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Prospective Randomized Phase II Trial of Pazopanib (NSC # 737754, IND 75648) Versus Placebo in Patients With Progressive Carcinoid Tumors

Phase 2
18 Years
Open (Enrolling)
Metastatic Gastrointestinal Carcinoid Tumor, Pulmonary Carcinoid Tumor, Recurrent Gastrointestinal Carcinoid Tumor, Recurrent Neuroendocrine Carcinoma of the Skin, Regional Gastrointestinal Carcinoid Tumor, Stage III Neuroendocrine Carcinoma of the Skin, Stage IV Neuroendocrine Carcinoma of the Skin, Thyroid Gland Medullary Carcinoma

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Trial Information

Prospective Randomized Phase II Trial of Pazopanib (NSC # 737754, IND 75648) Versus Placebo in Patients With Progressive Carcinoid Tumors


I. For patients with progressive carcinoid tumors, progression-free survival (PFS) (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.


I. Overall survival 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 as assessed by central radiology review and local radiology
review will be compared overall and within treatment arms.

IV. PFS at 6 months and 12 months will be estimated within each treatment arm. V. Safety and
tolerability of treatment with pazopanib/placebo will be evaluated within each treatment

VI. Biochemical response (for chromogranin A, defined as a decrease of 50% or more in plasma
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

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


I. Average time to submission of scans to the Imaging Core Laboratory (ICL) and average ICL
"turn-around" time will be estimated.

II. Discordance between the local and central radiology review in assessment of progression
will be estimated.

III. The rates and quality of radiographic progression (pre-study, on-study, and
post-progression) will be characterized.

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

V. 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).

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

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.
Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

ARM II: Patients receive placebo PO QD on days 1-28. Courses 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 (measureable 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 brochi 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)

- 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 4 weeks
prior to registration, and any treatment-related toxicities must have improved to =<
grade 1

- 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

- 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

- 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

- 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

- 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 mmHg)

- 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,
unstable angina or angina requiring surgical or medical intervention in 6 months
prior to registration, or myocardial infarction (MI); 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, 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

- No ongoing cardiac dysrhythmias, atrial fibrillation, or prolongation of corrected
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) >

- 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; patients
receiving anticoagulant therapy 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)

- 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 (UPC) ratio < 1, or, 24-hour urine protein < 1g; if 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

Type of Study:


Study Design:

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Crossover Assignment, Masking: Double Blind (Subject, Investigator), Primary Purpose: Treatment

Outcome Measure:

Progression-free survival

Outcome Description:

PFS will be estimated within treatment arm using the Kaplan-Meier method.

Outcome Time Frame:

From date of patient entry until documented progression of disease or death from any cause, assessed up to 5 years

Safety Issue:


Principal Investigator

Emily Bergsland

Investigator Role:

Principal Investigator

Investigator Affiliation:

Cancer and Leukemia Group B


United States: Food and Drug Administration

Study ID:




Start Date:

June 2013

Completion Date:

Related Keywords:

  • Metastatic Gastrointestinal Carcinoid Tumor
  • Pulmonary Carcinoid Tumor
  • Recurrent Gastrointestinal Carcinoid Tumor
  • Recurrent Neuroendocrine Carcinoma of the Skin
  • Regional Gastrointestinal Carcinoid Tumor
  • Stage III Neuroendocrine Carcinoma of the Skin
  • Stage IV Neuroendocrine Carcinoma of the Skin
  • Thyroid Gland Medullary Carcinoma
  • Carcinoid Tumor
  • Carcinoma
  • Carcinoma, Merkel Cell
  • Carcinoma, Medullary
  • Thyroid Neoplasms
  • Carcinoma, Neuroendocrine
  • Malignant Carcinoid Syndrome
  • Gastrointestinal Neoplasms
  • Skin Neoplasms
  • Carcinoma, Basal Cell
  • Carcinoma, Basosquamous
  • Carcinoma, Squamous Cell



Cancer and Leukemia Group B Chicago, Illinois  60606