Protocol Number: 01-C-0124

Title:

A Phase I Study of an Oral Histone Deacetylase Inhibitor, MS-275, in Refractory Solid Tumors and Lymphomas

Number:

01-C-0124

Summary:

This study will investigate the safety of a new drug called MS-275 in patients with solid tumors and lymphomas. In animal studies, MS-75 has been shown to block the growth of cancer cells. This study will examine how the drug works in humans, what side effects are commonly seen with the drug and what doses are safe.

Patients 18 years of age and older with solid tumors and lymphomas that do not respond to standard treatment and whose disease has not metastasized (spread) to the brain may be eligible for this study. Candidates are screened with a medical history and physical examination, blood and urine tests, chest x-ray and electrocardiogram, computed tomography (CT) scans of the chest, abdomen, and pelvis, and a MUltiple Gated Acquisition (MUGA) scan, a noninvasive heart nuclear medicine test, to see how well the heart muscle is contracting.

Participants receive MS-275 in one of two dosing schedules: Group 1 receives the drug in 6-week cycles of one dose a week for four weeks with a 2-week break; Group 2 receives the drug once every other week. Patients in both groups receive their first dose in the hospital and remain in the hospital for one week for observation and for safety (blood and urine) tests.

Group 1 patients come to the NIH clinic for an examination and blood work the first and fourth week of every cycle. They may be asked to stay in the hospital overnight every fourth week for blood tests to study how the body handles MS-275. Imaging studies (bone scans, CTs and chest x-rays) are repeated every 12 weeks to evaluate the tumor's response to MS-275, and blood tests are done weekly for safety monitoring.

Group 2 patients return to NIH every two weeks for an examination and blood work. Imaging studies are repeated every 6 weeks to determine the response to treatment, and blood tests for safety are done weekly.

Treatment in both groups may continue for more than 6 months, depending on benefits and side effects. Patients who experience severe side effects from the medication may receive a lower dose of the drug or fewer doses. Patients in both groups who have a superficial tumor that is easy to reach may be asked to have a needle biopsy (withdrawal of some tumor cells through a needle for microscopic study) at days 1 and 3 of the first treatment to evaluate the anti-cancer activity of MS-275. Patients may also be asked to have a second MUGA scan to check heart function.

Sponsoring Institute:

National Cancer Institute (NCI)

Recruitment Detail

Type: Active Accrual Of New Subjects

Gender: Male & Female

Referral Letter Required: Yes

Population Exclusion(s): Children

Eligibility Criteria:

INCLUSION CRITERIA:

1. Patients must have a pathologically confirmed malignancy that is metastatic or unresectable and for which standard curative or palliative measures do not exist or would likely not be effective.

2. ECOG performance status of less than or equal to 2 (Karnofsky greater than or equal to 50 percent), with no recent (within 2 month) weight loss of greater than 10 percent of average body weight.

3. Life expectancy is greater than 3 months.

4. Age greater than or equal to 18 years.

5. Patients must have normal organ and marrow functions as defined below:

- Leukocytes greater than or equal to 3000/microL.

- Absolute neutrophil count greater than or equal to 1500/microL.

- Platelets greater than or equal to 100,000/microL.

- Creatinine within normal limits or measured creatinine clearance equal to or greater than 60 ml/min/1.73m(2).

- Total bilirubin less than or equal to 1.5 upper limit of normal.

- AST (SGOT)/ALT (SGPT) less than or equal to 2.5 x upper limit of normal.

6. Adequate oral intake and serum albumin greater than or equal to 75% of lower limit normal.

7. Willingness and ability to return to the NCI for follow-up.

8. Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately.

9. Ability to understand and the willingness to sign a written informed consent document.

10. Willingness and ability to self-administer and document the doses of MS 275.

EXCLUSION CRITERIA:

1. Patients who have had anticancer therapy (chemotherapy, radiotherapy, vaccines and hormone therapy with the exception of GnRH agonists) within the last 4 weeks (6 weeks for nitrosoureas or mitomycin C, 8 weeks for UCN-01); or those who have not recovered from adverse events due to agents administered more than 4 weeks earlier.

2. Patients may not be receiving any other investigational agents.

3. Patients with known brain metastases should be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events. However, patients who have had treatment for their brain metastases and whose brain metastatic disease status has remained stable for at least 6 months without steroids or anti-seizure medications may be enrolled at the discretion of the principal investigator.

4. History of allergic reactions attributed to compounds of similar chemical or biologic composition to MS-275.

5. Uncontrolled intercurrent illness including, but not limited to ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, seizure disorder or psychiatric illness/social situations that would limit compliance with study requirements.

6. Pregnant women are excluded from this study. Breastfeeding should be discontinued if the mother is treated with MS-275.

7. HIV-positive patients are excluded from this study.

8. Men and women of reproductive potential without adequate contraception.

9. Recent (within two months of therapy inception) acute or chronic gastrointestinal conditions (e.g., peptic ulcer or colitis) that might predispose for drug intolerability or poor drug absorption.

10. Major surgery within the past 21 days.

11. Intercurrent radiation, chemotherapy, immunotherapy or hormonal therapy (except for GnRH agonists).

12. Patients with Gilbert's Syndrome and bilirubin above 3 mg/dl.

Special Instructions: Currently Not Provided

Keywords:

Histone Deacetylase

Differentiation

Pharmacology

Pharmacokinetics

Recruitment Keywords:

Non-Hodgkin's Lymphoma

Solid Tumors

Conditions:

Cancer

Lymphoma

Investigational Drug(s):

MS-275

Investigational Device(s):

None

Contacts:

CSSC
Clinical Studies Support Center/NCI
164 Rollins Avenue
2nd FLoor
Rockville, MD 20852
Phone: (888) 624-1937
Fax: (301) 881-8239

Electronic Address: ncicssc@mail.nih.gov

Citations:

A class of hybrid polar inducers of transformed cell differentiation inhibits histone deacetylases

A synthetic inhibitor of histone deacetylase, MS-27-275, with marked in vivo anti tumor activity against human tumors

Transcription: gene control by targeted histone acetylation

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