Blastic Phase, Childhood Acute Promyelocytic Leukemia With PML-RARA, Childhood Chronic Myelogenous Leukemia, BCR-ABL1 Positive, Childhood Solid Neoplasm, Chronic Myelogenous Leukemia, BCR-ABL1 Positive, Juvenile Myelomonocytic Leukemia, Philadelphia Chromosome Negative, BCR-ABL1 Positive Chronic Myelogenous Leukemia, Recurrent Childhood Acute Lymphoblastic Leukemia, Recurrent Childhood Acute Myeloid Leukemia, Recurrent Disease
Conditions
Brief summary
This phase I/II trial is studying the side effects and best dose of sorafenib in treating young patients with relapsed or refractory solid tumors or leukemia. Sorafenib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth and by blocking blood flow to the cancer.
Detailed description
PRIMARY OBJECTIVES: I. Determine the maximum-tolerated dose (MTD) and recommended phase II dose of sorafenib in pediatric patients with relapsed or refractory solid tumors. II. Determine whether pediatric patients with relapsed or refractory leukemia can tolerate the MTD of sorafenib for solid tumors. III. Determine the tolerability, active N-oxide metabolite, pharmacodynamics, and activity of sorafenib a the MTD in a subset of patients with acute myeloid leukemia (AML) and FLT3-ITD mutation. IV. Determine the toxicities of this drug in these patients. V. Determine the pharmacokinetics of this drug in these patients. SECONDARY OBJECTIVES: I. Determine, preliminarily, the antitumor activity of this drug within the confines of a phase I trial. II. Assess the biologic effect of sorafenib on circulating endothelial cells (CEC), circulating CEC precursors (CECP), VEGF, and VEGF-2 in peripheral blood. III. Assess the gene expression, proteomic profile, and ERK phosphorylation in blasts of patients with refractory leukemia treated with this regimen. IV. Assess the effect of sorafenib on solid tumor vascularity and tumor blood flow using dynamic contrast-enhanced MRI (DEMRI) in patients with measurable soft tissue tumors. V. Analyze tumor samples and leukemic blasts for the presence of ras, raf, or FLT3 (leukemias) mutations. VI. Analyze the plasma inhibitory activity for FLT3 phosphorylation in peripheral blood of patients with AML and FLT3-ITD mutation. VII. Determine the tolerability, pharmacokinetics of sorafenib and sorafenib?s active N-oxide metabolite, pharmacodynamics, and activity of sorafenib administered at the MTD for refractory leukemias in a subset of patients with AML and FLT3-ITD mutation. VIII. Analyze the plasma inhibitory activity for FLT3 phosphorylation in peripheral blood samples obtained at the time of PK studies in patients with FLT3-ITD mutation AML. OUTLINE: This is a dose-escalation, multicenter study. Patients are stratified according to diagnosis (malignant solid tumor vs leukemia). STRATUM I(REFRACTORY SOLID TUMOR PATIENTS): Patients receive oral sorafenib twice daily on days 1-28. Treatment repeats every 28 days for up to 24 courses in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6 patients receive escalating doses of sorafenib until the maximum-tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity (DLT). Once the MTD is determined, up to 6 additional patients under 12 years of age may be treated at the MTD. The MTD dose level is also expanded to enroll up to 6 patients with refractory leukemia. STRATUM II (REFRACTORY LEUKEMIA PATIENTS): A cohort of 3-6 patients with leukemia receives treatment as in stratum 1 at the MTD determined in stratum 1. If 2 of 3 or 2 of 6 patients experience a DLT at the solid tumor MTD, sorafenib is reduced by one dose level. The leukemia MTD is defined as the dose at which \< 1/3 of patients experience DLT during course 1 of treatment. STRATUM III (ACUTE MYELOID LEUKEMIA AND FLT3-ITD MUTATION PATIENTS): Patients receive sorafenib as in stratum 1 at the MTD determined in stratum 2. Patients undergo blood sample collection for pharmacokinetics, pharmacodynamics (in leukemia blasts only), circulating endothelial cells (CEC), circulating CEC precursors (CECP), VEGF and VEGF-2 , gene expression, proteomic profile, ERK phosphorylation, and FLT3 phosphorylation activity. Tumor tissue samples may also be analyzed for the presence of ras, raf, or FLT3. After completion of study treatment, patients are followed periodically.
Interventions
OTHERLaboratory Biomarker Analysis
Correlative studies
OTHERPharmacological Study
Correlative studies
DRUGSorafenib Tosylate
Given orally
Sponsors
National Cancer Institute (NCI)
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
2 Years to 21 Years
Healthy volunteers
No
Inclusion criteria
* Diagnosis of 1 of the following: * Histologically confirmed malignant solid tumor at original diagnosis or relapse * Measurable or evaluable disease by CT scan or MRI * Histologically confirmed leukemia, including 1 of the following: * Acute lymphoblastic leukemia (ALL) * Greater than 25% blasts in the bone marrow (M3 bone marrow) * Acute myeloid leukemia (AML) * Greater than 25% blasts in the bone marrow (M3 bone marrow) * AML and FLT3-ITD mutation * Patients must have ? 5% blasts in the bone marrow * Active extramedullary disease (except leptomeningeal disease) allowed * Juvenile myelomonocytic leukemia (JMML) meeting the following criteria: * Peripheral blood monocytosis \> 1,000/mm\^3 * Blasts (including promonocytes) are \< 20% of the WBCs in the blood and of the nucleated bone marrow cells * No Philadelphia chromosome (Ph) or BCR/ABL fusion gene * Has ? 2 of the following additional diagnostic criteria: * Hemoglobin F increased for age * Immature granulocytes in the peripheral blood * WBC \> 10,000/mm\^3 * Clonal chromosomal abnormality (e.g., may be monosomy 7) * Sargramostim (GM-CSF) hypersensitivity of myeloid progenitors in vitro * Chronic myelogenous leukemia (CML) in blast crisis * Greater than 25% blasts in the bone marrow (M3 bone marrow) * Patients with Ph-positive CML must be refractory to imatinib mesylate * Relapsed or refractory disease * Patients with acute promyelocytic leukemia (APL) must be refractory to treatment with tretinoin and arsenic trioxide * Standard curative therapies or therapies proven to prolong survival with an acceptable quality of life do not exist * Active extramedullary disease, except active leptomeningeal leukemia, allowed * No brain tumors or known brain metastases * Karnofsky performance status (PS) 50-100% (for patients \> 10 years of age) * Lansky PS 50-100% (for patients ? 10 years of age) * Patients with solid tumors must have adequate bone marrow function, as defined by the following: * Absolute neutrophil count ? 1,000/mm\^3 * Platelet count ? 75,000/mm\^3 (transfusion independent) * Hemoglobin ? 8.0 g/dL (red blood cell \[RBC\] transfusions allowed) * Patients with leukemia may have abnormal blood counts but must meet the following criteria: * Platelet count ? 20,000/mm\^3 (platelet transfusions allowed) * Hemoglobin ? 8.0 g/L (RBC transfusions allowed) * Patients with acute myeloid leukemia and FLT3-ITD mutation * Platelet count ? 20,000/mm\^3 * Lipase and amylase normal * Creatinine clearance or radioisotope glomerular filtration rate ? 70 mL/min OR creatinine normal based on age as follows: * No greater than 0.8 mg/dL (for patients 5 years of age and under) * No greater than 1.0 mg/dL (for patients 6-10 years of age) * No greater than 1.2 mg/dL (for patients 11-15 years of age) * No greater than 1.5 mg/dL (for patients over 15 years of age) * Patients with solid tumors must meet the following criteria: * Bilirubin normal for age * ALT normal for age (for the purpose of this study, the upper limit of normal \[ULN\] for ALT is 45 ?/L) * Serum albumin ? 2 g/dL * Patients with leukemia must meet the following criteria: * Bilirubin (sum of conjugated + unconjugated) ? 1.5 times ULN for age * ALT ? 5.0 times ULN for age (? 225 ?/L) (for the purpose of this study, the ULN for ALT is 45 ?/L) * Serum albumin ? 2 g/dL * Albumin ? 2 g/dL * PT, PTT, and INR normal (for patients on prophylactic anticoagulation) * No evidence of dyspnea at rest * No exercise intolerance * Pulse oximetry \>94% on room air, if there is clinical indication for determination * Diastolic blood pressure ? the 95th percentile for age and gender (height included for AML and FLT3-ITD mutation patients) * Not pregnant or nursing * Negative pregnancy test * Fertile patients must use effective contraception * No uncontrolled infection * Able to swallow tablets * No evidence of bleeding diathesis * No other medical condition or situation that would preclude study compliance * No known Gilbert syndrome * Fully recovered from prior chemotherapy, immunotherapy, or radiotherapy (for patients with solid tumors) * Recovered from the non-hematologic toxic effects of all prior therapy (for patients with leukemia) * Recovered from acute non-hematologic toxic effects of all prior anti-cancer chemotherapy (for patients with AML and FLT3-ITD mutation) * At least 7 days since prior hematopoietic growth factors * At least 7 days since prior biologic agents * At least 2 weeks since prior local palliative radiotherapy (small port) * At least 3 months since prior total-body irradiation, craniospinal radiotherapy, or radiation to ? 50% of the pelvis * At least 6 weeks since other prior substantial bone marrow radiation (e.g., skull, spine, pelvis, ribs) * At least 3 months since prior stem cell transplantation or rescue (for patients with solid tumors) * No evidence of active graft-vs-host disease * At least 3 months since prior myeloablative therapy followed by bone marrow or stem cell transplantation (for patients with leukemia) * At least 3 weeks since prior myelosuppressive chemotherapy (6 weeks for nitrosoureas) (for patients with solid tumors) * At least 24 hours since prior nitrosoureas (for patients with AML and FLT3-ITD mutation) * At least 2 weeks since prior chemotherapy (for patients with leukemia) * At least 3 weeks since prior monoclonal antibody therapy * No prior sorafenib * No other concurrent investigational drugs * No other concurrent anticancer agents or therapies, including chemotherapy, radiotherapy, immunotherapy, or biologic therapy * Concurrent maintenance-like chemotherapy for patients with AML and FLT3-ITD mutation allowed * No concurrent administration of any of the following: * Cytochrome P450 enzyme-inducing antiepileptic drugs (e.g., phenytoin, carbamazepine, or phenobarbital) * Rifampin * Grapefruit juice * Hypericum perforatum (St. John wort) * No concurrent therapeutic anticoagulation * Concurrent prophylactic anticoagulation (e.g., low-dose warfarin) of venous or arterial access devices allowed provided the requirements for PT, INR, or PTT are met
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Volume of Distribution at Steady State (Vss) of Sorafenib | 8 hours post dose on day 1 of cycle 1 | Volume of distribution at steady state (Vss) of sorefenib administered orally as tablets, BID approximately every 12 hours for cycles of 28 days with no rest period between cycles to children with refractory solid tumors, leukemia, or AML and FLT3-ITD mutation. |
| Number of Patients With Treatment-related Adverse Events | Up to 2 years | Number of patients with treatment-related adverse events stratified by dose level through study completion. |
| Area Under the Plasma Concentration Versus Time Curve (AUC) of Sorafenib | During cycle 1 or cycle 2 after at least 14 consecutive days of sorafenib administration Pre-dose, 0.5, 1, 2, 3, 5, 8 hours post dose | Area under the plasma concentration versus time curve (AUC) of sorefenib administered orally as tablets, BID approximately every 12 hours for cycles of 28 days with no rest period between cycles to children with refractory solid tumors or leukemias. |
| Clearance (Cl) of Sorafenib | During cycle 1 or cycle 2 after at least 14 consecutive days of sorafenib administration Pre-dose, 0.5, 1, 2, 3, 5, 8 hours post dose | Clearance of sorefenib administered orally as tablets, BID approximately every 12 hours for cycles of 28 days with no rest period between cycles to children with refractory solid tumors or leukemias. |
| Half-life of Sorafenib | During cycle 1 or cycle 2 after at least 14 consecutive days of sorafenib administration Pre-dose, 0.5, 1, 2, 3, 5, 8 hours post dose | Half-life of sorefenib administered orally as tablets, BID approximately every 12 hours for cycles of 28 days with no rest period between cycles to children with refractory solid tumors or leukemias. |
| Maximum Serum Concentration (Cmax) of Sorafenib | During cycle 1 or cycle 2 after at least 14 consecutive days of sorafenib administration Pre-dose, 0.5, 1, 2, 3, 5, 8 hours post dose | Maximum serum concentration (Cmax) of sorefenib administered orally as tablets, BID approximately every 12 hours for cycles of 28 days with no rest period between cycles to children with refractory solid tumors or leukemias. |
| Number of Patients With Treatment-related Dose Limiting Toxicities in Later Cycles by Dose Level | Up to 2 years | Number of patients with treatment-related dose limiting toxicities in later cycles, as defined by study protocol, stratified by dose level. |
| Number of Patients With Treatment-related Dose Limiting Toxicity in Cycle 1 by Dose Level | Up to 28 days | Number of patients with treatment-related dose limiting toxicities in cycle 1, as defined by study protocol, stratified by dose level. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Mean Concentration of VEGF2 | 28 days | Mean concentration of VEGF2 in peripheral blood sample. |
| Pharmacodynamics (PD) Blood Flow Part C | 1 week prior to enrollment, then every 28 days | Pharmacodynamics: tumor blood flow in patients with AML and FLT3-ITD mutation using dynamic contrast enhanced MRI (DEMRI) (Part C). |
| Number of Patients With DEMRI | Up to 2 years | Assess effect on tumor blood flow via DEMRI in patients with measurable soft tissue tumors. |
| Leukemia Mutations | 1 week prior to enrollment | Analyze tumor samples and leukemic blasts from patients entered on this study for the presence of ras, raf, or FLT3 (leukemia) mutations. |
| Plasma Inhibitory Activity (PIA) | 1 week prior to enrollment and then every 28 days | Analyze the plasma inhibitory activity (PIA) for FLT3 phosphorylation in peripheral blood samples obtained at the time of PK studies in patients with FLT3-ITD mutation AML (Part C). |
| Number of Patients Who Respond Using RECIST Criteria | Up to 2 years | Frequency (%) of patients with Partial Response (PR) or Complete Response (CR) using the RECIST criteria by study part and dose level |
Countries
Canada, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Part A: Refractory Solid Tumors: BAY 43-9006 105 mg/m^2 Patients receive oral sorafenib 105 mg/m\^2 every 12 hours | 7 |
| Part A: Refractory Solid Tumors: BAY 43-9006 130 mg/m^2 Patients receive oral sorafenib 130 mg/m\^2 every 12 hours | 5 |
| Part A: Refractory Solid Tumors: BAY 43-9006 150 mg/m^2 Patients receive oral sorafenib 150 mg/m\^2 every 12 hours | 12 |
| Part A: Refractory Solid Tumors: BAY 43-9006 200 mg/m^2 Patients receive oral sorafenib 200 mg/m\^2 every 12 hours | 8 |
| Part A: Refractory Solid Tumors: BAY 43-9006 250 mg/m^2 Patients receive oral sorafenib 250 mg/m\^2 every 12 hours | 4 |
| Part B: Refractory Leukemia: BAY 43-9006 150 mg/m^2 Patients receive oral sorafenib 150 mg/m\^2 every 12 hours | 9 |
| Part B: Refractory Leukemia: BAY 43-9006 200 mg/m^2 Patients receive oral sorafenib 200 mg/m\^2 every 12 hours | 2 |
| Part C: Refractory AML With FLT3-ITD Mutation:150 mg/m^2 Patients receive oral sorafenib 150 mg/m\^2 every 12 hours | 5 |
| PK Cohort Expanded: BAY 43-9006 200 mg/m^2 Patients receive oral sorafenib 200 mg/m\^2 every 12 hours | 18 |
| Total | 70 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 | FG008 |
|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 5 | 3 | 11 | 6 | 2 | 3 | 0 | 3 | 10 |
| Overall Study | Ineligible/Inevaluable | 1 | 2 | 0 | 1 | 2 | 3 | 0 | 0 | 6 |
| Overall Study | Physician Decision | 0 | 0 | 1 | 0 | 0 | 3 | 2 | 2 | 0 |
| Overall Study | Withdrawal by Subject | 1 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 2 |
Baseline characteristics
| Characteristic | Part A: Refractory Solid Tumors: BAY 43-9006 130 mg/m^2 | Part A: Refractory Solid Tumors: BAY 43-9006 150 mg/m^2 | Part A: Refractory Solid Tumors: BAY 43-9006 200 mg/m^2 | Part A: Refractory Solid Tumors: BAY 43-9006 250 mg/m^2 | Part B: Refractory Leukemia: BAY 43-9006 150 mg/m^2 | Part B: Refractory Leukemia: BAY 43-9006 200 mg/m^2 | Part C: Refractory AML With FLT3-ITD Mutation:150 mg/m^2 | Part A: Refractory Solid Tumors: BAY 43-9006 105 mg/m^2 | PK Cohort Expanded: BAY 43-9006 200 mg/m^2 | Total |
|---|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical <=18 years | 5 Participants | 11 Participants | 6 Participants | 4 Participants | 8 Participants | 2 Participants | 5 Participants | 4 Participants | 15 Participants | 60 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants | 1 Participants | 2 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 3 Participants | 3 Participants | 10 Participants |
| Age, Continuous | 16 years | 13.5 years | 13.5 years | 11.5 years | 13 years | 10.5 years | 12 years | 17 years | 14.5 years | 14 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 3 Participants | 0 Participants | 2 Participants | 1 Participants | 0 Participants | 1 Participants | 1 Participants | 2 Participants | 11 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 4 Participants | 8 Participants | 8 Participants | 1 Participants | 8 Participants | 2 Participants | 4 Participants | 5 Participants | 16 Participants | 56 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 3 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 4 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 0 Participants | 3 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 3 Participants | 7 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 2 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants | 0 Participants | 6 Participants |
| Race (NIH/OMB) White | 2 Participants | 10 Participants | 5 Participants | 2 Participants | 8 Participants | 1 Participants | 3 Participants | 6 Participants | 15 Participants | 52 Participants |
| Sex: Female, Male Female | 1 Participants | 9 Participants | 3 Participants | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 4 Participants | 4 Participants | 23 Participants |
| Sex: Female, Male Male | 4 Participants | 3 Participants | 5 Participants | 3 Participants | 8 Participants | 2 Participants | 5 Participants | 3 Participants | 14 Participants | 47 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 | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 7 / 7 | 5 / 5 | 12 / 12 | 8 / 8 | 2 / 4 | 9 / 9 | 2 / 2 | 5 / 5 | 18 / 18 |
| other Total, other adverse events | 7 / 7 | 5 / 5 | 12 / 12 | 8 / 8 | 2 / 4 | 9 / 9 | 2 / 2 | 5 / 5 | 18 / 18 |
| serious Total, serious adverse events | 7 / 7 | 5 / 5 | 12 / 12 | 8 / 8 | 2 / 4 | 9 / 9 | 2 / 2 | 5 / 5 | 18 / 18 |
Outcome results
Primary
Area Under the Plasma Concentration Versus Time Curve (AUC) of Sorafenib
Area under the plasma concentration versus time curve (AUC) of sorefenib administered orally as tablets, BID approximately every 12 hours for cycles of 28 days with no rest period between cycles to children with AML and FLT3-ITD mutation.
Time frame: 8 hours post dose on day 1 of cycle 1
Population: Data was and never will be collected
Primary
Area Under the Plasma Concentration Versus Time Curve (AUC) of Sorafenib
Area under the plasma concentration versus time curve (AUC) of sorefenib administered orally as tablets, BID approximately every 12 hours for cycles of 28 days with no rest period between cycles to children with refractory solid tumors or leukemias.
Time frame: During cycle 1 or cycle 2 after at least 14 consecutive days of sorafenib administration Pre-dose, 0.5, 1, 2, 3, 5, 8 hours post dose
Population: Pharmacokinetic (PK) studies were completed for stratums I and II. Summary statistics for PK analysis was performed regardless of dose level as pre-specified in the protocol. PK was not performed in stratum III
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Part A: Refractory Solid Tumors: BAY 43-9006 105 mg/m^2 | Area Under the Plasma Concentration Versus Time Curve (AUC) of Sorafenib | 38.66 µg•h/ml |
| Part A: Refractory Solid Tumors: BAY 43-9006 130 mg/m^2 | Area Under the Plasma Concentration Versus Time Curve (AUC) of Sorafenib | 50.03 µg•h/ml |
Primary
Clearance (Cl) of Sorafenib
Clearance of Sorefenib administered orally as tablets, BID approximately every 12 hours for cycles of 28 days with no rest period between cycles to children with AML and FLT3-ITD mutation.
Time frame: 8 hours post dose on day 1 of cycle 1
Population: Data was and never will be collected
Primary
Clearance (Cl) of Sorafenib
Clearance of sorefenib administered orally as tablets, BID approximately every 12 hours for cycles of 28 days with no rest period between cycles to children with refractory solid tumors or leukemias.
Time frame: During cycle 1 or cycle 2 after at least 14 consecutive days of sorafenib administration Pre-dose, 0.5, 1, 2, 3, 5, 8 hours post dose
Population: Pharmacokinetic (PK) studies were completed for stratums I and II. Summary statistics for PK analysis was performed regardless of dose level as pre-specified in the protocol. PK was not performed in stratum III
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Part A: Refractory Solid Tumors: BAY 43-9006 105 mg/m^2 | Clearance (Cl) of Sorafenib | 57.2 mL/min/m^2 |
| Part A: Refractory Solid Tumors: BAY 43-9006 130 mg/m^2 | Clearance (Cl) of Sorafenib | 72.6 mL/min/m^2 |
Primary
Half-life of Sorafenib
Half-life of sorefenib administered orally as tablets, BID approximately every 12 hours for cycles of 28 days with no rest period between cycles to children with refractory solid tumors or leukemias.
Time frame: During cycle 1 or cycle 2 after at least 14 consecutive days of sorafenib administration Pre-dose, 0.5, 1, 2, 3, 5, 8 hours post dose
Population: Data was and never will be collected
Primary
Half-life of Sorafenib
Half-life of sorefenib administered orally as tablets, BID approximately every 12 hours for cycles of 28 days with no rest period between cycles to children with AML and FLT3-ITD mutation.
Time frame: 8 hours post dose on day 1 of cycle 1
Population: Data was and never will be collected
Primary
Maximum Serum Concentration (Cmax) of Sorafenib
Maximum serum concentration (Cmax) of sorefenib administered orally as tablets, BID approximately every 12 hours for cycles of 28 days with no rest period between cycles to children with refractory solid tumors or leukemias.
Time frame: During cycle 1 or cycle 2 after at least 14 consecutive days of sorafenib administration Pre-dose, 0.5, 1, 2, 3, 5, 8 hours post dose
Population: Data was not collected for patients from Part A:130 mg/m\^2
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part A: Refractory Solid Tumors: BAY 43-9006 105 mg/m^2 | Maximum Serum Concentration (Cmax) of Sorafenib | 0.71 µg/ml | Standard Error 0.53 |
| Part A: Refractory Solid Tumors: BAY 43-9006 130 mg/m^2 | Maximum Serum Concentration (Cmax) of Sorafenib | 1.88 µg/ml | Standard Error 1.55 |
| Part A: Refractory Solid Tumors: BAY 43-9006 150 mg/m^2 | Maximum Serum Concentration (Cmax) of Sorafenib | 1.98 µg/ml | Standard Error 1.25 |
| Part A: Refractory Solid Tumors: BAY 43-9006 200 mg/m^2 | Maximum Serum Concentration (Cmax) of Sorafenib | 1.80 µg/ml | Standard Error 0 |
| Part A: Refractory Solid Tumors: BAY 43-9006 250 mg/m^2 | Maximum Serum Concentration (Cmax) of Sorafenib | 5.97 µg/ml | Standard Error 4.45 |
| Part B: Refractory Leukemia: BAY 43-9006 150 mg/m^2 | Maximum Serum Concentration (Cmax) of Sorafenib | 5.02 µg/ml | Standard Error 0 |
| Part B: Refractory Leukemia: BAY 43-9006 200 mg/m^2 | Maximum Serum Concentration (Cmax) of Sorafenib | 7.95 µg/ml | Standard Error 0.43 |
Primary
Maximum Serum Concentration (Cmax) of Sorafenib
Maximum serum concentration (Cmax) of Sorefenib administered orally as tablets, BID approximately every 12 hours for cycles of 28 days with no rest period between cycles to children with AML and FLT3-ITD mutation.
Time frame: 8 hours post dose on day 1 of cycle 1
Population: Data was and never will be collected
Primary
Number of Patients With Treatment-related Adverse Events
Number of patients with treatment-related adverse events stratified by dose level through study completion.
Time frame: Up to 2 years
Population: There were 55 evaluable patients.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part A: Refractory Solid Tumors: BAY 43-9006 105 mg/m^2 | Number of Patients With Treatment-related Adverse Events | 6 Participants |
| Part A: Refractory Solid Tumors: BAY 43-9006 130 mg/m^2 | Number of Patients With Treatment-related Adverse Events | 3 Participants |
| Part A: Refractory Solid Tumors: BAY 43-9006 150 mg/m^2 | Number of Patients With Treatment-related Adverse Events | 12 Participants |
| Part A: Refractory Solid Tumors: BAY 43-9006 200 mg/m^2 | Number of Patients With Treatment-related Adverse Events | 7 Participants |
| Part A: Refractory Solid Tumors: BAY 43-9006 250 mg/m^2 | Number of Patients With Treatment-related Adverse Events | 2 Participants |
| Part B: Refractory Leukemia: BAY 43-9006 150 mg/m^2 | Number of Patients With Treatment-related Adverse Events | 6 Participants |
| Part B: Refractory Leukemia: BAY 43-9006 200 mg/m^2 | Number of Patients With Treatment-related Adverse Events | 2 Participants |
| Part C: Refractory AML With FLT3-ITD Mutation:150 mg/m^2 | Number of Patients With Treatment-related Adverse Events | 5 Participants |
| PK Cohort Expanded: BAY 43-9006 200 mg/m^2 | Number of Patients With Treatment-related Adverse Events | 12 Participants |
Primary
Number of Patients With Treatment-related Dose Limiting Toxicities in Later Cycles by Dose Level
Number of patients with treatment-related dose limiting toxicities in later cycles, as defined by study protocol, stratified by dose level.
Time frame: Up to 2 years
Population: There were 55 evaluable patients
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part A: Refractory Solid Tumors: BAY 43-9006 105 mg/m^2 | Number of Patients With Treatment-related Dose Limiting Toxicities in Later Cycles by Dose Level | 0 Participants |
| Part A: Refractory Solid Tumors: BAY 43-9006 130 mg/m^2 | Number of Patients With Treatment-related Dose Limiting Toxicities in Later Cycles by Dose Level | 0 Participants |
| Part A: Refractory Solid Tumors: BAY 43-9006 150 mg/m^2 | Number of Patients With Treatment-related Dose Limiting Toxicities in Later Cycles by Dose Level | 1 Participants |
| Part A: Refractory Solid Tumors: BAY 43-9006 200 mg/m^2 | Number of Patients With Treatment-related Dose Limiting Toxicities in Later Cycles by Dose Level | 1 Participants |
| Part A: Refractory Solid Tumors: BAY 43-9006 250 mg/m^2 | Number of Patients With Treatment-related Dose Limiting Toxicities in Later Cycles by Dose Level | 1 Participants |
| Part B: Refractory Leukemia: BAY 43-9006 150 mg/m^2 | Number of Patients With Treatment-related Dose Limiting Toxicities in Later Cycles by Dose Level | 1 Participants |
| Part B: Refractory Leukemia: BAY 43-9006 200 mg/m^2 | Number of Patients With Treatment-related Dose Limiting Toxicities in Later Cycles by Dose Level | 0 Participants |
| Part C: Refractory AML With FLT3-ITD Mutation:150 mg/m^2 | Number of Patients With Treatment-related Dose Limiting Toxicities in Later Cycles by Dose Level | 0 Participants |
| PK Cohort Expanded: BAY 43-9006 200 mg/m^2 | Number of Patients With Treatment-related Dose Limiting Toxicities in Later Cycles by Dose Level | 2 Participants |
Primary
Number of Patients With Treatment-related Dose Limiting Toxicity in Cycle 1 by Dose Level
Number of patients with treatment-related dose limiting toxicities in cycle 1, as defined by study protocol, stratified by dose level.
Time frame: Up to 28 days
Population: There were 55 evaluable patients.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part A: Refractory Solid Tumors: BAY 43-9006 105 mg/m^2 | Number of Patients With Treatment-related Dose Limiting Toxicity in Cycle 1 by Dose Level | 0 Participants |
| Part A: Refractory Solid Tumors: BAY 43-9006 130 mg/m^2 | Number of Patients With Treatment-related Dose Limiting Toxicity in Cycle 1 by Dose Level | 0 Participants |
| Part A: Refractory Solid Tumors: BAY 43-9006 150 mg/m^2 | Number of Patients With Treatment-related Dose Limiting Toxicity in Cycle 1 by Dose Level | 5 Participants |
| Part A: Refractory Solid Tumors: BAY 43-9006 200 mg/m^2 | Number of Patients With Treatment-related Dose Limiting Toxicity in Cycle 1 by Dose Level | 1 Participants |
| Part A: Refractory Solid Tumors: BAY 43-9006 250 mg/m^2 | Number of Patients With Treatment-related Dose Limiting Toxicity in Cycle 1 by Dose Level | 2 Participants |
| Part B: Refractory Leukemia: BAY 43-9006 150 mg/m^2 | Number of Patients With Treatment-related Dose Limiting Toxicity in Cycle 1 by Dose Level | 0 Participants |
| Part B: Refractory Leukemia: BAY 43-9006 200 mg/m^2 | Number of Patients With Treatment-related Dose Limiting Toxicity in Cycle 1 by Dose Level | 2 Participants |
| Part C: Refractory AML With FLT3-ITD Mutation:150 mg/m^2 | Number of Patients With Treatment-related Dose Limiting Toxicity in Cycle 1 by Dose Level | 0 Participants |
| PK Cohort Expanded: BAY 43-9006 200 mg/m^2 | Number of Patients With Treatment-related Dose Limiting Toxicity in Cycle 1 by Dose Level | 3 Participants |
Primary
Volume of Distribution at Steady State (Vss) of Sorafenib
Volume of distribution at steady state (Vss) of sorefenib administered orally as tablets, BID approximately every 12 hours for cycles of 28 days with no rest period between cycles to children with refractory solid tumors, leukemia, or AML and FLT3-ITD mutation.
Time frame: 8 hours post dose on day 1 of cycle 1
Population: Data was and never will be collected
Secondary
Leukemia Mutations
Analyze tumor samples and leukemic blasts from patients entered on this study for the presence of ras, raf, or FLT3 (leukemia) mutations.
Time frame: 1 week prior to enrollment
Population: This data were not and will never be collected
Secondary
Mean Concentration of VEGF2
Mean concentration of VEGF2 in peripheral blood sample.
Time frame: 28 days
Population: Data were not collected for Part A: 250 mg/m\^2, Part B:150 mg/m\^2, Part B: 200 mg/m\^2, and Part C:150 mg/m\^2
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part A: Refractory Solid Tumors: BAY 43-9006 105 mg/m^2 | Mean Concentration of VEGF2 | 2650 cells/ml | Standard Deviation 2243.49 |
| Part A: Refractory Solid Tumors: BAY 43-9006 130 mg/m^2 | Mean Concentration of VEGF2 | 247.5 cells/ml | Standard Deviation 258.09 |
| Part A: Refractory Solid Tumors: BAY 43-9006 150 mg/m^2 | Mean Concentration of VEGF2 | 3531.5 cells/ml | Standard Deviation 4775.11 |
| Part A: Refractory Solid Tumors: BAY 43-9006 200 mg/m^2 | Mean Concentration of VEGF2 | 430 cells/ml | Standard Deviation 324.5 |
| Part A: Refractory Solid Tumors: BAY 43-9006 250 mg/m^2 | Mean Concentration of VEGF2 | 100 cells/ml | Standard Deviation 124.9 |
Secondary
Number of Patients Who Respond Using RECIST Criteria
Frequency (%) of patients with Partial Response (PR) or Complete Response (CR) using the RECIST criteria by study part and dose level
Time frame: Up to 2 years
Population: There were 55 evaluable patients
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part A: Refractory Solid Tumors: BAY 43-9006 105 mg/m^2 | Number of Patients Who Respond Using RECIST Criteria | 0 participants |
| Part A: Refractory Solid Tumors: BAY 43-9006 130 mg/m^2 | Number of Patients Who Respond Using RECIST Criteria | 0 participants |
| Part A: Refractory Solid Tumors: BAY 43-9006 150 mg/m^2 | Number of Patients Who Respond Using RECIST Criteria | 0 participants |
| Part A: Refractory Solid Tumors: BAY 43-9006 200 mg/m^2 | Number of Patients Who Respond Using RECIST Criteria | 0 participants |
| Part A: Refractory Solid Tumors: BAY 43-9006 250 mg/m^2 | Number of Patients Who Respond Using RECIST Criteria | 0 participants |
| Part B: Refractory Leukemia: BAY 43-9006 150 mg/m^2 | Number of Patients Who Respond Using RECIST Criteria | 1 participants |
| Part B: Refractory Leukemia: BAY 43-9006 200 mg/m^2 | Number of Patients Who Respond Using RECIST Criteria | 0 participants |
| Part C: Refractory AML With FLT3-ITD Mutation:150 mg/m^2 | Number of Patients Who Respond Using RECIST Criteria | 4 participants |
| PK Cohort Expanded: BAY 43-9006 200 mg/m^2 | Number of Patients Who Respond Using RECIST Criteria | 0 participants |
Secondary
Number of Patients With DEMRI
Assess effect on tumor blood flow via DEMRI in patients with measurable soft tissue tumors.
Time frame: Up to 2 years
Population: There were 55 evaluable patients
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part A: Refractory Solid Tumors: BAY 43-9006 105 mg/m^2 | Number of Patients With DEMRI | 0 Participants |
| Part A: Refractory Solid Tumors: BAY 43-9006 130 mg/m^2 | Number of Patients With DEMRI | 0 Participants |
| Part A: Refractory Solid Tumors: BAY 43-9006 150 mg/m^2 | Number of Patients With DEMRI | 0 Participants |
| Part A: Refractory Solid Tumors: BAY 43-9006 200 mg/m^2 | Number of Patients With DEMRI | 1 Participants |
| Part A: Refractory Solid Tumors: BAY 43-9006 250 mg/m^2 | Number of Patients With DEMRI | 0 Participants |
| Part B: Refractory Leukemia: BAY 43-9006 150 mg/m^2 | Number of Patients With DEMRI | 0 Participants |
| Part B: Refractory Leukemia: BAY 43-9006 200 mg/m^2 | Number of Patients With DEMRI | 0 Participants |
| Part C: Refractory AML With FLT3-ITD Mutation:150 mg/m^2 | Number of Patients With DEMRI | 0 Participants |
| PK Cohort Expanded: BAY 43-9006 200 mg/m^2 | Number of Patients With DEMRI | 0 Participants |
Secondary
Pharmacodynamics (PD) Blood Flow Part C
Pharmacodynamics: tumor blood flow in patients with AML and FLT3-ITD mutation using dynamic contrast enhanced MRI (DEMRI) (Part C).
Time frame: 1 week prior to enrollment, then every 28 days
Population: This data were not and will never be collected
Secondary
Plasma Inhibitory Activity (PIA)
Analyze the plasma inhibitory activity (PIA) for FLT3 phosphorylation in peripheral blood samples obtained at the time of PK studies in patients with FLT3-ITD mutation AML (Part C).
Time frame: 1 week prior to enrollment and then every 28 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part A: Refractory Solid Tumors: BAY 43-9006 105 mg/m^2 | Plasma Inhibitory Activity (PIA) | 5 Participants |