A Phase II Study of UCN-01 in Metastatic Melanoma

Study Overview
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Brief Summary
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UCN-01 may stop the growth of tumor cells by blocking the enzymes necessary for their growth. This phase II trial is studying how well UCN-01 works in treating patients with metastatic melanoma.

Detailed Description
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PRIMARY OBJECTIVES: I. To assess the anti-tumor activity of UCN-01 (7-hydroxystaurosporine) in metastatic melanoma, as determined by the response rate. II. To assess the clinical and laboratory toxicities of UCN-01. III. To study the effects of UCN-01 administration on potential markers of specific G1-phase cell cycle regulators. OUTLINE: This is a multicenter study. Patients receive UCN-01 IV over 3 hours on day 1. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients are followed for survival. PROJECTED ACCRUAL: A total of 17-33 patients will be accrued for this study within 18 months.

Official Title
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A Phase II Study of UCN-01 in Metastatic Melanoma

Conditions
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Recurrent Melanoma, Stage IV Melanoma

Intervention / Treatment
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* Drug: 7-hydroxystaurosporine
* Other: laboratory biomarker analysis
* Other: pharmacological study


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients have histologically or cytologically confirmed melanoma that is incurable by other means such as surgery, radiotherapy, or limb perfusion Patients must have measurable disease, defined as lesions that can be accurately measured in at least one dimension (longest diameter to be recorded) as >= 10 mm with conventional techniques or with spiral CT scan, and which has clearly progressed during the observation interval prior to participation in this study Patients must have received =< 1 prior chemotherapy and/or =< biological therapies; isolated limb perfusion with a biological and/or chemotherapeutic agent is allowed if the measurable disease and the lesion that will be biopsied for this protocol are outside the area of prior perfusion; at least 4 weeks must have elapsed since prior therapy (6 weeks for nitrosoureas or mitomycin C) and the patient must have recovered from all toxicities attributable to prior therapy Life expectancy greater than 4 months Eastern Cooperative Oncology Group (ECOG) performance status #2 (Karnofsky >= 60%) Leukocytes >= 3000/uL Absolute neutrophil count >= 1500/uL Platelets >= 100000/uL Total bilirubin =< 1.5 mg/dL Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2 X institutional upper limit of normal Creatinine < 1.6 mg/dL Creatinine clearance >= 50 mL/min for patients with creatinine levels above 1.6 mg/dL The effects of UCN-01 on the developing human fetus at the recommended therapeutic dose are unknown; for this reason, 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 willingness to sign a written informed consent document Patient must have a central venous catheter Patients are requested to submit archival tissue for pre-study and undergo a tumor biopsy 24 hours post UCN-01 administration if feasible 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 who have not recovered from adverse events to agents administered more than 4 weeks earlier Patients must not be receiving any other investigational agents Patients with known brain metastases are eligible only if disease is controlled and patient is asymptomatic (i.e. at least 4 weeks from completion of whole brain irradiation, stereotactic radiosurgery, or gamma knife irradiation) and not receiving corticosteroids History of allergic reactions attributed to compounds of similar chemical or biologic composition to UCN-01 Patients with only non-measurable disease, defined as all other lesions, including small lesions (longest diameter >= 10 mm with conventional techniques or with spiral CT scan) and truly non-measurable lesions, which include the following: Bone lesions Leptomeningeal disease Ascites Pleural or pericardial effusion Abdominal masses that are not confirmed and followed by imaging techniques Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, systematic congestive heart failure, symptomatic pulmonary diseases, unstable angina pectoris, cardiac arrhythmia, prior mediastinal radiation or psychiatric illness/social situations that would limit compliance with study requirements Pregnant women are excluded from this study because UCN-01 is a serine-threonine kinase inhibitor with the potential for teratogenic or abortifacient effects; because there is an unknown but potential risk for adverse effects in nursing infants secondary to treatment of the mother with UCN-01, breastfeeding should be discontinued if the mother is treated with UCN-01 Because patients with immune deficiency are at increased risk of lethal infections when treated with marrow-suppressive therapy, HIV-positive patients receiving combination anti-retroviral therapy are excluded from the study because of possible pharmacokinetic interactions with UCN-01; appropriate studies will be undertaken in patients receiving combination anti-retroviral therapy when indicated Due to the incidence of hyperglycemia with UCN-01, patients with a history of diabetes will be excluded from the study

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 (7-hydroxystaurosporine)<br>Patients receive UCN-01 IV over 3 hours on day 1. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. | Drug: 7-hydroxystaurosporine<br>* Given IV<br>Other: laboratory biomarker analysis<br>* Correlative studies<br>Other: pharmacological study<br>* Correlative studies<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response Rate | Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR | Up to 7 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival | Estimated using the product-limit method of Kaplan and Meier. | Up to 7 years | 
| Progression-free Survival | Estimated using the product-limit method of Kaplan and Meier. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions. | From the date of study registration to the first documentation of progressive tumor, assessed up to 7 years |