grade 5 | Phase I and Phase II: Safety and Tolerability of Regimen as Measured by Grade and Frequency of Adverse Events Exceeding 10% in Total Frequency | INR increased | 0 number of events |
| Grade 5 | Phase I and Phase II: Safety and Tolerability of Regimen as Measured by Grade and Frequency of Adverse Events Exceeding 10% in Total Frequency | Alanine aminotransferase increased | 0 number of events |
| Grade 5 | Phase I and Phase II: Safety and Tolerability of Regimen as Measured by Grade and Frequency of Adverse Events Exceeding 10% in Total Frequency | Neutrophil count decreased | 0 number of events |
| Grade 5 | Phase I and Phase II: Safety and Tolerability of Regimen as Measured by Grade and Frequency of Adverse Events Exceeding 10% in Total Frequency | Activated partial thromboplastin time prolonged | 0 number of events |
| Grade 5 | Phase I and Phase II: Safety and Tolerability of Regimen as Measured by Grade and Frequency of Adverse Events Exceeding 10% in Total Frequency | Platelet count decreased | 0 number of events |
Secondary
Time to Hematologic Recovery as Measured by Time to Neutrophil Recovery
-Neutrophil recovery is defined as absolute neutrophil count \>= 1000/mm\^3
Time frame: Up to 62 days after treatment
Population: All participants enrolled in the study (both Phase I or Phase II) who had a CR/CRi whose ANC was \>=1000/mm\^3 were evaluable for this outcome measure.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase I (Includes Levels 1-5) | Time to Hematologic Recovery as Measured by Time to Neutrophil Recovery | 40 days |
Secondary
Time to Hematologic Recovery as Measured by Time to Neutrophil Recovery
-Neutrophil recovery is defined as absolute neutrophil count (ANC) \>= 500/mm\^3
Time frame: Up to 62 days after treatment
Population: All participants enrolled in the study (both Phase I or Phase II) who had a CR/CRi whose ANC was \>=500/mm\^3 were evaluable for this outcome measure.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase I (Includes Levels 1-5) | Time to Hematologic Recovery as Measured by Time to Neutrophil Recovery | 38 days |
Secondary
Time to Hematologic Recovery as Measured by Time to Platelet Recovery
-Platelet recovery is defined as platelets \>= 100,000/mm3
Time frame: Up to 62 days after treatment
Population: All participants enrolled in the study (both Phase I or Phase II) who had a CR whose platelets were \>=100,000/mm\^3 were evaluable for this outcome measure.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase I (Includes Levels 1-5) | Time to Hematologic Recovery as Measured by Time to Platelet Recovery | 32 days |
Secondary
Time to Hematologic Recovery as Measured by Time to Platelet Recovery
-Platelet recovery is defined as platelets \>= 50,000/mm\^3
Time frame: Up to 62 days after treatment
Population: All participants enrolled in the study (both Phase I or Phase II) who had CR whose platelets were \>=50,000/mm\^3 were evaluable for this outcome measure.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase I (Includes Levels 1-5) | Time to Hematologic Recovery as Measured by Time to Platelet Recovery | 32 days |
Secondary
Time to Progression
Recurrence / morphologic relapse: Defined as reappearance of blasts in the blood or the finding of \> 5% blasts in the BM, not attributable to any other cause. New dysplastic changes are considered a relapse. If there are no blasts in the peripheral blood and 5-19% blasts in the BM, the BM biopsy and aspirate should be repeated in \> 1 week to confirm relapse.
Time frame: 2 years
Population: Data was not collected for this outcome measure. Progression is very hard to define acute myeloid leukemia and including it as a pre-specified secondary outcome measure in the protocol was an oversight.
Secondary
Time to Treatment Failure
Time frame: 8 days
Population: Data was not collected for this outcome measure. It is not well defined in the literature as when to measure treatment failure. Relapse free survival is a better way to measure response duration (this outcome measure was added to the results).
Post Hoc
Relapse Free-survival Rate
Time frame: 2 years
Population: All participants enrolled in the study (both Phase I or Phase II) who had a CR/CRi were evaluable for this outcome measure.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase I (Includes Levels 1-5) | Relapse Free-survival Rate | 75 percentage of participants |