Alternate Title
Basic Trial Information
Objectives
Entry Criteria
Expected Enrollment
Outcomes
Outline
Trial Contact Information
Registry Information

Alternate Title

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

Basic Trial Information

Phase Type Status Age Sponsor Protocol IDs Phase I Treatment Completed 18 and over NCI JHOC-J0438 6798, NCI-6798, JHOC-04060103, NCT00098891

Objectives

Primary

1. 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

1. Determine, preliminarily, tumor response in patients treated with this regimen.
2. Determine the pharmacokinetic profile of this regimen in these patients.

Entry 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

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

Patient Characteristics:

Age

• 18 and over

Performance status

• ECOG 0-2

Life expectancy

• More than 3 months

Hematopoietic

• Absolute neutrophil count ≥ 1,500/mm³
• Platelet count ≥ 100,000/mm³
• WBC ≥ 3,000/mm³
• 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

Expected Enrollment

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

Outcomes

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

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

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.

Trial Contact Information

Trial Lead Organizations

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Roberto Pili, MD, Protocol chair		Ph: 410-502-7482

Registry Information
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
Trial Start Date		2004-12-06
Trial Completion Date		2008-03-24
Registered in ClinicalTrials.gov		NCT00098891
Date Submitted to PDQ		2004-10-07
Information Last Verified		2006-09-17
NCI Grant/Contract Number		CA70095, CA06973

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