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.
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.
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
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.
Inclusion Criteria:
Histologically confirmed solid tumor or lymphoma
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
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