Blastic PhasePhase 1/2NCT01445080
Sorafenib in Treating Young Patients With Relapsed or Refractory Solid Tumors or Leukemia
A Phase 1/2 study testing Laboratory Biomarker Analysis, Pharmacological Study and Sorafenib Tosylate in people with Blastic Phase and Childhood Acute Promyelocytic Leukemia With PML-RARA, run by National Cancer Institute (NCI) at 25 sites in 2 countries.
Trial 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. Read more about this study
- Who is it for?
- Ages 2 to 21 years
- Conditions the study is for
- Blastic Phase, Childhood Acute Promyelocytic Leukemia With PML-RARA, Childhood Chronic Myelogenous Leukemia, BCR-ABL1 Positive
- What is being tested?
- Laboratory Biomarker Analysis, Pharmacological Study and Sorafenib Tosylate
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 70 participants
- Where
- 25 sitesin 2 countries
- Study dates
- 30 May 2006to 10 Dec 2012
- Phase
- Phase 1/2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 2 to 21 years
- All sexes
- No healthy volunteers
- Child, Adult
Who may be able to join
- 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)
Show all 94Show fewer
- 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
Who cannot join
None listed.
Trial locations and contacts
25 sites in 2 countries.
25 sites in 2 countries
United States23 sites
C S Mott Children's Hospital
Ann Arbor, Michigan, 48109
National Institutes of Health Clinical Center
Bethesda, Maryland, 20892
University of Alabama at Birmingham Cancer Center
Birmingham, Alabama, 35233
Dana-Farber Cancer Institute
Boston, Massachusetts, 02215
Lurie Children's Hospital-Chicago
Chicago, Illinois, 60611
Cincinnati Children's Hospital Medical Center
Cincinnati, Ohio, 45229
UT Southwestern/Simmons Cancer Center-Dallas
Dallas, Texas, 75390
Baylor College of Medicine/Dan L Duncan Comprehensive Cancer Center
Houston, Texas, 77030
Indiana University/Melvin and Bren Simon Cancer Center
Indianapolis, Indiana, 46202
Riley Hospital for Children
Indianapolis, Indiana, 46202
St. Jude Children's Research Hospital
Memphis, Tennessee, 38105
Children's Hospital of Wisconsin
Milwaukee, Wisconsin, 53226
University of Minnesota/Masonic Cancer Center
Minneapolis, Minnesota, 55455
Columbia University/Herbert Irving Cancer Center
New York, New York, 10032
Children's Hospital of Orange County
Orange, California, 92868
Lucile Packard Children's Hospital Stanford University
Palo Alto, California, 94304
Children's Hospital of Philadelphia
Philadelphia, Pennsylvania, 19104
Children's Hospital of Pittsburgh of UPMC
Pittsburgh, Pennsylvania, 15224
Oregon Health and Science University
Portland, Oregon, 97239
Seattle Children's Hospital
Seattle, Washington, 98105
Washington University School of Medicine
St Louis, Missouri, 63110
State University of New York Upstate Medical University
Syracuse, New York, 13210
Children's National Medical Center
Washington D.C., District of Columbia, 20010
Canada2 sites
Centre Hospitalier Universitaire Sainte-Justine
Montreal, Quebec, H3T 1C5
Hospital for Sick Children
Toronto, Ontario, M5G 1X8
About this study
Official title: A Phase I/II Study of the Raf Kinase and Receptor Tyrosine Kinase Inhibitor Sorafenib (BAY 43-9006, NSC# 724772) in Children With Refractory Solid Tumors or Refractory Leukemias
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.
Read the detailed description
PRIMARY OBJECTIVES:
- 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:
- 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.
- 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.
- Conditions
- 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
- Being tested
- Laboratory Biomarker Analysis, Pharmacological Study, Sorafenib Tosylate
- Medical subject headings
- Blast Crisis, Leukemia, Myelogenous, Chronic, BCR-ABL Positive, Leukemia, Myelomonocytic, Juvenile, Precursor Cell Lymphoblastic Leukemia-Lymphoma, Recurrence
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Laboratory Biomarker AnalysisOther
Correlative studies
Correlative studies
Sorafenib TosylateDrug
Also called BAY 43-9006 Tosylate, BAY 54-9085, Nexavar, sorafenib
Given orally
| Study group | Role | What they receive |
|---|---|---|
| Treatment (sorafenib tosylate) | Experimental | 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. Receives: Other: Laboratory Biomarker Analysis; Other: Pharmacological Study; Drug: Sorafenib Tosylate |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: Up to 28 days
Number of Patients With Treatment-related Adverse Events
Number of patients with treatment-related adverse events stratified by dose level through study completion.
Measured: Up to 2 years
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.
Measured: 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 (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.
Measured: 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 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.
Measured: 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 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.
Measured: 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
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.
Measured: Up to 2 years
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.
Measured: 8 hours post dose on day 1 of cycle 1
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.
Measured: 8 hours post dose on day 1 of cycle 1
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.
Measured: 8 hours post dose on day 1 of cycle 1
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.
Measured: 8 hours post dose on day 1 of cycle 1
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.
Measured: 8 hours post dose on day 1 of cycle 1
Secondary outcomes (6)
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
Measured: Up to 2 years
Mean Concentration of VEGF2
Mean concentration of VEGF2 in peripheral blood sample.
Measured: 28 days
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).
Measured: 1 week prior to enrollment, then every 28 days
Number of Patients With DEMRI
Assess effect on tumor blood flow via DEMRI in patients with measurable soft tissue tumors.
Measured: Up to 2 years
Leukemia Mutations
Analyze tumor samples and leukemic blasts from patients entered on this study for the presence of ras, raf, or FLT3 (leukemia) mutations.
Measured: 1 week prior to enrollment
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).
Measured: 1 week prior to enrollment and then every 28 days
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted3 Oct 2011 (estimated)
- Study start30 May 2006
- Primary completion16 Mar 2012
- Study completion10 Dec 2012
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Other trials for Blastic PhaseStudies of the same condition, open and under way.
- More trials run by National Cancer Institute (NCI)The sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1/2
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 70 participants (actual)
Sponsor and investigators
- Lead sponsor
- National Cancer Institute (NCI)
- Sponsor type
- US National Institutes of Health
- Responsible party
- Sponsor
- Investigators
- Brigitte C Widemann, Principal investigator, COG Phase I Consortium
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01445080
- Sponsor's protocol ID
- NCI-2009-00358
- Other IDs
- NCI-2009-00358, 06-C-0233, CDR0000483040, COG-ADVL0413, NCI-06-C-0233, 060233, ADVL0413, ADVL0413
- Status last verified
- Jan 2021
- First submitted
- 30 Sep 2011
- Last updated
- 2 Feb 2021
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
Study at a glance
From the registry record, last updated by the sponsor on 2 Feb 2021. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Phase I/II Study of the Raf Kinase and Receptor Tyrosine Kinase Inhibitor Sorafenib (BAY 43-9006, NSC# 724772) in Children With Refractory Solid Tumors or Refractory Leukemias
- ClinicalTrials.gov ID
- NCT01445080
- Acronym / sponsor ID
- NCI-2009-00358
- Conditions
- 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
- Phase
- Phase 1/2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 70 participants (actual)
- Lead sponsor
- National Cancer Institute (NCI)US National Institutes of Health
- Study start
- 30 May 2006 (actual)
- Primary completion
- 16 Mar 2012 (actual)
- Study completion
- 10 Dec 2012 (actual)
- First posted
- 3 Oct 2011 (estimated)
- Results
- Posted 2 Feb 2021
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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:
- 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:
- 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.
- 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.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Treatment (sorafenib tosylate) | Experimental | Other: Laboratory Biomarker Analysis, Other: Pharmacological Study, Drug: Sorafenib TosylatePatients 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. |
Who may qualify
- Ages
- 2 to 21 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult
Key inclusion criteria (94 listed)
- Diagnosis of 1 of the following:
- Relapsed or refractory disease
- 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
Key exclusion criteria (0 listed)
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Laboratory Biomarker AnalysisCorrelative studies | Other | Treatment (sorafenib tosylate) |
| Pharmacological StudyCorrelative studies | Other | Treatment (sorafenib tosylate) |
| Sorafenib TosylateAlso: BAY 43-9006 Tosylate, BAY 54-9085, Nexavar, sorafenibGiven orally | Drug | Treatment (sorafenib tosylate) |
Primary outcome
Number of Patients With Treatment-related Dose Limiting Toxicity in Cycle 1 by Dose Level
Time frame: 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.
Number of Patients With Treatment-related Adverse Events
Time frame: 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
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
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
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
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
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
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
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
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
Time frame: 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.
Area Under the Plasma Concentration Versus Time Curve (AUC) of Sorafenib
Time frame: 8 hours post dose on day 1 of cycle 1
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.
Clearance (Cl) of Sorafenib
Time frame: 8 hours post dose on day 1 of cycle 1
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.
Half-life of Sorafenib
Time frame: 8 hours post dose on day 1 of cycle 1
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.
Volume of Distribution at Steady State (Vss) of Sorafenib
Time frame: 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.
Maximum Serum Concentration (Cmax) of Sorafenib
Time frame: 8 hours post dose on day 1 of cycle 1
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.
6 secondary outcomes
Number of Patients Who Respond Using RECIST Criteria
Time frame: Up to 2 years
Mean Concentration of VEGF2
Time frame: 28 days
Pharmacodynamics (PD) Blood Flow Part C
Time frame: 1 week prior to enrollment, then every 28 days
Number of Patients With DEMRI
Time frame: Up to 2 years
Leukemia Mutations
Time frame: 1 week prior to enrollment
Plasma Inhibitory Activity (PIA)
Time frame: 1 week prior to enrollment and then every 28 days
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 2 Feb 2021.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Brigitte C Widemann principal investigator
COG Phase I Consortium
25 sites in 2 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1/2 study testing Laboratory Biomarker Analysis, Pharmacological Study and Sorafenib Tosylate in people with Blastic Phase and Childhood Acute Promyelocytic Leukemia With PML-RARA, run by National Cancer Institute (NCI) at 25 sites in 2 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 94 inclusion and 0 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 2 Feb 2021. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 25 sites in United States, Canada. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this combined phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 2 Feb 2021). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Number of Patients With Treatment-related Dose Limiting Toxicity in Cycle 1 by Dose Level (time frame: Up to 28 days). The study lists 12 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 2 Feb 2021.