Sorafenib in Treating Young Patients With Relapsed or Refractory Solid Tumors or Leukemia

Phase 1

Completed

Conditions: Blastic Phase
Childhood Chronic Myelogenous Leukemia, BCR-ABL1 Positive
Recurrent Childhood Acute Lymphoblastic Leukemia
Recurrent Childhood Acute Myeloid Leukemia
Chronic Myelogenous Leukemia, BCR-ABL1 Positive
Childhood Acute Promyelocytic Leukemia With PML-RARA
Childhood Solid Neoplasm
Juvenile Myelomonocytic Leukemia
Philadelphia Chromosome Negative, BCR-ABL1 Positive Chronic Myelogenous Leukemia
Recurrent Disease

Interventions: Other: Laboratory Biomarker Analysis
Other: Pharmacological Study
Drug: Sorafenib Tosylate

Registration Number: NCT01445080

Lead Sponsor: National Cancer Institute (NCI)

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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 70

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

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Treatment (sorafenib tosylate)	Laboratory Biomarker Analysis	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.
Treatment (sorafenib tosylate)	Pharmacological Study	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.
Treatment (sorafenib tosylate)	Sorafenib Tosylate	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.

Primary Outcome Measures

Name	Time	Method
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.
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 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.
Half-life of Sorafenib	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.
Area Under the Plasma Concentration Versus Time Curve (AUC) of Sorafenib	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.
Maximum Serum Concentration (Cmax) of Sorafenib	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.
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.
Clearance (Cl) of Sorafenib	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.

Secondary Outcome Measures

Name	Time	Method
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.
Number of Patients With DEMRI	Up to 2 years	Assess effect on tumor blood flow via DEMRI in patients with measurable soft tissue tumors.
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
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).
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).

Trial Locations

Locations (25): Children's National Medical Center
🇺🇸
Washington, District of Columbia, United States
Lurie Children's Hospital-Chicago
🇺🇸
Chicago, Illinois, United States
Seattle Children's Hospital
🇺🇸
Seattle, Washington, United States
Dana-Farber Cancer Institute
🇺🇸
Boston, Massachusetts, United States
UT Southwestern/Simmons Cancer Center-Dallas
🇺🇸
Dallas, Texas, United States
Children's Hospital of Pittsburgh of UPMC
🇺🇸
Pittsburgh, Pennsylvania, United States
Washington University School of Medicine
🇺🇸
Saint Louis, Missouri, United States
Children's Hospital of Orange County
🇺🇸
Orange, California, United States
Lucile Packard Children's Hospital Stanford University
🇺🇸
Palo Alto, California, United States
Columbia University/Herbert Irving Cancer Center
🇺🇸
New York, New York, United States
State University of New York Upstate Medical University
🇺🇸
Syracuse, New York, United States
Centre Hospitalier Universitaire Sainte-Justine
🇨🇦
Montreal, Quebec, Canada
Hospital for Sick Children
🇨🇦
Toronto, Ontario, Canada
Cincinnati Children's Hospital Medical Center
🇺🇸
Cincinnati, Ohio, United States
Riley Hospital for Children
🇺🇸
Indianapolis, Indiana, United States
Indiana University/Melvin and Bren Simon Cancer Center
🇺🇸
Indianapolis, Indiana, United States
Baylor College of Medicine/Dan L Duncan Comprehensive Cancer Center
🇺🇸
Houston, Texas, United States
University of Alabama at Birmingham Cancer Center
🇺🇸
Birmingham, Alabama, United States
University of Minnesota/Masonic Cancer Center
🇺🇸
Minneapolis, Minnesota, United States
National Institutes of Health Clinical Center
🇺🇸
Bethesda, Maryland, United States
Oregon Health and Science University
🇺🇸
Portland, Oregon, United States
C S Mott Children's Hospital
🇺🇸
Ann Arbor, Michigan, United States
Children's Hospital of Wisconsin
🇺🇸
Milwaukee, Wisconsin, United States
Children's Hospital of Philadelphia
🇺🇸
Philadelphia, Pennsylvania, United States
St. Jude Children's Research Hospital
🇺🇸
Memphis, Tennessee, United States