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

This study is currently recruiting participants. (see Contacts and Locations)
Verified May 2014 by Masonic Cancer Center, University of Minnesota
Sponsor:
Collaborator:
Susan G. Komen Breast Cancer Foundation
Information provided by (Responsible Party):
Masonic Cancer Center, University of Minnesota
ClinicalTrials.gov Identifier:
NCT01009437
First received: November 5, 2009
Last updated: May 15, 2014
Last verified: May 2014
  Purpose

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.


Condition Intervention Phase
Breast Cancer
Drug: ritonavir
Procedure: therapeutic conventional surgery
Phase 1
Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Diagnostic
Official Title: A Phase I/II Trial of Short Course Pre-Operative Ritonavir To Determine Akt Inhibition in Breast Cancer

Resource links provided by NLM:


Further study details as provided by Masonic Cancer Center, University of Minnesota:

Primary Outcome Measures:
  • Inhibition of breast cancer by targeting Hsp90-Akt pathway [ Time Frame: Pre and Post Treatment ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Activation of apoptosis markers [ Time Frame: Pre and Post Treatment ] [ Designated as safety issue: No ]
  • Modulation of autophagy markers [ Time Frame: Pre and Post Treatment ] [ Designated as safety issue: No ]
  • Alteration of plasma levels of eicosanoids [ Time Frame: Pre Treatment and 3 Hours Post Treatment ] [ Designated as safety issue: No ]
  • Induction of Hsp70 in peripheral blood mononuclear cells [ Time Frame: Pre Treatment and 3 Hours Post Treatment ] [ Designated as safety issue: No ]
  • Reduction of ERα in ERα+ tumors [ Time Frame: Pre and Post Treatment ] [ Designated as safety issue: No ]
  • Changes in TNF-α and IL-6 levels as well as reduction in intratumoral nuclear NF-kB and phospho-Stat3 [ Time Frame: Pre and Post Treatment ] [ Designated as safety issue: No ]
  • Alteration of urine eicosanoid levels [ Time Frame: Pre and Post Treatment ] [ Designated as safety issue: No ]
  • Alteration of plasma and urine eicosanoid levels resulting from tumor resection. [ Time Frame: Pre and Post Treatment ] [ Designated as safety issue: No ]
  • Induction of the unfolded protein response (UPR) assayed by grp78 or related markers (phospho-PERK, ATF-4, and CHOP) [ Time Frame: pre- and post-surgery ] [ Designated as safety issue: No ]
  • inhibition of tumor growth markers (Ki67 LI, Hsp90, phosphorylated AKT) [ Time Frame: pre- and post-surgery ] [ Designated as safety issue: No ]

Estimated Enrollment: 52
Study Start Date: May 2010
Estimated Study Completion Date: October 2014
Estimated Primary Completion Date: October 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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 Name: 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:

  1. ER+, HER2-
  2. ER+, HER2+
  3. ER-, HER2+
  4. ER-, PR+, HER2-
  5. ER-, PR-, HER2-
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 Name: NORVIR® tablets
Procedure: therapeutic conventional surgery
Tissue collection is from all patients, including the control, phase I and phase II patients.
Other Name: Surgery
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.
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 Name: NORVIR® tablets
Procedure: therapeutic conventional surgery
Tissue collection is from all patients, including the control, phase I and phase II patients.
Other Name: Surgery

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.

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.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Female
Accepts Healthy Volunteers:   No
Criteria

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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01009437

Contacts
Contact: David A. Potter, M.D., Ph.D. 612-625-8933 dapotter@umn.edu

Locations
United States, Minnesota
Masonic Cancer Center, University of Minnesota Recruiting
Minneapolis, Minnesota, United States, 55455
Contact: David A. Potter, M.D., Ph.D.    612-625-8933    dapotter@umn.edu   
Principal Investigator: David A. Potter, M.D., Ph.D.         
United States, Pennsylvania
The Kimmel Cancer Center at Jefferson University Not yet recruiting
Philadelphia, Pennsylvania, United States, 19107
Contact: Adam C. Berger, MD, FACS    215-955-1622    acb130@jefferson.edu   
Principal Investigator: Adam C. Berger, MD, FACS         
Sponsors and Collaborators
Masonic Cancer Center, University of Minnesota
Susan G. Komen Breast Cancer Foundation
Investigators
Principal Investigator: David A. Potter, M.D., Ph.D. Masonic Cancer Center, University of Minnesota
  More Information

Additional Information:
No publications provided

Responsible Party: Masonic Cancer Center, University of Minnesota
ClinicalTrials.gov Identifier: NCT01009437     History of Changes
Other Study ID Numbers: 2008NTLS083, UMN-0809M45461
Study First Received: November 5, 2009
Last Updated: May 15, 2014
Health Authority: United States: Food and Drug Administration

Keywords provided by Masonic Cancer Center, University of Minnesota:
HER2-negative breast cancer
HER2-positive breast cancer
estrogen receptor-positive breast cancer
triple-negative breast cancer
stage I breast cancer
stage II breast cancer
stage IIIA breast cancer
stage IIIB breast cancer
stage IIIC breast cancer
stage IV breast cancer
ductal breast carcinoma in situ

Additional relevant MeSH terms:
Breast Neoplasms
Neoplasms by Site
Neoplasms
Breast Diseases
Skin Diseases
Ritonavir
HIV Protease Inhibitors
Protease Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Anti-HIV Agents
Anti-Retroviral Agents
Antiviral Agents
Anti-Infective Agents
Therapeutic Uses

ClinicalTrials.gov processed this record on July 20, 2014