Clinical trial NCT00031681: 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)
Official title: 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)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: 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
Lead sponsor: National Cancer Institute (NCI)
Sponsor class: NIH
Collaborators: name: Washington University Siteman Cancer Center
First posted: 2003-01-27
Enrollment: 41
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility 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

Primary outcomes:
measure: MTD of irinotecan hydrochloride in combination with 7-hydroxystaurosporine in patients with resistant solid tumor malignancies (Part I)
timeFrame: Part I
measure: DLT of irinotecan hydrochloride in combination with 7-hydroxystaurosporine in patients with resistant solid tumor malignancies (Part I)
timeFrame: Part I
measure: Toxicities associated with irinotecan hydrochloride in combination with 7-hydroxystaurosporine in patients with resistant solid tumor malignancies (Part I)
timeFrame: Continuously over study treatment
measure: 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)
timeFrame: Every 6 weeks
measure: Side effect profile of 7-hydroxystaurosporine in combination with irinotecan hydrochloride in triple negative recurrent breast cancer (Part II)
timeFrame: Continuously over study treatment
Secondary outcomes:
measure: Anti-tumor activity of the combination of irinotecan hydrochloride and 7-hydroxystaurosporine in treatment of patients with resistant solid tumor malignancies
timeFrame: Every 6 weeks
measure: Pharmacokinetics of irinotecan hydrochloride and 7-hydroxystaurosporine when administered in combination
timeFrame: Weekly during the first 4 weeks of course 1
measure: Serum alpha-acid glycoprotein and correlate this level with free 7-hydroxystaurosporine concentrations
timeFrame: Weekly during the first 4 weeks of course 1
measure: In vivo mechanistic basis for 7-hydroxystaurosporine activity
timeFrame: Weekly during the first 4 weeks of course 1
Other outcomes:
Locations:
city: Charlottesville
country: United States
facility: University of Virginia
state: Virginia
Study officials:
affiliation: University of Virginia
name: Paula Fracasso
role: PRINCIPAL_INVESTIGATOR
References: