Cabozantinib S-malate in Treating Patients With Metastatic Pheochromocytomas or Paragangliomas That Cannot Be Removed by Surgery
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|ClinicalTrials.gov Identifier: NCT02302833|
Recruitment Status : Active, not recruiting
First Posted : November 27, 2014
Last Update Posted : May 18, 2023
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|Condition or disease||Intervention/treatment||Phase|
|Locally Advanced Paraganglioma Metastatic Adrenal Gland Pheochromocytoma Metastatic Paraganglioma Regional Adrenal Gland Pheochromocytoma Unresectable Adrenal Gland Pheochromocytoma Unresectable Paraganglioma||Drug: Cabozantinib S-malate Other: Laboratory Biomarker Analysis Other: Questionnaire Administration||Phase 2|
I. To estimate best overall response rate in patients with measurable disease determined by computed tomography (CT) or magnetic resonance imaging (MRI).
I. To estimate progression-free survival at 1-year. II. To correlate blood pressure control and change/discontinuation of antihypertensive medications with tumor responses.
III. To correlate symptomatology evaluation by the MD Anderson Symptom Inventory (MDASI) with tumor responses.
IV. To correlate plasma metanephrines and chromogranin A with tumor responses. V. To correlate plasma C-reactive protein and interleukin-6 with symptoms and tumor responses.
VI. Toxicity assessment by the Common Terminology Criteria for Adverse Events (CTCAE).
VII. To correlate both c-MET expression by immunohistochemistry (IHC) as well as MET amplification by fluorescence in situ hybridization (FISH) in archived samples and correlate these biomarkers with overall prognosis and responsiveness to cabozantinib (cabozantinib s-malate).
I. Best overall response rate in patients with bone metastases only (8 patients) as determined by fludeoxyglucose F 18 positron emission tomography/computed tomography (FDG-PET/CT).
II. FDG-PET/CT maximum standard uptake value (SUVmax), advanced volumetric measures including peak standard uptake value (SUVpeak), metabolic tumor volume (MTV), and total lesion glycolysis (TLG).
III. Time to skeletal related events. IV. Incidence of skeletal related events at 4 months and one year. V. Markers of bone turnover (bone specific alkaline phosphatase and C-terminal telopeptide [CTx]).
Patients receive cabozantinib s-malate orally (PO) once daily (QD) on days 1-28. Courses repeat every 4 weeks through week 24 and then every 8 weeks in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up at 30-37 days.
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||22 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|Official Title:||A Phase II Study to Evaluate the Effects of Cabozantinib in Patients With Unresectable Metastatic Pheochromocytomas and Paragangliomas|
|Actual Study Start Date :||February 17, 2015|
|Estimated Primary Completion Date :||December 31, 2023|
|Estimated Study Completion Date :||December 31, 2023|
Experimental: Treatment (cabozantinib s-malate)
Patients receive cabozantinib s-malate PO QD on days 1-28. Courses repeat every 4 weeks in the absence of disease progression or unacceptable toxicity.
Drug: Cabozantinib S-malate
Other: Laboratory Biomarker Analysis
Other: Questionnaire Administration
- Best overall response rate [ Time Frame: Up to 37 days after completion of study treatment ]As measured per Response Evaluation Criteria In Solid Tumors (RECIST) 1.1 criteria. Will be determined by computed tomography or magnetic resonance imaging. Response will include complete response, partial response, and stable disease. Response rates and their 95% confidence intervals will be estimated.
- Progression-free survival [ Time Frame: At 1 year ]Kaplan Meier survival curves will be used to estimate survival outcomes. Cox proportional hazards regression analysis may be used to assess the association between survival and covariates of interest.
- Blood pressure control and change/discontinuation of antihypertensive medications [ Time Frame: Up to 37 days after completion of study treatment ]Will be correlated with tumor responses.
- Symptomatology evaluation [ Time Frame: Up to 37 days after completion of study treatment ]Assessed by the MD Anderson Symptom Inventory. Will be correlated with tumor responses.
- Plasma metanephrines and chromogranin A [ Time Frame: Up to 37 days after completion of study treatment ]Will be correlated with tumor responses
- Plasma C-reactive protein and interleukin-6 [ Time Frame: Up to 37 days after completion of study treatment ]Will be correlated with symptom and tumor responses.
- Incidence of adverse events (AEs) [ Time Frame: Up to 37 days after completion of study treatment ]Seriousness, severity grade and relationship to study treatment will be assessed by the investigator. Severity grade will be defined by the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version (v)4.0. Listings of AEs will be provided.
- c-MET expression [ Time Frame: Baseline ]Evaluated by immunohistochemistry and MET amplification by fluorescence in situ hybridization in archived samples. Will be correlated with overall prognosis and responsiveness to cabozantinib s-malate.
- Best overall response rate in patients with bone metastases only [ Time Frame: Up to 37 days after completion of study treatment ]As determined by fluorodeoxyglucose-positron emission tomography/computed tomography. Response rates and their 95% confidence intervals will be estimated.
- Fluorodeoxyglucose -positron emission tomography/computed tomography Maximum standardized uptake value, advanced volumetric measures including peak standardized uptake value, metabolic tumor volume, and total lesion glycolysis [ Time Frame: Up to 37 days after completion of study treatment ]
- Time to skeletal related events [ Time Frame: Up to 37 days after completion of study treatment ]
- Incidence of skeletal related events at 4 months and one year [ Time Frame: Up to 1 year ]
- Markers of bone turnover (bone specific alkaline phosphatase and CTx) [ Time Frame: Up to 37 days after completion of study treatment ]
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|Ages Eligible for Study:||18 Years and older (Adult, Older Adult)|
|Sexes Eligible for Study:||All|
|Accepts Healthy Volunteers:||No|
- Histological confirmation of pheochromocytoma (PH)/paraganglioma (PG)
- Locally advanced or metastatic disease not amenable to surgery
- Patients enrolled in the main branch should have measurable disease; patients with a predominance of bone disease who have small, non-measurable or small measurable lesions other than bone, may be included per the principal investigator's discretion, in the exploratory branch of the study for patients with bone metastases only
- Progressive disease per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 as determined by the investigator within the 12 months preceding study enrollment
- Assessment of all known disease sites, e.g., by CT scan, MRI, bone scan as appropriate, and/or FDG-PET scan within 28 days before the first dose of cabozantinib
- Eastern Cooperative Oncology Group (ECOG) performance status =< 2
- Life expectancy of at least 3 months
- Absolute neutrophil count (ANC) >= 1500/mm^3 without colony stimulating factor support (within 4 days prior to the first dose of cabozantinib)
- Platelets >= 100,000/mm^3 (within 4 days prior to the first dose of cabozantinib)
- Hemoglobin >= 9 g/dL (within 4 days prior to the first dose of cabozantinib)
- Bilirubin =< 1.5 x the upper limit of normal (ULN) (for subjects with known Gilbert's disease, bilirubin =< 3.0 mg/dL) (within 4 days prior to the first dose of cabozantinib)
- Serum albumin >= 2.8 g/dl (within 4 days prior to the first dose of cabozantinib)
- Serum creatinine =< 1.5 x ULN or creatinine clearance (CrCl) >= 50 mL/min (for creatinine clearance estimation, the Cockcroft and Gault equation should be used) (within 4 days prior to the first dose of cabozantinib)
- Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 3.0 x ULN (within 4 days prior to the first dose of cabozantinib)
- Lipase < 2.0 x ULN and no radiologic or clinical evidence of pancreatitis (within 4 days prior to the first dose of cabozantinib)
- Urine protein/creatinine ratio (UPCR) =< 1 (within 4 days prior to the first dose of cabozantinib)
- Serum phosphorus, calcium, potassium >= lower limit of normal (LLN) (within 4 days prior to the first dose of cabozantinib)
- Serum magnesium >= 1.2 mg/dL (within 4 days prior to the first dose of cabozantinib)
- Capable of understanding and complying with the protocol requirements and has signed the informed consent document
- Sexually active patients (men and women) must agree to use medically accepted barrier methods of contraception (e.g., male or female condom) during the course of the study and for 4 months after the last dose of study drug(s), even if oral contraceptives are also used; all subjects of reproductive potential must agree to use both a barrier method and a second method of birth control during the course of the study and for 4 months after the last dose of study drug(s)
- Women of childbearing potential must have a negative pregnancy test at screening; women of childbearing potential include women who have experienced menarche and who have not undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or are not postmenopausal; postmenopause is defined as amenorrhea >= 12 consecutive months; note: women who have been amenorrheic for 12 or more months are still considered to be of childbearing potential if the amenorrhea is possibly due to prior chemotherapy, antiestrogens, ovarian suppression or any other reversible reason
- Received cytotoxic chemotherapy (including investigational cytotoxic chemotherapy) or biologic agents (e.g., cytokines or antibodies) within 3 weeks, or nitrosoureas/mitomycin C within 6 weeks before the first dose of study treatment
- Prior treatment with cabozantinib
- Radiation therapy for bone metastasis within 2 weeks, or any other external radiation therapy within 4 weeks before the first dose of study treatment; subjects with clinically relevant ongoing complications from prior radiation therapy are not eligible
- Received radionuclide treatment (i.e. iodine [I]-131 meta-iodo-benzyl guanidine) within 6 months of the first dose of study treatment
- Receipt of any type of small molecule kinase inhibitor (including investigational kinase inhibitor) within 14 days before the first dose of study treatment
- Receipt of any other type of investigational agent within 28 days before the first dose of study treatment
- The subject has not recovered to baseline or CTCAE =< grade 1 from toxicity due to all prior therapies except alopecia and other non-clinically significant adverse events (AEs)
- Prothrombin time (PT)/international normalized ratio (INR) or partial thromboplastin time (PTT) test >= 1.3 x the laboratory ULN within 7 days before the first dose of study treatment
- The subject requires concomitant treatment, in therapeutic doses, with anticoagulants such as warfarin or warfarin-related agents, heparin, thrombin or Factor Xa inhibitors, or antiplatelet agents (eg, clopidogrel); low dose aspirin (=< 81 mg/day), low-dose warfarin (=< 1 mg/day), and prophylactic low molecular weight heparin (LMWH) are permitted
- The subject requires chronic concomitant treatment of strong cytochrome P450 family 3, subfamily A, polypeptide 4 (CYP3A4) inducers (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital, and St. John's wort)
- The subject has experienced any of the following: a. clinically-significant gastrointestinal bleeding within 6 months before the first dose of study treatment, b. hemoptysis of >= 0.5 teaspoon (2.5 ml) of red blood within 3 months before the first dose of study treatment, c. any other signs indicative of pulmonary hemorrhage within 3 months before the first dose of study treatment
- Radiographic evidence of cavitating pulmonary lesion(s)
- Tumor invading or encasing any major blood vessels
- Evidence of tumor invading the gastrointestinal (GI) tract (esophagus, stomach, small or large bowel, rectum or anus), or any evidence of endotracheal or endobronchial tumor within 28 days before the first dose of cabozantinib
Uncontrolled, significant intercurrent or recent illness including, but not limited to, the following conditions: a. cardiovascular disorders including: i. congestive heart failure (CHF): New York Heart Association (NYHA) class III (moderate) or class IV (severe) at the time of screening, ii. concurrent uncontrolled hypertension defined as sustained blood pressure > 150 mm Hg systolic, or > 90 mm Hg diastolic despite optimal antihypertensive treatment within 7 days of the first dose of study treatment, iii. any history of congenital long QT syndrome, or iv. any of the following within 6 months before the first dose of study treatment: unstable angina pectoris, clinically-significant cardiac arrhythmias, stroke (including transient ischemic attack [TIA], or other ischemic event), myocardial infarction, or thromboembolic event requiring therapeutic anticoagulation (note: subjects with a venous filter [e.g. vena cava filter] are not eligible for this study)
- Gastrointestinal disorders, particularly those associated with a high risk of perforation or fistula formation, including: i. any of the following within 28 days before the first dose of study treatment: intra-abdominal tumor/metastases invading GI mucosa, active peptic ulcer disease (patients must be completely recovered), inflammatory bowel disease (including ulcerative colitis and Crohn's disease), diverticulitis, cholecystitis, symptomatic cholangitis or appendicitis (patient must be completely recovered from these conditions), malabsorption syndrome; ii. any of the following within 6 months before the first dose of study treatment: abdominal fistula, gastrointestinal perforation, bowel obstruction or gastric outlet obstruction, or intra-abdominal abscess (complete resolution of an intra-abdominal abscess must be confirmed prior to initiating treatment with cabozantinib even if the abscess occurred more than 6 months before the first dose of study treatment); c. other disorders associated with a high risk of fistula formation including percutaneous endoscopic gastrostomy (PEG) tube placement within 3 months before the first dose of study therapy, d. other clinically significant disorders such as: i. active infection requiring systemic treatment within 28 days before the first dose of study treatment, ii. serious non-healing wound/ulcer/bone fracture within 28 days before the first dose of study treatment, iii. history of organ transplant, iv. concurrent uncompensated hypothyroidism or thyroid dysfunction within 7 days before the first dose of study treatment, or v. major surgery within 12 weeks before the first dose of study treatment; complete wound healing from major surgery must have occurred 1 month before the first dose of study treatment; minor surgery within 28 days before the first dose of study treatment with complete wound healing at least 10 days before the first dose of study treatment; subjects with clinically relevant ongoing complications from prior surgery are not eligible
- Unable to swallow tablets
- A corrected QT interval calculated by the Fridericia formula (QTcF) > 500 ms within 28 days before first dose of study treatment; three electrocardiograms (ECGs) must be performed; if the average of these three consecutive results for QTcF is =< 500 msec, the subject meets eligibility in this regard
- Pregnant or breastfeeding
- A previously identified allergy or hypersensitivity to components of the study treatment formulation
- Unable or unwilling to abide by the study protocol or cooperate fully with the investigator or designee
- Evidence within 2 years of the start of study treatment of another malignancy which required systemic treatment except for cured nonmelanoma skin cancer or cured in situ cervical carcinoma
- Any other severe acute or chronic medical or psychiatric condition or laboratory abnormality which, in the judgment of the investigator, would have made the patient inappropriate for entry into this study
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02302833
|United States, Texas|
|M D Anderson Cancer Center|
|Houston, Texas, United States, 77030|
|Principal Investigator:||Camilo Jimenez||M.D. Anderson Cancer Center|
|Responsible Party:||M.D. Anderson Cancer Center|
|Other Study ID Numbers:||
NCI-2014-02607 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
2014-0081 ( Other Identifier: M D Anderson Cancer Center )
|First Posted:||November 27, 2014 Key Record Dates|
|Last Update Posted:||May 18, 2023|
|Last Verified:||May 2023|
|Studies a U.S. FDA-regulated Drug Product:||Yes|
|Studies a U.S. FDA-regulated Device Product:||No|
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