A Study on the Safety and Effectiveness of Anlotinib for Neoadjuvant Treatment of PPGL

This phase II trial studies the effectiveness of anlotinib hydrochloride in the neoadjuvant therapy of locally advanced, or unresectable pheochromocytoma or paragangliom(PPGL). Anrotinib is used preoperatively in order to change unresectable tumors to resectable and reduce the high risk of surgery.

This prospective, single arm phase II study is designed to evaluate the efficacy of neoadjuvant therapy with anlotinib hydrochloride in locally advanced,or unresectable PPGL patients. Locally advanced,or unresectable PPGL patients receive anlotinib hydrochloride(10-12mg orally once daily on days 1-14, courses repeat every 21 days). Imaging examinations will be conducted after 4 courses to re-evaluate the surgical possibility. If the patient's tumor shrinks after 4 courses but is still unresectable, the patients will continue antirotinib therapy for another 4 courses.

PRIMARY OBJECTIVES:

The proportion of patients whose PPGL change from unresectable to resectable tumor.

SECONDARY OBJECTIVES:

To determine the objective response rate (ORR) . To determine the ratio of tumor shrinkage. To determine the biochemical response . To determine the R0 resection rate. To determine the Major pathological response rate (MPR). To determine the pathologic complete remission（pCR). To assess the safety of anlotinib treatment.

Eligibility Criteria:
Inclusion Criteria:

* Provide written informed consent.
* Eastern Cooperative Oncology Group (ECOG) performance status 0, 1, or 2.
* The patient is diagnosed as pheochromocytoma or paraganglioma which is unresectable with R0 surgery, or extensive and thus maybe requiring resection of important organs, or with very high surgical risk.
* 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%).
* Confirmed non-pregnancy and lactation. During the entire study period and within 6 months after the last administration, the subjects and their spouses are willing to use efficient contraceptive measures.

Exclusion Criteria:

* 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.).
* 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).
* 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.
* Participated in other clinical trials within 4 weeks.
* Patients are using drugs that interact with anlotinib.
* Any of the following: Pregnant women, Nursing women, Men or women of childbearing potential who are unwilling to employ adequate contraception.
* Patients with stable disease, and no desire for surgery.