Genetic Testing Plus Irinotecan in Treating Patients With Solid Tumors or Lymphoma

Phase 1

Completed

• Conditions: AIDS-related Peripheral/Systemic Lymphoma; AIDS-related Primary CNS Lymphoma; Anaplastic Large Cell Lymphoma; Angioimmunoblastic T-cell Lymphoma; Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Intraocular Lymphoma; Nodal Marginal Zone B-cell Lymphoma; Primary Central Nervous System Non-Hodgkin Lymphoma; Recurrent Adult Burkitt Lymphoma; Recurrent Adult Diffuse Large Cell Lymphoma
• Interventions: Drug: irinotecan hydrochloride

• Registration Number: NCT00003970
• Lead Sponsor: National Cancer Institute (NCI)

Brief Summary

Phase I trial to study genetic testing and the effectiveness of irinotecan in treating patients who have solid tumors and lymphoma. Drugs used in chemotherapy use different ways to stop cancer cells from dividing so they stop growing or die. Genetic testing for a specific enzyme may help doctors determine whether side effects from or response to chemotherapy are related to a person's genetic makeup

Detailed Description

OBJECTIVES:

I. Classify patients with solid tumors or lymphoma according to UGT1A1 promoter (TATA box) and coding region (Gly71Arg) mutation, and CYP3A4 promoter (G to A) polymorphisms.

II. Identify UGT1A1 enzyme glucuronidator and irinotecan oxidizer phenotypes in these patients and determine the correlation between the two metabolic reactions in vivo.

III. Determine the relationship between UGT1A1 genotype (promoter and/or coding region mutation) and CYP3A4 promoter genotype vs gastrointestinal or bone marrow toxicity, and pharmacokinetics of irinotecan in these patients.

IV. Determine the pharmacokinetics of irinotecan in these patients.

OUTLINE: Patients are genotyped for UGT1A1 enzyme and classified as "Gilbert's" (7/7), "heterozygotes" (6/7), and "homozygotes for allele 6" (6/6). The DNA is analyzed for the UGT1A1 coding region mutation (Gly71Arg) and CYP3A4 promoter polymorphism. Patients are also examined for glucuronidator ratio of SN-38, the active metabolite of irinotecan, and classified as "low/slow" (very low or zero SN-38G/SN-38 ratio), "intermediate" (less than 50% normal ratio), or "normal".

Patients receive irinotecan IV over 90 minutes once every 3 weeks. Treatment continues for at least 2 courses in the absence of disease progression or unacceptable toxicity.

Study Timeline

• Study Start: 1999-01
• Study First Submitted: 1999-11-01
• Study First Submitted QC: 2003-01-26
• Study First Posted: 2003-01-27
• Primary Completion: 2003-10
• Status Verified: 2013-01
• Last Update Submitted: 2013-01-23
• Last Update Posted: 2013-01-24

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 60

Inclusion Criteria

• Histologically proven solid tumor or lymphoma

  • Responded to irinotecan OR no existing curative therapy

• No leukemia

• Measurable or evaluable disease

• Performance status - Karnofsky 70-100%

• WBC at least 3500/mm^3

• Absolute neutrophil count at least 1500/mm^3

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

• Bilirubin normal

• SGOT/SGPT less than 5 times upper limit of normal (unless due to disease)

• Creatinine no greater than 1.5 mg/dL

• Creatinine clearance at least 60 mL/min

• Not pregnant or nursing

• Fertile patients must use effective contraception

• No inflammatory bowel disease requiring therapy

• No chronic diarrhea syndrome or paralytic ileus

• At least 2 weeks since prior colony stimulating factor

• At least 4 weeks since prior biologic therapy

• No concurrent biologic therapy

• See Disease Characteristics

• At least 4 weeks since prior chemotherapy (6 weeks for nitrosoureas or mitomycin)

• No other concurrent chemotherapy

• At least 4 weeks since prior radiotherapy to greater than 25% of bone marrow

• No concurrent palliative radiotherapy

• No prior transplant

• No concurrent substrates of UGT1A1 enzyme

• No concurrent inducers or inhibitors of UGT1A1 enzyme activity

Exclusion Criteria

Not provided

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Treatment (irinotecan hydrochloride)	irinotecan hydrochloride	Patients receive irinotecan IV over 90 minutes once every 3 weeks. Treatment continues for at least 2 courses in the absence of disease progression or unacceptable toxicity.

Primary Outcome Measures

Name	Time	Method
Grade 3-4 diarrhea	Up to 4 years	A Cochran-Armitage test for trend will be used to determine whether there is a linear trend in the proportion of patients within each genotype experiencing grade 3-4 diarrhea. Similarly, trend analysis will be performed to determine if there is a linear trend in the proportion of patients within each phenotype experiencing grade 3-4 myelosuppression. Genotype (3 ordered levels) will be modeled as a function of metabolic ratios and biliary index to determine whether these are independent.

Secondary Outcome Measures

Name	Time	Method
Genotype	Up to 4 years	A chi-squared test will be used to determine whether genotype and phenotype are independent.
Phenotype	Up to 4 years	A chi-squared test will be used to determine whether genotype and phenotype are independent. Modeled as a function of metabolic ratios and biliary index.

Trial Locations

Locations (1)

University of Chicago Comprehensive Cancer Center; 🇺🇸 Chicago, Illinois, United States