Bendamustine and Erlotinib in Treating Patients With Stage IIIB, Stage IIIC, or Stage IV Breast Cancer

OBJECTIVES:

Primary

- To determine the phase II dose and assess the toxicity of bendamustine hydrochloride and
erlotinib hydrochloride in patients with triple-receptor (estrogen receptor,
progesterone receptor, and HER-2)-negative, stage IIIB, IIIC, or IV breast cancer.
(Phase I)

- To determine the efficacy of this regimen in these patients. (Phase II)

Secondary (Correlative)

- To assess the correlation between tumor EGFR expression and EGFR gene amplification and
treatment efficacy and toxicity.

- To assess for differences in treatment efficacy between basal-like and non-basal-like
cancers.

- To assess for differences in treatment efficacy between tumors with and without
expression of DNA damage-response (DDR) checkpoint proteins.

- To assess for differences in the activation state of DDR checkpoint proteins based on
breast cancer subtype.

OUTLINE: This is a multicenter, phase I dose-escalation study followed by a phase II study.

Patients receive bendamustine hydrochloride IV over 30 minutes on days 1-2 and oral erlotinib
hydrochloride once daily on days 5-21. Treatment repeats every 28 days for at least 6 courses
in the absence of disease progression or unacceptable toxicity.

Patients with no evidence of disease progression may continue with daily single-agent oral
erlotinib hydrochloride on days 1-28. Treatment continues every 28 days in the absence of
disease progression or unacceptable toxicity.

Breast cancer tissue blocks from prior procedures are obtained for correlative studies. After
a tissue microarray (TMA) and a TMA map are prepared, TMA slides are used for hematoxylin and
eosin (H&E) staining, FISH, and IHC.

After completion of study treatment, patients are followed every 3 months for 2 years.

DISEASE CHARACTERISTICS:

- Histologically confirmed breast cancer meeting 1 of the following criteria:

- Unresectable stage IIIB or IIIC disease

- Stage IV disease

- Must be negative for all of the following:

- Estrogen receptor (< 10%)

- Progesterone receptor (<10%)

- HER-2 (negative FISH, IHC 0 - 1+, or IHC +2 with negative FISH)

- Measurable or evaluable disease

- No symptomatic or progressive CNS (central nervous system) metastases

- Previously treated CNS metastases allowed provided all of the following criteria
are met:

- At least 8 weeks since prior radiation to brain or CNS metastases

- No concurrent steroids

- No leptomeningeal disease

PATIENT CHARACTERISTICS:

- Menopausal status not specified

- ECOG (Eastern Cooperative Oncology Group) performance status 0-2

- Life expectancy ≥ 6 months

- WBC > 1,500/mm³

- Platelet count > 100,000/mm³

- Creatinine clearance > 40 mL/min

- Normal electrolytes (i.e., Na, K, and Ca normal; minor deviations are allowed if they
do not impact on patient safety in the clinical judgment of the treating physician)

- Bilirubin ≤ 1.5 times upper limit of normal (ULN)

- ALT and AST ≤ 2.5 times ULN (≤ 5 times ULN in the presence of documented liver
metastases)

- Alkaline phosphatase ≤ 2.5 times ULN (≤ 5 times ULN in the presence of liver or bone
metastases)

- Not pregnant or nursing

- Fertile patients must use effective barrier contraception

- No uncontrolled intercurrent illness

- No active infection requiring systemic therapy

- Able to swallow oral medications and with no medical problems or prior surgeries that
may interfere with the absorption of oral medications including the following:

- Uncontrolled nausea, vomiting, or diarrhea

- Lack of the physical integrity of the upper gastrointestinal tract

- Malabsorption syndrome

- No known hypersensitivity to bendamustine hydrochloride, mannitol, or erlotinib
hydrochloride

- No prior malignancy in the past 5 years except for adequately treated basal cell or
squamous cell skin carcinoma, or adequately treated stage I-II cancer for which the
patient is in complete remission

PRIOR CONCURRENT THERAPY:

- See Disease Characteristics

- Prior adjuvant or neoadjuvant chemotherapy and 1 prior chemotherapy regimen in the
metastatic setting allowed provided recovered from all acute toxicities

- No prior bendamustine hydrochloride or EGFR-directed therapy

- No other concurrent antineoplastic treatments, including radiotherapy, chemotherapy,
biological therapy, hormonal therapy, immunotherapy, gene therapy, and surgery

- Intravenous bisphosphonates allowed

- No concurrent antiretroviral therapy for HIV-positive patients

- No other concurrent investigational agents