Ritonavir and Its Effects on Biomarkers in Women Undergoing Surgery for Newly Diagnosed Breast Cancer
Ritonavir and Its Effects on Biomarkers in Women Undergoing Surgery for Newly Diagnosed Breast Cancer
RATIONALE: Ritonavir may stop the growth of tumor cells by blocking some of the enzymes
 needed for cancer cell growth. Studying samples of blood and tissue from patients with breast
 cancer in the laboratory may help doctors learn more about the effects of ritonavir on
 biomarkers involved in breast cancer growth.

 PURPOSE: This phase I/II trial is studying the best dose of 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