Pazopanib in Treating Patients With Advanced Neuroendocrine Cancer

Official Title: “A Phase II Study of GW786034 (Pazopanib) in Advanced Low-Grade or Intermediate-Grade Neuroendocrine Carcinoma”

RATIONALE: Pazopanib 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.

PURPOSE: This phase II trial is studying how well pazopanib works in treating patients with advanced neuroendocrine cancer.

OBJECTIVES:

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

Secondary - Determine the progression-free survival of patients treated with this drug. - 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 months.

PROJECTED ACCRUAL: A total of 60 patients will be accrued for this study.

Intervention(s) in this Clinical Trial

• Drug: Pazopanib
  • Starting dose 800 mg administered orally once daily, 28 day cycle.

Arms, Groups and Cohorts in this Clinical Trial

• Experimental: GW786034 (Pazopanib)

Primary Measures

• Number of Patients with Response (Complete + Partial Response)
  • Time Frame: Every 12 weeks
    Safety Issue?: No

Inclusion Criteria:

• 1. Patients must have histologically or cytologically confirmed low or intermediate grade carcinoid or islet cell carcinoma. Patients with carcinoid or islet cell carcinoma associated with MEN1 syndrome will be eligible and entered in the islet cell cohort
• 2. Patients must have 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.
• 3. Patients may have received 0, or 1 prior cytotoxic therapy. Chemotherapy used as a radiosensitizer will be considered one prior chemotherapy regimen. Patient must not have received prior bevacizumab or any other therapy targeting VEGF or VEGF receptors (ie, SU11248, PTK787/ZK222584, Sorafenib, GW786034).
• 4. Patients 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.
• 5. Prior radiation therapy is permitted. A recovery period of at least 4 weeks after completion of radiotherapy is required prior to enrollment.
• 6. Patients may have received prior interferon (not counted toward prior cytotoxic chemotherapy).
• 7. Patients may have received prior therapy targeting c-kit, abl, PDGFR, or EGFR (imatinib, gefitinib, erlotinib, cetuximab; not counted toward prior cytotoxic chemotherapy).
• 8. Age >/= 21 years. GW786034 (pazopanib) is contraindicated in the pediatric population due to the potential effect on the epiphyseal growth plates.
• 9. Patients must have unresectable or metastatic disease.
• 10. ECOG performance status of 0, or 1 (Karnofsky >/= 70%).
• 11. Patients 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) </= 3.0 X institutional upper limit of normal; creatinine </= 2.0 OR creatinine clearance >/= 60 mL/min/1.73 m^2 for patients with creatinine levels above institutional normal.
• (Calculated by Cockcroft Gault formula)
• 12. Patients must have PT/INR/PTT within 1.2 X the upper limit of normal.
• 13. Patients 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.
• 14. 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 participation.
• 15. 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.
• 16. 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;
• 17. 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 interaction.
• 18. Ability to understand and the willingness to sign a written informed consent document.
• 19. Ability to swallow and retain oral medication
• 20. Both men and women and members of all races and ethnic groups are eligible for this trial.

Exclusion Criteria:

• 1. Patients who 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.
• 2. Patients may not be receiving any other investigational agents.
• 3. Patients with QTc > 480msecs
• 4. Patients with greater than +1 (>/= 100 mg/dl) proteinuria on two consecutive routine urinalyses taken at least 1 week apart are ineligible.
• 5. 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.
• 6. Patients 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.
• 7. Patients 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.
• 8. Patients 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.
• 9. Patients 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 events.
• 10. 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.
• 11. 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.
• 12. HIV-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with GW786034 (pazopanib).
• 13. Uncontrolled diarrhea (8 or more bowel movements per day)

Gender Eligibility for this Clinical Trial: Both

Minimum Age for this Clinical Trial: 21 Years

Maximum Age for this Clinical Trial: N/A

Are Healthy Volunteers Accepted for this Clinical Trial?: No

Lead Investigator: M.D. Anderson Cancer Center Other

Overall Clinical Trial Officials and Contacts

Alexandra Phan, MD Study Chair M.D. Anderson Cancer Center  

Information obtained from ClinicalTrials.gov on February 12, 2012

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00454363

Study ID Number: 2006-0077

ClinicalTrials.gov Identifier: NCT00454363

Health Authority: United States: Food and Drug Administration

Clinical trial summary from the National Cancer Institute's PDQ® database

UT MD Anderson Cancer Center website