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

NCT01967576 | Completed Phase 2 Results FDA Drug

• 2 other identifiers: 14000114-C-0001
• Study Type: interventional
• Target: 14
• Locations: 1 country
• Sites: 1

Brief 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

Conditions

Pheochromocytoma; Paraganglioma

Keywords

Mutation in SDHB gene; Mutation in SDHV gene; Mutation in VHL gene; Pharmacogenomics analyses; Germline DNA examination

Outcome Measures

Primary Outcomes (1)

• Number of Participants With Clinical Response (Partial Response + Complete Response)

  Response was assessed by the Response Evaluation Criteria in Solid Tumors (RECIST). Partial Response (PR) is at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters. Complete Response (CR) is disappearance of all target lesions. Any pathological lymph nodes (whether target or no-target) must have reduction in short axis to \<10 mm. Stable Disease (SD) is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. Progressive Disease (PD) is at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study).

  Patients were assessed every 12 weeks (+/- week) up to 40.6 months

Secondary Outcomes (5)

• Progression - Free Survival (PFS)

  time from start of treatment to time of progression or death, up to 5 years and 9 months

• Change in Vascular Endothelial Growth Factor Receptors (VEGFR) in Blood in Metastatic, Recurrent or Primary Unresectable Pheochromocytoma/Paraganglioma

  up to 3 years

• Pharmacogenomics Analyses

  up to 3 years

• Change From Baseline in Plasma Levels of Axitinib

  Baseline and 3 years

• Number of Participants With Serious and Non-serious Adverse Events Assessed by the Common Terminology Criteria in Adverse Events (CTCAE v4.0)

  Date treatment consent signed to date off study, approximately 54 months and 29 days.

Study Arms (1)

1/Arm 1-Axitinib

EXPERIMENTAL

Axitinib 5 mg twice a day on a 28-day cycle

Drug: Axitinib (AG-013736)

Interventions

Axitinib (AG-013736) DRUG

5 mg twice a day on a 28-day cycle.

Also known as: INLYTA

1/Arm 1-Axitinib

Eligibility Criteria

• Age: 18 Years - 100 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Adults with a confirmed pathologic diagnosis of pheochromocytoma/paraganglioma by the Laboratory of Pathology, National Cancer Institute (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 (Fluorodopa (F-DOPA), Dotatate, F-Dopamine or Metaiodobenzylguanidine (MIBG))
• Imaging confirmation of metastatic disease
• Measurable disease at the time of enrollment per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1.
• A life expectancy of at least 3 months and Eastern Cooperative Oncology Group (ECOG) performance status less than or equal to 2
• Age greater than or equal to 18 years. Because no dosing or adverse event data are currently available on the use of Axitinib in patients \<18 years of age, children are excluded from this study, but will be eligible for future pediatric trials.
• Information available or pending regarding possible genetic alterations that can explain the patient's pheochromocytoma/paraganglioma (mutations in succinate dehydrogenase-B (SDHB), SDHV or Von Hippel-Lindau (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 Investigational New Drug (IND) trial. Last surgery more than 4 weeks prior to enrollment, to allow for wound healing. Core biopsies or fine needle aspiration (FNA) will not require any waiting period
• 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
• Prior therapeutic Metaiodobenzylguanidine (MIBG) is allowed
• Organ and marrow function as defined below:
• Total bilirubin less than or equal to 1.5 x upper limit of normal (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 complete blood count (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.

You may not qualify if:

• 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 6 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 two years can be enrolled in this study.
• Patients with evidence of a bleeding diathesis
• Patients must not have received prior therapy with a tyrosine kinase inhibitor (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

Sponsors & Collaborators

• National Cancer Institute (NCI): lead

Study Sites (1)

National Institutes of Health Clinical Center, 9000 Rockville Pike

Bethesda, Maryland, 20892, United States

Location

Related Publications (4)

• Stein PP, Black HR. A simplified diagnostic approach to pheochromocytoma. A review of the literature and report of one institution's experience. Medicine (Baltimore). 1991 Jan;70(1):46-66. doi: 10.1097/00005792-199101000-00004.

  PMID: 1988766 BACKGROUND

• Pacak K, Linehan WM, Eisenhofer G, Walther MM, Goldstein DS. Recent advances in genetics, diagnosis, localization, and treatment of pheochromocytoma. Ann Intern Med. 2001 Feb 20;134(4):315-29. doi: 10.7326/0003-4819-134-4-200102200-00016.

  PMID: 11182843 BACKGROUND

• Bravo EL. Pheochromocytoma: new concepts and future trends. Kidney Int. 1991 Sep;40(3):544-56. doi: 10.1038/ki.1991.244. No abstract available.

  PMID: 1787652 BACKGROUND

• Burotto M, Edgerly M, Poruchynsky M, Velarde M, Wilkerson J, Kotz H, Bates S, Balasubramaniam S, Fojo T. Phase II Clinical Trial of Ixabepilone in Metastatic Cervical Carcinoma. Oncologist. 2015 Jul;20(7):725-6. doi: 10.1634/theoncologist.2015-0104. Epub 2015 Jun 3.

  PMID: 26040622 DERIVED

Related Links

• NIH Clinical Center Detailed Web Page

MeSH Terms

Conditions

Pheochromocytoma; Paraganglioma

Interventions

Axitinib

Condition Hierarchy (Ancestors)

Neuroendocrine Tumors; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Nerve Tissue

Intervention Hierarchy (Ancestors)

Benzamides; Amides; Organic Chemicals; Benzoates; Acids, Carbocyclic; Carboxylic Acids; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Indazoles; Pyrazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring

Results Point of Contact

• Title: Dr. Andrea Apolo
• Organization: National Cancer Institute

apoloab@nih.gov

301-480-0536

Study Officials

• Andrea B Apolo, M.D.

  National Cancer Institute (NCI)

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: NIH
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: October 19, 2013
• First Posted: October 23, 2013
• Study Start: October 19, 2013
• Primary Completion: June 29, 2015
• Study Completion: December 1, 2020
• Last Updated: January 6, 2021
• Results First Posted: August 31, 2020

Record last verified: 2020-12

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)