Recurrent Childhood Acute Lymphoblastic Leukemia Clinical Trial
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
Verified date | January 2021 |
Source | National Cancer Institute (NCI) |
Contact | n/a |
Is FDA regulated | No |
Health authority | |
Study type | Interventional |
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.
Status | Completed |
Enrollment | 70 |
Est. completion date | December 10, 2012 |
Est. primary completion date | March 16, 2012 |
Accepts healthy volunteers | No |
Gender | All |
Age group | 2 Years to 21 Years |
Eligibility | 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 |
Country | Name | City | State |
---|---|---|---|
Canada | Centre Hospitalier Universitaire Sainte-Justine | Montreal | Quebec |
Canada | Hospital for Sick Children | Toronto | Ontario |
United States | C S Mott Children's Hospital | Ann Arbor | Michigan |
United States | National Institutes of Health Clinical Center | Bethesda | Maryland |
United States | University of Alabama at Birmingham Cancer Center | Birmingham | Alabama |
United States | Dana-Farber Cancer Institute | Boston | Massachusetts |
United States | Lurie Children's Hospital-Chicago | Chicago | Illinois |
United States | Cincinnati Children's Hospital Medical Center | Cincinnati | Ohio |
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 | Indiana University/Melvin and Bren Simon Cancer Center | Indianapolis | Indiana |
United States | Riley Hospital for Children | Indianapolis | Indiana |
United States | St. Jude Children's Research Hospital | Memphis | Tennessee |
United States | Children's Hospital of Wisconsin | Milwaukee | Wisconsin |
United States | University of Minnesota/Masonic Cancer Center | Minneapolis | Minnesota |
United States | Columbia University/Herbert Irving Cancer Center | New York | New York |
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 Hospital of Philadelphia | Philadelphia | Pennsylvania |
United States | Children's Hospital of Pittsburgh of UPMC | Pittsburgh | Pennsylvania |
United States | Oregon Health and Science University | Portland | Oregon |
United States | Washington University School of Medicine | Saint Louis | Missouri |
United States | Seattle Children's Hospital | Seattle | Washington |
United States | State University of New York Upstate Medical University | Syracuse | New York |
United States | Children's National Medical Center | Washington | District of Columbia |
Lead Sponsor | Collaborator |
---|---|
National Cancer Institute (NCI) |
United States, Canada,
Type | Measure | Description | Time frame | Safety issue |
---|---|---|---|---|
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. | Up to 28 days | |
Primary | Number of Patients With Treatment-related Adverse Events | Number of patients with treatment-related adverse events stratified by dose level through study completion. | Up to 2 years | |
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. | 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 | |
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. | 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 | |
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. | 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 | |
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. | 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 | |
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. | Up to 2 years | |
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. | 8 hours post dose on day 1 of cycle 1 | |
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. | 8 hours post dose on day 1 of cycle 1 | |
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. | 8 hours post dose on day 1 of cycle 1 | |
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. | 8 hours post dose on day 1 of cycle 1 | |
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. | 8 hours post dose on day 1 of cycle 1 | |
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 | Up to 2 years | |
Secondary | Mean Concentration of VEGF2 | Mean concentration of VEGF2 in peripheral blood sample. | 28 days | |
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). | 1 week prior to enrollment, then every 28 days | |
Secondary | Number of Patients With DEMRI | Assess effect on tumor blood flow via DEMRI in patients with measurable soft tissue tumors. | Up to 2 years | |
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. | 1 week prior to enrollment | |
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). | 1 week prior to enrollment and then every 28 days |
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