Depsipeptide/Flavopiridol Infusion for Cancers of the Lungs, Esophagus, Pleura, Thymus or Mediastinum

Carcinoma, Non-Small-Cell Lung Clinical Trial

Official title: Phase I Study of Sequential Depsipeptide/Flavopiridol Infusion for Malignancies Involving Lungs, Esophagus, Pleura, Thymus or Mediastinum

Status Terminated

Clinical Trial Summary

This study will test the safety and effectiveness of two experimental medicines - depsipeptide and flavopiridol - given together to treat cancers of the lung, esophagus, and pleura. It will determine the highest dose that these drugs can safely be given together and will test whether giving them together works better at shrinking tumors than giving either one alone.

Patients 18 years of age and older with cancer of the lung, esophagus, or pleura, or other cancers that have spread to the lungs or pleura may be eligible for this study. Candidates are screened with a medical history and physical examination, blood tests, electrocardiogram (EKG), x-rays and scans, pulmonary function tests, and a tumor biopsy (removal of a small piece of tumor tissue for microscopic examination).

Participants are admitted to the hospital for treatment for approximately 10 days during each 28-day treatment cycle. Depsipeptide is infused through an arm vein or central venous catheter (tube placed in a large vein in the neck or chest) for 4 hours. When this infusion is complete, flavopiridol is infused over 72 hours. The dose of depsipeptide is increased four times over the period of the study with successive groups of patients, and flavopiridol is increased once to determine the maximum safe dose of giving these drugs together.

Blood tests are done before and after each depsipeptide infusion and 3 more times for the next 24 hours, and at various times over 4 days during the flavopiridol infusion to evaluate the effects of the medicines. Samples are also drawn periodically throughout the treatment cycle to evaluate safety. Heart function is monitored with several EKGs before and during the depsipeptide doses. The drug has shown effects on EKG tracings, but does not appear to injure the heart muscle.

Tumor biopsies are done before treatment begins and on the fifth day of the first treatment cycle. The biopsies may be done either in the operating room by passing a tube (bronchoscope) down the throat and into the lungs or in the Radiology Department using a thin needle put through the chest wall into the tumor. For the bronchoscopy, numbing medicine is sprayed into the back of the throat to reduce discomfort, and for the needle biopsy, the skin over the biopsy area is numbed. Optional repeat biopsies may be requested before the start of the second treatment cycle and on day 5 of that cycle. (The repeat biopsies are not required for participation in the study.) At the time of each tumor biopsy, a buccal mucosal biopsy is also done. This involves scraping a tongue depressor along the inside of the mouth to collect cells for examination.

At the end of the first treatment cycle, patients return to NIH for evaluation with a physical examination, blood work, x-rays, and scans of the chest, abdomen, pelvis, and brain. Patients who are not experiencing significant drug side effects are offered a second cycle, exactly like the first. The two cycles complete one course of treatment, after which patients once again return to NIH for evaluation. Additional treatment cycles may be offered to patients whose tumors have shrunk or remained stable with therapy. Patients whose tumors have not responded to therapy or who have developed severe drug side effects are taken off the study.

Clinical Trial Description

Background:

In preclinical studies we have demonstrated that the histone deacetylase (HDAC) inhibitor Depsipeptide FR901228 (DP) mediates cell cycle arrest and apoptosis in cultured lung and esophageal cancer, and malignant pleural mesothelioma cells.

We have observed that the cdk inhibitor Flavopiridol (FLA) markedly potentiates Depsipeptide-mediated apoptosis in cultured cancer cells, but not cultured normal epithelial cells.

Patients with advanced malignancies involving lungs, esophagus, or pleura will receive 4-hour Depsipeptide infusion followed by 72-hour FLA infusion using a phase I study design.

Tumor and buccal mucosa biopsies as well as PBMC may be obtained prior to, and after therapy to evaluate gene expression using cDNA array long-oligo and protein lysate array techniques, and determine if sequential DP/FLA mediates apoptosis in target tissues.

Results of these studies may provide the rationale for phase II evaluation of sequential DP/FLA infusion in thoracic oncology patients.

Objectives:<TAB>

Primary objectives:

To define the maximum tolerated dose (MTD) and dose limiting toxicities (DLT) of sequential 4 hour Depsipeptide(DP)/72 hour Flavopiridol (FLA)

To evaluate the pharmacokinetics of sequential DP/FLA infusion

Secondary objectives

To analyze gene expression profiles in laser-captured tumor cells, buccal mucosa, and PBMC before and after sequential DP/FLA exposure.

To analyze mcl-1 protein expression and apoptosis in tumor biopsies before and after sequential DP/FLA treatment.

Tertiary objectives:

The development of tissue and serum proteomic techniques to assess treatment response in patients receiving sequential DP/FLA infusions.

Eligibility:

Patients with histologically or cytologically proven primary small cell or non-small cell lung cancers, esophageal cancers, malignant pleural mesotheliomas or chest wall sarcoma, or thymomas are eligible for evaluation. In addition, patients with cancers of nonthoracic origin with metastases to the lungs or pleura, or germ cell tumors refractory to standard therapy are eligible for evaluation.

Patients must have an ECOG performance status of 0 - 2.

Patients must have adequate pulmonary reserve evidenced by FEV1 and DLCO greater than the 30 percent predicted, and pCO2 less than 50 mm Hg and pO2 greater than 60 mm Hg on room air ABG.

Patients must be 18 years of age or older.

Adequate organ function as evidenced by standard laboratory parameters.

The patient must be willing to sign an informed consent.

Design:<TAB><TAB>

A phase 1 study where patient cohorts will receive escalating doses of Depsipeptide, administered on day 1 and day 21, and a dose of flavopiridol (either 40 mg/m2/d or 50 mg/m2/d) administered on days 1-3, and 21-24 of a 42-day course.

Pharmacokinetics, systemic toxicity, and response to therapy will be recorded.

Two cycles of therapy (one course) will be administered, following which treatment evaluation will be performed using standard clinical criteria.

48 patients will be enrolled over a period of 2-4 years. ;

Related Conditions & MeSH terms

• Carcinoma
• Carcinoma, Non-Small-Cell Lung
• Carcinoma, Small Cell
• Esophageal Neoplasms
• Mesothelioma

• NCT number: NCT00094978
• Study type: Interventional
• Source: National Institutes of Health Clinical Center (CC)
• Status: Terminated
• Phase: Phase 1
• Start date: October 25, 2004
• Completion date: May 20, 2013