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

University of Minnesota (UMN)

Status and phase: Completed; Phase 1

Conditions: Breast Cancer

Treatments: Procedure: therapeutic conventional surgery; Drug: ritonavir

Study type: Interventional

Funder types: Other

Identifiers

NCT01009437

2008NTLS083

UMN-0809M45461 (Other Identifier)

Details and patient eligibility

About

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.

Full description

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.

Enrollment: 28 patients

Sex: Female

Ages: 18+ years old

Volunteers: No Healthy Volunteers

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

Trial design

Primary purpose: Diagnostic

Allocation: Non-Randomized

Interventional model: Single Group Assignment

Masking: None (Open label)

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28 participants in 3 patient groups

Control Arm - No Ritonavir

Active Comparator group

Description:

Five ER+, HER2- breast cancer patients meeting all study eligibility will be enrolled prior to the start of phase I recruitment to act as controls (no ritonavir will be given-will receive therapeutic conventional surgery) to confirm that anesthesia does not affect EET levels. Core biopsies, surgical tumor/normal tissue and pre- and post- surgery blood samples will be collected for comparison with the treatment group.

Treatment:

Procedure: therapeutic conventional surgery

Ritonavir - Escalating Doses (I)

Experimental group

Description:

Standard phase I dose escalation (with therapeutic conventional surgery) will be used with 3 levels of ritonavir given - 200 mg bid, 400 mg bid, and 600 mg bid for the following groups: 1. ER+, HER2- 2. ER+, HER2+ 3. ER-, HER2+ 4. ER-, PR+, HER2- 5. ER-, PR-, HER2-

Treatment:

Procedure: therapeutic conventional surgery

Drug: ritonavir

Ritonavir - Maximum Tolerated Dose (II)

Experimental group

Description:

Phase II: Once the maximum tolerated dose (MTD) of ritonavir is established, 19 ER+, HER2- patients will be enrolled at MTD during the phase II component along with therapeutic conventional surgery.

Treatment:

Procedure: therapeutic conventional surgery

Drug: ritonavir