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Phase I Trial of OSI-774 and CPT-11 in Patients With Advanced Solid Tumors

Phase 1
18 Years
Open (Enrolling)
Unspecified Adult Solid Tumor, Protocol Specific

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Trial Information

Phase I Trial of OSI-774 and CPT-11 in Patients With Advanced Solid Tumors


I. Determine the maximum tolerated dose (MTD) of erlotinib (erlotinib hydrochloride) and
irinotecan (irinotecan hydrochloride), in relation to presence or absence of UGT1A1*28
polymorphism, in patients with advanced solid tumors that overexpress epidermal growth
factor receptor.

II. Determine the dose-limiting toxicity of these regimens in these patients. III. Determine
whether erlotinib alters the disposition of irinotecan using a previously described limited
sampling model.

IV. Determine factors that influence the disposition of these drugs, including genetic
variation in UGT1A1 and BCRP, in patients treated with these regimens.

V. Determine factors that influence the disposition of these drugs, in terms of tumor
BCRP-expression, in tumor samples from patients treated with these drugs at the MTD.

VI. Evaluate the effect of this regimen on epidermal growth factor receptor phosphorylation
in these patients.

VII. Assess, preliminarily, any antitumor activity in patients treated with these regimens.

VIII. Correlate, preliminarily, EGFR phosphorylation and/or BCRP -expression with response
in tumor samples from these patients.

OUTLINE: This is a dose-escalation study. Patients are stratified according to UGTA1A
genotype (all patients regardless of genotype [closed to accrual as of 9/15/04] vs UGT1A1
6/6 genotype vs UGTA1A 6/7 or 7/7 genotype).

Patients receive oral erlotinib hydrochloride daily on days -6 to -1. Patients then receive
irinotecan hydrochloride intravenously (IV) over 90 minutes on day 1 and oral erlotinib once
daily on days 1-21. Courses repeat every 21 days in the absence of disease progression or
unacceptable toxicity.

Cohorts of 3-6 patients per stratum receive escalating doses of erlotinib hydrochloride and
irinotecan hydrochloride until the MTD is determined. The MTD is defined as the dose
preceding that at which at least 2 of 3 or 2 of 6 patients experience dose-limiting
toxicity. Additional patients are treated at the MTD.

Patients are followed for 3 months.

Inclusion Criteria:

- Histologically confirmed malignancy that overexpresses epidermal growth factor
receptor (EGFR)

- Unresectable disease for which there is no known standard therapy that ispotentially
curative or definitely capable of extending life expectancy

- UGT1A1 genotype 6/6, 6/7, or 7/7

- Willing to provide biologic specimens

- Lesions amenable for 2 biopsies from the same tumor site (only patients receiving MTD
in groups 2 and 3)

- No known brain metastases

- Performance status - ECOG 0-2

- At least 12 weeks

- Absolute neutrophil count at least 1,500/mm^3

- Platelet count at least 100,000/mm^3

- Hemoglobin at least 9.0 g/dL

- Bilirubin no greater than 1.5 times upper limit of normal (ULN)

- AST ≤ 2.5 times ULN (5 times ULN if liver metastases present)

- Creatinine no greater than 1.5 times ULN

- No symptomatic congestive heart failure

- No unstable angina pectoris

- No cardiac arrhythmia

- No New York Heart Association class III or IV heart disease

- No gastrointestinal tract disease resulting in an inability to take oral or
nasogastric medication

- No requirement for IV alimentation

- No active peptic ulcer disease

- No abnormalities of the cornea (e.g., dry eye syndrome or Sjögren's syndrome)

- No congenital abnormality (e.g., Fuch's dystrophy)

- No abnormal slit-lamp examination using a vital dye (e.g., fluorescein or

- No abnormal corneal sensitivity test (e.g., Schirmer test or similar tear production

- No other uncontrolled concurrent illness

- No ongoing or active infection

- No significant traumatic injury within the past 21 days

- No seizure disorder

- No psychiatric illness or social situation that would preclude study compliance

- Not pregnant or nursing

- Negative pregnancy test

- Fertile patients must use effective contraception

- No concurrent grapefruit or grapefruit juice

- No smoking during study

- More than 4 weeks since prior immunotherapy or biologic therapy

- No concurrent immunotherapy

- More than 4 weeks since prior chemotherapy (6 weeks for nitrosoureas or mitomycin)
and recovered

- No other concurrent chemotherapy

- Not specified

- More than 4 weeks since prior radiotherapy

- No prior radiotherapy to more than 25% of bone marrow

- No concurrent radiotherapy

- More than 3 weeks since prior major surgery

- No prior surgical procedures affecting absorption

- No prior EGFR-targeting therapy (e.g., gefitinib or EKB-569)

- No other concurrent investigational therapy

- No concurrent enzyme-inducing anticonvulsants (e.g., phenytoin, phenobarbital,
carbamazepine, or valproic acid)

- No concurrent combination antiretroviral therapy for HIV-positive patients

- No concurrent enrollment on another study involving pharmacological agents for
symptom control or therapeutic intent

Type of Study:


Study Design:

Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

MTD of erlotinib hydrochloride and irinotecan hydrochloride in patients with advanced solid tumors that overexpress epidermal growth factor receptor

Outcome Description:

Defined as the highest safely tolerated dose where at most one patient experiences DLT with the next higher dose having at least 2 patients who experience DLT. Three patients will be entered at a given dose level and observed for at least 4 weeks to assess toxicity. MTD will be determined independently for each cohort.

Outcome Time Frame:

At least 4 weeks

Safety Issue:


Principal Investigator

Henry Pitot

Investigator Role:

Principal Investigator

Investigator Affiliation:

Mayo Clinic


United States: Food and Drug Administration

Study ID:




Start Date:

August 2002

Completion Date:

Related Keywords:

  • Unspecified Adult Solid Tumor, Protocol Specific
  • Neoplasms



Mayo Clinic Rochester, Minnesota  55905