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

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.

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