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

Breast Cancer Clinical Trial

Official title:

A Phase I/II Trial of Short Course Pre-Operative Ritonavir To Determine Akt Inhibition in Breast Cancer

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01009437
• Other study ID #: 2008NTLS083
• Secondary ID: UMN-0809M45461
• Status: Completed
• Phase: Phase 1
• First received: November 5, 2009
• Last updated: December 3, 2017
• Start date: May 26, 2010
• Est. completion date: July 2014

Study information

• Verified date: December 2017
• Source: Masonic Cancer Center, University of Minnesota
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 28
• Est. completion date: July 2014
• Est. primary completion date: July 2014
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Breast Cancer
• Breast Neoplasms

Intervention

Drug:
• ritonavir
Phase I: Dose escalation will be used with 3 levels of ritonavir given - 200 mg twice a day (bid), 400 mg bid, and 600 mg bid. Phase II: Dose will be maximum tolerated dose from Phase I.

Procedure:
• therapeutic conventional surgery
Tissue collection is from all patients, including the control, phase I and phase II patients.

Locations

Country	Name	City	State
United States	Masonic Cancer Center, University of Minnesota	Minneapolis	Minnesota
United States	The Kimmel Cancer Center at Jefferson University	Philadelphia	Pennsylvania

Sponsors (2)

Lead Sponsor	Collaborator
Masonic Cancer Center, University of Minnesota	Susan G. Komen Breast Cancer Foundation

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Inhibition of breast cancer by targeting Hsp90-Akt pathway		Pre and Post Treatment
Secondary	Activation of apoptosis markers		Pre and Post Treatment
Secondary	Modulation of autophagy markers		Pre and Post Treatment
Secondary	Alteration of plasma levels of eicosanoids		Pre Treatment and 3 Hours Post Treatment
Secondary	Induction of Hsp70 in peripheral blood mononuclear cells		Pre Treatment and 3 Hours Post Treatment
Secondary	Reduction of ERa in ERa+ tumors		Pre and Post Treatment
Secondary	Changes in TNF-a and IL-6 levels as well as reduction in intratumoral nuclear NF-kB and phospho-Stat3		Pre and Post Treatment
Secondary	Alteration of urine eicosanoid levels		Pre and Post Treatment
Secondary	Alteration of plasma and urine eicosanoid levels resulting from tumor resection.		Pre and Post Treatment
Secondary	Induction of the unfolded protein response (UPR) assayed by grp78 or related markers (phospho-PERK, ATF-4, and CHOP)		pre- and post-surgery
Secondary	inhibition of tumor growth markers (Ki67 LI, Hsp90, phosphorylated AKT)		pre- and post-surgery