7-Hydroxystaurosporine and Irinotecan Hydrochloride in Treating Patients With Metastatic or Unresectable Solid Tumors or Triple Negative Breast Cancer (Currently Accruing Only Triple-negative Breast Cancer Patients Since 6/8/2007)

Study Overview
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Brief Summary
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This phase I trial is studying the side effects and best dose of giving 7-hydroxystaurosporine together with irinotecan hydrochloride in treating patients with metastatic or unresectable solid tumors, including triple-negative breast cancer (currently enrolling only patients with triple-negative breast cancer since 6/8/2007). Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. Giving 7-hydroxystaurosporine together with irinotecan hydrochloride may help kill more cancer cells by making tumor cells more sensitive to the drug.

Detailed Description
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PRIMARY OBJECTIVES: I. Determine the maximum tolerated dose of UCN-01 (7-hydroxystaurosporine) and irinotecan (irinotecan hydrochloride) in patients with resistant solid tumors. (Part I [closed to accrual as of 6/8/2007]) II. Determine the dose-limiting toxicity of this regimen in these patients. (Part I [closed to accrual as of 6/8/2007]) III. Determine the types of toxic effects of this regimen in these patients. (Part I [closed to accrual as of 6/8/2007]) IV. Determine the anti-tumor activity in terms of overall response rate (partial response [PR] and complete response [CR]), clinical benefit rate (PR, CR, and stable disease), and time to disease progression in patients with estrogen receptor-negative, progesterone receptor-negative, and HER-2 not amplified (triple negative) locally recurrent or metastatic breast cancer treated with this regimen. (Part II) V. Determine the side effect profile of this regimen in patients with triple negative recurrent breast cancer. (Part II) SECONDARY OBJECTIVES: I. Determine any anti-tumor activity of this regimen in these patients. (Part I [closed to accrual as of 6/8/2007]) II. Determine the pharmacokinetics of this regimen in these patients. (Part I [closed to accrual as of 6/8/2007]) III. Determine the activity of the serum α-acid glycoprotein and correlate this level with free UCN-01 concentrations. (Part I [closed to accrual as of 6/8/2007]) IV. Determine the in vivo mechanisms of UCN-01 activity in these patients. OUTLINE: This is a dose-escalation study. PART I: Patients receive irinotecan hydrochloride intravenously (IV) over 90 minutes on days 1, 8, 15, and 22 and 7-hydroxystaurosporine IV over 3 hours on days 2 and 23. Courses repeat every 42 days in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6 patients receive escalating doses of irinotecan hydrochloride and 7-hydroxystaurosporine 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. Blood samples are collected periodically during study treatment. PART II: (treatment of triple negative recurrent breast cancer): Patients receive irinotecan hydrochloride IV and 7-hydroxystaurosporine IV as in part I at the MTD and undergo blood sample collection.

Official Title
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A Phase I Study of UCN-01 in Combination With Irinotecan in Resistant Solid Tumor Malignancies (Part I) and in Triple Negative (ER-Negative, PgR-Negative, HER-2 Not-Amplified) Recurrent Breast Cancers (Part II)

Conditions
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Advanced Adult Primary Liver Cancer, Carcinoma of the Appendix, Estrogen Receptor-negative Breast Cancer, Extensive Stage Small Cell Lung Cancer, Gastrointestinal Stromal Tumor, HER2-negative Breast Cancer, Metastatic Gastrointestinal Carcinoid Tumor, Ovarian Sarcoma, Ovarian Stromal Cancer, Progesterone Receptor-negative Breast Cancer, Recurrent Adenoid Cystic Carcinoma of the Oral Cavity, Recurrent Adult Primary Liver Cancer, Recurrent Anal Cancer, Recurrent Basal Cell Carcinoma of the Lip, Recurrent Borderline Ovarian Surface Epithelial-stromal Tumor, Recurrent Breast Cancer, Recurrent Cervical Cancer, Recurrent Colon Cancer, Recurrent Endometrial Carcinoma, Recurrent Esophageal Cancer, Recurrent Esthesioneuroblastoma of the Paranasal Sinus and Nasal Cavity, Recurrent Extrahepatic Bile Duct Cancer, Recurrent Gallbladder Cancer, Recurrent Gastric Cancer, Recurrent Gastrointestinal Carcinoid Tumor, Recurrent Inverted Papilloma of the Paranasal Sinus and Nasal Cavity, Recurrent Lymphoepithelioma of the Nasopharynx, Recurrent Lymphoepithelioma of the Oropharynx, Recurrent Metastatic Squamous Neck Cancer With Occult Primary, Recurrent Midline Lethal Granuloma of the Paranasal Sinus and Nasal Cavity, Recurrent Mucoepidermoid Carcinoma of the Oral Cavity, Recurrent Non-small Cell Lung Cancer, Recurrent Ovarian Epithelial Cancer, Recurrent Ovarian Germ Cell Tumor, Recurrent Pancreatic Cancer, Recurrent Prostate Cancer, Recurrent Rectal Cancer, Recurrent Salivary Gland Cancer, Recurrent Small Cell Lung Cancer, Recurrent Small Intestine Cancer, Recurrent Squamous Cell Carcinoma of the Hypopharynx, Recurrent Squamous Cell Carcinoma of the Larynx, Recurrent Squamous Cell Carcinoma of the Lip and Oral Cavity, Recurrent Squamous Cell Carcinoma of the Nasopharynx, Recurrent Squamous Cell Carcinoma of the Oropharynx, Recurrent Squamous Cell Carcinoma of the Paranasal Sinus and Nasal Cavity, Recurrent Verrucous Carcinoma of the Larynx, Recurrent Verrucous Carcinoma of the Oral Cavity, Small Intestine Adenocarcinoma, Small Intestine Leiomyosarcoma, Small Intestine Lymphoma, Stage IV Adenoid Cystic Carcinoma of the Oral Cavity, Stage IV Anal Cancer, Stage IV Basal Cell Carcinoma of the Lip, Stage IV Borderline Ovarian Surface Epithelial-stromal Tumor, Stage IV Breast Cancer, Stage IV Colon Cancer, Stage IV Endometrial Carcinoma, Stage IV Esophageal Cancer, Stage IV Esthesioneuroblastoma of the Paranasal Sinus and Nasal Cavity, Stage IV Gastric Cancer, Stage IV Inverted Papilloma of the Paranasal Sinus and Nasal Cavity, Stage IV Lymphoepithelioma of the Nasopharynx, Stage IV Lymphoepithelioma of the Oropharynx, Stage IV Midline Lethal Granuloma of the Paranasal Sinus and Nasal Cavity, Stage IV Mucoepidermoid Carcinoma of the Oral Cavity, Stage IV Non-small Cell Lung Cancer, Stage IV Ovarian Epithelial Cancer, Stage IV Ovarian Germ Cell Tumor, Stage IV Pancreatic Cancer, Stage IV Prostate Cancer, Stage IV Rectal Cancer, Stage IV Salivary Gland Cancer, Stage IV Squamous Cell Carcinoma of the Hypopharynx, Stage IV Squamous Cell Carcinoma of the Larynx, Stage IV Squamous Cell Carcinoma of the Lip and Oral Cavity, Stage IV Squamous Cell Carcinoma of the Nasopharynx, Stage IV Squamous Cell Carcinoma of the Oropharynx, Stage IV Squamous Cell Carcinoma of the Paranasal Sinus and Nasal Cavity, Stage IV Verrucous Carcinoma of the Larynx, Stage IV Verrucous Carcinoma of the Oral Cavity, Stage IVA Cervical Cancer, Stage IVB Cervical Cancer, Triple-negative Breast Cancer, Unresectable Extrahepatic Bile Duct Cancer, Unresectable Gallbladder Cancer, Unspecified Adult Solid Tumor, Protocol Specific, Untreated Metastatic Squamous Neck Cancer With Occult Primary

Intervention / Treatment
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* Drug: 7-hydroxystaurosporine
* Drug: irinotecan hydrochloride
* Other: diagnostic laboratory biomarker analysis


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Part I (closed to accrual as of 6/8/2007) Histologically confirmed solid tumor that is metastatic or unresectable for which standard curative measures do not exist or are no longer effective, including the following: Gastrointestinal tract cancer Lung cancer Breast cancer Ovarian cancer Endometrial cancer Cervical cancer Prostate cancer Head and neck cancer Patients with or without measurable or evaluable disease allowed Measurable disease, defined as ≥ 1 unidimensionally measurable lesion > 20 mm by conventional techniques or ≥ 10 mm with spiral CT scan Tumor markers allowed for evaluable disease Positive bone scan, osteoblastic metastases, and pleural or peritoneal effusions are not considered measurable or evaluable disease No known brain metastases Part II Histologically confirmed (either primary or the recurrent site) locally recurrent or metastatic breast cancer not amendable to surgery Measurable disease For skin lesions, documentation by color photography and estimation of lesion size with a ruler are required Must have undergone prior therapy with an anthracycline and a taxane either in the adjuvant or metastatic setting CNS metastasis allowed provided stable disease (i.e., no evidence of local progression) ≥ 3 months after local therapy Hormone receptor status: Estrogen receptor negative Progesterone receptor negative HER-2 not amplified by fluorescence in situ hybridization Performance status - ECOG 0-2 Performance status - Karnofsky 60-100% More than 12 weeks WBC at least 3,000/mm^3 Absolute neutrophil count at least 1,500/mm^3 Platelet count at least 100,000/mm^3 Hemoglobin ≥ 10 g/dL Bilirubin normal AST/ALT no greater than 3 times upper limit of normal (ULN) No Gilbert's disease No chronic unconjugated hyperbilirubinemia Creatinine no greater than 1.5 times ULN Creatinine clearance at least 60 mL/min No symptomatic cardiac dysfunction No symptomatic pulmonary dysfunction Oxygen saturation at least 90% by pulse oximetry on room air at rest and after walking 6 minutes No insulin-dependent diabetes mellitus No other uncontrolled concurrent illness No active or ongoing infection No psychiatric illness or social situation that would preclude study entry No prior allergic reactions attributed to compounds of similar chemical or biological composition to UCN-01 or irinotecan Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception No concurrent granulocyte colony-stimulating factors (filgrastim [G-CSF] or sargramostim [GM-CSF]) during the first course of study See Disease Characteristics (Part II) More than 4 weeks since prior chemotherapy (6 weeks for nitrosoureas or mitomycin) and recovered Prior irinotecan allowed Less than 4 prior chemotherapy regimens in the adjuvant and/or metastatic setting (Part II) More than 4 weeks since prior radiotherapy and recovered Concurrent warfarin allowed Concurrent subcutaneous heparin allowed No other concurrent investigational agents No concurrent anticonvulsants (e.g., carbamazepine, phenobarbital, or phenytoin) No concurrent combination antiretroviral therapy for HIV-positive patients

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 (combination chemotherapy)<br>PART I: Patients receive irinotecan hydrochloride IV over 90 minutes on days 1, 8, 15, and 22 and 7-hydroxystaurosporine IV over 3 hours on days 2 and 23. Courses repeat every 42 days in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6 patients receive escalating doses of irinotecan hydrochloride and 7-hydroxystaurosporine until the 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. Blood samples are collected periodically during study treatment. PART II: (treatment of triple negative recurrent breast cancer): Patients receive irinotecan hydrochloride IV and 7-hydroxystaurosporine IV as in part I at the MTD and undergo blood sample collection. | Drug: 7-hydroxystaurosporine<br>* Given IV<br>* Other names: UCN-01;Drug: irinotecan hydrochloride<br>* Given IV<br>* Other names: U-101440E;Other: diagnostic laboratory biomarker analysis<br>* Correlative studies<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| MTD of irinotecan hydrochloride in combination with 7-hydroxystaurosporine in patients with resistant solid tumor malignancies (Part I) | Defined as the highest dose given to at least 6 patients in which =< 1 out of 6 experience dose limiting toxicity (DLT). | Part I | 
| DLT of irinotecan hydrochloride in combination with 7-hydroxystaurosporine in patients with resistant solid tumor malignancies (Part I) |  | Part I | 
| Toxicities associated with irinotecan hydrochloride in combination with 7-hydroxystaurosporine in patients with resistant solid tumor malignancies (Part I) | Graded using the Cancer Therapy Evaluation Program (CTEP) Active Version of the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE). | Continuously over study treatment | 
| Anti-tumor activity of 7-hydroxystaurosporine in combination with irinotecan hydrochloride in ER-negative, PgR-negative, HER-2 not-amplified (triple negative) recurrent breast cancer (Part II) | Including overall response rate (partial response [PR] +complete response [CR]), clinical benefit rate (PR+CR+stable disease [SD]), and time to disease progression. 95% confidence interval will be calculated. Evaluated by the Response Evaluation Criteria in Solid Tumors (RECIST) criteria. | Every 6 weeks | 
| Side effect profile of 7-hydroxystaurosporine in combination with irinotecan hydrochloride in triple negative recurrent breast cancer (Part II) | 95 % confidence interval will be calculated. | Continuously over study treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Anti-tumor activity of the combination of irinotecan hydrochloride and 7-hydroxystaurosporine in treatment of patients with resistant solid tumor malignancies | Evaluated by the RECIST criteria. | Every 6 weeks | 
| Pharmacokinetics of irinotecan hydrochloride and 7-hydroxystaurosporine when administered in combination | Using the high-performance liquid chromatography (HPLC) assays. | Weekly during the first 4 weeks of course 1 | 
| Serum alpha-acid glycoprotein and correlate this level with free 7-hydroxystaurosporine concentrations |  | Weekly during the first 4 weeks of course 1 | 
| In vivo mechanistic basis for 7-hydroxystaurosporine activity | Explored by subgroup analysis (responders versus non-responders) on pharmacodynamic measures. | Weekly during the first 4 weeks of course 1 |