Phase II Study of Axitinib (AG-013736) With Evaluation of the VEGF-pathway in Metastatic, Recurrent or Primary Unresectable Pheochromocytoma/Paraganglioma
Condition: Pheochromocytoma; Paraganglioma
MeSH terms: Pheochromocytoma; Paraganglioma
Intervention: Axitinib (AG-013736)
Intervention description: 5 mg twice a day on a 28-day cycle.
Intervention MeSH terms: Axitinib
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 14.0
Sex: All
Minimum age: 18 Years
Maximum age: 100 Years
Healthy volunteers: No
Keywords: Mutation in SDHB gene; Mutation in SDHV gene; Mutation in VHL gene; Pharmacogenomics analyses; Germline DNA examination

Summary:

      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.

        -  Vascular endothelial growth factor (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 deoxyribonucleic acid (DNA) examination.

      Eligibility:

        -  Adults with a confirmed pathologic diagnosis of PHEO/PGL by the Laboratory of Pathology,
           National Cancer Institute (NCI)

        -  Biochemical evidence of PHEO/PGL

        -  Imaging confirmation of metastatic, locally advanced or unresectable disease.

        -  Measurable disease at presentation

        -  Eastern Cooperative Oncology Group (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
           twice a day (BID)) in eight-week cycles

        -  Patients will be evaluated for response every eight weeks using Response Evaluation
           Criteria in Solid Tumors (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
    

Eligibility criteria:

        -  INCLUSION CRITERIA

        2.1.1 Adults with a confirmed pathologic diagnosis of pheochromocytoma/paraganglioma by the
        Laboratory of Pathology, National Cancer Institute (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 (Fluorodopa (F-DOPA), Dotatate, F-Dopamine
             or Metaiodobenzylguanidine (MIBG))

        2.1.1.1 Imaging confirmation of metastatic disease

        2.1.1.2 Measurable disease at the time of enrollment per Response Evaluation Criteria in
        Solid Tumors (RECIST) 1.1.

        2.1.1.3 A life expectancy of at least 3 months and Eastern Cooperative Oncology Group
        (ECOG) performance status less than or equal to 2

        2.1.1.4 Age greater than or equal to 18 years. Because no dosing or adverse event data are
        currently available on the use of Axitinib in patients <18 years of age, children are
        excluded from this study, but will be eligible for future pediatric trials.

        2.1.1.5 Information available or pending regarding possible genetic alterations that can
        explain the patient's pheochromocytoma/paraganglioma (mutations in succinate
        dehydrogenase-B (SDHB), SDHV or Von Hippel-Lindau (VHL) genes)

        2.1.1.6 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 Investigational New Drug (IND) trial. Last surgery more
        than 4 weeks prior to enrollment, to allow for wound healing. Core biopsies or fine needle
        aspiration (FNA) will not require any waiting period

        2.1.1.7 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

        2.1.1.8 Prior therapeutic Metaiodobenzylguanidine (MIBG) is allowed

        2.1.1.9 Organ and marrow function as defined below:

        2.1.1.10 Total bilirubin less than or equal to 1.5 x upper limit of normal (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 complete blood count
        (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.

        2.1.1.11 Aspartate aminotransferase (AST) less than or equal to 2.5 x ULN, alanine
        aminotransferase (ALT) less than or equal to 2.5 x ULN

        2.1.1.12 Amylase and lipase equal to, or less than, the institutional ULN.

        2.1.1.13 Creatinine clearance greater than or equal to 40 ml/min (estimated or measured
        creatinine clearance) or serum creatinine less than or equal to 1.6 mg/dl

        2.1.1.14 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 National Institute of Child Health and Human Development (NICHD) and
        National Cancer Institute (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.

        EXCLUSION CRITERIA

        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 tyrosine kinase inhibitor
        (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
        Cytochrome P450 3A4 (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
        Cytochrome P450 1A2, (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