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”

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.

Study Type: Interventional

Study Design: Treatment, Open Label

Study Primary Completion Date: March 2008

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.

Intervention(s) in this Clinical Trial

• Drug: entinostat
• Drug: isotretinoin

Primary Measures

• Dose-limiting toxicity and maximum tolerated dose as assessed by radiological measurements every 8 weeks
  • Safety Issue?: Yes

Secondary Measures

• Tumor response as assessed by radiological measurements every 8 weeks
  • Safety Issue?: No
• Pharmacokinetic profile and pharmacokinetic effects assessed before beginning treatment, every 8 weeks during treatment, and after completion of study treatment
  • Safety Issue?: No
• Antiproliferative and apoptic effects as assessed by radiological measurements every 8 weeks
  • Safety Issue?: No
• 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
  • Safety Issue?: No
• Antiangiogenic effects on tumor samples from treated patients every 8 weeks
  • Safety Issue?: No
• Histone acetylation in peripheral blood mononuclear cells before beginning treatment, every 8 weeks during treatment, and after completion of study treatment
  • Safety Issue?: No
• Adverse events and changes in laboratory parameters every 8 weeks
  • Safety Issue?: Yes

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

Gender Eligibility for this Clinical Trial: Both

Minimum Age for this Clinical Trial: 18 Years

Maximum Age for this Clinical Trial: N/A

Are Healthy Volunteers Accepted for this Clinical Trial?: No

Lead Sponsor: Sidney Kimmel Comprehensive Cancer Center

Overall Clinical Trial Officials and Contacts

Roberto Pili, MD Study Chair Sidney Kimmel Comprehensive Cancer Center  

Information obtained from ClinicalTrials.gov on July 02, 2009

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00098891

Study ID Number: CDR0000396776

ClinicalTrials.gov Identifier: NCT00098891

Health Authority: United States: Federal Government

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