UCN-01 and Carboplatin in Treating Patients With Advanced Solid Tumors

PRIMARY OBJECTIVES:

I. Determine the maximum tolerated dose, dose limiting toxicity and other toxicities of UCN-01 when combined with carboplatin.

II. Preliminarily evaluate the antitumor effect of the combination of carboplatin and UCN-01.

III. Determine the pharmacokinetics of UCN-01 and carboplatin.

OUTLINE: This is a dose-escalation study.

Patients receive carboplatin IV over 1 hour followed by UCN-01 IV over 3 hours on day 1. Treatment repeats every 21 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.

Cohorts of 3-6 patients receive escalating doses of carboplatin and UCN-01 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.

Inclusion criteria

• Patients must have histologically confirmed malignancy that is metastatic or unresectable and for which standard curative or palliative measures do not exist or are no longer effective
• At least 4 weeks since prior chemotherapy or radiation therapy, 6 weeks if the last regimen included BCNU or mitomycin C; include site/total dose for prior radiation exposure as needed (e.g., no more than 3000 cGy to fields including substantial marrow)
• ECOG performance status =< 2 (Karnofsky >= 60%)
• Life expectancy of greater than 12 weeks
• Leukocytes >= 3,000/microl
• Absolute neutrophil count >= 1,500/microl
• Platelets >= 100,000/microl
• Total bilirubin within normal institutional limits
• AST(SGOT)/ALT(SGPT) >= 2.5 X institutional upper limit of normal
• Creatinine within normal institutional limits OR creatinine clearance >= 60 mL/min/1.73 m^2 for patients with creatinine levels above institutional normal
• Women of childbearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control) prior to study entry and for the duration of study participation; should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately
• Ability to understand and the willingness to sign a written informed consent document

Exclusion criteria

• Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study or those who have not recovered from adverse events due to agents administered more than 4 weeks earlier
• Patients may not be receiving any other investigational agents
• Patients with known brain metastases are eligible providing the brain metastases are, in the opinion of the site investigator, asymptomatic or clinically stable after treatment with surgery and/or radiation therapy; patients should not require steroids or antiseizure medications and should have fully recovered from all therapy; at least two weeks should elapse between completion of any treatment for brain metastases (surgery, CNS irradiation) and commencement of protocol therapy
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to UCN-01 or other agents used in study
• Because of cardiopulmonary toxicity seen in patients on other studies, patients with a symptomatic cardiac disease should be excluded; patients with a history of coronary artery disease or mediastinal radiation should undergo testing of ventricular function (cardiac echocardiogram, MUGA or equivalent) and are eligible if LVEF is >= 45%; if there is a history of prior pulmonary disease then pulmonary function tests should be performed and patients are eligible if FEV1 >= 1 liter
• Because UCN-01 may cause hyperglycemia, patients with insulin dependent diabetes mellitus should be excluded
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, or psychiatric illness/social situations that would limit compliance with study requirements
• Pregnant women are excluded from this; breastfeeding should be discontinued if the mother is treated with UCN-01
• HIV-positive patients receiving combination anti-retroviral therapy are excluded from the study
• Other drugs: Though not an exclusion criteria, every effort should be made to avoid drugs which may bind alpha-acid glycoprotein (AGP)
• Patients with a history of severe allergic reactions to cisplatin or carboplatin