Romidepsin in Treating Patients With Locally Advanced or Metastatic Neuroendocrine Tumors

Study Overview
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Brief Summary
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Phase II trial to study the effectiveness of romidepsin in treating patients who have locally advanced or metastatic neuroendocrine tumors. Drugs used in chemotherapy, such as romidepsin, work in different ways to stop tumor cells from dividing so they stop growing or die.

Detailed Description
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PRIMARY OBJECTIVES: I. Determine objective response rate in patients with locally advanced or metastatic neuroendocrine tumors treated with FR901288 (romidepsin). SECONDARY OBJECTIVES: I. Determine the toxicity of this drug in these patients. II. To measure serum tumor markers (pancreastatin, gastrin, pancreatic polypeptide, glucagon, substance-P, neurotensin, calcitonin, somatostatin, vasoactive intestinal peptide, gastrin releasing polypeptide, ACTH) depending on the tumor type pre-, during-, and post-treatment. III. To perform a nuclear medicine functional imaging scan (octreoscan) to evaluate the disease status pre-, during-, and post-treatment. IV. To perform histone acetylation assay in cytospins from peripheral blood mononuclear cells (PBMCs) to correlate with disease response and with immunologic parameters. V. To quantify gene expression by Real Time PCR of type 1 and type 2 cytokines, co-stimulatory molecules, and adhesion molecules in PBMCs obtained from the pre-, during-, and post-treatment blood samples. VI. To perform a multicolor flow cytometric analysis on fresh blood to assess activation of lymphocyte subsets and presence of co-stimulatory and adhesion molecules. VII. To perform in vitro functional assays for innate as well as antigen-specific T cell immune responses in PBMCs obtained from the pre-, during-, and post-treatment blood samples. OUTLINE: Patients receive romidepsin IV over 4 hours on days 1, 8, and 15. Treatment repeats every 28 days for 6 courses in the absence of disease progression or unacceptable toxicity. Patients achieving complete remission (CR) receive 2 additional courses beyond CR. Patients are followed at 2-4 weeks.

Official Title
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Phase II Study of Depsipeptide in Metastatic Neuroendocrine Tumors

Conditions
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Gastrinoma, Glucagonoma, Insulinoma, Metastatic Gastrointestinal Carcinoid Tumor, Pancreatic Polypeptide Tumor, Pulmonary Carcinoid Tumor, Recurrent Gastrointestinal Carcinoid Tumor, Recurrent Islet Cell Carcinoma, Regional Gastrointestinal Carcinoid Tumor, Somatostatinoma

Intervention / Treatment
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* Drug: romidepsin
* Other: laboratory biomarker analysis


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically confirmed carcinoid tumor or islet cell neuroendocrine tumor Well- or moderately-differentiated tumor Metastatic and/or locally advanced disease Measurable disease Unidimensionally measurable lesion at least 20 mm by conventional techniques OR at least 10 mm by spiral CT scan Lesions in a previously irradiated area are not considered measurable No truly non-measurable lesions, including the following: Bone lesions Leptomeningeal disease Ascites Pleural or pericardial effusion Lymphangitis cutis/pulmonis Abdominal masses not confirmed and followed by imaging Cystic lesions Ineligible for standard treatment Performance status - ECOG 0-1 At least 6 months WBC >= 3,000/mm^3 Absolute neutrophil count >= 1,500/mm^3 Platelet count >= 100,000/mm^3 Bilirubin =< 1.5 mg/dL AST and ALT =< 2.5 times upper limit of normal Creatinine =< 1.5 mg/dL No New York Heart Association class III or IV congestive heart failure No myocardial infarction within the past year No uncontrolled dysrhythmias No poorly controlled angina No serious ventricular arrhythmia, defined as ventricular tachycardia or ventricular fibrillation >= 3 beats in a row No left ventricular hypertrophy by EKG No other significant cardiac disease QTc < 500 msec LVEF > 40% by resting MUGA No prior allergic reaction attributed to compounds of similar chemical or biological composition to study drug No ongoing or active infection No psychiatric illness or social situation that would preclude study compliance No other concurrent uncontrolled illness Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception More than 4 weeks since prior immunotherapy (e.g., interferon alfa) More than 4 weeks since prior chemotherapy More than 12 weeks since prior hepatic artery chemoembolization unless liver lesions are not the only indicator lesions No prior FR901228 (depsipeptide) No more than 1 prior systemic chemotherapy regimen for carcinoid or islet cell tumor (other than hepatic artery chemoembolization) More than 4 weeks since prior oral or IV steroids (first 16 patients only) Concurrent long-acting octreotide allowed at standard doses if dose has been stable for the past 12 weeks Concurrent subcutaneous octreotide for breakthrough use for symptomatic relief allowed No concurrent systemic steroids (first 16 patients only) More than 4 weeks since prior radiotherapy More than 4 weeks since prior investigational tumor-specific therapy No other prior histone deacetylase inhibitors (e.g., valproic acid) No concurrent hydrochlorothiazide No concurrent combination antiretroviral therapy for HIV-positive patients No other concurrent investigational or commercial agents or therapies for the malignancy

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (romidepsin)<br>Patients receive romidepsin IV over 4 hours on days 1, 8, and 15. Treatment repeats every 28 days for 6 courses in the absence of disease progression or unacceptable toxicity. Patients achieving CR receive 2 additional courses beyond CR. | Drug: romidepsin<br>* Given IV<br>* Other names: Istodax;Other: laboratory biomarker analysis<br>* Correlative studies<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective response rate | Frequency of response will be estimated with a 95% confidence interval. | Up to 4 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of toxicity |  | Up to 4 weeks |