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

NCT ID: NCT01445080

Last Updated: 2021-02-02

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1/PHASE2
• Total Enrollment: 70 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2006-05-30
• Study Completion Date: 2012-12-10

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.

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; Philadelphia Chromosome Negative, BCR-ABL1 Positive Chronic Myelogenous Leukemia; Recurrent Childhood Acute Lymphoblastic Leukemia; Recurrent Childhood Acute Myeloid Leukemia; Recurrent Disease

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Treatment (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.

Group Type: EXPERIMENTAL

Laboratory Biomarker Analysis

Intervention Type: OTHER

Correlative studies

Pharmacological Study

Intervention Type: OTHER

Correlative studies

Sorafenib Tosylate

Intervention Type: DRUG

Given orally

Interventions

Laboratory Biomarker Analysis

Correlative studies

Intervention Type: OTHER

Pharmacological Study

Correlative studies

Intervention Type: OTHER

Sorafenib Tosylate

Given orally

Intervention Type: DRUG

Other Intervention Names

BAY 43-9006 Tosylate; BAY 54-9085; Nexavar; sorafenib

Eligibility Criteria

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

• Minimum Eligible Age: 2 Years
• Maximum Eligible Age: 21 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Cancer Institute (NCI)

NIH

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Brigitte C Widemann

Role: PRINCIPAL_INVESTIGATOR

COG Phase I Consortium

Locations

University of Alabama at Birmingham Cancer Center

Birmingham, Alabama, United States

Children's Hospital of Orange County

Orange, California, United States

Lucile Packard Children's Hospital Stanford University

Palo Alto, California, United States

Children's National Medical Center

Washington D.C., District of Columbia, United States

Lurie Children's Hospital-Chicago

Chicago, Illinois, United States

Indiana University/Melvin and Bren Simon Cancer Center

Indianapolis, Indiana, United States

Riley Hospital for Children

Indianapolis, Indiana, United States

National Institutes of Health Clinical Center

Bethesda, Maryland, United States

Dana-Farber Cancer Institute

Boston, Massachusetts, United States

C S Mott Children's Hospital

Ann Arbor, Michigan, United States

University of Minnesota/Masonic Cancer Center

Minneapolis, Minnesota, United States

Washington University School of Medicine

St Louis, Missouri, 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

Cincinnati Children's Hospital Medical Center

Cincinnati, Ohio, United States

Oregon Health and Science University

Portland, Oregon, United States

Children's Hospital of Philadelphia

Philadelphia, Pennsylvania, United States

Children's Hospital of Pittsburgh of UPMC

Pittsburgh, Pennsylvania, United States

St. Jude Children's Research Hospital

Memphis, Tennessee, United States

UT Southwestern/Simmons Cancer Center-Dallas

Dallas, Texas, United States

Baylor College of Medicine/Dan L Duncan Comprehensive Cancer Center

Houston, Texas, United States

Seattle Children's Hospital

Seattle, Washington, United States

Children's Hospital of Wisconsin

Milwaukee, Wisconsin, United States

Hospital for Sick Children

Toronto, Ontario, Canada

Centre Hospitalier Universitaire Sainte-Justine

Montreal, Quebec, Canada

Countries

United States; Canada

Other Identifiers

NCI-2009-00358

Identifier Type: REGISTRY

Identifier Source: secondary_id

06-C-0233

Identifier Type: -

Identifier Source: secondary_id

CDR0000483040

Identifier Type: -

Identifier Source: secondary_id

COG-ADVL0413

Identifier Type: -

Identifier Source: secondary_id

NCI-06-C-0233

Identifier Type: -

Identifier Source: secondary_id

060233

Identifier Type: -

Identifier Source: secondary_id

ADVL0413

Identifier Type: -

Identifier Source: secondary_id

ADVL0413

Identifier Type: OTHER

Identifier Source: secondary_id

ADVL0413

Identifier Type: OTHER

Identifier Source: secondary_id

U01CA097452

Identifier Type: NIH

Identifier Source: secondary_id

View Link

NCI-2009-00358

Identifier Type: -

Identifier Source: org_study_id

NCT00343694

Identifier Type: -

Identifier Source: nct_alias

NCT01648413

Identifier Type: -

Identifier Source: nct_alias