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)

National Cancer Institute (NCI)

Status and phase: Completed; Phase 1

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

Treatments: Other: diagnostic laboratory biomarker analysis; Drug: 7-hydroxystaurosporine; Drug: irinotecan hydrochloride

Study type: Interventional

Funder types: Other; NIH

Identifiers

NCT00031681

P30CA044579 (U.S. NIH Grant/Contract)

5582 (Other Identifier)

UVACC-SCC-0102

WUSM-SCC-0102

NCI-2009-00019 (Registry Identifier)

SCC 01-02 (Other Identifier)

NCI-5582

CDR0000069215

Details and patient eligibility

About

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.

Full description

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.

Enrollment: 41 patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion criteria

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

Trial design

Primary purpose: Treatment

Allocation: N/A

Interventional model: Single Group Assignment

Masking: None (Open label)

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41 participants in 1 patient group

Treatment (combination chemotherapy)

Experimental group

Description:

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.

Treatment:

Drug: irinotecan hydrochloride

Drug: 7-hydroxystaurosporine

Other: diagnostic laboratory biomarker analysis