Pazopanib Hydrochloride in Treating Patients With Advanced or Progressive Malignant Pheochromocytoma or Paraganglioma
Condition: Extra-Adrenal Paraganglioma; Metastatic Adrenal Gland Pheochromocytoma; Paraganglioma; Recurrent Adrenal Gland Pheochromocytoma
MeSH terms: Pheochromocytoma; Paraganglioma; Paraganglioma, Extra-Adrenal
Intervention: Laboratory Biomarker Analysis; Pazopanib Hydrochloride
Intervention description: Correlative studies; Given PO
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 7.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

Summary:

      This phase II trial studies how well pazopanib hydrochloride works in treating patients with
      advanced or progressive malignant pheochromocytoma or paraganglioma. Pazopanib hydrochloride
      may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth and
      by blocking blood flow to the tumor.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Histologically or cytologically confirmed malignant secretory or non-secretory
             pheochromocytoma or paraganglioma that is unresectable and deemed inappropriate for
             alternative local regional therapeutic approaches

          -  Objective evidence of tumor progression =< 185 days prior to registration as assessed
             by:

               -  Unequivocal progression of objectively measured disease on successive appropriate
                  imaging (e.g. computed tomography [CT] scan); in cases of uncertainty of tumor
                  progression, the principal investigator of the study will be available to assist
                  in decisions

          -  Measurable disease defined as:

               -  At least one non-nodal lesion whose longest diameter can be accurately measured
                  as >= 2.0 cm with chest x-ray, or as >= 1.0 cm with CT scan, CT component of a
                  positron emission tomography (PET)/CT, or magnetic resonance imaging (MRI);
                  and/or

               -  A lymph node whose short axis must be > 1.5 cm when assessed by CT scan (CT scan
                  slice thickness recommended to be no greater than 5 mm)

               -  Note: Tumor lesions in a previously irradiated area are not considered measurable
                  disease

          -  Life expectancy > 24 weeks

          -  Eastern Cooperative Oncology Group (ECOG) performance status =< 2

          -  Leukocytes >= 3,000/uL

          -  Absolute neutrophil count >= 1,500/uL

          -  Platelets >= 100,000/uL

          -  Hemoglobin >= 9 g/dL (5.6 mmol/L); transfusions not permitted =< 7 days of
             registration

          -  Total bilirubin =< 1.5 x institutional upper limit of normal (ULN) (except in cases of
             Gilbert's syndrome, where indirect bilirubin may be elevated, but the direct bilirubin
             remains within 1.5 x ULN)

          -  Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase
             [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
             =< 2.5 x ULN

          -  NOTE: Subjects who have both bilirubin > ULN and AST/ALT > ULN are not eligible

          -  Alkaline phosphatase =< 2.5 x ULN

          -  Creatinine =< 1.5 mg/dL (133 umol/L) or within normal institutional limits OR
             creatinine clearance >= 50 mL/min/1.73m^2 for subjects with creatinine levels about
             institutional normal

          -  Urine protein/creatinine ratio =< 1 OR 24-hour urine < 1 gram

          -  Prothrombin time (PT)/international normalized ratio (INR)/partial thromboplastin time
             (PTT) =< 1.2 x ULN unless a subject is receiving Coumadin and has stable INR which is
             in range for the desired level of anticoagulation

          -  Blood pressure (BP) < 140 mmHg (systolic) and < 90 mmHg (diastolic); initiation or
             adjustment of BP medication is permitted prior to registration provided that the
             average of three BP readings at a visit prior to registration is < 140/90 mmHg

               -  NOTE: All patients with secretory pheochromocytomas or paragangliomas are
                  required to: 1) be evaluated in consultation by a hypertension specialist (at the
                  registering institution) with experience in the management of hypertension in the
                  setting of catecholamine-secreting tumors (usually an endocrinologist,
                  nephrologist, or a cardiologist), and in the setting of hormone-associated
                  hypertension 2) receive alpha- and beta-adrenergic blockade for at least 7 days
                  prior to initiation of pazopanib (GW786034); the hypertension specialist of
                  record for each patient should be committed to following the patient during the
                  clinical study with evaluation by said specialist required at all run-in cycle
                  evaluations (cycles 1 and 2) and also after the first continuous dosing cycle
                  (cycle 3) and thereafter on an as needed basis

          -  Negative serum pregnancy test done =< 7 days prior to registration, for women of
             childbearing potential only

          -  Ability to understand and the willingness to sign a written informed consent document

          -  Willingness to donate blood and tissue for correlative marker studies

        Exclusion Criteria:

          -  Any of the following:

               -  Pregnant women

               -  Nursing women

               -  Men or women of childbearing potential who are unwilling to employ adequate
                  contraception NOTE: breastfeeding should be discontinued if the mother is treated
                  with pazopanib (GW786034)

          -  Any of the following:

               -  Chemotherapy/systemic therapy =< 4 weeks prior to registration

               -  Radiotherapy =< 4 weeks prior to registration

               -  Surgery =< 4 weeks prior to registration

               -  Nitrosoureas or mitomycin C =< 6 weeks prior to registration

               -  Those who have not recovered from adverse events due to agents administered more
                  than 4 weeks earlier NOTE: Concurrent therapy with octreotide is allowed
                  providing that tumor progression on this therapy has been demonstrated;
                  concurrent therapy with bisphosphonates (e.g. zoledronic acid) or denosumab is
                  also allowed.

        NOTE: An unlimited number of prior chemotherapeutic or biologic therapies for malignant
        pheochromocytoma or paraganglioma is permitted; this includes prior anti-angiogenesis
        therapies such as tyrosine kinase inhibitors

          -  Any other ongoing investigational agents

          -  History of allergic reactions attributed to compounds of similar chemical or biologic
             composition to pazopanib (GW786034) or other agents used in the study

          -  Any of the following:

               -  Corrected QT (QTc) prolongation (defined as a QTc interval >= 500 msecs)

               -  Left ventricular ejection fraction (LVEF) < institutional lower limit of normal
                  (LLN)

               -  Frequent ventricular ectopy

               -  Evidence of ongoing myocardial ischemia

          -  Receiving prohibited cytochrome P450 (CYP) interactive concomitant medications within
             7 days prior to registration

          -  Any condition (e.g., gastrointestinal tract disease resulting in an inability to take
             oral medication or a requirement for intravenous (IV) alimentation, prior surgical
             procedures affecting absorption, or active peptic ulcer disease) that impairs their
             ability to swallow and retain pazopanib (GW786034)

          -  Receiving any medications or substances with risk of torsades de pointes; note:
             medications or substances with risk of torsades de pointes are prohibited; medications
             or substances with possible or conditional risk of torsades de pointes may be used
             while on study with extreme caution and careful monitoring; patients receiving these
             later cautionary agents must be monitored serially with electrocardiogram (ECG) weekly
             during the run-in and first cycle of therapy and at each evaluation thereafter NOTE:
             These medications should be discontinued or replaced with drugs that do not carry
             these risks, if possible

          -  Any of the following conditions:

               -  Active peptic ulcer disease

               -  Known intraluminal bowel metastatic lesions

               -  Inflammatory bowel disease (e.g., ulcerative colitis, Crohn's disease) or other
                  gastrointestinal conditions which increase the risk of perforation

               -  History of new abdominal fistula, gastrointestinal perforation or intra-abdominal
                  abscess =< 84 days prior to registration; enrollment of patients with
                  chronic/canalized fistulous tracts (present for > 84 days) is allowed

               -  Serious or non-healing wound, ulcer, or bone fracture

               -  History of familial QTc prolongation syndrome

          -  Any of the following conditions =< 185 days prior to registration:

               -  Cerebrovascular accident (CVA) or transient ischemic attack (TIA)

               -  Cardiac arrhythmia

               -  Admission for unstable angina

               -  Cardiac angioplasty or stenting

               -  Coronary artery bypass graft surgery

               -  Pulmonary embolism, untreated deep venous thrombosis (DVT) or DVT which has been
                  treated with therapeutic anticoagulation < 42 days

               -  Arterial thrombosis

               -  Symptomatic peripheral vascular disease

               -  Class III or IV heart failure as defined by the New York Heart Association (NYHA)
                  functional classification system

          -  Hemoptysis in excess of 2.5 mL (1/2 teaspoon) =< 60 days prior to registration

          -  Any of the following:

               -  Known active and/or untreated brain metastases

               -  Brain metastases requiring ongoing therapy (e.g. corticosteroids)

          -  Uncontrolled intercurrent illness including, but not limited to, ongoing or active
             infection or psychiatric illness/social situations that would limit compliance with
             study requirements

          -  Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral
             therapy

          -  Require heparin other than low-molecular weight heparin

          -  Prior use of pazopanib (GW786034)