Ritonavir and Its Effects on Biomarkers in Women Undergoing Surgery for Newly Diagnosed Breast Cancer

OBJECTIVES:

- Determine the effects of ritonavir on Akt activity, UPR, Ki67 LI, and ROS in a
triple-negative breast cancer model.

- Determine the maximum tolerated dose of ritonavir in women with newly diagnosed breast
cancer. (Phase I - enrollment complete)

OUTLINE: This is a multicenter, phase I dose-escalation study followed by a phase II study.
*Note: This trial never moved forward to Phase ll.

Control Group - Five patients with estrogen receptor positive (ER+) and human epidermal
growth factor 2 negative (HER2-) breast cancer are enrolled before the start of phase I
recruitment.

Phase I Group - Twelve breast cancer patients with either 1)ER+, HER2-, or 2)ER+, HER2+, or
3) ER-, HER2+, or 4) ER-, PR+, HER2-, or 5) ER-, PR-, HER2- will be enrolled for dose
escalation study.

Phase II Group - Nineteen ER+, HER2- patients will be enrolled for ritonavir pharmacokinetic
study after maximum tolerated dose (MTD) is established.

- Control: Patients do not receive ritonavir.

- Phases I and II: Patients receive oral ritonavir twice daily for 5 days in the absence
of disease progression or unacceptable toxicity. Patients then undergo surgery as deemed
appropriate by the surgeon and based on patient preference (mastectomy or lumpectomy
with sentinel node procedure and/or axillary node dissection).

All patients undergo blood and tissue sample collection periodically for biomarker research
studies. Samples from patients enrolled in the control group are compared with the samples
from patients enrolled in phase I and II.

Inclusion criteria:

- Newly diagnosed biopsy proven breast cancer for which a lumpectomy or mastectomy is
planned.

- Control Selection

- ER+, HER2-: estrogen receptor positive (ER+) and human epidermal growth factor
receptor 2 negative (HER2 -) as defined according to institutional standards.

- Phase I Selection

- ER+, HER2-

- ER+, HER2+

- ER-, HER2+

- ER-, PR+, HER2-

- ER-, PR-, HER2-

- Phase II Selection

- ER+HER2-: as defined for controls Menstrual status will be noted as either pre- or
postmenopausal. For the purpose of this study, postmenopausal is defined as no
menstrual period for 12 months or longer or bilateral oophorectomy

- Sufficient tumor tissue from the diagnostic core biopsy, either as a block or a
minimum of 5 slides

- Tumor must be greater than 1 centimeter as measured by clinical exam, mammogram,
ultrasound or MRI. - No prior treatment for breast cancer in the affected breast.

- Karnofsky performance status >70%

- No prior treatment for breast cancer in the affected breast

- Adequate organ function for receiving study drug within 14 days 1st dose of study drug

- Women of childbearing potential are required to use an effective method of
contraception

- Voluntary written consent

Exclusion criteria:

- Pregnant or lactating.

- Known positive HIV status or on medications for HIV

- Diagnosis of diabetes due to potential problems with insulin resistance and
hyperglycemia

- Any pre-existing gastrointestinal complaints including nausea, abdominal pain and/or
diarrhea

- Known hypersensitivity to ritonavir or any of the tablet ingredients

- Co-administration of ritonavir is contraindicated with any of the drugs -
Contraindicated Drugs because competition for primarily CYP3A by ritonavir could
result in inhibition of the metabolism of these drugs and create the potential for
serious and/or life-threatening reactions such as cardiac arrhythmias, prolonged or
increased sedation, and respiratory depression. Voriconazole is an exception in that
co-administration of ritonavir and voriconazole results in a significant decrease in
plasma concentrations of voriconazole. If the patient cannot discontinue a
contraindicated drug, she is not eligible for the trial.

- Incompatible Drugs