AzTrials
AzTrials

PheochromocytomaPhase 2NCT01967576

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

A Phase 2 study testing Axitinib (AG-013736) in people with Pheochromocytoma and Paraganglioma, run by National Cancer Institute (NCI) at 1 site in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
Search all trials

Trial 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%… Read more about this study

Who is it for?
Ages 18 to 100 years
Conditions the study is for
Pheochromocytoma, Paraganglioma
What is being tested?
Axitinib (AG-013736)
Could I receive a placebo?
No, everyone receives an active treatment
How many people
14 participants
Where
1 siteUnited States
Study dates
19 Oct 2013to 1 Dec 2020
Phase
Phase 2
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 to 100 years
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 2.1.1 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))
  • 2.1.1.1 Imaging confirmation of metastatic disease
  • 2.1.1.2 Measurable disease at the time of enrollment per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1.
Show all 24Show fewer
  • 2.1.1.3 A life expectancy of at least 3 months and Eastern Cooperative Oncology Group (ECOG) performance status less than or equal to 2
  • 2.1.1.4 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.
  • 2.1.1.5 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)
  • 2.1.1.6 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
  • 2.1.1.7 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
  • 2.1.1.8 Prior therapeutic Metaiodobenzylguanidine (MIBG) is allowed
  • 2.1.1.9 Organ and marrow function as defined below:
  • 2.1.1.10 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.
  • 2.1.1.11 Aspartate aminotransferase (AST) less than or equal to 2.5 x ULN, alanine aminotransferase (ALT) less than or equal to 2.5 x ULN
  • 2.1.1.12 Amylase and lipase equal to, or less than, the institutional ULN.
  • 2.1.1.13 Creatinine clearance greater than or equal to 40 ml/min (estimated or measured creatinine clearance) or serum creatinine less than or equal to 1.6 mg/dl
  • 2.1.1.14 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 National Institute of Child Health and Human Development (NICHD) and National Cancer Institute (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.

Who cannot join

  • 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.
Show all 22Show fewer
  • 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 tyrosine kinase inhibitor (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 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).
  • 2.1.2.12 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).
  • 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

Trial locations and contacts

1 site in 1 country.

United States1 site

  • National Institutes of Health Clinical Center, 9000 Rockville Pike

    Bethesda, Maryland, 20892

Other trials in United States

About this study

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.
Read more

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
Read the 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.
  • 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 twelve weeks (+/- 1 week) using Response Evaluation Criteria in Solid Tumors (RECIST) criteria
  • Approximately 12 to 37 patients will be needed to achieve the objectives of the trial
Being tested
Axitinib (AG-013736)
Keywords
Mutation in SDHB gene, Mutation in SDHV gene, Mutation in VHL gene, Pharmacogenomics analyses, Germline DNA examination
Medical subject headings
Pheochromocytoma, Paraganglioma

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Axitinib (AG-013736)Drug

    Also called INLYTA

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

Study groups in NCT01967576
Study groupRoleWhat they receive
1/Arm 1-AxitinibExperimentalAxitinib 5 mg twice a day on a 28-day cycle
Receives: Drug: Axitinib (AG-013736)

What is being measured

The primary outcome is the main question the study is designed to answer.

  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).

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

Secondary outcomes (5)

  1. Progression - Free Survival (PFS)

    PFS is defined as the duration of time from start of treatment to time of progression or death, whichever comes first. Disease progression was assessed by the Response Evaluation Criteria in Solid Tumors (RECIST) and is defined as 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). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progressions).

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

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

    The measurement of VEGFR in blood will be performed using a semi-quantitative immunohistochemistry assay.

    Measured: up to 3 years

  3. Pharmacogenomics Analyses

    Measuring genetic alterations.

    Measured: up to 3 years

  4. Change From Baseline in Plasma Levels of Axitinib

    Pharmacokinetic analysis will be done to determine drug levels in blood.

    Measured: Baseline and 3 years

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

    Here is the count of participants with serious and non-serious adverse events assessed by the Common Terminology Criteria in Adverse Events (CTCAE v4.0). A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned.

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

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted23 Oct 2013 (estimated)
  2. Study start19 Oct 2013
  3. Primary completion29 Jun 2015
  4. Study completion1 Dec 2020

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
14 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT01967576
Sponsor's protocol ID
140001
Other IDs
14-C-0001
Status last verified
Dec 2020
First submitted
19 Oct 2013
Last updated
6 Jan 2021
Data monitoring committee
No
FDA-regulated drug
Yes
FDA-regulated device
No
Individual data sharing
No

Publications

  • 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.

    PubMed 1988766

  • 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.

    PubMed 11182843

  • 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.

    PubMed 1787652

  • 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.

    PubMed 26040622

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Axitinib (AG-013736) in people with Pheochromocytoma and Paraganglioma, run by National Cancer Institute (NCI) at 1 site in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 24 inclusion and 22 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 6 Jan 2021. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 31 Aug 2020). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Number of Participants With Clinical Response (Partial Response + Complete Response) (time frame: Patients were assessed every 12 weeks (+/- week) up to 40.6 months). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT01967576, which also lists 4 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 6 Jan 2021.

AzTrials uses cookies for analytics and advertising. You can accept or reject them; the site works either way. Privacy Policy.

Free account

Log in to keep searching

You’ve used your 3 free searches. AzTrials is free: log in or create a free account to keep searching clinical trials and save the ones you want to follow.

Create a free accountLog in