Phase II Study of Axitinib (AG-013736) With Evaluation of the VEGF-pathway in Metastatic, Recurrent or Primary Unresectable Pheochromocytoma/Paraganglioma
- Registration Number
- NCT01967576
- Lead Sponsor
- National Cancer Institute (NCI)
- 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
- 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
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 14
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SINGLE_GROUP
- Arm && Interventions
Group Intervention Description 1/Arm 1-Axitinib Axitinib (AG-013736) Axitinib 5 mg twice a day on a 28-day cycle
- Primary Outcome Measures
Name Time Method Number of Participants With Clinical Response (Partial Response + Complete Response) Patients were assessed every 12 weeks (+/- week) up to 40.6 months 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).
- Secondary Outcome Measures
Name Time Method Progression - Free Survival (PFS) time from start of treatment to time of progression or death, up to 5 years and 9 months 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).
Pharmacogenomics Analyses up to 3 years Measuring genetic alterations.
Change From Baseline in Plasma Levels of Axitinib Baseline and 3 years Pharmacokinetic analysis will be done to determine drug levels in blood.
Change in Vascular Endothelial Growth Factor Receptors (VEGFR) in Blood in Metastatic, Recurrent or Primary Unresectable Pheochromocytoma/Paraganglioma up to 3 years The measurement of VEGFR in blood will be performed using a semi-quantitative immunohistochemistry assay.
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. 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.
Trial Locations
- Locations (1)
National Institutes of Health Clinical Center, 9000 Rockville Pike
🇺🇸Bethesda, Maryland, United States