Protocol Number: 03-C-0030

Title:

Phase I Trial of Depsipeptide Given on Days 1, 3, & 5 in Patients with Thyroid and Other Advanced Cancers

Number:

03-C-0030

Summary:

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.

Sponsoring Institute:

National Cancer Institute (NCI)

Recruitment Detail

Type: Active Accrual Of New Subjects

Gender: Male & Female

Referral Letter Required: No

Population Exclusion(s): None

Eligibility 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.

Special Instructions: Currently Not Provided

Keywords:

Histone Acetylation

Recruitment Keywords:

Cancer

Conditions:

Neoplasms

Investigational Drug(s):

Depsipeptide

Investigational Device(s):

None

Contacts:

Patient Recruitment and Public Liaison Office
Building 61
10 Cloister Court
Bethesda, Maryland 20892-4754
Toll Free: 1-800-411-1222
TTY: 301-594-9774 (local),1-866-411-1010 (toll free)
Fax: 301-480-9793

Electronic Mail:prpl@mail.cc.nih.gov

Citations:

Ueda H, Nakajima H, Hori Y, Fujita T, Nishimura M, Goto T, Okuhara M. FR901228, a novel antitumor bicyclic depsipeptide produced by Chromobacterium violaceum No. 968. I. Taxonomy, fermentation, isolation, physico-chemical and biological properties, and antitumor activity. J Antibiot (Tokyo). 1994 Mar;47(3):301-10.

Ueda H, Manda T, Matsumoto S, Mukumoto S, Nishigaki F, Kawamura I, Shimomura K. FR901228, a novel antitumor bicyclic depsipeptide produced by Chromobacterium violaceum No. 968. III. Antitumor activities on experimental tumors in mice. J Antibiot (Tokyo). 1994 Mar;47(3):315-23.

Ueda H, Nakajima H, Hori Y, Goto T, Okuhara M. Action of FR901228, a novel antitumor bicyclic depsipeptide produced by Chromobacterium violaceum no. 968, on Ha-ras transformed NIH3T3 cells. Biosci Biotechnol Biochem. 1994 Sep;58(9):1579-83.

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