Depsipeptide to Treat Thyroid and Other Advanced Cancers
This phase I study will evaluate the experimental drug Romidepsinin patients with advanced cancer. The study will: 1) determine how well patients tolerate Romidepsin; 2) measure blood levels of Romidepsin during treatment; 3) analyze the cellular and molecular effects of the drug; and 4) determine if Romidepsin can shrink tumors. Romidepsin 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 Romidepsin 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 Romidepsin 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 Romidepsin 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.
|Study Design:||Primary Purpose: Treatment|
|Official Title:||Phase I Trial of Romidepsin Given on Days One, Three, and Five in Patients With Thyroid and Other Advanced Cancers|
- To define the MTD of romidepsin when administered on a multi-daly regimen of days 1, 3, and 5.
- To correlate laboratory assays of the molecular effects of romidepsin with the administered dose.
|Study Start Date:||October 26, 2002|
|Study Completion Date:||April 1, 2010|
|Primary Completion Date:||April 1, 2010 (Final data collection date for primary outcome measure)|
Romidepsin (NSC 630176, FR901228, FK228, formerly referred to as depsipeptide) is a histone deacetylase inhibitor with potent cytotoxic activity against human tumor cell lines and in vivo efficacy against both human tumor xenografts and murine tumors (1-3).
Laboratory studies suggest that longer exposure to non-toxic doses of romidepsin can enhance its molecular effects to a greater degree than short toxic doses that rapidly cause cell death.
NIS is responsible for enabling uptake of RAI in thyroid cancer, with decreased levels in tumors resistant or refractory to RAI therapy.
Our group has demonstrated that NIS expression is upregulated by romidepsin, resulting in increased sensitivity to RAI.
To determine the MTD of romidepsin when administered on days 1, 3 and 5.
To examine the effect of a multi-day regimen of romidepsin 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.
- Age 18 and over
- Evaluable disease
- Performance status ECOG 0-2
- Excluding patients that are pregnant, HIV positive, have CNS metastasis, or acute leukemia
- Left ventricular ejection fraction within normal limits. Additional cardiac criteria are noted in protocol
- Phase I
- Romidepsin administered as a 4-hour intravenous infusion on days 1, 3 and 5
- Dose escalation
- Enrollment of additional cohort of 10 patients with thyroid cancer at MTD
Please refer to this study by its ClinicalTrials.gov identifier: NCT00048334
|United States, Maryland|
|National Institutes of Health Clinical Center, 9000 Rockville Pike|
|Bethesda, Maryland, United States, 20892|
|Principal Investigator:||Richard L Piekarz, M.D.||National Cancer Institute (NCI)|