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

STATUS

Recruiting
End date

Jan 22, 2024
participants needed

25
sponsor

Columbia University

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Updated on 22 October 2022

See if I qualify

platelet count

dopamine

absolute neutrophil count

amylase

metastatic disease

measurable disease

lipase

neutrophil count

immunohistochemistry

paraganglioma

dotatate

pheochromocytoma

vascular endothelial growth factor

iobenguane

experimental therapy

axitinib

dopa

ag-013736

transport proteins

adrenal pheochromocytoma

Summary

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.

Description

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.

Details

Condition	Pheochromocytoma, Paraganglioma
Treatment	Axitinib
Clinical Study Identifier	NCT03839498
Sponsor	Columbia University
Last Modified on	22 October 2022

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Eligibility		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 MIBG)
	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
	Prior therapeutic MIBG is allowed
	case of nitrosourea) prior to enrollment date; 2 weeks if the last therapy was
	Organ and marrow function as defined below
	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
	Amylase and lipase equal to, or less than, the institutional ULN
	and there must be sites of measurable disease that did not receive radiation
	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
	Ability to understand and sign an informed consent document
	Gilbert's Syndrome is less than 3 mg/dl
	Ability and willingness to follow the guidelines of the clinical protocol
	o 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
	Creatinine clearance ≥ 40 ml/min (estimated or measured creatinine clearance) or serum
	creatinine ≤ 1.6 mg/dl
	o 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
	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
	Pregnancy, due to the possible adverse effects on the developing fetus
	Patients with evidence of a bleeding diathesis
	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
	Malabsorption syndrome
	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
	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 must not have received prior therapy with a TKI. Prior TKI usage in
	pheochromocytoma affects the same pathway as axitinib
	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
	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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Phase II Study of Axitinib (AG-013736) With Evaluation of the VEGF-pathway in Metastatic, Recurrent or Primary Unresectable Pheochromocytoma/Paraganglioma