Prediction and Evaluation of Anlotinib Treatment Response Using Contrast Enhanced Ultrasound PPGL Patients

Overview

Anlotinib is a multi-target receptor tyrosine kinase inhibitor (TKI) targeting tumor angiogenesis and growth. The purpose of this study is to evaluate the efficiency of contrast enhanced ultrasound in assessing effectiveness of anlotinib in patients with locally advanced, metastatic, or unresectable pheochromocytoma or paraganglioma(PPGL).

Description

Contrast-enhanced ultrasound (CEUS) is a non-invasive and efficient imaging technique which can observe the blood flow at the tissue perfusion level with microbubble contrast agents and obtain information about tumor perfusion. There have been several studies demonstrating the utility of CEUS for early prediction of response to neoadjuvant chemotherapy in breast cancer, pancrearic cancer as well as lymphoma. However, few studies have reported the use of CEUS for the evaluation of therapeutic response in PPGL. What quantitative parameters of CEUS can early reflect the neovascular changes after treatment with anlotinib in patients with locally advanced, metastatic, or unresectable PPGL? The aim of our study is to evaluate the parameters for CEUS imaging and the therapeutic response of PPGL before and after anlotinib therapy and to determine the most useful CEUS response parameters.

Eligibility

Inclusion Criteria:

• 18 years of age or older.
• Provide written informed consent.
• Willing to return to enrolling institution for follow-up.
• Eastern Cooperative Oncology Group (ECOG) performance status 0, 1, or 2.
• Life expectancy > 3 months.
• Patients diagnosis with pheochromocytoma or paraganglioma will received anlotinib treatment.
• Laboratory requirements:
  • Absolute granulocyte count (AGC) greater than 1.5 x 109/L;
  • Platelet count greater than 80 x 109/L;
  • Hemoglobin greater than 90g/L;
  • Serum bilirubin less than 1.5 x upper limit of normal (ULN);
  • Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) less than 2.5 x ULN;
  • Serum creatinine less than 1.5 x ULN or creatinine clearance (CCr)≥60ml/min;
  • Doppler ultrasound assessment: left ventricular ejection fraction (LVEF) ≥ lower limit of normal value (50%).

Exclusion Criteria:

• Patients who are allergic to ultrasound contrast agents.
• Any of the following:Pregnant women,Nursing women,Men or women of childbearing potential who are unwilling to employ adequate contraception.
• Patients who have previously used other anti-vascular targeted drugs, such as sunitinib, bevacizumab, endurance, etc.
• Chemotherapy/systemic therapy, radiotherapy, immunotherapy or surgery within 4 weeks prior to kinase inhibitor therapy.
• Patients with another primary malignancy within 5 years prior to starting study drug.

        Those who have multiple factors that affect oral medications (such as inability to swallow,
        chronic diarrhea, intestinal obstruction, etc.).
          -  Patients with known untreated brain metastases are excluded. Patients having a history
             of brain metastasis that have been previously irradiated or resected greater than 2
             months prior to enrollment and are clinically and radiographically stable will be
             considered for enrollment. Patients with brain metastases with symptoms or symptom
             control for less than 2 months.
          -  Active or uncontrolled intercurrent illness including, but not limited to
               -  Patients with unsatisfactory blood pressure control (systolic blood pressure ≥150
                  mmHg, diastolic blood pressure ≥100 mmHg);
               -  Patients with uncontrolled myocardial ischemia or myocardial infarction,
                  arrhythmia (including QTC≥480ms), and uncontrolled congestive heart failure，grade
                  ≥2（New York Heart Association )
               -  ongoing or active infection;
               -  Liver cirrhosis, decompensated liver disease, active hepatitis or chronic
                  hepatitis require antiviral treatment;
               -  Renal failure requires hemodialysis or peritoneal dialysis;
               -  Have a history of immunodeficiency, including HIV or other acquired or congenital
                  immunodeficiency diseases, or a history of organ transplantation;
               -  Diabetes is poorly controlled (fasting blood glucose (FBG)> 10mmol/L);
               -  Urine routines suggest that urine protein is ≥++, and the 24-hour urine protein
                  content is confirmed to be greater than 1.0 g;
               -  Patients who have seizures and need treatment;
          -  Any of the following conditions =< 6 months prior to registration: Cerebrovascular
             accident (CVA) or transient ischemic attack (TIA); Serious or unstable cardiac
             arrhythmia; Pulmonary embolism, untreated deep venous thrombosis (DVT).
        Received major surgical treatment, open biopsy or obvious traumatic injury within 28 days
        before enrollment.
          -  Those who have a history of psychotropic drug abuse and cannot be quit or have mental
             disorders.
          -  Imaging shows that the tumor has invaded important blood vessels or the investigator
             judges that the tumor is very likely to invade important blood vessels and cause fatal
             bleeding during the follow-up study.
          -  Regardless of the severity, patients with any signs of bleeding or medical history;
             within 4 weeks before enrollment, patients with any bleeding or bleeding event ≥ CTCAE
             grade 3, unhealed wounds, ulcers or fractures.
          -  Patients are using drugs that interact with Anlotinib.