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

National Cancer Institute (NCI)

Status and phase: Completed; Phase 1

Conditions: AIDS-related Peripheral/Systemic Lymphoma; Stage IV Small Lymphocytic Lymphoma; Stage III Mantle Cell Lymphoma; Stage IV Marginal Zone Lymphoma; Stage IV Adult Diffuse Small Cleaved Cell Lymphoma; Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Splenic Marginal Zone Lymphoma; Recurrent Adult Diffuse Small Cleaved Cell Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Marginal Zone Lymphoma; Stage III Grade 3 Follicular Lymphoma; Small Intestine Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Stage IV Adult Lymphoblastic Lymphoma; Angioimmunoblastic T-cell Lymphoma; Stage III Adult Diffuse Mixed Cell Lymphoma; Stage III Adult Immunoblastic Large Cell Lymphoma; Stage III Adult Diffuse Large Cell Lymphoma; Recurrent Small Lymphocytic Lymphoma; Stage III Adult Burkitt Lymphoma; Stage III Adult Hodgkin Lymphoma; AIDS-related Primary CNS Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Stage III Adult Diffuse Small Cleaved Cell Lymphoma; Stage III Adult Lymphoblastic Lymphoma; Nodal Marginal Zone B-cell Lymphoma; Recurrent Adult Burkitt Lymphoma; Stage III Marginal Zone Lymphoma; Recurrent Mycosis Fungoides/Sezary Syndrome; Stage III Grade 1 Follicular Lymphoma; Stage III Grade 2 Follicular Lymphoma; Recurrent Adult Hodgkin Lymphoma; Stage IV Grade 2 Follicular Lymphoma; Stage IV Adult Diffuse Mixed Cell Lymphoma; Stage IV Adult T-cell Leukemia/Lymphoma; Anaplastic Large Cell Lymphoma; Stage IV Cutaneous T-cell Non-Hodgkin Lymphoma; Recurrent Adult Diffuse Mixed Cell Lymphoma; Stage IV Adult Hodgkin Lymphoma; Recurrent Adult Immunoblastic Large Cell Lymphoma; Stage IV Grade 3 Follicular Lymphoma; Recurrent Cutaneous T-cell Non-Hodgkin Lymphoma; Stage III Mycosis Fungoides/Sezary Syndrome; Recurrent Adult Lymphoblastic Lymphoma; Stage IV Mycosis Fungoides/Sezary Syndrome; Stage III Small Lymphocytic Lymphoma; Intraocular Lymphoma; Stage IV Adult Diffuse Large Cell Lymphoma; Unspecified Adult Solid Tumor, Protocol Specific; Stage III Cutaneous T-cell Non-Hodgkin Lymphoma; Stage IV Adult Immunoblastic Large Cell Lymphoma; Recurrent Adult Diffuse Large Cell Lymphoma; Stage III Adult T-cell Leukemia/Lymphoma; Stage IV Adult Burkitt Lymphoma; Stage IV Mantle Cell Lymphoma; Primary Central Nervous System Non-Hodgkin Lymphoma; Recurrent Adult T-cell Leukemia/Lymphoma; Stage IV Grade 1 Follicular Lymphoma

Treatments: Drug: irinotecan hydrochloride

Study type: Interventional

Funder types: NIH

Identifiers

NCT00003970

9531

CDR0000067173 (Registry Identifier)

U01CA069852 (U.S. NIH Grant/Contract)

NCI-2012-02304

Details and patient eligibility

About

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

Full 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.

Enrollment: 60 patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion criteria

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

Trial design

Primary purpose: Treatment

Allocation: N/A

Interventional model: Single Group Assignment

Masking: None (Open label)

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60 participants in 1 patient group

Treatment (irinotecan hydrochloride)

Experimental group

Description:

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.

Treatment:

Drug: irinotecan hydrochloride