MS-275 and Isotretinoin in Treating Patients With Metastatic or Advanced Solid Tumors or Lymphomas

Condition(s) targeted: Lymphoma; Small Intestine Cancer; Unspecified Adult Solid Tumor, Protocol Specific

Intervention: HDAC inhibitor SNDX-275 (Drug); isotretinoin (Drug)

Phase: Phase 1

Status: Completed

Sponsored by: Sidney Kimmel Comprehensive Cancer Center

Official(s) and/or principal investigator(s):
Roberto Pili, MD, Study Chair, Affiliation: Sidney Kimmel Comprehensive Cancer Center

RATIONALE: MS-275 may stop the growth of cancer cells by blocking the enzymes necessary for their growth. Isotretinoin may help cancer cells develop into normal cells. MS-275 may increase the effectiveness of isotretinoin by making cancer cells more sensitive to the drug. MS-275 and isotretinoin may also stop the growth of solid tumors or lymphomas by stopping blood flow to the cancer. Combining MS-275 with isotretinoin may kill more cancer cells.

PURPOSE: Phase I trial to study the effectiveness of combining MS-275 with isotretinoin in treating patients who have metastatic or advanced solid tumors or lymphomas.

Official title: A Phase I Study of an Oral Histone Deacetylase Inhibitor, MS-275 (NSC 706995, IND 61,196), in Combination With 13-Cis-Retinoic Acid in Metastatic Progressive Cancer

Study design: Treatment, Open Label

Primary outcome: Dose-limiting toxicity and maximum tolerated dose as assessed by radiological measurements every 8 weeks

Secondary outcome:

Tumor response as assessed by radiological measurements every 8 weeks

Pharmacokinetic profile and pharmacokinetic effects assessed before beginning treatment, every 8 weeks during treatment, and after completion of study treatment

Antiproliferative and apoptic effects as assessed by radiological measurements every 8 weeks

Methylation status and expression of retinoic acid receptor beta (RAR-B) as assessed by descriptive statistics before beginning treatment, every 8 weeks during treatment, and after completion of study treatment

Antiangiogenic effects on tumor samples from treated patients every 8 weeks

Histone acetylation in peripheral blood mononuclear cells before beginning treatment, every 8 weeks during treatment, and after completion of study treatment

Adverse events and changes in laboratory parameters every 8 weeks

Detailed description: OBJECTIVES:

Primary

- Determine the dose-limiting toxicity and maximum tolerated dose of MS-275 when

administered with isotretinoin in patients with metastatic, progressive, refractory, or unresectable solid tumors or lymphomas.

Secondary

- Determine, preliminarily, tumor response in patients treated with this regimen.

- Determine the pharmacokinetic profile of this regimen in these patients.

OUTLINE: This is an open-label, dose-escalation study of MS-275.

Patients receive oral MS-275 once on days 1, 8, and 15 and oral isotretinoin twice daily on days 1-21. Courses repeat every 28 days in the absence of unacceptable toxicity or disease progression.

Cohorts of 3-6 patients receive escalating doses of MS-275 until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity. Up to 12 patients are treated at the MTD.

Patients are followed monthly.

PROJECTED ACCRUAL: A total of 12-24 patients will be accrued for this study.

Minimum age: 18 Years. Maximum age: N/A. Gender(s): Both.

Criteria:

DISEASE CHARACTERISTICS:

- Histologically confirmed solid tumor or lymphoma

- Metastatic, progressive, refractory, or unresectable disease

- Not amenable to standard curative measures

- No known brain metastases

PATIENT CHARACTERISTICS:

Age

- 18 and over

Performance status

- ECOG 0-2

Life expectancy

- More than 3 months

Hematopoietic

- Absolute neutrophil count ≥ 1,500/mm^3

- Platelet count ≥ 100,000/mm^3

- WBC ≥ 3,000/mm^3

- Hemoglobin > 9 g/dL

Hepatic

- Bilirubin ≤ 1. 5 times upper limit of normal (ULN)

- AST and ALT ≤ 2. 5 times ULN

- No suspected Gilbert's syndrome

Renal

- Creatinine ≤ 1. 5 times ULN OR

- Creatinine clearance ≥ 60 mL/min

Cardiovascular

- No symptomatic congestive heart failure

- No unstable angina pectoris

- No unstable cardiac arryhthmia

Gastrointestinal

- Able to take and retain oral medications

- No malabsorption problems

- No acute or chronic gastrointestinal condition

Other

- Not pregnant or nursing

- Negative pregnanct test

- Fertile patients must use effective double-method contraception 1 month before,

during, and 3 months after study treatment

- No known HIV positivity

- No weight loss > 10% within the past 2 months

- No history of allergic reaction attributed to compounds of similar chemical or

biologic composition to MS-275 or isotretinoin

- No other uncontrolled illness

- No ongoing or active infection

- No seizure disorder

- No psychiatric illness or social situation that would preclude study participation

PRIOR CONCURRENT THERAPY:

Biologic therapy

- More than 4 weeks since prior anticancer vaccine therapy

- More than 4 weeks since prior anticancer immunotherapy

- No concurrent anticancer vaccine therapy

- No concurrent anticancer immunotherapy

Chemotherapy

- More than 4 weeks since prior anticancer chemotherapy (6 weeks for nitrosoureas,

mitomycin, or other agents known to cause prolonged marrow supression)

- No concurrent anticancer chemotherapy

Endocrine therapy

- More than 4 weeks since prior anticancer hormonal therapy except

gonadotropin-releasing hormone (GnRH) agonist therapy for non-castrated patients with prostate cancer

- Concurrent GnRH agonist therapy for non-castrated patients with prostate cancer

allowed

- Concurrent luteinizing hormone-releasing hormone agonist therapy allowed provided

there is evidence of tumor progression

- Concurrent adrenal steroid replacement therapy allowed

- No concurrent ketoconazole as second-line hormonal treatment for prostate cancer

- No concurrent corticosteroids except for treatment of refractory nausea or vomiting

- No other concurrent anticancer hormonal therapy

Radiotherapy

- More than 4 weeks since prior anticancer radiotherapy

- More than 2 weeks since prior palliative radiotherapy

- No concurrent anticancer radiotherapy

Surgery

- More than 4 weeks since prior major surgery

Other

- Recovered from all prior therapy

- No prior MS-275

- No prior oral isotretinoin

- Isotretinoin for the treatment of acne allowed provided > 3 years since prior

administration

- More than 4 weeks since other prior anticancer therapy

- No concurrent tetracycline

- No concurrent high-dose vitamin A

- No concurrent valproic acid

- No other concurrent investigational agents

- No other concurrent anticancer therapy

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland 21231-2410, United States

Warren Grant Magnuson Clinical Center - NCI Clinical Studies Support, Bethesda, Maryland 20892-1182, United States

Clinical trial summary from the National Cancer Institute's PDQ® database

Starting date: December 2004
Last updated: May 23, 2008