Safingol and Cisplatin in Treating Patients With Locally Advanced or Metastatic Solid Tumors

OBJECTIVES:

Primary

• Determine the maximum tolerated dose (MTD) of safingol when administered with cisplatin in patients with locally advanced or metastatic solid tumors.

Secondary

• Determine the toxic effects of this regimen in these patients.
• Determine the clinical pharmacokinetics of this regimen in these patients.
• Determine, preliminarily, the therapeutic activity of this regimen in these patients.
• Determine a safe dose (i.e., near the MTD) for phase II evaluation of this regimen in these patients.
• Determine, preliminarily, the role of ceramide and S1P, relative to response and apoptosis, in patients treated with this regimen.

OUTLINE: This is an open-label, non-randomized, dose-escalation study of safingol.

Patients receive safingol IV over 1 hour and cisplatin IV over 1 hour on day 1. Courses repeat every 21 days* in the absence of disease progression or unacceptable toxicity.

NOTE: *Patients receive safingol on days 1 and 8 and cisplatin on day 8 for course 1 only; course 1 is 28 days in duration.

Cohorts of 3-6 patients receive escalating doses of safingol 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. Once the MTD is determined, 10 additional patients are treated at that dose level.

DISEASE CHARACTERISTICS:

• Histologically confirmed solid tumor

• Locally advanced or metastatic disease
• Refractory to standard therapy OR not amenable to standard therapy
• No known CNS metastasis or CNS primary

PATIENT CHARACTERISTICS:

Age

• 18 and over

Performance status

• Karnofsky 70-100%

Life expectancy

• At least 12 weeks

Hematopoietic

• Neutrophil count ≥ 1,500/mm^3
• Platelet count ≥ 100,000/mm^3
• WBC count ≥ 3,500/mm^3
• Hemoglobin ≥ 9.5 g/dL
• Haptoglobin ≥ 30 mg/dL
• No concurrent hemolysis or history of non-drug-induced hemolysis (e.g., spherocytosis)

Hepatic

• AST and ALT ≤ 2.5 times upper limit of normal
• Bilirubin ≤ 1.5 mg/dL
• PT and PTT normal

Renal

• Creatinine ≤ 1.5 mg/dL

Cardiovascular

• No cardiac arrhythmias
• No congestive heart failure
• No myocardial infarction within the past 6 months

Other

• Not pregnant
• Negative pregnancy test
• No nursing during and for at least 2 months after study participation
• Fertile patients must use effective contraception during and for at least 2 months after study participation
• HIV negative
• No mental incapacity that would preclude giving informed consent
• No moderate-to-severe high-frequency hearing loss
• No persistent severe (grade 2) drug-induced peripheral neuropathy
• No known allergy to cisplatin or any other platinum-containing compound
• No serious or uncontrolled infection
• No other medical condition or reason that would preclude study participation

PRIOR CONCURRENT THERAPY:

Biologic therapy

• At least 4 weeks since prior immunotherapy

Chemotherapy

• Prior cisplatin allowed
• At least 4 weeks since prior chemotherapy (6 weeks for nitrosoureas and mitomycin)

Endocrine therapy

• Not specified

Radiotherapy

• At least 4 weeks since prior radiotherapy

Surgery

• Not specified

Other

• Recovered from all prior therapy
• No concurrent vitamins, antioxidants, herbal preparations, or supplements

• Concurrent single tablet multivitamin allowed
• No other concurrent investigational medications