A Pilot Study of Irinotecan in Patients With Breast Cancer and CNS Metastases

Study Overview
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Brief Summary
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This pilot clinical trial studies irinotecan hydrochloride in treating patients with breast cancer and brain metastases that progressed after whole brain radiation therapy or stereotactic radiosurgery. Drugs used in chemotherapy, such as irinotecan hydrochloride, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing.

Detailed Description
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PRIMARY OBJECTIVES; I. To evaluate the safety and efficacy of irinotecan (irinotecan hydrochloride) in breast cancer patients with brain metastases who progressed after radiation therapy. II. To estimate central nervous system (CNS) objective response and clinical benefit rate in patients with breast cancer and brain metastases treated with irinotecan. III. To estimate progression free survival. IV. To estimate overall survival. V. To assess the toxicity of Irinotecan. OUTLINE: Patients receive irinotecan hydrochloride intravenously (IV) over 90 minutes on days 1, 8, 15, 22, and 29. Courses repeat every 42 days in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up for up to 24 months.

Official Title
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A Pilot Study of Irinotecan in Patients With Breast Cancer and CNS Metastases

Conditions
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Central Nervous System Metastases, Male Breast Cancer, Recurrent Breast Cancer, Stage IV Breast Cancer

Intervention / Treatment
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* Drug: irinotecan hydrochloride
* Other: laboratory biomarker analysis


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically confirmed diagnosis of breast cancer (irrespective of receptor status), with evidence of CNS disease by computed tomography (CT) or magnetic resonance imaging (MRI), who have progressed after whole brain radiation therapy or stereotactic radiosurgery Patients must not be a candidate for surgical resection and/or further stereotactic radiosurgery Patients may have had an unlimited number of prior treatments, including any systemic chemotherapy (excluding prior progression of disease with topoisomerase inhibitors as explained below), surgical resection, whole brain radiation, stereotactic radiosurgery, or radioimmunotherapy Patient must have MRI of brain obtained within two weeks of study initiation for staging and patients must also receive first dose within two weeks of study enrollment Patients must have at least one measurable brain lesion prior to start of treatment (≥ 10 mm on T1-weighted, gadolinium-enhanced MRI) Karnofsky performance score greater than 60 At least two weeks must have elapsed since prior chemotherapy, three weeks must have elapsed since last surgery, and six weeks since completion of radiation therapy Hemoglobin > 9 Absolute neutrophil count (ANC) > 1500 Platelet count (plt) > 125 Creatinine < 1.5 Total bilirubin < 1.5 Aspartate aminotransferase and alanine aminotransferase levels within five times the upper limit of normal Patients may be on oral corticosteroids at stable dose (no dose change within two weeks of enrollment), and may be on antiepileptic medication (except for cytochrome P450 3A4 (CYP3A4) enzyme-inducing antiepileptic medications) Fertile patients must use effective contraception Exclusion Criteria: Pregnancy, lactation, immunosuppression other than corticosteroids Patient may be on hormonal therapy or Herceptin, but no other concurrent chemotherapy is allowed Patients who had progression of their breast cancer after prior administration of irinotecan are excluded Patients with leptomeningeal carcinomatosis as the only site of CNS involvement are excluded No other active malignancy except for any of the following: curatively treated basal or squamous cell carcinoma of the skin, carcinoma in situ of the cervix, other malignancies considered disease-free Patients using valproic acid within the last two weeks and patients with contraindications to anticholinergic agents will be excluded Concurrent administration of CYP3A4 enzyme-inducing antiepileptic medications (e.g. phenytoin) will not be allowed (if patients are taking one of these agents, they must switch to a non- enzyme-inducing antiepileptic medication prior to start of treatment) No history of immediate or delayed-type hypersensitivity reaction to gadolinium contrast agents or other contraindication to gadolinium contrast, and no other known contraindication to MRI Homozygous for uridine diphosphate (UDP) glucuronosyltransferase 1 family, polypeptide A1 (UGT1A1)*28 allele * All patients will be tested for UGT1A genotype prior to starting treatment and be excluded if they are homozygous for the UGT1A1*28 allele (UGT1A1 7/7 genotype); irinotecan's active metabolite glucuronidation of 7-ethyl-10-hydroxycamptothecin (SN-38) is inactivated through glucuronidation by uridine diphosphate glucuronosyltransferases (UGTs) mainly in the liver and is excreted through the bile ducts; a meta-analysis demonstrated that the UGT1A1*28 genotype is moderately predictive of severe irinotecan induced hematologic toxicity at moderate doses and strongly predictive at high doses, and in 2005, the Food and Drug Administration (FDA) added a warning to the irinotecan packaging label that patients with the UGT1A1*28 genotype were at increased risk for neutropenia

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (irinotecan hydrochloride)<br>Patients receive irinotecan hydrochloride IV over 90 minutes on days 1, 8, 15, 22, and 29. Courses repeat every 42 days in the absence of disease progression or unacceptable toxicity. This arm also includes laboratory biomarker analysis as an intervention. | Drug: irinotecan hydrochloride<br>* Given IV<br>* Other names: U-101440E;Other: laboratory biomarker analysis<br>* Correlative studies<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| CNS objective response (complete response or partial response), defined as at least 20% volumetric reduction of CNS lesions in absence of increasing steroid use, progressive neurologic signs and symptoms, or progressive extra-CNS disease, based on MRI |  | Up to 24 months | 
| Response rate of patients who have remained progression-free, based on MRI |  | Up to 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival | The product limit estimator developed by Kaplan and Meier was used to graphically describe the distribution of survival among patients with recurrent disease. | Time between treatment initiation and death, assessed up to 24 months | 
| Progression free survival (PFS) | The product limit estimator developed by Kaplan and Meier was used to graphically describe the distribution of PFS among patients with recurrent disease. | Time between treatment initiation and disease progression/relapse/death, assessed up to 24 months | 
| Clinical benefit rate (objective response + stable disease at least 16 weeks) |  | Up to 24 months | 
| Frequency of toxicity occurrence, assessed by National Cancer Institute's Common Terminology Criteria (CTC) for Adverse Events version 4.0 | Tabulated by type, and worst grade experienced by the patient. Toxicity will initially be summarized within each cohort or patient subgroup, and then collectively summarized. | Up to 24 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Irinotecan hydrochloride, Irinotecan, CAMPTOSAR