Study of Axitinib (AG-013736) With Evaluation of the VEGF-pathway in Pheochromocytoma/Paraganglioma

  • End date
    Jan 14, 2024
  • participants needed
  • sponsor
    Columbia University
Updated on 7 February 2022
platelet count
absolute neutrophil count
metastatic disease
measurable disease
neutrophil count
vascular endothelial growth factor
experimental therapy
transport proteins
adrenal pheochromocytoma


Primary Objective:

To determine the response rate (RR) of metastatic or locally advanced pheochromocytoma/paraganglioma to axitinib administered daily.

Secondary Objectives:

  • Determine the progression-free survival.
  • In an exploratory manner examine the extent of activation of the VEGFR pathway in pheochromocytoma/paraganglioma using a semi-quantitative immunohistochemistry assay and examine the relationship with response to therapy.
  • Perform pharmacogenomics analyses of drug metabolism and transport proteins through germline DNA examination.


The long-term survival for malignant pheochromocytoma/paraganglioma (PHEO/PGL) may be limited because of its hormonal effects as well as its aggressive behavior and dissemination, particularly in some hereditary PHEO/PGL. Although several therapeutic modalities have been used to palliate malignant PHEO/PGL, a continued search for new agents to address the malignancy is needed to improve outcomes. One approach is to utilize drugs that target signaling pathways leading to decreased proliferation and survival of cancer cells. Some data in the literature suggests that in malignant PHEO/PGL, VEGF seems to play a role in the biology of the cancer and thus, its inhibition could reduce tumor growth. Sunitinib and imatinib has been used in a limited number of malignant pheochromocytomas with varying responses. Axitinib was designed to inhibit VEGFR that participates in tumor angiogenesis. In order to determine the activity of axitinib in tumor and hormonal responses in malignant PHEO/PGL, it will be used as a single agent in this study. The combination of cyclophosphamide; vincristine and dacarbazine have been shown to produce partial responses in malignant PHEO/PGL. The majority of the patients may have already received this combination or will receive this combination chemotherapy in the future. The goal is to develop multiple lines of effective treatments for this disease.

Condition Pheochromocytoma, Paraganglioma
Treatment Axitinib
Clinical Study IdentifierNCT03839498
SponsorColumbia University
Last Modified on7 February 2022


Yes No Not Sure

Inclusion Criteria

Adults with a confirmed pathologic diagnosis of pheochromocytoma/paraganglioma
by a CUMC/NYPH laboratory when such tissue is available to confirm
In the event that outside tissue is not available
An outside pathology report confirms the diagnosis of Pheo/PGL, 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
Imaging confirmation of metastatic disease
Measurable disease at the time of enrollment as per RECIST 1.1
A life expectancy of at least 3 months and ECOG performance status 2
Age 18 years
Information available or pending regarding possible genetic alterations that can explain the patient's pheochromocytoma/paraganglioma (mutations in SDHB, SDHV or VHL genes)
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
Last radiotherapy treatment 4 weeks prior to starting treatment with this protocol and there must be sites of measurable disease that did not receive radiation
Prior therapeutic MIBG is allowed
Organ and marrow function as defined below
Total bilirubin 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
AST 2.5 x ULN, ALT 2.5 x ULN
Amylase and lipase equal to, or less than, the institutional ULN
Creatinine clearance 40 ml/min (estimated or measured creatinine clearance) or serum creatinine 1.6 mg/dl
Random urine protein < 20 mg/dL. If 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
Absolute neutrophil count 500/mm3
Platelet count 50,000/ mm3
Ability to understand and sign an informed consent document
Ability and willingness to follow the guidelines of the clinical protocol
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

Patients with pheochromocytoma/paraganglioma tumors potentially curable by surgical excision alone as determined by the Principal Investigator in discussions with the surgical consultants
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
Unstable hypertension defined as a systolic blood pressure >150 mm Hg or diastolic pressure > 90 mmHg despite optimal medical management
Untreated brain metastases (or local treatment of brain metastases within the last 3 months) due to the poor prognosis of these patients and difficulty ascertaining the cause of neurologic adverse events
Pregnancy, due to the possible adverse effects on the developing fetus
Lactating women who are breast-feeding due to the possibility of transmitting axitinib to the child
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 one year can be enrolled in this study
Patients with evidence of a bleeding diathesis
Patients must not have received prior therapy with a TKI. Prior TKI usage in pheochromocytoma affects the same pathway as axitinib
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
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)
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)
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
Active seizure disorder or evidence of brain metastases, spinal cord compression, or carcinomatous meningitis
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
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
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