Clinical Trials /

VEGF Receptor Tyrosine Kinase Inhibitor Axitinib in Children With Recurrent or Refractory Solid Tumors

NCT02164838

Description:

This trial will be the first study of axitinib in children and adolescents. The primary objective of this Phase 1 trial is to determine a maximum tolerated dose (MTD) or recommended Phase 2 dose (RP2D) of axitinib in pediatric patients with refractory solid tumors. Additional objectives include measurement of pharmacokinetic and pharmacodynamic parameters, description of the toxicity profile of this agent in children and adolescents, and assessment of response within the confines of a Phase 1 trial. A standard rolling 6 design will be used for dose escalation. Further development of axitinib will focus on development of a joint cooperative group (COG/ECOG) Phase 2 study of axitinib in pediatric, adolescent and young adult translocation renal cell carcinoma.

Related Conditions:
  • Malignant Solid Tumor
  • Renal Cell Carcinoma
Recruiting Status:

Completed

Phase:

Phase 1

Trial Eligibility

Document

<span class="go-doc-concept go-doc-intervention">VEGF</span> Receptor <span class="go-doc-concept go-doc-intervention">Tyrosine Kinase Inhibitor</span> <span class="go-doc-concept go-doc-intervention">Axitinib</span> in Children With Recurrent or Refractory Solid Tumors

Title

  • Brief Title: VEGF Receptor Tyrosine Kinase Inhibitor Axitinib in Children With Recurrent or Refractory Solid Tumors
  • Official Title: A Phase 1 Study of the VEGF Receptor Tyrosine Kinase Inhibitor Axitinib (INLYTA, IND# TBD) in Children With Recurrent or Refractory Solid Tumors
  • Clinical Trial IDs

    NCT ID: NCT02164838

    ORG ID: ADVL1315

    Trial Conditions

    Refractory or Recurrent Solid Tumors, Excluding CNS Tumors

    Trial Interventions

    Drug Synonyms Arms
    Axitinib AG-013736, INLYTA Axitinib

    Trial Purpose

    This trial will be the first study of axitinib in children and adolescents. The primary
    objective of this Phase 1 trial is to determine a maximum tolerated dose (MTD) or
    recommended Phase 2 dose (RP2D) of axitinib in pediatric patients with refractory solid
    tumors. Additional objectives include measurement of pharmacokinetic and pharmacodynamic
    parameters, description of the toxicity profile of this agent in children and adolescents,
    and assessment of response within the confines of a Phase 1 trial. A standard rolling 6
    design will be used for dose escalation. Further development of axitinib will focus on
    development of a joint cooperative group (COG/ECOG) Phase 2 study of axitinib in pediatric,
    adolescent and young adult translocation renal cell carcinoma.

    Detailed Description

    Trial Arms

    Name Type Description Interventions
    Axitinib Experimental Axitinib

    Eligibility Criteria

    Inclusion Criteria

    - Age: Patients must be > than 12 months and < 18 years of age at the time of study
    enrollment.

    - Body Surface Area: Patients must have a BSA of 0.53 m2 at the time of study
    enrollment.

    - Diagnosis: Patients with refractory or recurrent solid tumors (excluding CNS tumors)
    and patients with unresectable translocation positive renal cell carcinoma (tRCC) are
    eligible. Patients must have had histologic verification of malignancy at original
    diagnosis or relapse.

    - The diagnosis of translocation morphology or TFE renal cell carcinoma is established
    by having characteristic morphology AND either a) strong nuclear TFE3 or TFEb
    staining on immunohistochemistry OR b) cytogenetic studies of the tumor demonstrating
    a TFE translocation OR c) fluorescent in situ hybridization (FISH) demonstrating a
    TFE translocation.

    - Disease Status: Patients must have either measurable or evaluable disease

    - Therapeutic Options: Patient's current disease state must be one for which there is
    no known curative therapy or therapy proven to prolong survival with an acceptable
    quality of life.

    - Performance Level: Karnofsky 50% for patients > 16 years of age and Lansky 50 for
    patients 16 years of age . Patients who are unable to walk because of paralysis,
    but who are up in a wheelchair, will be considered ambulatory for the purpose of
    assessing the performance score.

    - Prior Therapy

    - Patients may have received bevacizumab, VEGF-Trap, or other VEGF blocking tyrosine
    kinase inhibitors, but may not have received axitinib.

    - Patients must have recovered from any VEGF blocking drug-related toxicity (e.g.,
    proteinuria, hypertension).

    - All patients must have fully recovered from the acute toxic effects of all prior
    anti-cancer chemotherapy.

    - Myelosuppressive chemotherapy: At least 21 days after the last dose of
    myelosuppressive chemotherapy (42 days if prior nitrosourea).

    - Hematopoietic growth factors: At least 14 days after the last dose of a long-acting
    growth factor (e.g. Neulasta) or 7 days for short-acting growth factor. For agents
    that have known adverse events occurring beyond 7 days after administration, this
    period must be extended beyond the time during which adverse events are known to
    occur. The duration of this interval must be discussed with the study chair.

    - Biologic (anti-neoplastic agent): At least 7 days after the last dose of a biologic
    agent. For agents that have known adverse events occurring beyond 7 days after
    administration, this period must be extended beyond the time during which adverse
    events are known to occur. The duration of this interval must be discussed with the
    study chair.

    - Immunotherapy: At least 42 days after the completion of any type of immunotherapy,
    e.g. tumor vaccines.

    - Monoclonal antibodies: At least 3 half-lives of the antibody after the last dose of a
    monoclonal antibody.

    - XRT: At least 14 days after local palliative XRT (small port); At least 150 days must
    have elapsed if prior TBI, craniospinal XRT or if 50% radiation of pelvis; At least
    42 days must have elapsed if other substantial BM radiation.

    - Stem Cell Infusion without TBI: No evidence of active graft vs. host disease and at
    least 84 days must have elapsed after transplant or stem cell infusion.

    - Organ Function Requirements

    - Adequate Bone Marrow Function Defined As:

    - Peripheral absolute neutrophil count (ANC) 1000/mm3

    - Platelet count 100,000/mm3 (transfusion independent, defined as not receiving
    platelet transfusions for at least 7 days prior to enrollment)

    Adequate Renal Function Defined As:

    Creatinine clearance or radioisotope GFR 70ml/min/1.73 m2 or

    Adequate Liver Function Defined as:

    - Bilirubin (sum of conjugated + unconjugated) 1.5 x upper limit of normal (ULN) for
    age

    - SGPT (ALT) 110 U/L. For the purpose of this study, the ULN for SGPT is 45 U/L.

    - SGOT (AST) 125 U/L. For the purpose of this study, the ULN for SGOT is 50 U/L.

    - Serum albumin 2 g/dL.

    Adequate Cardiac Function Defined As:

    - Shortening fraction of 27% by echocardiogram, or Ejection fraction of 50% by
    gated radionuclide study.

    - Must not have a history of myocardial infarction, severe or unstable angina, or
    peripheral vascular disease.

    Adequate Blood Pressure Control Defined As:

    A blood pressure (BP) the 95th percentile for age, height, and gender

    Adequate Coagulation Defined As:

    - No evidence of active bleeding

    - PT and PTT 1.2 x upper limit of normal (ULN)

    - INR 1.2

    Adequate Pancreatic Function Defined as:

    Lipase 1.5 x upper limit of normal (ULN).

    Exclusion Criteria

    - Pregnancy or Breast-Feeding

    - Corticosteroids: Patients receiving chronically dosed corticosteroids within 7 days
    prior to enrollment are not eligible for this trial.

    - Investigational Drugs: Patients who are currently receiving another investigational
    drug are not eligible.

    - Anti-cancer Agents: Patients who are currently receiving other anti-cancer agents are
    not eligible.

    - Anti-GVHD agents post-transplant:

    Patients who are receiving cyclosporine, tacrolimus or other agents to prevent
    graft-versus-host disease post bone marrow transplant are not eligible for this trial.

    - CYP3A4/5 Inhibitors:

    Patients chronically receiving drugs that are known potent CYP3A4/5 inhibitors within 7
    days prior to study enrollment, including but not limited to ketoconazole, itraconazole,
    clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir,
    telithromycin, voriconazole, grapefruit, and grapefruit juice are not eligible

    - CYP3A4/5 Inducers:

    Patients chronically receiving drugs that are known potent CYP3A4/5 inducers within 7 days
    prior to study enrollment, including but not limited to rifampin, dexamethasone,
    phenytoin, carbamazepine, rifabutin, rifapentine, phenobarbital, and St John's wort are
    not eligible.

    - Anti-hypertensives: Patients who are receiving anti-hypertensive medications for
    control of blood pressure at the time of enrollment are not eligible for this trial.

    - Anti-coagulation: Patients who are currently receiving therapeutic anti-coagulation
    with heparin, low-molecular weight heparin or coumadin are not eligible for this
    trial.

    - Anti-inflammatory or anti-platelet agents: Patients who are currently receiving
    aspirin, ibuprofen or other non-steroidal anti-inflammatory drugs or anti-platelet
    agents are not eligible.

    - Patients must be able to swallow tablets whole.

    - Thyroid Replacement Therapy: Patients who require thyroid replacement therapy are not
    eligible if they have not been receiving a stable replacement dose for at least 28
    days prior to study enrollment. Patients who enter the study on thyroid replacement
    should have their medication adjusted to maintain TSH in the normal range.

    Bleeding and Thrombosis:

    Patients with evidence of active bleeding, intratumoral hemorrhage, or bleeding diathesis
    are not eligible:

    - History (within 180 days prior to study enrollment) of arterial thromboembolic
    events, including transient ischemic attack (TIA) or cerebrovascular accident (CVA).

    - History (within 180 days prior to study enrollment) of pulmonary embolism, DVT, or
    other venous thromboembolic event.

    - History of hemoptysis within 42 days prior to study enrollment.

    Surgery: Patients who have had or are planning to have the following invasive procedures
    are not eligible:

    - Major surgical procedure, laparoscopic procedure, open biopsy or significant
    traumatic injury within 28 days prior to enrollment.

    - Subcutaneous port placement or central line placement is not considered major surgery
    but must be placed at least 3 days prior to enrollment for external lines and at
    least 7 days prior to enrollment for subcutaneous port.

    - Core biopsy within 7 days prior to enrollment.

    - Fine needle aspirate or central line placement within 7 days prior to enrollment.

    CNS disease:

    - Patients who have a known primary or metastatic CNS tumor at the time of study
    enrollment are not eligible. A prior history of metastatic CNS tumor is allowed as
    long as there is no evidence of CNS disease at study enrollment.

    - Patients who have a serious or non-healing wound, ulcer, or bone fracture at the time
    of study enrollment are not eligible.

    - Patients who have a history of abdominal fistula, gastrointestinal perforation, or
    intra-abdominal abscess within 28 days of study enrollment are not eligible.

    - Infection: Patients who have known HIV or an uncontrolled infection are not eligible.

    - Patients who have received a prior solid organ transplantation are not eligible.

    Minimum Eligible Age: 12 Months

    Maximum Eligible Age: 17 Years

    Eligible Gender: Both

    Primary Outcome Measures

    Adverse events as assessed by (CTCAE) version 4.0

    MTD of axitinib based on dose-limiting toxicity (DLT) at which fewer than one-third of patients experience DLT, as assessed by CTCAE version 4.0

    Pharmacokinetic Assessment of Axitinib Concentrations in Plasma Samples

    Secondary Outcome Measures

    Evaluation of disease response to preliminarily define the antitumor activity of axitinib

    Biomarkers of kidney injury during axitinib treatment

    Trial Keywords