7-hydroxystaurosporine and Topotecan Hydrochloride in Treating Patients With Relapsed or Progressed Small Cell Lung Cancer

Study Overview
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Brief Summary
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This phase II trial is studying how well giving UCN-01 together with topotecan works in treating patients with small cell lung cancer that relapsed or progressed after previous chemotherapy. Drugs used in chemotherapy, such as topotecan, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. UCN-01 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. It may also increase the effectiveness of topotecan by making tumor cells more sensitive to the drug. Giving UCN-01 together with topotecan may kill more tumor cells.

Detailed Description
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PRIMARY OBJECTIVES: I. To determine the anti tumour activity of UCN-01 in combination with topotecan in patients with SCLC who relapsed or progressed >= 3 months after completing first-line platinum-based chemotherapy (patient with sensitive disease) using objective response rates (complete and partial). SECONDARY OBJECTIVES: I. To determine the anti tumour activity of UCN-01 in combination with topotecan with regards to stable disease rate, median and overall survival rates as well as to determine the safety and tolerability of this combination. OUTLINE: This is a multicenter study. Patients receive topotecan IV over 30 minutes on days 1-5 and 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. Patients achieving complete response (CR) or partial response (PR) receive 2 additional courses beyond CR or PR. Patients are followed for survival.

Official Title
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A Phase II Study of UCN-01 in Combination With Topotecan in Patients With SCLC Who Relapsed or Progressed &gt;= 3 Months After Completing First-Line Platinum-Based Chemotherapy

Conditions
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Extensive Stage Small Cell Lung Cancer, Recurrent Small Cell Lung Cancer

Intervention / Treatment
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* Drug: topotecan hydrochloride
* Drug: 7-hydroxystaurosporine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients must have histologically confirmed extensive stage small cell lung cancer that is incurable but amenable to treatment with chemotherapy Patients must have measurable disease as defined by the Response Evaluation Criteria in Solid Tumours (RECIST); they must have either measurable disease outside the field or progression post radiation therapy Patient must have received ONLY first-line platinum-based chemotherapy and relapsed or progressed >= 3 months post completion of therapy (patients with chemo-sensitive disease) Patient must have completed any prior chemotherapy at least 3 months before study entry, have completed surgery or radiotherapy at least 4 weeks before study entry and must have recovered from the toxic effects from any prior therapy; patient must not have had more than 40% of their bone marrow radiated ECOG performance status =< 2 (Karnofsky >= 60%) Leucocytes >= 3 x 10^9/L OR ANC >= 1.5 x 10^9/L Platelets >= 100 x 10^9/L Total serum bilirubin =< 1.5 x UNL AST/ALT =< 3 x UNL (=< 5 x UNL if documented liver metastases) Creatinine =< institutional upper limit of normal OR creatinine clearance >= 50 ml/min/1.73m^2 for patients with creatinine levels above institutional normal The effects of UCN-01 on the developing human fetus 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; contraception should be continued at least 3 months after the last dose of UCN-01; 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 prior therapy with a topoisomerase I inhibitor (topotecan or irinotecan) will be excluded Patients who have had other chemotherapy regimens other than first-line platinum-based chemotherapy will be excluded Patients may not be receiving any other investigational agents Patients may not be receiving concurrent radiation therapy while on study treatment Patients with uncontrolled/symptomatic CNS metastases; routine CT scans are not required to rule these out except when there is clinical suspicion of CNS disease 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 history of coronary artery disease and/or symptomatic cardiac dysfunction should be excluded Because UCN-01 may cause hyperglycemia, patients with insulin dependent diabetes mellitus will be excluded; patients with diet-controlled diabetes mellitus or those on oral hypoglycemic agents can be entered at the discretion of the investigator Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, 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 events in nursing infants secondary to treatment of the mother with UCN-01, breastfeeding should be discontinued if the mother is treated with UCN-01; these potential risks may also apply to other agents used in this study 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 or other agents administered during the study; appropriate studies will be undertaken in patients receiving combination anti-retroviral therapy when indicated Patients may not have had any other active malignancy in the past 5 years except for cervical carcinoma in situ and non-melanomatous skin cancer

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 (topotecan hydrochloride, UCN-01)<br>Patients receive topotecan IV over 30 minutes on days 1-5 and 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. Patients achieving CR or PR receive 2 additional courses beyond CR or PR. | Drug: topotecan hydrochloride<br>* Given IV<br>* Other names: TOPO;Drug: 7-hydroxystaurosporine<br>* Given IV<br>* Other names: UCN-01;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rates (Complete and Partial) Evaluated Using RECIST Criteria | 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; Objective Response (OR) = CR + PR. | Up to 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Stable Disease Rate Evaluated Using RECIST Criteria | Per Response Evaluation Criteria In Solid Tumours Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), disappearance of all target lesions; Partial Response (PR), at least 30% decrease in the sum of the longest diameter of target lesions; Objective Response (OR) = CR + PR. | Up to 5 years | 
| Duration of Responses |  | From the time measurement criteria are met for CR or PR (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented, assessed up to 5 years | 
| Progression-free Survival |  | From the date of enrollment to progression, death or last contact, or last tumor assessment before the start of further anti-tumor therapy, assessed up to 5 years | 
| Overall Survival |  | From the date of enrollment to death or last contact, assessed up to 5 years | 
| Adverse Events, Graded Using the CTCAE Version 3.0 |  | Up to 5 years |