Gefitinib in Treating Patients With Progressive Metastatic Neuroendocrine Tumors

Brief Title

Gefitinib in Treating Patients With Progressive Metastatic Neuroendocrine Tumors

Official Title

A Phase II Trial of ZD1839 (Iressa®) in Metastatic Neuroendocrine Tumors

Brief Summary

      This phase II trial is studying how well gefitinib works in treating patients with
      progressive metastatic neuroendocrine tumors. Gefitinib may stop the growth of tumor cells by
      blocking the enzymes necessary for their growth.
    

Detailed Description

      PRIMARY OBJECTIVES:

      I. To determine the 6 month progression free survival rate in patients with progressive,
      advanced neuroendocrine tumors treated with ZD1839.

      SECONDARY OBJECTIVES:

      I. Objective tumor response rate. II. Progression free survival and time to progression. III.
      Improvement in circulating hormone levels. IV. Overall survival V. We will explore the
      molecular characterization of these tumors in attempt to understand the role of EGFR
      expression and its inhibition with ZD1839 in neuroendocrine tumors. The measurements will be
      performed on pretreatment and post-treatment tumor biopsies when possible: EGFR expression
      and gene amplification (IHC for EGFR and phosphorylated EGFR, ISH for gene amplification);
      Activation of the Ras/Raf/MAPK pathway (IHC for phosphorylated MAPK); Cell proliferation
      (Ki-67 staining); Apoptosis (TUNEL assay).

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

      Patients receive oral gefitinib once daily on days 1-28. Courses repeat every 28 days in the
      absence of disease progression or unacceptable toxicity.

      Patients are followed every 3 months until disease progression and then every 6 months for up
      to 2 years from study entry.
    

Study Phase

Phase 2

Study Type

Interventional


Primary Outcome

Proportion of patients progression-free at 6 months

Secondary Outcome

 Incidence of adverse events graded according to NCI CTCAE version 3.0

Condition

Gastrinoma

Intervention

gefitinib

Study Arms / Comparison Groups

 Arm I
Description:  Patients receive oral gefitinib once daily on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Drug

Estimated Enrollment

90

Start Date

December 2003


Primary Completion Date

May 2007

Eligibility Criteria

        Inclusion Criteria:

          -  Histologically confirmed metastatic neuroendocrine neoplasms or histologic
             confirmation of primary neuroendocrine tumor with clear clinical evidence of
             metastases

          -  Measurable disease

          -  Radiographic evidence of disease progression, following any prior systemic therapy,
             chemoembolization, embolization, or observation; for eligibility purposes, disease
             progression will be defined as follows:

               -  Either of the following documented by comparison of the on-study radiographic
                  assessment with a prior assessment of the same type performed within the previous
                  60 calendar weeks:

                    -  Appearance of a new lesion

                    -  At least 20% increase in the longest diameter (LD) of any previously
                       documented lesion or an increase in the sum of the LDs of multiple lesions
                       in aggregate of 20%

          -  ≥4 weeks from the completion of major surgery, chemotherapy or other systemic therapy
             and hepatic artery embolization/chemoembolization to study registration

          -  ≥3 weeks from the completion of radiation therapy to study registration

          -  Recovered sufficiently from side effects of prior therapy

          -  Absolute neutrophil count (ANC) ≥ 1000/mm3

          -  PLT ≥ 75,000/ mm3

          -  Hgb ≥ 8.0 g/dL

          -  Total bilirubin ≤ 2 x upper normal limit (UNL)

          -  Alkaline phosphatase ≤ 3 x UNL (5 x UNL if liver metastases present)

          -  AST ≤ 3 x UNL (≤ 5 x UNL if liver metastases present)

          -  Creatinine ≤ 1.5 x UNL

          -  ECOG performance score (ps) ≤ 2

          -  Life expectancy ≥ 24 weeks

          -  Capable of understanding the investigational nature, potential risks and benefits of
             the study and able to provide valid informed consent

        Exclusion Criteria:

          -  Thyroid carcinoma of any histology or pheochromocytoma/paraganglioma

          -  Any of the following as this regimen may be harmful to a developing fetus or nursing
             child:

               -  Pregnant women

               -  Breastfeeding women

               -  Men or women of childbearing potential or their sexual partners who are unwilling
                  to employ adequate contraception (condoms, diaphragm, birth control pills,
                  injections, intrauterine device [IUD], surgical sterilization, subcutaneous
                  implants, or abstinence, etc.)

               -  NOTE: The effects of the agent(s) on the developing human fetus at the
                  recommended therapeutic dose are unknown

          -  Anaplastic or high-grade histology

          -  Any of the following prior therapies:

               -  > 1 prior systemic chemotherapy regimen (chemoembolization not counted as
                  systemic chemotherapy)

               -  Prior EGFR targeted regimen (e.g. OSI-774, EKB-569, ZD1839)

               -  < 4 weeks from last Interferon injection

               -  < 2 weeks from last octreatide short acting injection or < 6 weeks long acting
                  injection; Note: concurrent octreatide allowed if stable dose has been
                  administered for ≥1 month, there is documented tumor progression on the current
                  dose, and there is no current plan for increasing dose • Other concurrent
                  treatment considered investigational

          -  Concurrent chemotherapy or radiation therapy

          -  Any of the following:

               -  Gastrointestinal tract disease resulting in an inability to take oral medication
                  (e.g. dysphagia or inability to swallow capsules intact).

               -  Requirement for IV alimentation

               -  Prior procedures clearly adversely affecting intestinal absorption

               -  Active peptic ulcer disease

               -  Failure to fully recover from adverse effects of prior therapies regardless of
                  interval since last treatment

          -  Known abnormality of cornea, such as:

               -  History of dry eye syndrome or Sjogren syndrome

               -  Congenital abnormality

               -  Abnormal slit-lamp examination using a vital dye (e.g.: fluorescein or
                  Bengal-rose)

               -  Abnormal corneal sensitivity test (Schirmer test)

          -  Uncontrolled intercurrent illness including, but not limited to:

               -  Ongoing or active infection

               -  Symptoms of congestive heart failure

               -  Unstable angina pectoris, cardiac arrhythmia

               -  Psychiatric illness/social situation that would limit compliance with study
                  requirement

          -  Known brain metastases; Note: These patients are 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

          -  Known HIV-positive patients receiving combination anti-retroviral therapy; Note: These
             patients are excluded from the study because of possible pharmacokinetic interactions
             with ZD1839 and because patients with immune deficiency are at increased risk of
             lethal infections when treated with marrow-suppressive therapy; appropriate studies
             will be undertaken in patients receiving combination and anti-retroviral therapy when
             indicated

          -  Concurrent or recent use (≤ 7 days prior to ZD1839 administration) of phenytoin,
             carbamazepine, barbiturates, rifampicin, oxcarbazepine, rifapentine, modafinil, or St.
             John's Wort; Note: Because these drugs induce CYP3A4 enzymes and can cause reductions
             in ZD1839 plasma concentrations below levels thought to be biologically active,
             patients with concurrent or recent use of these drugs are excluded from the study

          -  History of other invasive malignancy ≤ the previous 3 years, except for adequately
             treated basal cell or squamous cell skin cancer, or carcinoma in situ of the cervix
      

Gender

All

Ages

18 Years - N/A

Accepts Healthy Volunteers

No

Contacts

Timothy Hobday, , 

Location Countries

United States

Location Countries

United States

Administrative Informations


NCT ID

NCT00075439

Organization ID

NCI-2012-02796

Secondary IDs

MC0279

Responsible Party

Sponsor

Study Sponsor

National Cancer Institute (NCI)


Study Sponsor

Timothy Hobday, Principal Investigator, Mayo Clinic


Verification Date

June 2013