Pazopanib Hydrochloride in Treating Patients With Progressive Carcinoid Tumors
Pazopanib Hydrochloride in Treating Patients With Progressive Carcinoid Tumors
This randomized phase II trial studies how well pazopanib hydrochloride works in treating
 patients with carcinoid tumors that are growing, spreading, or getting worse. Pazopanib
 hydrochloride may stop the growth of tumor cells by blocking some of the enzymes needed for
 cell growth.
PRIMARY OBJECTIVES:

 I. For patients with progressive carcinoid tumors, progression-free survival (PFS defined by
 central review according to Response Evaluation Criteria in Solid Tumors [RECIST] 1.1) will
 be compared between patients randomized to treatment with pazopanib (pazopanib hydrochloride)
 versus placebo.

 SECONDARY OBJECTIVES:

 I. Overall survival (OS) will be compared between treatment arms. II. Objective response
 rate, duration of response, and time to treatment failure will be compared between treatment
 arms.

 III. Progression free survival (PFS) as assessed by central radiology review and local
 radiology review will be compared overall and within treatment arms.

 IV. Safety and tolerability of treatment with pazopanib/placebo will be evaluated within each
 treatment arm.

 V. PFS and other indicators of efficacy will be estimated in patients who crossover to
 pazopanib from placebo.

 VI. To determine the turn-around time for timely adjudicated central review. VII. To
 characterize the nature of discordance between local and central radiology review in
 assessment of progression.

 VIII. To characterize the type and rate of progression in carcinoid (at study entry,
 on-study, and at progression).

 IX. To develop new methods for modeling carcinoid growth and detecting treatment effects, and
 to perform simulations that advance new clinical trial designs to apply to future trials of
 carcinoid therapeutics.

 X. To assess for differences in quality of life (QOL)-related domains between the two
 treatment groups (pazopanib versus placebo).

 XI. To determine if the more brief measures of QOL-related domains provide comparable
 information to that which is provided by the longer assessments (European Organization for
 Research and Treatment of Cancer [EORTC], neuroendocrine tumors [NET]21).

 XII. To provide validation data for the EORTC NET21 module in terms of responsiveness over
 time and differences across arms.

 XIII. To determine whether components of the plasma angiome panel that have been shown to be
 predictive previously (interleukin-6 [IL-6] and vascular endothelial growth factor [VEGF]-D)
 are predictive of a therapeutic advantage for pazopanib treatment in baseline samples from
 the patients treated on A021202.

 XIV. To determine whether other components of the plasma angiome panel tested (not IL-6 and
 VEGF-D) are predictive of a therapeutic advantage for pazopanib treatment in baseline samples
 from the patients treated on A021202.

 XV. To evaluate the changes in the plasma angiome markers after treatment with or without
 pazopanib over time.

 EXPLORATORY OBJECTIVES:

 I. PFS at 6 months will be estimated within each treatment arm. II. Biochemical response (for
 chromogranin A, defined as a decrease of 50% or more in chromogranin A levels from baseline
 and for 5-hydroxyindoleacetic acid [5-HIAA], defined as a decrease of 50% or more in urinary
 5-HIAA levels from baseline) will be compared between treatment arms among patients with
 elevated baseline levels of chromogranin A (CGA) and 5-HIAA.

 OUTLINE: Patients are randomized to 1 of 2 treatment arms.

 ARM I: Patients receive pazopanib hydrochloride 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. At the time of progressive disease,
 patients may cross-over to Arm I.

 After completion of study treatment, patients are followed up every 3-6 months for 5 years.
Inclusion Criteria:

 -  Low- or intermediate-grade neuroendocrine carcinoma, including the following subtypes:
 carcinoid tumor, low- to intermediate-grade or well- to moderately-differentiated
 neuroendocrine carcinoma or tumor, atypical carcinoid tumor; documentation from a
 primary tumor or metastatic site is sufficient; patients with poorly differentiated
 neuroendocrine carcinoma, high-grade neuroendocrine carcinoma, adenocarcinoid tumor,
 or goblet cell carcinoid tumor are not eligible

 -  Locally unresectable or metastatic carcinoid tumors

 -  Patients must have histologic documentation or clinical evidence of a carcinoid tumor
 of primary site (including foregut, midgut, hindgut or other non-pancreatic site);
 tumors of unknown primary site are eligible provided the treating physician does not
 suspect medullary thyroid cancer, pancreatic neuroendocrine tumor, paraganglioma, or
 pheochromocytoma; unknown primary tumors will be classified as small bowel tumors for
 the purpose of stratification; functional (associated with a clinical syndrome) or
 nonfunctional tumors are allowed; target lesions must have shown disease progression
 if therapy included peptide receptor radiotherapy (PRRT) and PRRT must be completed at
 least 8 weeks prior to registration

 -  Radiological evidence for progressive disease (measurable or non-measurable) within 12
 months prior to registration; patients who have received anti-tumor therapy during the
 past 12 months (including octreotide analogs) must have had radiological documentation
 of progression of disease while on or after receiving therapy

 -  No known endobronchial lesions and/or lesions infiltrating major pulmonary vessels
 that increase the risk of pulmonary hemorrhage; patients with lesions infiltrating
 major pulmonary vessels (contiguous tumor and vessels) are excluded; however, the
 presence of a tumor that is touching, but not infiltrating (abutting) the vessels is
 acceptable (computed tomography [CT] with contrast is strongly recommended to evaluate
 such lesions); patients with large protruding endobronchial lesions in the main or
 lobar bronchi are excluded; however, endobronchial lesions in the segmented bronchi
 are allowed

 -  Patients must have measurable disease per RECIST 1.1 by computed 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); index lesions for the purpose of RECIST 1.1 measurements will not
 be selected from within the radiation therapy treatment field; however, if there is
 evidence of disease progression within the radiation treatment field, measurement of
 the progressing lesions will be documented

 -  No prior treatment with an inhibitor of vascular endothelial growth factor (VEGF) or
 vascular endothelial growth factor receptor (VEGFR)

 -  Prior treatment (somatostatin analogs excepted) must be completed at least 2 weeks
 prior to registration; in addition, prior treatment (somatostatin analogs excepted)
 must be completed at least 4 weeks prior to initiation of study drug;
 treatment-related toxicities must have improved to =< grade 1 prior to registration,
 with the exception of alopecia

 -  Concurrent use of somatostatin analogs (SSTa) is allowed, provided that the patient is
 on a stable dose for at least two months and progressive disease on somatostatin
 analog has been documented; progression on octreotide is required for patients with
 tumors arising in the midgut

 -  Prior treatment with 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 there is documented disease
 progression in a treated site; there is no limit on the prior number of procedures;
 prior liver-directed or other ablative treatment must be completed at least 8 weeks
 prior to registration; index lesions for the purpose of RECIST 1.1 measurements will
 not be selected from within the radiation therapy treatment field; however, if there
 is evidence of disease progression within the radiation treatment field, measurement
 of the progressing lesions will be documented

 -  Patients should have completed any major surgery >= 4 weeks prior to registration and
 must have completed any minor surgery >= 2 weeks prior to registration; patients must
 have fully recovered from the procedure

 -  The following are examples of procedures considered to be minor: port placement,
 laparoscopy, thoracoscopy, bronchoscopy, mediastinoscopy, skin biopsies,
 incisional biopsies, imaging-guided biopsy for diagnostic purposes, and dental
 extraction procedures

 -  Insertion of a vascular access device, thoracentesis, paracentesis, and
 endoscopic ultrasonographic procedures are not considered to be major or minor
 surgeries

 -  No concurrent condition resulting in immune compromise, including chronic treatment
 with corticosteroids or other immunosuppressive agents

 -  No clinical evidence of central nervous system (CNS) metastases (including
 carcinomatous meningitis) at baseline, with the exception of those patients who have
 previously-treated CNS metastases (surgery +/- radiotherapy, radiosurgery, or gamma
 knife) and who meet both of the following criteria: a) are asymptomatic and b) had no
 requirement for steroids or enzyme-inducing anticonvulsants within 6 months prior to
 registration

 -  No history of abdominal fistula, gastrointestinal perforation, or intra-abdominal
 abscess within 28 days prior to registration

 -  No clinically significant gastrointestinal abnormalities that may increase the risk
 for gastrointestinal bleeding within 28 days prior to registration including, but not
 limited to:

 -  Active peptic ulcer

 -  Known endoluminal metastatic lesion(s) with history of bleeding

 -  Inflammatory bowel disease (e.g. ulcerative colitis, Crohn's disease), or other
 gastrointestinal conditions with increased risk of perforation

 -  No history of serious (i.e., requiring active medical therapy with medication or
 medical device under the supervision of a physician) non-healing wound, ulcer, trauma,
 or bone fracture within 28 days prior to study entry

 -  Patients with a history of hypertension must have blood pressure that is adequately
 controlled on antihypertensives; (< 140/90 mm Hg)

 -  No symptomatic congestive heart failure (New York Heart Association class II, III, or
 IV) within 6 months prior to registration

 -  No arterial thrombotic events within 6 months of registration, including transient
 ischemic attack (TIA), cerebrovascular accident (CVA), peripheral arterial thrombus,
 myocardial infarction (MI), or unstable angina or angina requiring surgical or medical
 intervention in 6 months prior to registration; patients with clinically significant
 peripheral artery disease (i.e., claudication on less than one block) are ineligible;
 patients who have experienced a deep venous thrombosis or pulmonary embolus within 6
 months prior to registration must be on stable therapeutic anticoagulation for at
 least 6 weeks prior to enrollment of this study

 -  Patients on therapeutic anticoagulation with low molecular weight heparins,
 fondaparinux, rivaroxaban or warfarin are eligible, provided that they are on a stable
 dose of anticoagulants; patients who are currently receiving antiplatelet therapy of
 prasugrel or clopidogrel or antiaggregation agents (e.g., eptifibatide, epoprostenol,
 dipyridamole) or low doses of acetylsalicylic acid (up to 100 mg daily) are also
 eligible

 -  No ongoing cardiac dysrhythmias, atrial fibrillation, or prolongation of corrected QT
 (QTc) interval to > 480 msec

 -  No evidence of active bleeding, bleeding diathesis, or hemoptysis (>= 1/2 teaspoon of
 red blood) within 8 weeks prior to registration

 -  No currently unstable angina and/or uncontrolled cardiac arrhythmias

 -  Patients with symptomatic peripheral vascular disease are ineligible

 -  Ejection fraction on echocardiogram (Echo) or multi gated acquisition scan (MUGA) >
 50%

 -  Chronic concomitant treatment with strong inhibitors of cytochrome P450, family 3,
 subfamily A, polypeptide 4 (CYP3A4) is not allowed on this trial; patients on strong
 CYP3A4 inhibitors must discontinue the drug 14 days prior to the start of study
 treatment

 -  Women must not be pregnant or nursing; women of child bearing potential must have a
 negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent
 units of human chorionic gonadotropin [HCG]) within 72 hours prior to registration;
 women of child-bearing potential include any female who has experienced menarche and
 who has not undergone surgical sterilization (hysterectomy, bilateral tubal ligation
 or bilateral oophorectomy) or is not postmenopausal (defined as amenorrhea >= 12
 consecutive months; or women on hormone replacement therapy [HRT] with documented
 serum follicle stimulating hormone [FSH] level > 35 mIU/mL)

 -  Eastern Cooperative Oncology Group (ECOG) performance status 0-1

 -  Granulocytes >= 1,500/mcL

 -  Platelets >= 100,000/mcL

 -  International normalized ratio (INR) =< 1.2 X upper limit of normal (ULN); only
 required for patients receiving anticoagulant therapy; patients are eligible if their
 INR is stable and within the recommended range for the desired level of
 anticoagulation

 -  QTc =< 480 msecs

 -  Thyroid stimulating hormone (TSH) within normal limits (WNL); medications for thyroid
 dysfunction are allowed as long as TSH is normal at registration; in patients with
 abnormal TSH, if the free thyroxine (free T4) and free thyroxine index (FTI) are
 normal and patient is clinically euthyroid, patient is eligible

 -  Bilirubin =< 1.5 x ULN

 -  Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) &
 alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x
 ULN; concomitant elevations in bilirubin and AST/ALT above 1.0 X ULN are NOT
 permitted; also, if liver metastases are present, AST & ALT =< 5 x ULN is allowed

 -  Serum creatinine =< 1.5 x ULN

 -  Urine protein to creatinine ratio < 1, or, 24-hour urine protein < 1 g; if urine
 protein to creatinine (UPC) >= 1, then a 24-hour urine protein must be assessed;
 patients must have a 24-hour urine protein value < 1 g to be eligible; use of urine
 dipstick for renal function assessment is not acceptable