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

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ClinicalTrials.gov Identifier: NCT01445080
Recruitment Status : Completed
First Posted : October 3, 2011
Results First Posted : February 2, 2021
Last Update Posted : February 2, 2021
Sponsor:
Information provided by (Responsible Party):
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.

Condition or disease Intervention/treatment Phase
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 Other: Laboratory Biomarker Analysis Other: Pharmacological Study Drug: Sorafenib Tosylate Phase 1 Phase 2

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 70 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : May 30, 2006
Actual Primary Completion Date : March 16, 2012
Actual Study Completion Date : December 10, 2012


Arm Intervention/treatment
Experimental: 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.
Other: Laboratory Biomarker Analysis
Correlative studies

Other: Pharmacological Study
Correlative studies

Drug: Sorafenib Tosylate
Given orally
Other Names:
  • BAY 43-9006 Tosylate
  • BAY 54-9085
  • Nexavar
  • sorafenib




Primary Outcome Measures :
  1. 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.

  2. 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.

  3. 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.

  4. 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.

  5. 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.

  6. 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.

  7. 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.

  8. 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.

  9. 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.

  10. 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.

  11. 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.

  12. 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.


Secondary Outcome Measures :
  1. Number of Patients Who Respond Using RECIST Criteria [ Time Frame: 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

  2. Mean Concentration of VEGF2 [ Time Frame: 28 days ]
    Mean concentration of VEGF2 in peripheral blood sample.

  3. Pharmacodynamics (PD) Blood Flow Part C [ Time Frame: 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).

  4. Number of Patients With DEMRI [ Time Frame: Up to 2 years ]
    Assess effect on tumor blood flow via DEMRI in patients with measurable soft tissue tumors.

  5. Leukemia Mutations [ Time Frame: 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.

  6. Plasma Inhibitory Activity (PIA) [ Time Frame: 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).



Information from the National Library of Medicine

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Ages Eligible for Study:   2 Years to 21 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01445080


Locations
Show Show 25 study locations
Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
Layout table for investigator information
Principal Investigator: Brigitte C Widemann COG Phase I Consortium
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Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT01445080    
Obsolete Identifiers: NCT00343694, NCT01648413
Other Study ID Numbers: NCI-2009-00358
NCI-2009-00358 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
06-C-0233
CDR0000483040
COG-ADVL0413
NCI-06-C-0233
060233
ADVL0413
ADVL0413 ( Other Identifier: COG Phase I Consortium )
ADVL0413 ( Other Identifier: CTEP )
U01CA097452 ( U.S. NIH Grant/Contract )
First Posted: October 3, 2011    Key Record Dates
Results First Posted: February 2, 2021
Last Update Posted: February 2, 2021
Last Verified: January 2021
Additional relevant MeSH terms:
Layout table for MeSH terms
Leukemia
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Leukemia, Myeloid
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Leukemia, Promyelocytic, Acute
Leukemia, Myelomonocytic, Juvenile
Philadelphia Chromosome
Neoplasms by Histologic Type
Neoplasms
Leukemia, Myeloid, Acute
Leukemia, Lymphoid
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Myeloproliferative Disorders
Bone Marrow Diseases
Hematologic Diseases
Translocation, Genetic
Chromosome Aberrations
Pathologic Processes
Myelodysplastic-Myeloproliferative Diseases
Sorafenib
Antineoplastic Agents
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action