Clinical Trials /

Phase II Study of Axitinib (AG-013736) With Evaluation of the VEGF-pathway in Metastatic, Recurrent or Primary Unresectable Pheochromocytoma/Paraganglioma

NCT01967576

Description:

Background: - Most treatments for malignant pheochromocytomas/paragangliomas (PHEO/PGL) are palliative and multidisciplinary. Chemotherapy using the combination of cyclophosphamide, vincristine, and dacarbazine has been successfully utilized in the management of rapidly progressive metastatic PHEO, with more than 50% complete or partial tumor response and more than 70% complete or partial biochemical response. - VEGF expression and evidence of angiogenesis has been found in many PHEO/PGL, so it is plausible that interfering with VEGF signaling may result in anti-tumor activity in patients with PHEO/PGL. - Axitinib (AG-013736) is an oral, potent and selective inhibitor of vascular endothelial growth factor (VEGF) receptors 1, 2, and 3. Pre-clinical data suggests that the anti-tumor activity of axitinib may result from its anti-angiogenic activity and that this is reversible when treatment is discontinued. - Given the known clinical safety and efficacy of axitinib, an assessment of its activity in PHEO/PGL and its impact on the VEGF pathway in PHEO/PGL could provide valuable information. Objectives: - Determine the response rate of metastatic PHEO/PGL to axitinib (AG-013736). - Determine the progression-free survival of metastatic PHEO/PGL treated with axitinib (AG-013736). - Explore the relationship of potential biological markers of axitinib activity with clinical outcomes. - Perform pharmacogenomics analyses of drug metabolism and transport proteins through germline DNA examination. Eligibility: - Adults with a confirmed pathologic diagnosis of PHEO/PGL by the Laboratory of Pathology, NCI - Biochemical evidence of PHEO/PGL - Imaging confirmation of metastatic, locally advanced or unresectable disease. - Measurable disease at presentation - ECOG performance status less than or equal to 2 - Patients must not have received prior therapy with a tyrosine kinase (TK) inhibitor Design: - Phase II, open label, non-randomized trial - Patients with metastatic pheochromocytoma/paraganglioma will receive axitinib (AG- 013736 BID) in eight-week cycles - Patients will be evaluated for response every eight weeks using RECIST criteria - Tumor biopsies are not mandatory but every attempt will be made to obtain these from patients prior to starting axitinib and again 20 -30 days after treatment has begun. - Approximately 12 to 37 patients will be needed to achieve the objectives of the trial

Related Conditions:
  • Paraganglioma
  • Pheochromocytoma
Recruiting Status:

Active, not recruiting

Phase:

Phase 2

Trial Eligibility

Document

Phase II Study of <span class="go-doc-concept go-doc-intervention">Axitinib (AG-013736)</span> With Evaluation of the <span class="go-doc-concept go-doc-intervention">VEGF</span>-pathway in Metastatic, Recurrent or Primary Unresectable Pheochromocytoma/Paraganglioma

Title

  • Brief Title: Phase II Study of Axitinib (AG-013736) With Evaluation of the VEGF-pathway in Metastatic, Recurrent or Primary Unresectable Pheochromocytoma/Paraganglioma
  • Official Title: Phase II Study of Axitinib (AG-013736) With Evaluation of the VEGF-pathway in Metastatic, Recurrent or Primary Unresectable Pheochromocytoma/Paraganglioma
  • Clinical Trial IDs

    NCT ID: NCT01967576

    ORG ID: 140001

    NCI ID: 14-C-0001

    Trial Conditions

    Pheochromocytoma

    Paraganglioma

    Trial Interventions

    Drug Synonyms Arms
    Axitinib (AG-013736) Single Arm

    Trial Purpose

    Background:

    - Most treatments for malignant pheochromocytomas/paragangliomas (PHEO/PGL) are
    palliative and multidisciplinary. Chemotherapy using the combination of
    cyclophosphamide, vincristine, and dacarbazine has been successfully utilized in the
    management of rapidly progressive metastatic PHEO, with more than 50% complete or
    partial tumor response and more than 70% complete or partial biochemical response.

    - VEGF expression and evidence of angiogenesis has been found in many PHEO/PGL, so
    it is plausible that interfering with VEGF signaling may result in anti-tumor activity
    in patients with PHEO/PGL.

    - Axitinib (AG-013736) is an oral, potent and selective inhibitor of vascular endothelial
    growth factor (VEGF) receptors 1, 2, and 3. Pre-clinical data suggests that the
    anti-tumor activity of axitinib may result from its anti-angiogenic activity and
    that this is reversible when treatment is discontinued.

    - Given the known clinical safety and efficacy of axitinib, an assessment of its activity
    in PHEO/PGL and its impact on the VEGF pathway in PHEO/PGL could provide valuable
    information.

    Objectives:

    - Determine the response rate of metastatic PHEO/PGL to axitinib (AG-013736).

    - Determine the progression-free survival of metastatic PHEO/PGL treated with axitinib
    (AG-013736).

    - Explore the relationship of potential biological markers of axitinib activity with
    clinical outcomes.

    - Perform pharmacogenomics analyses of drug metabolism and transport proteins through
    germline DNA examination.

    Eligibility:

    - Adults with a confirmed pathologic diagnosis of PHEO/PGL by the Laboratory of
    Pathology, NCI

    - Biochemical evidence of PHEO/PGL

    - Imaging confirmation of metastatic, locally advanced or unresectable disease.

    - Measurable disease at presentation

    - ECOG performance status less than or equal to 2

    - Patients must not have received prior therapy with a tyrosine kinase (TK) inhibitor

    Design:

    - Phase II, open label, non-randomized trial

    - Patients with metastatic pheochromocytoma/paraganglioma will receive axitinib (AG-
    013736 BID) in eight-week cycles

    - Patients will be evaluated for response every eight weeks using RECIST criteria

    - Tumor biopsies are not mandatory but every attempt will be made to obtain these from
    patients prior to starting axitinib and again 20 -30 days after treatment has begun.

    - Approximately 12 to 37 patients will be needed to achieve the objectives of the trial

    Detailed Description

    Background:

    - Most treatments for malignant pheochromocytomas/paragangliomas (PHEO/PGL) are
    palliative and multidisciplinary. Chemotherapy using the combination of
    cyclophosphamide, vincristine, and dacarbazine has been successfully utilized in the
    management of rapidly progressive metastatic PHEO, with more than 50% complete or
    partial tumor response and more than 70% complete or partial biochemical response.

    - VEGF expression and evidence of angiogenesis has been found in many PHEO/PGL, so
    it is plausible that interfering with VEGF signaling may result in anti-tumor activity
    in patients with PHEO/PGL.

    - Axitinib (AG-013736) is an oral, potent and selective inhibitor of vascular endothelial
    growth factor (VEGF) receptors 1, 2, and 3. Pre-clinical data suggests that the
    anti-tumor activity of axitinib may result from its anti-angiogenic activity and
    that this is reversible when treatment is discontinued.

    - Given the known clinical safety and efficacy of axitinib, an assessment of its activity
    in PHEO/PGL and its impact on the VEGF pathway in PHEO/PGL could provide valuable
    information.

    Objectives:

    - Determine the response rate of metastatic PHEO/PGL to axitinib (AG-013736).

    - Determine the progression-free survival of metastatic PHEO/PGL treated with axitinib
    (AG-013736).

    - Explore the relationship of potential biological markers of axitinib activity with
    clinical outcomes.

    - Perform pharmacogenomics analyses of drug metabolism and transport proteins through
    germline DNA examination.

    Eligibility:

    - Adults with a confirmed pathologic diagnosis of PHEO/PGL by the Laboratory of
    Pathology, NCI

    - Biochemical evidence of PHEO/PGL

    - Imaging confirmation of metastatic, locally advanced or unresectable disease.

    - Measurable disease at presentation

    - ECOG performance status less than or equal to 2

    - Patients must not have received prior therapy with a tyrosine kinase (TK) inhibitor

    Design:

    - Phase II, open label, non-randomized trial

    - Patients with metastatic pheochromocytoma/paraganglioma will receive axitinib (AG-
    013736 BID) in eight-week cycles

    - Patients will be evaluated for response every eight weeks using RECIST criteria

    - Tumor biopsies are not mandatory but every attempt will be made to obtain these from
    patients prior to starting axitinib and again 20 -30 days after treatment has begun.

    - Approximately 12 to 37 patients will be needed to achieve the objectives of the trial

    Trial Arms

    Name Type Description Interventions
    Single Arm Experimental Single Arm dose escalation study Axitinib (AG-013736)

    Eligibility Criteria

    - INCLUSION CRITERIA

    2.1.1 Adults with a confirmed pathologic diagnosis of pheochromocytoma/paraganglioma by
    the Laboratory of Pathology, NCI when such tissue is available to confirm or

    In the event that outside tissue is not available:

    - an outside pathology report confirms the diagnosis of Pheo-PGI, AND

    - the patient has nuclear medicine imaging studies that would only be positive in an
    adult patient with a diagnosis of Pheo/PGL (F-DOPA, Dotatate, F-Dopamine or MIBG)

    2.1.1.2 Imaging confirmation of metastatic disease

    2.1.1.3 Measurable disease at the time of enrollment.

    2.1.1.4 A life expectancy of at least 3 months and ECOG performance status less than or
    equal to 2

    2.1.1.5 Age greater than or equal to 18 years

    2.1.1.6 Information available or pending regarding possible genetic alterations that can
    explain the patient s pheochromocytoma/paraganglioma (mutations in SDHB, SDHV or VHL
    genes)

    2.1.1.7 Last dose of chemotherapy or experimental therapy more than 4 weeks (6 weeks in
    the case of nitrosourea) prior to enrollment date; 2 weeks if the last therapy was
    received as part of a phase 0 or exploratory IND trial. Last surgery more than
    4 weeks prior to enrollment, to allow for wound healing. Core biopsies or FNA will not
    require any waiting period

    2.1.1.8 Last radiotherapy treatment greater than or equal to 4 weeks prior to starting
    treatment with this protocol and there must be sites of measurable disease that did not
    receive radiation

    2.1.1.9 Prior therapeutic MIBG is allowed

    2.1.1.10 Organ and marrow function as defined below:

    2.1.1.11 Total bilirubin less than or equal to 1.5 x ULN (upper limit of normal), unless
    the patient meets the criteria for Gilbert s Syndrome. The upper limit value for
    bilirubin for subjects with Gilbert s Syndrome is less than 3 mg/dl.

    Note: A diagnosis of Gilbert s disease will be made in the presence of (1) unconjugated
    hyperbilirubinemia noted on several occasions; (2) normal results from CBC count,
    reticulocyte count, and blood smear; (3) normal liver function test results; and (4) an
    absence of other disease processes that can explain the unconjugated hyperbilirubinemia.

    2.1.1.12 AST less than or equal to 2.5 x ULN, ALT less than or equal to 2.5 x ULN

    2.1.1.13 Amylase and lipase equal to, or less than, the institutional ULN.

    2.1.1.14 Creatinine clearance (Bullet) 40 ml/min (estimated or measured creatinine
    clearance) or serum creatinine 1.6 mg/dl

    Note: Random urine protein < 20 mg/dL. If greater than or equal to 20 mg/dL then a
    24-hour urine protein collection will be performed to accurately demonstrate that the
    24-hour total is < 1000 mg, the level acceptable for enrollment on study

    2.1.1.15 Absolute neutrophil count greater than or equal to 500/mm(3)

    2.1.1.16 Platelet count greater than or equal to 50,000/ mm(3)

    2.1.1.17 Ability to understand and sign an informed consent document.

    2.1.1.18 Ability and willingness to follow the guidelines of the clinical protocol
    including visits to NICHD and NCI, Bethesda, Maryland for treatment and follow up visits.

    2.1.1.19 Because the effects of chemotherapy on the developing human fetus are potentially
    harmful, women of childbearing potential and men who participate in the study must agree
    to use adequate contraception (hormonal or barrier methods) before, during the study and
    for a period of 3 months after the last dose of chemotherapy.

    EXCLUSIONCRITERIA

    2.1.2.1 Patients with pheochromocytoma/paraganglioma tumors potentially curable by
    surgical excision alone as determined by the Principal Investigator in discussions with
    the surgical consultants

    2.1.2.2 Patients who have large abdominal masses impinging on bowel or pulmonary masses
    with encroached vessels and a potential to bleed will be considered on case by case basis
    after careful consultation with multiple disciplines such as radiologists and surgeons
    with main intent being patient safety.

    2.1.2.3 Unstable hypertension defined as a systolic blood pressure > 150 mm Hg or
    diastolic pressure > 90 mmHg despite optimal medical management.

    2.1.2.4 Untreated brain metastases (or local treatment of brain metastases within the last
    6 months) due to the poor prognosis of these patients and difficulty ascertaining the
    cause of neurologic adverse events.

    2.1.2.5 Pregnancy, due to the possible adverse effects on the developing fetus.

    2.1.2.6 Lactating women who are breast-feeding due to the possibility of transmitting
    axitinib to the child.

    2.1.2.7 The presence of a second malignancy, other than squamous cell carcinoma of the
    skin or in situ cervical cancer because it will complicate the primary objective of the
    study. Cancer survivors who have been free of disease for at least two years can be
    enrolled in this study.

    2.1.2.8 Patients with evidence of a bleeding diathesis

    2.1.2.9 Patients must not have received prior therapy with a TKI. Prior TKI usage in
    pheochromocytoma affects the same pathway as axitinib.

    2.1.2.10 Gastrointestinal abnormalities including:

    - Inability to take oral medications

    - Requirement for intravenous alimentation

    - Prior surgical procedure affecting absorption including total gastric resection

    - Treatment for active peptic ulcer disease in the past 6 months

    - Active gastrointestinal bleeding, unrelated to cancer, as evidenced by hematemesis,
    hematochezia or melena in the past 3 months without evidence of resolution documented
    by endoscopy or colonoscopy

    - Malabsorption syndrome

    2.1.2.11 Current use or anticipated need for treatment with drugs that are known potent
    CYP3A4 inhibitors (i.e., grapefruit juice, verapamil, ketoconazole, miconazole,
    itraconazole, erythromycin, telithromycin, clarithromycin, indinavir, saquinavir,
    ritonavir, nelfinavir, lopinavir, atazanavir, amprenavir, fosamprenavir, and delavirdine).

    2.1.2.12 Current use or anticipated need for treatment with drugs that are known CYP3A4 or
    CYP1A2 inducers (i.e., carbamazepine, dexamethasone, felbamate, omeprazole, phenobarbital,
    phenytoin, amobarbital, nevirapine, primidone, rifabutin, rifampin, and St. John s
    wort).

    2.1.2.13 Requirement of anticoagulant therapy with oral vitamin K antagonists. Low-dose
    anticoagulants for maintenance of patency of central venous access devices or prevention
    of deep venous thrombosis is allowed. Therapeutic use of low molecular weight heparin is
    allowed.

    2.1.2.14 Active seizure disorder or evidence of brain metastases, spinal cord compression,
    or carcinomatous meningitis.

    2.1.2.15 Any of the following within 12 months prior to study drug administration:
    myocardial infarction, uncontrolled angina, coronary/peripheral artery bypass graft,
    symptomatic congestive heart failure, cerebrovascular accident or transient ischemic
    attack and within 6 months before study drug administration for deep vein thrombosis or
    pulmonary embolism.

    2.1.2.16 Other severe acute or chronic medical or psychiatric condition, or laboratory
    abnormality that may increase the risk associated with study participation or study drug
    administration, or may interfere with the interpretation of study results, and in the
    judgment of the investigator would make the patient inappropriate for entry into this
    study

    Minimum Eligible Age: 18 Years

    Maximum Eligible Age: N/A

    Eligible Gender: Both

    Primary Outcome Measures

    Response rate

    Secondary Outcome Measures

    Progression- free survival.

    Examine the extent of activation of the VEGRF pathway inpheochromocytoma/paraganglioma using a semi-quantitativeimmunohistochemistry assay and examine the relationship withresponse to therapy

    Pharmacogenomics analyses

    Trial Keywords

    Mutation in SDHB gene

    Mutation in SDHV gene

    Mutation in VHL gene

    Pharmacogenomics analyses

    Germline DNA examination