Alternate Title
Basic Trial Information
Objectives
Entry Criteria
Expected Enrollment
Outcomes
Outline
Trial Contact Information
Registry Information

Alternate Title

UCN-01 and Irinotecan in Treating Patients With Metastatic or Unresectable Solid Tumors

Basic Trial Information

Phase	Type	Status	Age	Sponsor	Protocol IDs
Phase I	Biomarker/Laboratory analysis, Treatment	Active	18 and over	NCI	WUSM-SCC-0102 NCI-5582, 5582, NCT00031681

Objectives

Primary

1. Determine the maximum tolerated dose of UCN-01 and irinotecan in patients with resistant solid tumors. (Part I [closed to accrual as of 6/8/2007])
2. Determine the dose-limiting toxicity of this regimen in these patients. (Part I [closed to accrual as of 6/8/2007])
3. Determine the types of toxic effects of this regimen in these patients. (Part I [closed to accrual as of 6/8/2007])
4. 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)
5. Determine the side effect profile of this regimen in patients with triple negative recurrent breast cancer. (Part II)

Secondary

1. Determine any anti-tumor activity of this regimen in these patients. (Part I [closed to accrual as of 6/8/2007])
2. Determine the pharmacokinetics of this regimen in these patients. (Part I [closed to accrual as of 6/8/2007])
3. 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])
4. Determine the in vivo mechanisms of UCN-01 activity in these patients.

Entry Criteria

Disease Characteristics:

• 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

Prior/Concurrent Therapy:

Biologic therapy:

• No concurrent granulocyte colony-stimulating factors (filgrastim [G-CSF] or sargramostim [GM-CSF]) during the first course of study

Chemotherapy:

• 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)

Endocrine therapy:

• Not specified

Radiotherapy:

• More than 4 weeks since prior radiotherapy and recovered

Surgery:

• Not specified

Other:

• 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

Patient Characteristics:

Age:

• 18 and over

Sex:

• Not specified

Menopausal status:

• Not specified

Performance status:

• ECOG 0-2

  OR

• Karnofsky 60-100%

Life expectancy:

• More than 12 weeks

Hematopoietic:

• WBC at least 3,000/mm³
• Absolute neutrophil count at least 1,500/mm³
• Platelet count at least 100,000/mm³
• Hemoglobin ≥ 10 g/dL

Hepatic:

• Bilirubin normal
• AST/ALT no greater than 3 times upper limit of normal (ULN)
• No Gilbert's disease
• No chronic unconjugated hyperbilirubinemia

Renal:

• Creatinine no greater than 1.5 times ULN

  OR

• Creatinine clearance at least 60 mL/min

Cardiovascular:

• No symptomatic cardiac dysfunction

Pulmonary:

• No symptomatic pulmonary dysfunction
• Oxygen saturation at least 90% by pulse oximetry on room air at rest and after walking 6 minutes

Other:

• 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

Expected Enrollment

A total of 41 patients (21 part I [closed to accrual as of 6/8/2007] and 20 part II) will be accrued for this study.

Outcomes

Anti-tumor activity (overall response rate [partial response and complete response], clinical benefit rate [partial response, complete response, and stable disease], and time to disease progression)
Side effect profile

In vivo mechanisms

Outline

• Part I (treatment of resistant solid tumors [closed to accrual as of 6/8/2007]):

  This is a dose-escalation study.

  Patients receive irinotecan IV over 90 minutes on days 1, 8, 15, and 22 and UCN-01 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 and UCN-01 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 IV and UCN-01 IV as in part I at the MTD and undergo blood sample collection.

Trial Contact Information

Trial Lead Organizations

Siteman Cancer Center at Barnes-Jewish Hospital - Saint Louis

Paula Fracasso, MD, PhD, Protocol chair		Ph: 434-243-6143; 800-223-9173

U.S.A.
Missouri
	Saint Louis
	Siteman Cancer Center at Barnes-Jewish Hospital - Saint Louis
		Cynthia Ma, MD, PhD	Ph:  314-362-8903 800-600-3606
Virginia
	Charlottesville
	University of Virginia Cancer Center
		Paula Fracasso, MD, PhD	Ph:  434-243-6143 800-223-9173

Registry Information
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)
Trial Start Date		2001-12-12
Trial Completion Date		2002-07-10 (estimated)
Registered in ClinicalTrials.gov		NCT00031681
Date Submitted to PDQ		2002-01-04
Information Last Verified		2008-03-30

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