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

Completed · Phase 2

Conditions studied: Pheochromocytoma, Paraganglioma

In brief

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

Key facts

Study ID

NCT01967576

Run by

National Cancer Institute (NCI)

People needed

14

Starts

2013-10-19

Expected to finish

2020-12-01

Last updated by the study team

2021-01-06

Who can join

Age: 18 and older, up to 100. Sex: any. Healthy volunteers: not accepted.

You may not qualify if…

• 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
• 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.
• 1.2.3 Unstable hypertension defined as a systolic blood pressure >150 mm Hg or diastolic pressure > 90 mmHg despite optimal medical management.
• 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.
• 1.2.5 Pregnancy, due to the possible adverse effects on the developing fetus.
• 1.2.6 Lactating women who are breast-feeding due to the possibility of transmitting axitinib to the child.
• 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.
• 1.2.8 Patients with evidence of a bleeding diathesis
• 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.
• 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
• 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).
• 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).
• 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.
• 1.2.14 Active seizure disorder or evidence of brain metastases, spinal cord compression, or carcinomatous meningitis.
• 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.
• 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

Where it is running

• National Institutes of Health Clinical Center, 9000 Rockville Pike — Bethesda, Maryland, United States

Full record on ClinicalTrials.gov

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