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

Alternate Title

Erlotinib and Irinotecan in Treating Patients With Advanced Solid Tumors

Basic Trial Information

Objectives

1. Determine the maximum tolerated dose (MTD) of erlotinib and irinotecan, in relation to presence or absence of UGT1A1*28 polymorphism, in patients with advanced solid tumors that overexpress epidermal growth factor receptor.
2. Determine the dose-limiting toxicity of these regimens in these patients.
3. Determine whether erlotinib alters the disposition of irinotecan using a previously described limited sampling model.
4. Determine factors that influence the disposition of these drugs, including genetic variation in UGT1A1 and BCRP, in patients treated with these regimens.
5. 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.
6. Evaluate the effect of this regimen on epidermal growth factor receptor phosphorylation in these patients.
7. Assess, preliminarily, any antitumor activity in patients treated with these regimens.
8. Correlate, preliminarily, EGFR phosphorylation and/or BCRP -expression with response in tumor samples from these patients.

Entry Criteria

Disease Characteristics:

• Histologically confirmed malignancy that overexpresses epidermal growth factor receptor (EGFR)
• Unresectable disease for which there is no known standard therapy that is potentially 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

Prior/Concurrent Therapy:

Biologic therapy

• More than 4 weeks since prior immunotherapy or biologic therapy
• No concurrent immunotherapy

Chemotherapy

• More than 4 weeks since prior chemotherapy (6 weeks for nitrosoureas or mitomycin) and recovered
• No other concurrent chemotherapy

Endocrine therapy

• Not specified

Radiotherapy

• More than 4 weeks since prior radiotherapy
• No prior radiotherapy to more than 25% of bone marrow
• No concurrent radiotherapy

Surgery

• More than 3 weeks since prior major surgery
• No prior surgical procedures affecting absorption

Other

• 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

Patient Characteristics:

Age

• 18 and over

Performance status

• ECOG 0-2

Life expectancy

• At least 12 weeks

Hematopoietic

• Absolute neutrophil count at least 1,500/mm³
• Platelet count at least 100,000/mm³
• Hemoglobin at least 9.0 g/dL

Hepatic

• Bilirubin no greater than 1.5 times upper limit of normal (ULN)
• AST ≤ 2.5 times ULN (5 times ULN if liver metastases present)

Renal

• Creatinine no greater than 1.5 times ULN

Cardiovascular

• No symptomatic congestive heart failure
• No unstable angina pectoris
• No cardiac arrhythmia
• No New York Heart Association class III or IV heart disease

Gastrointestinal

• No gastrointestinal tract disease resulting in an inability to take oral or nasogastric medication
• No requirement for IV alimentation
• No active peptic ulcer disease

Ophthalmic

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

Other

• 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

Expected Enrollment

A total of 92 patients (20 in stratum 1 [closed to accrual as of 9/15/04], 42 in stratum 2, and 30 in stratum 3) will be accrued for this study within 3.25-5 years.

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 daily on days -6 to -1. Patients then receive irinotecan 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 and irinotecan until the maximum tolerated dose (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.

Pitot H, Reid J, Goetz M, et al.: UGT1A1*28 genotype determines the maximally tolerated dose (MTD) of OSI-774 and CPT-11 in patients with advanced solid tumors. [Abstract] American Association for Cancer Research: Molecular Targets and Cancer Therapeutics, October 22-26, 2007, San Francisco, CA A-B86, 2007.

Trial Contact Information

Trial Lead Organizations

Mayo Clinic Cancer Center

Henry Pitot, MD, Protocol chair		Ph: 507-284-2511 Email: pitot.henry@mayo.edu

Registry Information
Official Title		Phase I Trial of OSI-774 and CPT-11 in Patients with Advanced Solid Tumors
Trial Start Date		2002-08-22
Trial Completion Date		2009-12-17 (estimated)
Registered in ClinicalTrials.gov		NCT00045201
Date Submitted to PDQ		2002-06-28
Information Last Verified		2009-08-02
NCI Grant/Contract Number		CA69912, CA15083

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