Paraganglioma, Pheochromocytoma
Conditions
Keywords
PARAGANGLIOMA, PHEOCHROMOCYTOMA, SUNITINIB, PHASE II, Metastatic or locally advanced malignant paraganglioma, Metastatic or locally advanced malignant pheochromocytoma
Brief summary
This is an open-label phase II study of an investigational drug, sunitinib malate in patients with advanced malignant paraganglioma or phaeochromocytoma cancer. Paragangliomas (PGs) are tumours that arise from the para-sympathetic system in the head and neck and sympathetic system in the thorax and abdomen. Paragangliomas that secrete hormones (catecholamines) from the adrenal glands are called pheochromocytomas (PCs). In this study, patients whose disease has advanced or spread despite prior standard therapy, will receive sunitinib for 4-weeks followed by a 2-week rest period, for up to 12 months, in the absence of disease progression. Sunitinib is an investigational drug, which has been shown to shrink tumours in several tumour models. The study will evaluate the efficacy as well as the toxicity profile of sunitinib when used as an alternative treatment for patients with PG/PC tumours.
Detailed description
This study will be a single arm, open-label, phase II trial of sunitinib in patients with metastatic or locally advanced malignant paraganglioma or phaeochromocytoma. Oral sunitinib (50 mg) will be administered to all patients daily for the first four weeks of a six week study cycle, followed by a 2-week rest. Patients will be assessed for response to study treatment using MRI/CT scans as well as bio-chemical tests, and will receive the study treatment for up to 12 months or until disease progression. Primary study outcomes include: To assess the efficacy (response rate) of sunitinib given orally daily for 4 out of every 6 weeks in patients with advanced or metastatic paraganglioma/ pheochromocytoma. To assess the toxicity of sunitinib in patients with advanced or metastatic paraganglioma/ pheochromocytoma. To document effects of sunitinib on markers of biochemical activity of advanced or metastatic paraganglioma/ pheochromocytoma.
Interventions
DRUGSunitinib
50 mg oral dose daily for 4 weeks, 2 week rest period (repeating 6 week cycles)
Sponsors
Pfizer
University Health Network, Toronto
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Histologically or cytologically confirmed diagnosis of malignant paraganglioma or pheochromocytoma and either evidence of metastases or unresectability. * Evidence of recent disease progression (radiological, biochemical, symptomatic). * Measurable disease defined as that which can be measured in at least one dimension with a minimum size of 10 mm by CT scan. * ECOG 0-2. * Life expectancy of greater than 24 weeks. * Age \> 18 years. * Patients must have normal organ and marrow function. * Patients must have PT/INR/PTT within 1.2 X the upper limit * Patients may have had prior radiation therapy. A minimum of 28 days must have elapsed between the end of radiotherapy and registration onto the study. * Previous Surgery: Previous major surgery is permitted provided that it has been at least 28 days prior to patient registration * Laboratory Requirements Parameter Limit granulocytes (AGC) \> 1.5 x 109/L platelets \> 100 x 109/L bilirubin \< 1.5XULN AST and ALT \< 2.5 x ULN Amylase \<1.5XULN Lipase \<1.5XULN Calcium \< 3 mmol/L creatinine \< 2.0XULN
Exclusion criteria
* History of other malignancies. * Patients with known brain metastases. * History of allergic reactions attributed to compounds of similar chemical or biologic composition to sunitinib. * Patients receiving concurrent treatment with other anti-cancer therapy given for paraganglioma or pheochromocytoma or other therapy or other investigational anticancer agents. * Patients who have received prior treatment with any other antiangiogenic agent or multi-targeted tyrosine kinase inhibitors are ineligible. * Patients with any of the following cardiovascular findings are to be excluded: * QTc prolongation or other significant ECG abnormalities. * Current or history of Class III or IV heart failure as defined by the NYHA functional classification system * Patients with prior anthracycline exposure, previous central thoracic radiation that included heart in radiation port, or a history of NYHA Class II cardiac function. * Poorly controlled hypertension * Myocardial infarction, cardiac arrhythmia, stable/unstable angina, symptomatic congestive heart failure, or coronary/peripheral artery bypass graft or stenting within 12 months prior to study entry * History of venous thrombosis or pulmonary embolism in the past 3 months * History of cerebrovascular accident (CVA) or transient ischemic attack within 12 months prior to study entry * Patients who require use of therapeutic doses of coumarin-derivative anticoagulants such as warfarin * Patients with bowel obstruction or any condition that impairs their ability to swallow and retain sunitinib tablets. * Use of agents with proarrhythmic potential is not permitted during the study. * Must be able to stop prohibited selected CYP3A4 inhibitors/inducers prior to starting sunitinib * Patients with pre-existing hypothyroidism prior to enrolment are ineligible unless they are euthyroid on medication. * Pregnant or lactating women, positive pregnancy test, women of childbearing potential who do not agree to use adequate contraception prior to study entry and for the duration of study participation. * Known HIV-positive patients on combination antiretroviral therapy * Greater than +1 proteinuria on urinary dipstick if also \>1g urinary protein/24hrs
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Clinical Benefit Rate (CBR) Which is Defined as Either a Partial Response (PR) Complete Response (CR) or Stable Disease (SD) for ≥ 12 Weeks Measured Using Response Evaluation Criteria in Solid Tumors (RECIST) Criteria. | Every 12 weeks (2 cycles) up to disease progression or study discontinuation (an average of 13.5 6-week cycles or about 1.5 years). | The primary endpoint of this study was disease control rate (DCR) defined as a partial response (PR), complete response (CR), or stable disease maintained for ≥12 weeks from the initiation of treatment. Tumour response to sunitinib was assessed as per RECIST 1.1 using CT-imaging. Clinically apparent lesions needed to be \>10mm by calliper measurement to be included as targets. The primary endpoint was met despite closing to accrual early. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Biochemical Response (BCR) of > 20% Drop in 24-hour Urinary Metanephrines, Catecholamines or Serum Chromogranin A, Sustained for > 12-week Period | Within 7 days of study registration and every 12 weeks (2 cycles) up to treatment discontinuation (an average of 13.5 6-week cycles or about 1.5 years). | Biochemical and symptom changes: timed urinary catecholamine collection over 24 h included measurements of norepinephrine, epinephrine, dopamine and total metanephrines. |
| Overall Survival | From time of enrollment until loss to follow-up or death (approximately 125 months for longest patient on treatment). | The median overall survival |
| Time to Progression | Every 12 weeks (2 cycles) up to disease progression or study discontinuation (an average of 13.5 6-week cycles or about 1.5 years). | Median Progression-Free Survival (PFS) |
| Overall Response Rate (PR) + (CR) | Every 12 weeks (2 cycles) up to disease progression or study discontinuation (an average of 13.5 6-week cycles or about 1.5 years). | Overall response rate (PR) + (CR) of participants |
Countries
Canada, Netherlands
Participant flow
Recruitment details
Patients were enrolled between May 2009 and May 2016 from three centres within Canada and one in the Netherlands.
Pre-assignment details
25 of the planned 28 patients were enrolled
Participants by arm
| Arm | Count |
|---|---|
| Single-Arm, Open Label - Sunitinib Sunitinib: 50 mg oral dose daily for 4 weeks, 2 week rest period (repeating 6 week cycles) | 25 |
| Total | 25 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Lost to Follow-up | 1 |
Baseline characteristics
| Characteristic | Single-Arm, Open Label - Sunitinib |
|---|---|
| Age, Continuous | 50 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 23 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 2 Participants |
| Histology Paraganglionoma | 11 Participants |
| Histology Pheochromocytoma | 14 Participants |
| Prior Local Therapy None | 5 Participants |
| Prior Local Therapy Radiation only | 4 Participants |
| Prior Local Therapy Surgery and radiation | 5 Participants |
| Prior Local Therapy Surgery only | 11 Participants |
| Prior Systemic Therapy None | 21 Participants |
| Prior Systemic Therapy Systemic adjuvant | 1 Participants |
| Prior Systemic Therapy Systemic advanced | 3 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 5 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants |
| Race (NIH/OMB) White | 17 Participants |
| Reason for Enrollment Radiologic and/or biochemical PD | 20 Participants |
| Reason for Enrollment Symptomatic PD | 5 Participants |
| Region of Enrollment Canada | 24 participants |
| Region of Enrollment Netherlands | 1 participants |
| Sex: Female, Male Female | 11 Participants |
| Sex: Female, Male Male | 14 Participants |
| Sites of Mestastases Bone | 12 participants |
| Sites of Mestastases Liver | 14 participants |
| Sites of Mestastases Lung | 12 participants |
| Sites of Mestastases Lymph Nodes | 11 participants |
| Stage Locally advanced | 2 Participants |
| Stage Metastatic | 23 Participants |
| Total Baseline Urine Metanephrines Elevated Missing | 4 Participants |
| Total Baseline Urine Metanephrines Elevated No | 6 Participants |
| Total Baseline Urine Metanephrines Elevated Yes | 15 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 1 / 25 |
| other Total, other adverse events | 25 / 25 |
| serious Total, serious adverse events | 10 / 25 |
Outcome results
Primary
Clinical Benefit Rate (CBR) Which is Defined as Either a Partial Response (PR) Complete Response (CR) or Stable Disease (SD) for ≥ 12 Weeks Measured Using Response Evaluation Criteria in Solid Tumors (RECIST) Criteria.
The primary endpoint of this study was disease control rate (DCR) defined as a partial response (PR), complete response (CR), or stable disease maintained for ≥12 weeks from the initiation of treatment. Tumour response to sunitinib was assessed as per RECIST 1.1 using CT-imaging. Clinically apparent lesions needed to be \>10mm by calliper measurement to be included as targets. The primary endpoint was met despite closing to accrual early.
Time frame: Every 12 weeks (2 cycles) up to disease progression or study discontinuation (an average of 13.5 6-week cycles or about 1.5 years).
Population: Twenty-three patients were evaluable for response.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Single-Arm, Open Label - Sunitinib | Clinical Benefit Rate (CBR) Which is Defined as Either a Partial Response (PR) Complete Response (CR) or Stable Disease (SD) for ≥ 12 Weeks Measured Using Response Evaluation Criteria in Solid Tumors (RECIST) Criteria. | CR, PR, SD > 12 weeks | 19 Participants |
| Single-Arm, Open Label - Sunitinib | Clinical Benefit Rate (CBR) Which is Defined as Either a Partial Response (PR) Complete Response (CR) or Stable Disease (SD) for ≥ 12 Weeks Measured Using Response Evaluation Criteria in Solid Tumors (RECIST) Criteria. | Not CR, PR, SD > 12 weeks | 4 Participants |
Secondary
Biochemical Response (BCR) of > 20% Drop in 24-hour Urinary Metanephrines, Catecholamines or Serum Chromogranin A, Sustained for > 12-week Period
Biochemical and symptom changes: timed urinary catecholamine collection over 24 h included measurements of norepinephrine, epinephrine, dopamine and total metanephrines.
Time frame: Within 7 days of study registration and every 12 weeks (2 cycles) up to treatment discontinuation (an average of 13.5 6-week cycles or about 1.5 years).
Population: Includes patients that had F/U measurements.
| Arm | Measure | Group | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|---|
| Single-Arm, Open Label - Sunitinib | Biochemical Response (BCR) of > 20% Drop in 24-hour Urinary Metanephrines, Catecholamines or Serum Chromogranin A, Sustained for > 12-week Period | 24-h urinary metanephrines | BCR >20% decline in values > 12 weeks | 7 Participants |
| Single-Arm, Open Label - Sunitinib | Biochemical Response (BCR) of > 20% Drop in 24-hour Urinary Metanephrines, Catecholamines or Serum Chromogranin A, Sustained for > 12-week Period | 24-h urinary metanephrines | No BCR >20% decline in values > 12 weeks | 5 Participants |
| Single-Arm, Open Label - Sunitinib | Biochemical Response (BCR) of > 20% Drop in 24-hour Urinary Metanephrines, Catecholamines or Serum Chromogranin A, Sustained for > 12-week Period | norepinephrine | BCR >20% decline in values > 12 weeks | 7 Participants |
| Single-Arm, Open Label - Sunitinib | Biochemical Response (BCR) of > 20% Drop in 24-hour Urinary Metanephrines, Catecholamines or Serum Chromogranin A, Sustained for > 12-week Period | norepinephrine | No BCR >20% decline in values > 12 weeks | 5 Participants |
| Single-Arm, Open Label - Sunitinib | Biochemical Response (BCR) of > 20% Drop in 24-hour Urinary Metanephrines, Catecholamines or Serum Chromogranin A, Sustained for > 12-week Period | Epinephrine | BCR >20% decline in values > 12 weeks | 4 Participants |
| Single-Arm, Open Label - Sunitinib | Biochemical Response (BCR) of > 20% Drop in 24-hour Urinary Metanephrines, Catecholamines or Serum Chromogranin A, Sustained for > 12-week Period | Epinephrine | No BCR >20% decline in values > 12 weeks | 1 Participants |
| Single-Arm, Open Label - Sunitinib | Biochemical Response (BCR) of > 20% Drop in 24-hour Urinary Metanephrines, Catecholamines or Serum Chromogranin A, Sustained for > 12-week Period | Dopamine | BCR >20% decline in values > 12 weeks | 3 Participants |
| Single-Arm, Open Label - Sunitinib | Biochemical Response (BCR) of > 20% Drop in 24-hour Urinary Metanephrines, Catecholamines or Serum Chromogranin A, Sustained for > 12-week Period | Dopamine | No BCR >20% decline in values > 12 weeks | 2 Participants |
| Single-Arm, Open Label - Sunitinib | Biochemical Response (BCR) of > 20% Drop in 24-hour Urinary Metanephrines, Catecholamines or Serum Chromogranin A, Sustained for > 12-week Period | Catecholamines (all) | BCR >20% decline in values > 12 weeks | 11 Participants |
| Single-Arm, Open Label - Sunitinib | Biochemical Response (BCR) of > 20% Drop in 24-hour Urinary Metanephrines, Catecholamines or Serum Chromogranin A, Sustained for > 12-week Period | Catecholamines (all) | No BCR >20% decline in values > 12 weeks | 5 Participants |
Secondary
Overall Response Rate (PR) + (CR)
Overall response rate (PR) + (CR) of participants
Time frame: Every 12 weeks (2 cycles) up to disease progression or study discontinuation (an average of 13.5 6-week cycles or about 1.5 years).
Population: 23 evaluable for response data
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Single-Arm, Open Label - Sunitinib | Overall Response Rate (PR) + (CR) | CR+PR | 3 Participants |
| Single-Arm, Open Label - Sunitinib | Overall Response Rate (PR) + (CR) | Not CR or PR | 20 Participants |
Secondary
Overall Survival
The median overall survival
Time frame: From time of enrollment until loss to follow-up or death (approximately 125 months for longest patient on treatment).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Single-Arm, Open Label - Sunitinib | Overall Survival | 112 months |
Secondary
Time to Progression
Median Progression-Free Survival (PFS)
Time frame: Every 12 weeks (2 cycles) up to disease progression or study discontinuation (an average of 13.5 6-week cycles or about 1.5 years).
Population: Includes patients that had a PFS event (up to 31 Jan 2018).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Single-Arm, Open Label - Sunitinib | Time to Progression | 13.4 months |