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)
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)
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.
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:
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
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
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:
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