• 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) [ Designated as safety issue: No ]
• Side effect profile [ Designated as safety issue: Yes ]

• 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

RATIONALE: Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. Giving UCN-01 together with irinotecan may help kill more cancer cells by making tumor cells more sensitive to the drug.

PURPOSE: This phase I trial is studying the side effects and best dose of giving UCN-01 together with irinotecan 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).

OBJECTIVES:

Primary

• 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])
• Determine the dose-limiting toxicity of this regimen in these patients. (Part I [closed to accrual as of 6/8/2007])
• Determine the types of toxic effects of this regimen in these patients. (Part I [closed to accrual as of 6/8/2007])
• 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)
• Determine the side effect profile of this regimen in patients with triple negative recurrent breast cancer. (Part II)

Secondary

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

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.

PROJECTED ACCRUAL: 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.

• Drug: 7-hydroxystaurosporine
• Drug: irinotecan hydrochloride
• Other: laboratory biomarker analysis

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

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/mm^3
• Absolute neutrophil count at least 1,500/mm^3
• Platelet count at least 100,000/mm^3
• 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

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

• National Cancer Institute (NCI)
• Siteman Cancer Center at Barnes-Jewish Hospital - Saint Louis