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
Study type: Interventional
Phase: Phase 2

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
    

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.

        -  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 twelve weeks (+/- 1 week) using Response
           Evaluation Criteria in Solid Tumors (RECIST) criteria

        -  Approximately 12 to 37 patients will be needed to achieve the objectives of the trial
    

Intervention name(s): Axitinib (AG-013736)
Intervention type(s): Drug
Intervention description(s): 5 mg twice a day on a 28-day cycle.
Other intervention name(s): INLYTA
Intervention MeSH terms: Axitinib
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Mutation in SDHB gene; Mutation in SDHV gene; Mutation in VHL gene; Pharmacogenomics analyses; Germline DNA examination