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A Phase II Study of GW786034 (Pazopanib) in Advanced Low-Grade or Intermediate-Grade Neuroendocrine Carcinoma

Phase 2
21 Years
Open (Enrolling)
Gastrinoma, Glucagonoma, Insulinoma, Metastatic Gastrointestinal Carcinoid Tumor, Multiple Endocrine Neoplasia Type 1, Multiple Endocrine Neoplasia Type 2, Pancreatic Polypeptide Tumor, Pulmonary Carcinoid Tumor, Recurrent Gastrointestinal Carcinoid Tumor, Recurrent Islet Cell Carcinoma, Regional Gastrointestinal Carcinoid Tumor, Somatostatinoma, WDHA Syndrome

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Trial Information

A Phase II Study of GW786034 (Pazopanib) in Advanced Low-Grade or Intermediate-Grade Neuroendocrine Carcinoma


I. Determine the objective response rate (complete and partial response) in patients with
low- or intermediate-grade advanced neuroendocrine carcinoma treated with pazopanib


I. Determine the progression-free survival of patients treated with this drug. II. Determine
the safety and tolerability of this drug in these patients.

OUTLINE: This is a multicenter study. Patients are stratified according to disease type
(carcinoid tumors vs islet cell carcinoma).

Patients receive oral pazopanib hydrochloride once daily on days 1-28. Treatment repeats
every 28 days for 12 courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed every 3 months for up to 18


- At least 4 weeks since prior major surgery

- No CYP2C9 inhibitors for 14 days prior to, during, and for 2 weeks after completion
of study therapy, including any of the following:

Oral hypoglycemics (e.g., glipizide, glyburide, tolbutamide, glimepiride, nateglinide)
Ergot derivatives (e.g., dihydroergotamine, ergonovine, ergotamine, methylergonovine)
Neuroleptics (e.g., pimozide)

- No CYP2C9 inhibitors for 14 days prior to, during, and for 2 weeks after completion
of study therapy, including any of the following: Erectile dysfunction agents (e.g.,
sildenafil, tadalafil, vardenafil) Antiarrhythmics (e.g., bepridil, flecainide,
lidocaine, mexiletine hydrochloride, amiodarone, quinidine, propafenone) Immune
modulators (e.g., cyclosporine, tacrolimus, sirolimus)

- No CYP2C9 inhibitors for 14 days prior to, during, and for 2 weeks after completion
of study therapy, including any of the following: Theophylline Quetiapine Risperidone
Tacrine Clozapine Atomoxetine

- No concurrent therapeutic warfarin Low molecular weight heparin or prophylactic
low-dose warfarin allowed provided inclusion criteria for PT and PTT are met

- No concurrent grapefruit or its juice

- No other concurrent investigational agents

- No other concurrent anticancer agents or therapies

- No concurrent antiretroviral therapy for HIV-positive patients

- No concurrent interferon for control of carcinoid syndrome

- WBC >= 3,000/mm³

Inclusion Criteria:

- Histologically or cytologically confirmed low or intermediate grade carcinoid or
islet cell carcinoma. Carcinoid or islet cell carcinoma associated with MEN1 syndrome
will be eligible and entered in the islet cell cohort.

- Measurable disease, defined as at least one lesion that can be accurately measured in
at least one dimension (longest diameter to be recorded) as >/= 20 mm with
conventional techniques or as >/= 10 mm with spiral CT scan.

- Received 0, or 1 prior cytotoxic therapy. Chemotherapy used as a radiosensitizer will
be considered one prior chemotherapy regimen. Must not have received prior
bevacizumab or any other therapy targeting VEGF or VEGF receptors (ie, SU11248,
PTK787/ZK222584, Sorafenib, GW786034).

- Must be on a stable dose (the same dose) of a somatostatin analogue (Lanreotide,
Octreotide or Vapreotide) for 2 months prior to start of protocol. A somatostatin
analogue does not count toward prior therapy.

- Prior radiation therapy is permitted. A recovery period of at least 4 weeks after
completion of radiotherapy is required prior to enrollment.

- Received prior interferon (not counted toward prior cytotoxic chemotherapy).

- Received prior therapy targeting c-kit, abl, PDGFR, or EGFR (imatinib, gefitinib,
erlotinib, cetuximab; not counted toward prior cytotoxic chemotherapy).

- Age >/= 21 years. GW786034 (pazopanib) is contraindicated in the pediatric population
due to the potential effect on the epiphyseal growth plates.

- Must have unresectable or metastatic disease.

- ECOG performance status of 0, or 1 (Karnofsky >/= 70%).

- Must have normal organ and marrow function as defined below: Leukocytes >/=
3,000/mcL; absolute neutrophil count >/= 1,500/mcL; platelets >/= 120,000/mcL; total
bilirubin within normal institutional limits; AST(SGOT)/ALT(SGPT) institutional upper limit of normal; creatinine /=
60 mL/min/1.73 m^2 for patients with creatinine levels above institutional normal.
(Calculated by Cockcroft Gault formula)

- Must have PT/INR/PTT within 1.2 X the upper limit of normal.

- Must have resting blood pressure (BP) no greater than 140 mmHg (systolic) or 90 mmHg
(diastolic) for eligibility. Initiation or adjustment of BP medication is permitted
prior to study entry.

- The effects of GW786034 (pazopanib) on the developing human fetus are unknown.
However, teratogenic effects and reduced fetal body weight have been seen in pregnant
rats and/or rabbits given GW786034 (pazopanib). For this reason and because
antiangiogenic agents as well as other therapeutic agents used in this trial are
known to be teratogenic, women of child-bearing potential and men must agree to use
adequate contraception prior to study entry and for the duration of study

- Women of child-bearing potential must have a negative blood pregnancy test prior to
study entry. Should a woman become pregnant or suspect she is pregnant while
participating in this study, she should inform her treating physician immediately.

- Acceptable contraceptive methods, when used consistently and in accordance with both
the product label and the instructions of the physician, are as follows: An
intrauterine device with a documented failure rate of less than 1% per year;
Vasectomized partner who is sterile prior to the female patient's entry and is the
sole sexual partner for that female;

- Acceptable contraceptive methods, when used consistently and in accordance with both
the product label and the instructions of the physician, are as follows; Complete
abstinence from sexual intercourse for 14 days before exposure to investigation
product, through the clinical trial, and for at least 21 days after the last dose of
investigational product; Double-barrier contraception (condom with spermicidal jelly,
foam suppository, or film; diaphragm with spermicide; or male condom and diaphragm
with spermicide). Oral contraceptives are not reliable due to potential drug-drug

- Ability to understand and the willingness to sign a written informed consent

- Ability to swallow and retain oral medication

- Both men and women and members of all races and ethnic groups are eligible for this

Exclusion Criteria:

- Have had chemotherapy or radiotherapy within 4 weeks prior to study enrollment. At
least 4 weeks must have elapsed since any major surgery prior to study enrollment.

- May not be receiving any other investigational agents.

- With QTc > 480msecs

- With greater than +1 (>/= 100 mg/dl) proteinuria on two consecutive routine
urinalyses taken at least 1 week apart are ineligible.

- Certain medications that act through the CYP450 system are specifically prohibited in
patients receiving GW786034 (pazopanib) because in vitro data indicate that the agent
has the potential to interact with the cytochrome P450 isoenzymes. Certain other
agents should be used with caution. A list of medications that are specifically
prohibited or that should be used with caution during this trial of GW786034
(pazopanib) can be found in Section 8. Selected lists of agents that could affect
GW786034 (pazopanib) through the cytochrome P450 system can be found in Appendix II.

- With any condition (e.g., gastrointestinal tract disease resulting in an inability to
take oral medication or a requirement for IV alimentation, prior surgical procedures
affecting absorption, or active peptic ulcer disease) that impairs their ability to
swallow and retain GSK786034 (pazopanib) tablets are excluded.

- With any of the following conditions are excluded: Serious or non-healing wound,
ulcer, or bone fracture; History of abdominal fistula, gastrointestinal perforation,
or intra-abdominal abscess within 28 days of treatment; History of known active
diverticulitis within the past 3 months; Any history of cerebrovascular accident
(CVA) within the last 6 months; Current use of therapeutic warfarin.(Low molecular
weight heparin and prophylactic low-dose warfarin are permitted); PT/PTT must meet
the inclusion criteria.

- With any of the following conditions are excluded: History of myocardial infarction,
cardiac arrhythmia, admission for unstable angina, cardiac angioplasty or stenting
within the last 12 weeks; History of venous thrombosis in last 12 weeks; Class III or
IV heart failure as defined by the NYHA functional classification system; A patient
who has a history of Class II heart failure and is asymptomatic on treatment may be
considered eligible.

- With known brain metastases should be excluded from this clinical trial because of
their poor prognosis and because they often develop progressive neurologic
dysfunction that would confound the evaluation of neurologic and other adverse

- No other prior malignancy is allowed except for the following: adequately treated
basal cell or squamous cell skin cancer, or other adequately treated in situ cancer,
or any other cancer from which the patient has been disease free for five years.

- Pregnant women are excluded from this study because GW786034 (pazopanib) is an
antiangiogenic agent which has produced teratogenic effects and reduced fetal body
weight in pregnant rats and/or rabbits, and therefore has the potential for
teratogenic or abortifacient effects in humans. Because there is an unknown but
potential risk for adverse events in nursing infants secondary to treatment of the
mother with GW786034 (pazopanib), breastfeeding should be discontinued if the mother
is treated with GW786034 (pazopanib). These potential risks may also apply to other
agents used in this study.

- HIV-positive on combination antiretroviral therapy are ineligible because of the
potential for pharmacokinetic interactions with GW786034 (pazopanib).

- Uncontrolled diarrhea (8 or more bowel movements per day)

Type of Study:


Study Design:

Endpoint Classification: Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Objective response rate (complete and partial response) for each cohort assessed by Response Evaluation Criteria in Solid Tumors (RECIST)

Outcome Time Frame:

Up to 18 months

Safety Issue:


Principal Investigator

Alexandria Phan

Investigator Role:

Principal Investigator

Investigator Affiliation:

M.D. Anderson Cancer Center


United States: Food and Drug Administration

Study ID:




Start Date:

March 2007

Completion Date:

Related Keywords:

  • Gastrinoma
  • Glucagonoma
  • Insulinoma
  • Metastatic Gastrointestinal Carcinoid Tumor
  • Multiple Endocrine Neoplasia Type 1
  • Multiple Endocrine Neoplasia Type 2
  • Pancreatic Polypeptide Tumor
  • Pulmonary Carcinoid Tumor
  • Recurrent Gastrointestinal Carcinoid Tumor
  • Recurrent Islet Cell Carcinoma
  • Regional Gastrointestinal Carcinoid Tumor
  • Somatostatinoma
  • WDHA Syndrome
  • Neoplasms
  • Carcinoid Tumor
  • Carcinoma
  • Endocrine Gland Neoplasms
  • Gastrinoma
  • Zollinger-Ellison Syndrome
  • Glucagonoma
  • Insulinoma
  • Multiple Endocrine Neoplasia Type 1
  • Multiple Endocrine Neoplasia Type 2a
  • Multiple Endocrine Neoplasia
  • Somatostatinoma
  • Carcinoma, Neuroendocrine
  • Malignant Carcinoid Syndrome
  • Gastrointestinal Neoplasms
  • Carcinoma, Islet Cell



Dana-Farber Cancer Institute Boston, Massachusetts  02115
M D Anderson Cancer Center Houston, Texas  77030