Testing Cabozantinib in Patients With Advanced Pancreatic Neuroendocrine and Carcinoid Tumors
Testing Cabozantinib in Patients With Advanced Pancreatic Neuroendocrine and Carcinoid Tumors
This randomized phase III trial studies cabozantinib to see how well it works compared with
 placebo in treating patients with neuroendocrine or carcinoid tumors that have spread to
 other places in the body (advanced). Cabozantinib is a chemotherapy drug known as a tyrosine
 kinase inhibitor, and it targets specific tyrosine kinase receptors, that when blocked, may
 slow tumor growth.
PRIMARY OBJECTIVES:

 I. To determine whether cabozantinib S-malate (cabozantinib) can significantly improve
 progression-free survival (PFS) compared to placebo in patients with advanced pancreatic
 neuroendocrine tumors (NET) whose disease has progressed after prior therapy.

 II. To determine whether cabozantinib can significantly improve progression-free survival
 (PFS) compared to placebo in patients with advanced carcinoid tumors whose disease has
 progressed after prior therapy.

 SECONDARY OBJECTIVES:

 I. To determine whether cabozantinib can significantly improve overall survival (OS) compared
 to placebo in patients with advanced pancreatic NET whose disease has progressed after prior
 therapy.

 II. To determine whether cabozantinib can significantly improve overall survival (OS)
 compared to placebo in patients with advanced carcinoid tumors whose disease has progressed
 after prior therapy.

 III. To evaluate safety and tolerability of cabozantinib versus placebo in patients with
 advanced pancreatic NET using Common Terminology Criteria for Adverse Events (CTCAE) and
 Patient-Reported Outcomes Version of the Common Terminology Criteria for Adverse Events
 (PRO-CTCAE).

 IV. To evaluate safety and tolerability of cabozantinib versus placebo in patients with
 advanced carcinoid tumors using CTCAE and PRO-CTCAE.

 V. To evaluate the overall radiographic response rate of cabozantinib versus placebo in
 patients with advanced pancreatic NET whose disease has progressed after prior therapy.

 VI. To evaluate the overall radiographic response rate of cabozantinib versus placebo in
 patients with advanced carcinoid tumors whose disease has progressed after prior therapy.

 OTHER OBJECTIVES:

 I. Results of the primary analysis will be examined for consistency, while taking into
 account the stratification factors and/or covariates of baseline quality of life (QOL) and
 fatigue.

 QUALITY OF LIFE SUBSTUDY OBJECTIVES:

 I. To compare overall quality of life, disease-related symptoms, and other domains between
 the two treatment groups (cabozantinib versus [vs.] placebo) within each cohort of patients
 (pancreatic NET vs. carcinoid tumor). (Quality of Life Substudy Objective - A021602-HO1)

 POPULATION PHARMACOKINETICS SUBSTUDY OBJECTIVES:

 I. To describe the population pharmacokinetic and exposure-response relationships of
 cabozantinib in patients with advanced neuroendocrine tumors.

 OUTLINE: Patients are randomized to 1 of 2 arms.

 ARM I: Patients receive cabozantinib S-malate orally (PO) once daily (QD) on days 1-28.
 Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

 ARM II: Patients receive placebo PO QD on days 1-28. Cycles repeat every 28 days in the
 absence of disease progression or unacceptable toxicity.

 After completion of study treatment, patients are followed up every 12 weeks until disease
 progression or start of new anticancer therapy, and then every 6 months until 8 years after
 registration.
Inclusion Criteria:

 -  Documentation of Disease:

 -  Histologic Documentation: Well- or moderately-differentiated neuroendocrine
 tumors of pancreatic and non-pancreatic (i.e. carcinoid) origin by local
 pathology

 -  The pathology report must state ONE of the following: 1) well- or
 moderately-differentiated neuroendocrine tumor, 2) low- or
 intermediate-grade neuroendocrine tumor, or 3) carcinoid tumor or atypical
 carcinoid tumor; documentation of histology from a primary or metastatic
 site is allowed

 -  Patients with poorly differentiated neuroendocrine carcinoma, high-grade
 neuroendocrine carcinoma, adenocarcinoid tumor, or goblet cell carcinoid
 tumor are not eligible

 -  Stage: Locally advanced/unresectable or metastatic disease

 -  Tumor Site: Histological documentation of neuroendocrine tumor of pancreatic,
 gastrointestinal (GI), lung, or unknown primary site; GI, lung, and unknown
 primary NETs will enroll in the carcinoid tumor cohort of the study

 -  Functional (associated with a clinical hormone syndrome) or nonfunctional
 tumors are allowed

 -  Radiologic Evaluation: Target lesions must have shown evidence of disease
 progression by Response Evaluation Criteria in Solid Tumors (RECIST) version
 (v)1.1 criteria in the 12 months prior to registration; the radiologic images,
 imaging reports, and clinic notes indicating growth of existing lesions,
 development of new lesions, or treatment changes must be submitted

 -  Measurable Disease

 -  Patients must have measurable disease per RECIST 1.1 by computer tomography (CT)
 scan or magnetic resonance imaging (MRI)

 -  Lesions must be accurately measured in at least one dimension (longest diameter
 to be recorded) as >= 1 cm with CT or MRI (or >= 1.5 cm for lymph nodes);
 non-measurable disease includes disease smaller than these dimensions or lesions
 considered truly non-measurable including: leptomeningeal disease, ascites,
 pleural or pericardial effusion, lymphangitic involvement of skin or lung

 -  Prior Treatment

 -  Patient must have experienced disease progression on or intolerance to treatment
 discontinuation of at least one Food and Drug Administration (FDA)-approved line
 of therapy (except somatostatin analogs); prior lins of therapy may include:
 everolimus, sunitinib, or lutetium Lu 177 dotatate in patients with pancreatic
 NET; everolimus in patients with lung NET; everolimus or lutetium Lu 177 dotatate
 in patients with gastrointestinal NET

 -  Prior treatment (except somatostatin analogs) with biologic therapy,
 immunotherapy, chemotherapy, investigational agent for malignancy, and/or
 radiation must be completed at least 28 days prior to registration

 -  Prior treatment with somatostatin analogs is allowed, and continuation of
 treatment with somatostatin analogs while on cabozantinib/placebo is allowed
 provided that the patient has been on a stable dose for at least two months

 -  Prior systemic treatment with radionuclide therapy must be completed at least 6
 weeks prior to registration

 -  Prior treatment with hepatic artery embolization (including bland embolization,
 chemoembolization, and selective internal radiation therapy) or ablative
 therapies is allowed if measurable disease remains outside of the treated area or
 if there is documented disease progression in a treated site; prior
 liver-directed or other ablative treatment must be completed at least 28 days
 prior to registration

 -  Prior treatment with cabozantinib is not allowed

 -  Patients should have resolution of any toxic effects of prior therapy (except
 alopecia and fatigue) to National Cancer Institute (NCI) CTCAE, version 5.0,
 grade 1 or less

 -  Patients must have completed any major surgery at least 12 weeks prior to
 registration and any minor surgery (including uncomplicated tooth extractions) at
 least 28 days prior to registration; complete wound healing from major surgery
 must have occurred at least 28 days prior to registration, and complete wound
 healing from minor surgery must have occurred at least 10 days prior to
 registration

 -  Patient History

 -  No class III or IV congestive heart failure (CHF) within 6 months of registration

 -  No clinically significant cardiac arrhythmia within 6 months of registration

 -  No unstable angina or MI within 6 months of registration

 -  No thromboembolic events within 6 months of registration (including [incl.]
 stroke, transient ischemic attack [TIA], deep vein thrombosis [DVT], & pulmonary
 embolism [PE])

 -  No known history of congenital long QT syndrome

 -  No uncontrolled hypertension within 14 days of registration (defined as systolic
 blood pressure [SBP] >= 150 mmHg and/or diastolic blood pressure [DBP] >= 90 mmHg
 despite optimal medical management)

 -  No clinically significant GI bleeding within 6 months of registration

 -  No clinically significant gastrointestinal abnormalities that may increase the
 risk for gastrointestinal bleeding within 6 months of registration including, but
 not limited to: active peptic ulcer, known endoluminal metastatic lesion(s) with
 history of bleeding, inflammatory bowel disease, or other gastrointestinal
 conditions with increased risk of perforation

 -  No GI perforation within 6 months of registration

 -  No known tumor with invasion into the GI tract from the outside causing increased
 risk of perforation or bleeding within 28 days of registration

 -  No radiologic or clinical evidence of pancreatitis

 -  No known cavitary lung lesions

 -  No known endobronchial lesions involving the main or lobar bronchi and/or lesions
 infiltrating major pulmonary vessels that increase the risk of pulmonary
 hemorrhage; (CT with contrast is recommended to evaluate such lesions)

 -  No hemoptysis greater than 1/2 teaspoon (2.5 mL) or any other signs of pulmonary
 hemorrhage within the 3 months prior to registration

 -  No known tumor invading or encasing any major blood vessels

 -  No history of non-healing wounds or ulcers within 28 days of registration

 -  No history of fracture within 28 days of registration

 -  No brain metastases or cranial epidural disease unless adequately treated,
 stable, and off steroid support for at least 4 weeks prior to registration

 -  No known medical condition causing an inability to swallow oral formulations of
 agents

 -  No history of allergic reaction attributed to compounds of similar chemical or
 biological composition to cabozantinib/placebo

 -  No "currently active" second malignancy other than non-melanoma skin cancers or
 cervical carcinoma in situ; patients are not considered to have a "currently
 active" malignancy if they have completed therapy and are free of disease for >=
 3 years

 -  Concomitant Medications

 -  Other planned concurrent investigational agents or other tumor directed therapies
 (chemotherapy, radiation) are not allowed while on this study

 -  Concurrent use of somatostatin analogs while on cabozantinib/placebo is allowed
 provided that the patient has been on a stable dose for at least two months

 -  Full dose oral anticoagulation/antiplatelet therapy is not permitted; low dose
 aspirin =< 81 mg/day is allowed; anticoagulation with therapeutic doses of low
 molecular weight heparin (LMWH) is allowed in patients who are on a stable dose
 of LMWH for at least 6 weeks prior to registration; treatment with warfarin is
 not allowed; anticoagulation in patients with brain metastases is not permitted

 -  Chronic concomitant treatment with strong inhibitors of CYP3A4 is not allowed;
 patients must discontinue the drug at least 14 days prior to registration on the
 study

 -  Chronic concomitant treatment with strong CYP3A4 inducers is not allowed;
 patients must discontinue the drug at least 14 days prior to the start of study
 treatment

 -  Not pregnant and not nursing

 -  Women of childbearing potential must have a negative pregnancy test done =< 14
 days prior to registration

 -  A female of childbearing potential is a sexually mature female who: 1) has not
 undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally
 postmenopausal for at least 12 consecutive months (i.e. has had menses at any
 time in the preceding 12 consecutive months)

 -  Eastern Cooperative Oncology Group (ECOG) performance status: 0-2

 -  Absolute neutrophil count (ANC) >= 1,500/mm^3

 -  Hemoglobin >= 9 g/dL

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

 -  Prothrombin time (PT)/ international normalized ratio (INR), partial thromboplastin
 time (PTT) < 1.3 x upper limit of normal (ULN)

 -  Aspartate aminotransferase (AST)/ alanine aminotransferase (ALT) =< 3 x ULN

 -  Total bilirubin =< 1.5 x ULN

 -  Except in the case of Gilbert disease, in which case total bilirubin must be =< 3
 x ULN

 -  Creatinine =< 1.5 mg/dL OR creatinine clearance >= 45 mL/min

 -  Albumin >= 2.8 g/dL

 -  Potassium within normal limits (WNL)

 -  Supplementation is acceptable to achieve a value WNL; in patients with low
 albumin levels, a corrected calcium value WNL is acceptable; in patients with
 abnormal TSH, if free T4 is normal and patient is clinically euthyroid, patient
 is eligible

 -  Phosphorus WNL

 -  Supplementation is acceptable to achieve a value WNL; in patients with low
 albumin levels, a corrected calcium value WNL is acceptable; in patients with
 abnormal TSH, if free T4 is normal and patient is clinically euthyroid, patient
 is eligible

 -  Calcium WNL Phosphorus WNL

 -  Supplementation is acceptable to achieve a value WNL; in patients with low
 albumin levels, a corrected calcium value WNL is acceptable; in patients with
 abnormal TSH, if free T4 is normal and patient is clinically euthyroid, patient
 is eligible

 -  Magnesium WNL

 -  Supplementation is acceptable to achieve a value WNL; in patients with low
 albumin levels, a corrected calcium value WNL is acceptable; in patients with
 abnormal TSH, if free T4 is normal and patient is clinically euthyroid, patient
 is eligible

 -  Urine protein to creatinine (UPC) ratio =< 1

 -  QT interval corrected for heart rate using Fridericia's formula (QTcF) =< 500 msec

 -  Thyroid-stimulating hormone (TSH) WNL

 -  Supplementation is acceptable to achieve a TSH WNL; in patients with abnormal
 TSH, if free T4 is normal and patient is clinically euthyroid, patient is
 eligible