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

Study Overview
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Brief Summary
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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. 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

Detailed Description
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PRIMARY OBJECTIVES: I. 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 OBJECTIVES: I. Determine, preliminarily, tumor response in patients treated with this regimen. II. 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.

Official Title
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A Phase I Study of an Oral Histone Deacetylase Inhibitor, MS-275 (NSC 706995, IND 61,198), in Combination With 13-Cis-Retinoic Acid in Metastatic Progressive Cancer.

Conditions
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Adult Grade III Lymphomatoid Granulomatosis, Anaplastic Large Cell Lymphoma, Angioimmunoblastic T-cell Lymphoma, Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue, Intraocular Lymphoma, Nodal Marginal Zone B-cell Lymphoma, Primary Central Nervous System Non-Hodgkin Lymphoma, Recurrent Adult Burkitt Lymphoma, Recurrent Adult Diffuse Large Cell Lymphoma, Recurrent Adult Diffuse Mixed Cell Lymphoma, Recurrent Adult Diffuse Small Cleaved Cell Lymphoma, Recurrent Adult Grade III Lymphomatoid Granulomatosis, Recurrent Adult Hodgkin Lymphoma, Recurrent Adult Immunoblastic Large Cell Lymphoma, Recurrent Adult Lymphoblastic Lymphoma, Recurrent Adult T-cell Leukemia/Lymphoma, Recurrent Cutaneous T-cell Non-Hodgkin Lymphoma, Recurrent Grade 1 Follicular Lymphoma, Recurrent Grade 2 Follicular Lymphoma, Recurrent Grade 3 Follicular Lymphoma, Recurrent Mantle Cell Lymphoma, Recurrent Marginal Zone Lymphoma, Recurrent Mycosis Fungoides/Sezary Syndrome, Recurrent Small Lymphocytic Lymphoma, Small Intestine Lymphoma, Splenic Marginal Zone Lymphoma, Stage IV Adult Burkitt Lymphoma, Stage IV Adult Diffuse Large Cell Lymphoma, Stage IV Adult Diffuse Mixed Cell Lymphoma, Stage IV Adult Diffuse Small Cleaved Cell Lymphoma, Stage IV Adult Hodgkin Lymphoma, Stage IV Adult Immunoblastic Large Cell Lymphoma, Stage IV Adult Lymphoblastic Lymphoma, Stage IV Adult T-cell Leukemia/Lymphoma, Stage IV Cutaneous T-cell Non-Hodgkin Lymphoma, Stage IV Grade 1 Follicular Lymphoma, Stage IV Grade 2 Follicular Lymphoma, Stage IV Grade 3 Follicular Lymphoma, Stage IV Mantle Cell Lymphoma, Stage IV Marginal Zone Lymphoma, Stage IV Mycosis Fungoides/Sezary Syndrome, Stage IV Small Lymphocytic Lymphoma, Unspecified Adult Solid Tumor, Protocol Specific, Waldenström Macroglobulinemia

Intervention / Treatment
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* Drug: entinostat
* Drug: isotretinoin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically confirmed solid tumor or lymphoma Metastatic, progressive, refractory, or unresectable disease Not amenable to standard curative measures No known brain metastases Performance status - ECOG 0-2 More than 3 months Absolute neutrophil count ≥ 1,500/mm^3 Platelet count ≥ 100,000/mm^3 WBC ≥ 3,000/mm^3 Hemoglobin > 9 g/dL Bilirubin ≤ 1.5 times upper limit of normal (ULN) AST and ALT ≤ 2.5 times ULN No suspected Gilbert's syndrome Creatinine ≤ 1.5 times ULN Creatinine clearance ≥ 60 mL/min No symptomatic congestive heart failure No unstable angina pectoris No unstable cardiac arryhthmia Able to take and retain oral medications No malabsorption problems No acute or chronic gastrointestinal condition Not pregnant or nursing Negative pregnancy 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 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 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 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 More than 4 weeks since prior anticancer radiotherapy More than 2 weeks since prior palliative radiotherapy No concurrent anticancer radiotherapy More than 4 weeks since prior major surgery 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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (entinostat, isotretinoin)<br>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. | Drug: entinostat<br>* Given orally<br>* Other names: SNDX-275;Drug: isotretinoin<br>* Given orally<br>* Other names: Sotret;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose limiting toxicities defined as an adverse event which is likely related to the study medication | Graded using the CTCAE version 3.0. | 28 days | 
| Maximum tolerated dose of entinostat and isotretinoin in combination |  | 28 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetics |  | Up to day 21 of course 2 | 
| Adverse events defined as any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily have a causal relationship with this treatment | Graded using the CTCAE version 3.0. Summarized by dose level. | Up to 30 days after completion of study treatment |