Phase I trial to study the effectiveness of combining UCN-01 with cisplatin in treating
patients who have advanced solid tumors. Drugs used in chemotherapy use different ways to
stop tumor cells from dividing so they stop growing or die. UCN-01 may stop the growth of
tumor cells by blocking the enzymes necessary for tumor cell growth and may help cisplatin
kill more cancer cells by making tumor cells more sensitive to the drug.
I. To establish the maximum tolerated dose (MTD) of cisplatin in combination with UCN-01 in
patients with advanced malignancies.
II. To assess the toxicity and observe the potential antitumor activity of UCN-01 plus
cisplatin in advanced malignancies at each dose level studies.
III. To determine the pharmacokinetics of UCN-01 and cisplatin on this treatment schedule.
IV. To perform laboratory correlative studies to investigate intermediate molecular markers
of the activity of UCN-01 and cisplatin at the cellular level.
OUTLINE: This is a dose-escalation study of cisplatin.
Patients receive cisplatin IV over 1 hour on day 1 and UCN-01 IV continuously over 36-72
hours on day 2. Treatment repeats every 4 weeks for up to 6 courses in the absence of
disease progression or unacceptable toxicity.
Cohorts of 3-6 patients receive escalating doses of cisplatin 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.
Patients are followed every 2-3 months for at least 1 year.
- Advanced or metastatic, histologcally/cytologically confirmed malignant solid tumor,
not expected to clinically benefit from standard therapy
- Life expectancy greater than 3 months
- Previous chemotherapy and/or radiotherapy must have been completed at least four
weeks (six weeks for prior treatment with mitomycin or nitrosoureas) and patients
should have recovered from all toxicities of that therapy before treatment under this
- All patients must have recovered from any surgical procedure
- Serum creatinine must be within the institutional limits of normal and an estimated
creatinine clearance of >= 60 ml/min
- Normal bilirubin is required
- SGOT/AST must be less than or equal to 2.5 times the upper limit of institutional
- WBC >= 4000/mm^3
- Absolute neutrophil count >= 2000/mm^3
- Platelet count >= 150,000/mm^3
- Patients must have a Karnofsky Performance Status of 60% or greater
- Subjects who are fertile must use a medically acceptable contraceptive throughout the
treatment period and for three months following cessation of treatment; subjects must
be made aware, before entering this trial, of the risk in becoming pregnant or in
- A signed informed consent (approved by the IRB) must be obtained prior to trial entry
- Tumor site accessible for both pre-treatment and post-treatment biopsy is preferred
during dose-finding, and is required for patients entering the expanded cohort at the
- All patients require a central indwelling venous catheter prior to treatment under
- Peripheral neuropathy > grade I
- Any prior mediastinal radiotherapy
- Any history of coronary artery disease
- Class III or IV congestive heart failure according to the New York Heart
- History of allergic reactions to appropriate diuretics or antiemetics (e.g., 5-HT3
antagonists) to be administered in conjunction with protocol directed chemotherapy
- Brain metastasis
- Uncontrolled intercurrent illness that would preclude tolerance and completion of the
protocol treatment, including vigorous hydration prior and subsequent to cisplatin
- Lactating or pregnant women are excluded to avoid potential harm to the unborn child
or infant; documentation of a negative, serum beta-HCG pregnancy test must be
available for pre-menopausal women with intact reproductive organs and for women less
than two years after menopause
- Receipt of any investigational drug within 30 days before beginning treatment with
- Medical, social, or psychological factors that would prevent the patient from
completing the treatment protocol
- Patients with clinically significant hearing loss