Clinical trial NCT01009437: Ritonavir and Its Effects on Biomarkers in Women Undergoing Surgery for Newly Diagnosed Breast Cancer
Official title: A Phase I/II Trial of Short Course Pre-Operative Ritonavir To Determine Akt Inhibition in Breast Cancer
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Breast Cancer
Keywords: 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
Lead sponsor: Masonic Cancer Center, University of Minnesota
Sponsor class: OTHER
Collaborators: name: Susan G. Komen Breast Cancer Foundation
First posted: 2009-11-06
Enrollment: 28
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: DIAGNOSTIC

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.

Eligibility 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

Primary outcomes:
measure: Inhibition of breast cancer by targeting Hsp90-Akt pathway
timeFrame: Pre and Post Treatment
Secondary outcomes:
measure: Activation of apoptosis markers
timeFrame: Pre and Post Treatment
measure: Modulation of autophagy markers
timeFrame: Pre and Post Treatment
measure: Alteration of plasma levels of eicosanoids
timeFrame: Pre Treatment and 3 Hours Post Treatment
measure: Induction of Hsp70 in peripheral blood mononuclear cells
timeFrame: Pre Treatment and 3 Hours Post Treatment
measure: Reduction of ERα in ERα+ tumors
timeFrame: Pre and Post Treatment
measure: Changes in TNF-α and IL-6 levels as well as reduction in intratumoral nuclear NF-kB and phospho-Stat3
timeFrame: Pre and Post Treatment
measure: Alteration of urine eicosanoid levels
timeFrame: Pre and Post Treatment
measure: Alteration of plasma and urine eicosanoid levels resulting from tumor resection.
timeFrame: Pre and Post Treatment
measure: Induction of the unfolded protein response (UPR) assayed by grp78 or related markers (phospho-PERK, ATF-4, and CHOP)
timeFrame: pre- and post-surgery
measure: inhibition of tumor growth markers (Ki67 LI, Hsp90, phosphorylated AKT)
timeFrame: pre- and post-surgery
Other outcomes:
Locations:
city: Minneapolis
country: United States
facility: Masonic Cancer Center, University of Minnesota
state: Minnesota
city: Philadelphia
country: United States
facility: The Kimmel Cancer Center at Jefferson University
state: Pennsylvania
Study officials:
affiliation: Masonic Cancer Center, University of Minnesota
name: David A. Potter, M.D., Ph.D.
role: PRINCIPAL_INVESTIGATOR
References: