This phase I study will evaluate the experimental drug depsipeptide in patients with advanced cancer. The study will: 1) determine how well patients tolerate depsipeptide; 2) measure blood levels of depsipeptide during treatment; 3) analyze the cellular and molecular effects of the drug; and 4) determine if depsipeptide can shrink tumors. Depsipeptide has been shown to kill cancer cells growing in the laboratory and to shrink tumors in animals with various tumor types. In preliminary studies, several patients with a type of lymphoma and one patient with kidney cancer responded to treatment.

Patients 18 years of age and older with advanced cancer (excluding acute leukemia) may be eligible for this study. Candidates are screened with a medical history and physical examination, x-rays and CT scans, and blood and urine tests. Patients with thyroid cancer may also have magnetic resonance imaging (MRI). This test uses a magnetic field instead of x-rays to obtain images or body organs and tissues.

Participants receive three infusions of depsipeptide administered through an intravenous line over 4 hours on days 1, 3 and 5 of a 21-day treatment cycle. The intravenous line is a catheter (plastic tube) placed in a vein and may be a peripheral line, inserted in a vein in the arm, or a central line, in which the tube is placed under the skin of the chest or neck into a major vein. Patients are hospitalized for the first 6 days of the first cycle to monitor heart rate. Those who tolerate the treatment well may continue as an outpatient.

In addition to drug therapy, participants undergo the following procedures:

- Blood tests: Small amounts of blood are drawn frequently during the first five days of treatment to measure depsipeptide levels and to see how the body uses and excretes the drug. A heparin lock (an indwelling device to keep the vein open) may be put in the vein to prevent the need for repeated needle sticks.

- Biopsies (removal of a small sample of tumor tissue): Tumors that are accessible may be biopsied at the start of the study and at different times during treatment. Biopsies are done no more than three times per cycle, and no more than nine biopsies are done within a year. The samples are examined for the effects of depsipeptide on proteins that control the way cells divide and stay alive.

- Apheresis: This procedure is done to collect white blood cells and cancer cells for research. Blood is collected through a needle in an arm vein and directed into a machine that separates it into its components by centrifugation (spinning). The white cells are removed and the red cells are returned to the patient through the same needle or through another needle in the other arm.

- Scans and x-rays: Imaging studies are usually done before starting treatment. Some of them are repeated at every 2 cycles (6 weeks), and some at the end of the patient's participation in the study. The tests may include chest x-rays, plain x-rays of affected bones, CT scans of the chest, abdomen, and pelvis, bone scans, and a MUGA scan (special X-ray of the heart) or echocardiogram (ultrasound of the heart) to test heart function before and during the study. MRI or positron emission tomography (PET) scans may also be done to detect tumors. PET scans use a small amount of a radioactive substance injected into a vein. The radioactivity is detected by a special camera during scanning to detect cancer cells.

- Other tests include an electrocardiogram (recording of the electrical activity of the heart) before and after each dose of depsipeptide. Eye exams are done if there are vision changes or if the doctor recommends an eye test.

Condition	Treatment or Intervention	Phase
Neoplasms	Drug: Depsipeptide	Phase I

Further Study Details: 

Expected Total Enrollment:  56

NSC 630176, FR901228, is a depsipeptide isolated from Chromobacterium violaceum by the Fujisawa Company (1). It has demonstrated potent cytotoxic activity against human tumor cell lines and in vivo efficacy against both human tumor xenografts and murine tumors (2, 3). NSC 630176, herein referred to as depsipeptide, shows a lack of cross resistance with several commonly used cytotoxic agents such as vincristine, 5-fluorouracil, mitomycin C and cyclophosphamide (2). However, it has been defined as a P-glycoprotein (Pgp) substrate by COMPARE analysis of the NCI drug screen cytotoxicity profile (4). Depsipeptide is a member of a novel class of antineoplastic agents, the histamine deacetylase inhibitors (HDIs).

A phase I trial of depsipeptide was completed at the NCI. The drug was given in a 4-hour infusion on days 1 and 5 of a 21-day cycle. The MTD was found to be 17.8 mg/m(2). The dose limiting toxicities were grade 3 fatigue, grade 3 nausea and vomiting and grade 4 thrombocytopenia. Other observed toxicities include hypocalcemia, granulocytopenia and reversible ST-T wave changes that were not associated with detectable myocardial damage or change in cardiac function. In that trial, several patients with cutaneous T-cell lymphoma had a complete response. A phase II study was initiated to evaluate the rate of response of patients with these specific types of lymphomas.

Clinical trials of histone deacetylase inhibitors allow for the use of surrogate markers of biological activity. In addition, these agents may be used to induce the expression of targets of other anti-neoplastic agents. Since laboratory studies suggest that longer exposure to non-toxic doses of depsipeptide can enhance its molecular effects to a greater degree than short toxic doses that rapidly cause cell death, we plan to examine the effect of a multi-day regimen of depsipeptide on surrogate markers and the expression of molecular targets. We are initiating a new phase I trial to administer depsipeptide on days 1, 3 and 5.

The goals of this trial are:

To determine the MTD of depsipeptide when administered on days 1, 3 and 5.

To examine the effect of a multi-day regimen of depsipeptide on surrogate markers and the expression of molecular targets.

To determine whether thyroid cancers that do not have detectable uptake of RAI will have detectable uptake after treatment.

Genders Eligible for Study:  Both

Criteria

INCLUSION CRITERIA
Patients must have histologic or cytologic confirmation of cancer (excluding acute leukemia) for which there is no known standard therapy capable of extending life expectancy.
Patients must:
-be greater than or equal to18 years of age.
-have evaluable disease.
-have a performance status of ECOG 0-2.
-have no serious or intercurrent illness that can not be medically controlled and have a life expectancy of greater than 12 weeks.
-give written informed consent.
-be willing to return to the National Cancer Institute for follow-up.
-female patients of childbearing potential must have a negative pregnancy test within 1 week and must use effective contraception (hormonal or barrier methods) while being treated on protocol.
Laboratory values:
-within 7 days prior to registration: absolute neutrophil count greater than or equal to 1000/microL, platelets greater than or equal to 100,000/microL, bilirubin (total and direct) less than or equal to 1.5x upper limit of normal, and AST less than or equal to 3x upper limit of normal, creatinine less than or equal to 1.5x upper limit of normal or documented creatinine clearance of greater than or equal to 60 mL/min.
-within 4 weeks of registration: ejection fraction within normal as determined by echocardiogram, MUGA scan, or cardiac MRI.
Criteria for cohort of patients with RAI refractory non-medullary thyroid cancer to be enrolled after the MTD has been defined:
-non-medullary thyroid carcinoma.
-progressive disease following total or near-total thyroidectomy and RAI therapy.
-documented evidence of no, or minimally (faint), RAI uptake on RAI whole body scan.
-no RAI therapy within 3 months prior to study entry.
-no history of administration of IV iodinated contrast or other large iodine loads (i.e. CT, amiodarone, SSKI) during the previous 3 months.
-24 hr. urinary iodine values less than or equal to 150 micrograms/day
EXCLUSION CRITERIA:
Patients with unconfirmed diagnosis will be excluded.
Prior or concurrent malignancies that have not been curatively treated.
Current or previous CNS metastasis.
Chemotherapy within 4 weeks, 6 weeks for nitrosoureas or mitomycin C, and 8 weeks for UCN-01.
HIV seropositivity
Pregnant or breast-feeding patients
Uncontrolled infection
Patients with MI within previous 6 months, EF below normal, QTc greater than 500 ms, or unstable angina. Patients with other cardiac disease will be considered for study following consultation with cardiology.

Maryland
      National Cancer Institute (NCI), 9000 Rockville Pike,  Bethesda,  Maryland,  20892,  United States; Recruiting

Study ID Numbers:  030030; 03-C-0030
Record last reviewed:  September 9, 2004
Last Updated:  November 23, 2004
Record first received:  October 29, 2002
ClinicalTrials.gov Identifier:  NCT00048334
Health Authority: United States: Federal Government
ClinicalTrials.gov processed this record on 2005-04-08