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

This study is currently recruiting participants. (see Contacts and Locations)
Verified August 2014 by National Institutes of Health Clinical Center (CC)
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )
ClinicalTrials.gov Identifier:
NCT01967576
First received: October 19, 2013
Last updated: September 9, 2014
Last verified: August 2014
  Purpose

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.
  • 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 DNA examination.

Eligibility:

  • Adults with a confirmed pathologic diagnosis of PHEO/PGL by the Laboratory of Pathology, NCI
  • Biochemical evidence of PHEO/PGL
  • Imaging confirmation of metastatic, locally advanced or unresectable disease.
  • Measurable disease at presentation
  • 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 BID) in eight-week cycles
  • Patients will be evaluated for response every eight weeks using 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

Condition Intervention Phase
Pheochromocytoma
Paraganglioma
Drug: Axitinib (AG-013736)
Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Phase II Study of Axitinib (AG-013736) With Evaluation of the VEGF-pathway in Metastatic, Recurrent or Primary Unresectable Pheochromocytoma/Paraganglioma

Resource links provided by NLM:


Further study details as provided by National Institutes of Health Clinical Center (CC):

Primary Outcome Measures:
  • Response rate [ Time Frame: 3 years ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Progression- free survival. [ Time Frame: 3 years ] [ Designated as safety issue: No ]
  • Examine the extent of activation of the VEGRF pathway inpheochromocytoma/paraganglioma using a semi-quantitativeimmunohistochemistry assay and examine the relationship withresponse to therapy [ Time Frame: 3 years ] [ Designated as safety issue: No ]
  • Pharmacogenomics analyses [ Time Frame: 3 years ] [ Designated as safety issue: No ]

Estimated Enrollment: 37
Study Start Date: October 2013
Estimated Study Completion Date: October 2016
Estimated Primary Completion Date: August 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Single Arm
Single Arm dose escalation study
Drug: Axitinib (AG-013736)
Axitinib will be given as self-administered oral doses at the initial level of 5 mg every 12 hours continuously in a 28-day cycle. All patients will be evaluated for dose escalation beginning at week 4. In addition to the starting dose level of 5 mg every 12 hours, two additional levels (7 and 10 mg on every-12-hour schedules) will be considered. An interval of at least 4 weeks must elapse between any dose escalations.

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.
  • 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 DNA examination.

Eligibility:

  • Adults with a confirmed pathologic diagnosis of PHEO/PGL by the Laboratory of Pathology, NCI
  • Biochemical evidence of PHEO/PGL
  • Imaging confirmation of metastatic, locally advanced or unresectable disease.
  • Measurable disease at presentation
  • 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 BID) in eight-week cycles
  • Patients will be evaluated for response every eight weeks using 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
  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria
  • INCLUSION CRITERIA

2.1.1 Adults with a confirmed pathologic diagnosis of pheochromocytoma/paraganglioma by the Laboratory of Pathology, NCI when such tissue is available to confirm or

In the event that outside tissue is not available:

  • an outside pathology report confirms the diagnosis of Pheo-PGI, 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)

2.1.1.2 Imaging confirmation of metastatic disease

2.1.1.3 Measurable disease at the time of enrollment.

2.1.1.4 A life expectancy of at least 3 months and ECOG performance status less than or equal to 2

2.1.1.5 Age greater than or equal to 18 years

2.1.1.6 Information available or pending regarding possible genetic alterations that can explain the patient s pheochromocytoma/paraganglioma (mutations in SDHB, SDHV or VHL genes)

2.1.1.7 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

2.1.1.8 Last radiotherapy treatment greater than or equal to 4 weeks prior to starting treatment with this protocol and there must be sites of measurable disease that did not receive radiation

2.1.1.9 Prior therapeutic MIBG is allowed

2.1.1.10 Organ and marrow function as defined below:

2.1.1.11 Total bilirubin less than or equal to 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.

2.1.1.12 AST less than or equal to 2.5 x ULN, ALT less than or equal to 2.5 x ULN

2.1.1.13 Amylase and lipase equal to, or less than, the institutional ULN.

2.1.1.14 Creatinine clearance (Bullet) 40 ml/min (estimated or measured creatinine clearance) or serum creatinine 1.6 mg/dl

Note: Random urine protein < 20 mg/dL. If greater than or equal to 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

2.1.1.15 Absolute neutrophil count greater than or equal to 500/mm(3)

2.1.1.16 Platelet count greater than or equal to 50,000/ mm(3)

2.1.1.17 Ability to understand and sign an informed consent document.

2.1.1.18 Ability and willingness to follow the guidelines of the clinical protocol including visits to NICHD and NCI, Bethesda, Maryland for treatment and follow up visits.

2.1.1.19 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.

EXCLUSIONCRITERIA

2.1.2.1 Patients with pheochromocytoma/paraganglioma tumors potentially curable by surgical excision alone as determined by the Principal Investigator in discussions with the surgical consultants

2.1.2.2 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.

2.1.2.3 Unstable hypertension defined as a systolic blood pressure > 150 mm Hg or diastolic pressure > 90 mmHg despite optimal medical management.

2.1.2.4 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.

2.1.2.5 Pregnancy, due to the possible adverse effects on the developing fetus.

2.1.2.6 Lactating women who are breast-feeding due to the possibility of transmitting axitinib to the child.

2.1.2.7 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.

2.1.2.8 Patients with evidence of a bleeding diathesis

2.1.2.9 Patients must not have received prior therapy with a TKI. Prior TKI usage in pheochromocytoma affects the same pathway as axitinib.

2.1.2.10 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

2.1.2.11 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).

2.1.2.12 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).

2.1.2.13 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.

2.1.2.14 Active seizure disorder or evidence of brain metastases, spinal cord compression, or carcinomatous meningitis.

2.1.2.15 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.

2.1.2.16 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

  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01967576

Contacts
Contact: Maureen E Edgerly, R.N. (301) 435-5604 edgerlym@pbmac.nci.nih.gov
Contact: Antonio T Fojo, M.D. (301) 496-2831 fojot@mail.nih.gov

Locations
United States, Maryland
National Institutes of Health Clinical Center, 9000 Rockville Pike Recruiting
Bethesda, Maryland, United States, 20892
Contact: For more information at the NIH Clinical Center contact National Cancer Institute Referral Office    888-624-1937      
Sponsors and Collaborators
Investigators
Principal Investigator: Antonio T Fojo, M.D. National Cancer Institute (NCI)
  More Information

Additional Information:
Publications:
Responsible Party: National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )
ClinicalTrials.gov Identifier: NCT01967576     History of Changes
Other Study ID Numbers: 140001, 14-C-0001
Study First Received: October 19, 2013
Last Updated: September 9, 2014
Health Authority: United States: Federal Government

Keywords provided by National Institutes of Health Clinical Center (CC):
Mutation in SDHB gene
Mutation in SDHV gene
Mutation in VHL gene
Pharmacogenomics analyses
Germline DNA examination

Additional relevant MeSH terms:
Pheochromocytoma
Paraganglioma
Neuroendocrine Tumors
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Nerve Tissue
Axitinib
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions

ClinicalTrials.gov processed this record on September 18, 2014