The Efficacy and Safety of Anlotinib in Patients With Metastatic Pheochromocytoma or Paraganglioma
The Efficacy and Safety of Anlotinib in Patients With Metastatic Pheochromocytoma or Paraganglioma
This phase II trial studies how well anlotinib hydrochloride works in treating patients with
 metastatic pheochromocytoma or paraganglioma. Anlotinib hydrochloride may stop the growth of
 tumor cells by blocking some of the enzymes needed for cell growth and by blocking blood flow
 to the tumor.
PRIMARY OBJECTIVES:

 To determine the anti-tumor activity of anlotinib hydrochloride (Objective Response rate,ORR)
 in patients with metastatic pheochromocytomas or paragangliomas.

 SECONDARY OBJECTIVES:

 I. To assess safety profile of anlotinib. II. To assess progression-free survival time. III.
 To assess disease control rate.

 OUTLINE:

 Patients receive anlotinib hydrochloride 12mg orally once daily on days 1-14. Courses repeat
 every 21 days in the absence of disease progression or unacceptable toxicity.

 Patients undergo urine and blood sample collection, imaging examinations at baseline and
 periodically during study.

 After completion of study therapy, patients are followed up every 3-6 months.
Inclusion Criteria:

 -  Histologically or cytologically confirmed malignant secretory or non-secretory
 pheochromocytoma or paraganglioma that is unresectable and deemed inappropriate for
 alternative local regional therapeutic approaches

 -  Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0, 1, or 2

 -  Life expectancy > 24 weeks

 -  Absolute neutrophil count (ANC) >= 1500/mm^3

 -  White blood cell (WBC) count >= 3,000/mm^3

 -  Platelet count >= 100,000/mm^3

 -  Hemoglobin >= 9.0 g/dL (5.6 mmol/L); NOTE: transfusions are not allowed =< 7 days
 prior to registration

 -  Total bilirubin =< 1.5 X upper limit of normal (ULN) (or total bilirubin =< 3.0 X ULN
 with direct bilirubin =< 1.5 X ULN in patients with well-documented Gilbert's
 Syndrome)

 -  Aspartate transaminase (AST/serum glutamic oxaloacetic transaminase [SGOT]) =< 2.5 X
 ULN

 -  Creatinine =< 1.5 x ULN

 -  Urine protein/creatinine ratio =< 1 OR 24-hour urine protein < 1.5 gram

 -  Negative pregnancy test done =< 7 days prior to registration, for women of
 childbearing potential only

 -  Blood pressure (BP) < 150 mmHg (systolic) and < 90 mmHg (diastolic); initiation or
 adjustment of BP medication is permitted prior to registration provided that the
 average of three BP readings at a visit prior to registration is < 150/90 mmHg; NOTE:
 all patients with secretory pheochromocytoma or paraganglioma are REQUIRED to: 1) be
 evaluated in consultation by a hypertension specialist with specific experience in the
 management of hypertension in the setting of catecholamine-secreting tumors (usually
 an endocrinologist, nephrologist, or a cardiologist), and in the setting of
 hormone-associated hypertension) receive alpha- and beta-adrenergic blockade for at
 least 7-14 days prior to initiation of lenvatinib; the hypertension specialist of
 record for each patient should be committed to closely following the patient during
 the clinical study with evaluation by said specialist required at cycle 1 and 2 and
 thereafter on an as needed basis

 -  Provide written informed consent

 -  Willing to return to enrolling institution for follow-up (during the active monitoring
 phase of the study)

 -  Ability to complete questionnaire(s) by themselves or with assistance

 Exclusion Criteria:

 -  Any of the following Pregnant women Nursing women Men or women of childbearing
 potential who are unwilling to employ adequate contraception

 -  Chemotherapy/systemic therapy, radiotherapy, immunotherapy or surgery =< 21 days prior
 to registration or kinase inhibitor therapy =< 14 days prior to registration or
 failure to recover from toxicities (to grade 1 or below) from treatment; NOTE:
 concurrent therapy with octreotide is allowed providing that tumor progression on this
 therapy has been demonstrated; concurrent therapy with bisphosphonates (e.g.
 zoledronic acid) or denosumab is also allowed.

 -  Active or uncontrolled intercurrent illness including, but not limited to, ongoing or
 active infection, symptomatic congestive heart failure, unstable angina pectoris,
 cardiac arrhythmia, or psychiatric illness/social situations that would limit
 compliance with study requirements

 -  Receiving any other investigational agent

 -  Current use of warfarin for any reason; NOTE: if patient can be safely transitioned to
 another anticoagulant, they may be eligible provided other criteria are satisfied

 -  Any of the following:

 Correct QT (QTc) prolongation (defined as a QTc interval >= 500 msecs) Left ventricular
 ejection fraction (LVEF) < institutional lower limits of normal (LLN) Frequent ventricular
 ectopy Evidence of ongoing myocardial ischemia Receiving any medications or substances with
 risk of torsades de pointes; NOTE: medications or substances with known risk of torsades de
 pointes are prohibited; consult pharmacist for review if needed Known active and/or
 untreated brain metastases Known severe allergic or other prohibitive reactions to other
 tyrosine kinase inhibitors (TKI)

 • Any of the following conditions: Active peptic ulcer disease Inflammatory bowel disease
 (e.g., ulcerative colitis, Crohn's disease) or other gastrointestinal conditions which
 increase the risk of perforation History of new abdominal fistula, gastrointestinal
 perforation or intra-abdominal abscess =< 84 days prior to registration; NOTE: enrollment
 of patients with chronic/canalized fistulous tracts (present for > 84 days) is allowed
 Serious or non-healing wound, ulcer, or bone fracture History of familial QTc prolongation
 syndrome

 • Any of the following conditions =< 6 months prior to registration: Cerebrovascular
 accident (CVA) or transient ischemic attack (TIA) Serious or unstable cardiac arrhythmia
 Admission for unstable angina or myocardial infarction Cardiac angioplasty or stenting
 Coronary artery bypass graft surgery Pulmonary embolism, untreated deep venous thrombosis
 (DVT) or DVT which has been treated with therapeutic anticoagulation =< 30 days Arterial
 thrombosis Symptomatic peripheral vascular disease

 • Other active malignancy =< 2 years prior to registration.