Romidepsin in Treating Patients With Locally Advanced or Metastatic Neuroendocrine Tumors

Phase II Study of Depsipeptide in Metastatic Neuroendocrine Tumors

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.

Study Overview

• Status: Terminated
• Conditions: Gastrinoma; Glucagonoma; Insulinoma; Metastatic Gastrointestinal Carcinoid Tumor; Pancreatic Polypeptide Tumor; Recurrent Gastrointestinal Carcinoid Tumor; Recurrent Islet Cell Carcinoma; Somatostatinoma; Regional Gastrointestinal Carcinoid Tumor; Pulmonary Carcinoid Tumor
• Intervention / Treatment: Other: laboratory biomarker analysis; Drug: romidepsin

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 25
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Ohio
    • Columbus, Ohio, United States, 43210
      • Ohio State University Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Treatment (romidepsin); 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.	Other: laboratory biomarker analysis; Correlative studies; Drug: romidepsin; Given IV; Other Names: FK228; FR901228; Istodax

What is the study measuring?

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	Time Frame
Incidence of toxicity	Up to 4 weeks

Collaborators and Investigators

• Sponsor: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Manisha Shah, Ohio State University

Study record dates

Study Major Dates

• Study Start: March 1, 2004
• Primary Completion (Actual): October 1, 2004

Study Registration Dates

• First Submitted: June 10, 2004
• First Submitted That Met QC Criteria: June 10, 2004
• First Posted (Estimate): June 11, 2004

Study Record Updates

• Last Update Posted (Estimate): June 4, 2013
• Last Update Submitted That Met QC Criteria: June 3, 2013
• Last Verified: June 1, 2013

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Neoplasms by Histologic Type; Neoplasms by Site; Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Endocrine System Diseases; Disease Attributes; Digestive System Neoplasms; Gastrointestinal Diseases; Endocrine Gland Neoplasms; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Pancreatic Diseases; Adenoma; Carcinoma, Neuroendocrine; Pancreatic Neoplasms; Adenoma, Islet Cell; Neoplasms; Recurrence; Gastrointestinal Neoplasms; Neuroendocrine Tumors; Carcinoid Tumor; Malignant Carcinoid Syndrome; Carcinoma, Islet Cell; Insulinoma; Gastrinoma; Glucagonoma; Somatostatinoma; Antineoplastic Agents; Antibiotics, Antineoplastic; Romidepsin
• Other Study ID Numbers: NCI-2012-01449; U01CA076576 (U.S. NIH Grant/Contract); 0425; NCI-6325; OSU-2003C0085; CDR0000365313