Working...
ClinicalTrials.gov
ClinicalTrials.gov Menu

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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
ClinicalTrials.gov Identifier: NCT01009437
Recruitment Status : Completed
First Posted : November 6, 2009
Last Update Posted : December 5, 2017
Sponsor:
Collaborator:
Susan G. Komen Breast Cancer Foundation
Information provided by (Responsible Party):
Masonic Cancer Center, University of Minnesota

Tracking Information
First Submitted Date  ICMJE November 5, 2009
First Posted Date  ICMJE November 6, 2009
Last Update Posted Date December 5, 2017
Actual Study Start Date  ICMJE May 26, 2010
Actual Primary Completion Date July 2014   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: May 15, 2014)
Inhibition of breast cancer by targeting Hsp90-Akt pathway [ Time Frame: Pre and Post Treatment ]
Original Primary Outcome Measures  ICMJE
 (submitted: November 5, 2009)
  • Inhibition of intratumoral Akt pathway markers (pGSK3 α/β, pPRAS40, pFKHR/FKHRL1, or p-p70S6K phosphorylation)
  • Inhibition of Ki67 LI
  • Induction of the UPR assayed by grp78 or related markers (phospho-PERK, ATF-4, and CHOP)
Change History Complete list of historical versions of study NCT01009437 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: May 15, 2014)
  • Activation of apoptosis markers [ Time Frame: Pre and Post Treatment ]
  • Modulation of autophagy markers [ Time Frame: Pre and Post Treatment ]
  • Alteration of plasma levels of eicosanoids [ Time Frame: Pre Treatment and 3 Hours Post Treatment ]
  • Induction of Hsp70 in peripheral blood mononuclear cells [ Time Frame: Pre Treatment and 3 Hours Post Treatment ]
  • Reduction of ERα in ERα+ tumors [ Time Frame: Pre and Post Treatment ]
  • 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 ]
  • Alteration of urine eicosanoid levels [ Time Frame: Pre and Post Treatment ]
  • Alteration of plasma and urine eicosanoid levels resulting from tumor resection. [ Time Frame: Pre and Post Treatment ]
  • 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 ]
  • inhibition of tumor growth markers (Ki67 LI, Hsp90, phosphorylated AKT) [ Time Frame: pre- and post-surgery ]
Original Secondary Outcome Measures  ICMJE
 (submitted: November 5, 2009)
  • Activation of ROS assayed by 8-OH-dG products of DNA damage
  • Activation of apoptosis markers
  • Modulation of autophagy markers
  • Alteration of plasma levels of eicosanoids
  • Induction of Hsp70 in peripheral blood mononuclear cells
Current Other Outcome Measures  ICMJE Not Provided
Original Other Outcome Measures  ICMJE Not Provided
 
Descriptive Information
Brief Title  ICMJE Ritonavir and Its Effects on Biomarkers in Women Undergoing Surgery for Newly Diagnosed Breast Cancer
Official Title  ICMJE A Phase I/II Trial of Short Course Pre-Operative Ritonavir To Determine Akt Inhibition in Breast Cancer
Brief 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.

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  ICMJE Interventional
Study Phase Phase 1
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Diagnostic
Condition  ICMJE Breast Cancer
Intervention  ICMJE
  • 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
Study Arms
  • 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.
    Intervention: Procedure: therapeutic conventional 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-
    Interventions:
    • Drug: ritonavir
    • Procedure: therapeutic conventional 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.
    Interventions:
    • Drug: ritonavir
    • Procedure: therapeutic conventional surgery
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: October 23, 2017)
28
Original Estimated Enrollment  ICMJE
 (submitted: November 5, 2009)
36
Actual Study Completion Date July 2014
Actual Primary Completion Date July 2014   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender
Sexes Eligible for Study: Female
Ages 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT01009437
Other Study ID Numbers  ICMJE 2008NTLS083
UMN-0809M45461 ( Other Identifier: IRB, University of Minnesota )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement Not Provided
Responsible Party Masonic Cancer Center, University of Minnesota
Study Sponsor  ICMJE Masonic Cancer Center, University of Minnesota
Collaborators  ICMJE Susan G. Komen Breast Cancer Foundation
Investigators  ICMJE
Principal Investigator: David A. Potter, M.D., Ph.D. Masonic Cancer Center, University of Minnesota
PRS Account Masonic Cancer Center, University of Minnesota
Verification Date December 2017

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP