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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)


Phase 1
18 Years
N/A
Open (Enrolling)
Both
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

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Trial Information

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)


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.


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

Type of Study:

Interventional

Study Design:

Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

MTD of irinotecan hydrochloride in combination with 7-hydroxystaurosporine in patients with resistant solid tumor malignancies (Part I)

Outcome Description:

Defined as the highest dose given to at least 6 patients in which =< 1 out of 6 experience dose limiting toxicity (DLT).

Outcome Time Frame:

Part I

Safety Issue:

Yes

Principal Investigator

Paula Fracasso

Investigator Role:

Principal Investigator

Investigator Affiliation:

University of Virginia

Authority:

United States: Food and Drug Administration

Study ID:

NCI-2009-00019

NCT ID:

NCT00031681

Start Date:

December 2001

Completion Date:

Related Keywords:

  • 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
  • Adenocarcinoma
  • Adenocarcinoma, Mucinous
  • Anus Neoplasms
  • Breast Neoplasms
  • Carcinoid Tumor
  • Carcinoma
  • Colonic Neoplasms
  • Rectal Neoplasms
  • Carcinoma, Basal Cell
  • Carcinoma, Non-Small-Cell Lung
  • Carcinoma, Squamous Cell
  • Uterine Cervical Neoplasms
  • Carcinoma, Adenoid Cystic
  • Esophageal Diseases
  • Esophageal Neoplasms
  • Granuloma
  • Laryngeal Diseases
  • Leiomyosarcoma
  • Liver Neoplasms
  • Lung Neoplasms
  • Lymphoma
  • Stomach Neoplasms
  • Pancreatic Neoplasms
  • Papilloma
  • Prostatic Neoplasms
  • Small Cell Lung Carcinoma
  • Duodenal Neoplasms
  • Ileal Neoplasms
  • Jejunal Neoplasms
  • Gallbladder Neoplasms
  • Bile Duct Neoplasms
  • Neoplasms, Germ Cell and Embryonal
  • Carcinoma, Mucoepidermoid
  • Carcinoma, Verrucous
  • Esthesioneuroblastoma, Olfactory
  • Papilloma, Inverted
  • Malignant Carcinoid Syndrome
  • Gastrointestinal Neoplasms
  • Head and Neck Neoplasms
  • Neoplasms, Unknown Primary
  • Salivary Gland Neoplasms
  • Adenoma
  • Gastrointestinal Stromal Tumors
  • Germinoma
  • Ovarian Neoplasms
  • Neoplasms
  • Hypopharyngeal Neoplasms
  • Laryngeal Neoplasms
  • Intestinal Neoplasms
  • Endometrial Neoplasms
  • Neoplasms, Glandular and Epithelial
  • Paranasal Sinus Neoplasms
  • Sarcoma
  • Oropharyngeal Neoplasms
  • Nasopharyngeal Neoplasms

Name

Location

Washington University School of MedicineSaint Louis, Missouri  63110
University of VirginiaCharlottesville, Virginia  22908