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

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

Study Overview

• Status: Completed
• Conditions: Breast Cancer
• Intervention / Treatment: Procedure: therapeutic conventional surgery; Drug: ritonavir

Detailed 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.

• Study Type: Interventional
• Enrollment (Actual): 28
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Minnesota
    • Minneapolis, Minnesota, United States, 55455
      • Masonic Cancer Center, University of Minnesota
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19107
      • The Kimmel Cancer Center at Jefferson University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: DIAGNOSTIC
• Allocation: NON_RANDOMIZED
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
ACTIVE_COMPARATOR: Control Arm - No Ritonavir; 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.	Procedure: therapeutic conventional surgery; Tissue collection is from all patients, including the control, phase I and phase II patients.; Other Names: Surgery
EXPERIMENTAL: Ritonavir - Escalating Doses (I); 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: ER+, HER2-; ER+, HER2+; ER-, HER2+; ER-, PR+, HER2-; ER-, PR-, HER2-	Procedure: therapeutic conventional surgery; Tissue collection is from all patients, including the control, phase I and phase II patients.; Other Names: Surgery; 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.; Other Names: NORVIR® tablets
EXPERIMENTAL: Ritonavir - Maximum Tolerated Dose (II); 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.	Procedure: therapeutic conventional surgery; Tissue collection is from all patients, including the control, phase I and phase II patients.; Other Names: Surgery; 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.; Other Names: NORVIR® tablets

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Inhibition of breast cancer by targeting Hsp90-Akt pathway	Pre and Post Treatment

Secondary Outcome Measures

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

Collaborators and Investigators

• Sponsor: Masonic Cancer Center, University of Minnesota
• Collaborators: Susan G. Komen Breast Cancer Foundation
• Investigators: Principal Investigator: David A. Potter, M.D., Ph.D., Masonic Cancer Center, University of Minnesota

Study record dates

Study Major Dates

• Study Start (ACTUAL): May 26, 2010
• Primary Completion (ACTUAL): July 1, 2014
• Study Completion (ACTUAL): July 1, 2014

Study Registration Dates

• First Submitted: November 5, 2009
• First Submitted That Met QC Criteria: November 5, 2009
• First Posted (ESTIMATE): November 6, 2009

Study Record Updates

• Last Update Posted (ACTUAL): December 5, 2017
• Last Update Submitted That Met QC Criteria: December 3, 2017
• Last Verified: December 1, 2017

More Information

Terms related to this study

• Keywords: stage IV breast cancer; stage IIIA breast cancer; stage IIIB breast cancer; stage II breast cancer; stage IIIC breast cancer; HER2-positive breast cancer; stage I breast cancer; estrogen receptor-positive breast cancer; triple-negative breast cancer; ductal breast carcinoma in situ; HER2-negative breast cancer
• Additional Relevant MeSH Terms: Skin Diseases; Neoplasms; Neoplasms by Site; Breast Diseases; Breast Neoplasms; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Enzyme Inhibitors; Anti-HIV Agents; Anti-Retroviral Agents; Protease Inhibitors; Cytochrome P-450 CYP3A Inhibitors; Cytochrome P-450 Enzyme Inhibitors; HIV Protease Inhibitors; Viral Protease Inhibitors; Ritonavir
• Other Study ID Numbers: 2008NTLS083; UMN-0809M45461 (OTHER: IRB, University of Minnesota)