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

Phase 1/Phase 2
18 Years
Open (Enrolling)
Breast Cancer

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Trial Information

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


- 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.
Fifteen patients with triple-negative breast cancer are enrolled into the control group
before the start of phase I recruitment.

- 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.

Inclusion Criteria

Inclusion criteria:

- Newly diagnosed biopsy proven breast cancer for which a lumpectomy or mastectomy is
planned and meets histological requirements based on enrolling group. Breast biopsy
may be by core biopsy, but not open biopsy.

- 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

- Triple negative: estrogen receptor negative (ER-), progesterone receptor negative
(PR-) and human epidermal growth factor receptor 2 negative (HER2/neu-) as defined
according to institutional standards

- ER+HER2- or ER+HER2+ : estrogen receptor positive (ER+) and human epidermal growth
factor receptor 2 (HER2/neu) as defined according to institutional standards.

- ER-HER2+: estrogen receptor negative (ER-) and human epidermal growth factor receptor
2 positive (HER2/neu+) as defined according to institutional standards

- ER-PR+HER2-: estrogen receptor negative (ER-), progesterone receptor positive (PR+)
and human epidermal growth factor receptor 2 negative (HER2/neu-) as defined
according to institutional standards

- 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 (if 55 years or younger must have estradiol
level in postmenopausal range) 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. If measurements are discordant, then the imaging modality that
determines the smallest tumor size will be used to determine eligibility. Multi-focal
disease and DCIS is allowed in the affected breast as long as at least one tumor is
greater than 1 centimeter.

- No prior treatment for breast cancer in the affected breast.

- Karnofsky performance status >70%

- Adequate organ function for receiving study drug within 14 days 1st dose of study
drug (or registration for controls) including the following:

- Adequate bone marrow reserve: absolute neutrophil count (ANC) > or = 1.5 x
10^9/L, platelets >100 x 10^9/L,hemoglobin > 9 g/dL

- Hepatic: aspartate transaminase (AST, SGOT) < 2 times upper limit of
institutional normal (ULN)

- Renal: BUN ≤ 30 mg/dL, Estimated GFR must be >50 ml/minute

- Women of childbearing potential are required to use an effective method of
contraception (ie, intra-uterine device, diaphragm with spermicide, condom with
spermicide, or abstinence) while taking ritonavir and for 1 week after the last dose
of study drug.

- Voluntary written consent before performance of any study-related procedure not part
of normal medical care, with the understanding that consent may be withdrawn by the
subject at any time without prejudice to future medical care.

Exclusion criteria:

- Pregnant or lactating. Ritonavir is Pregnancy Category B - no evidence of risk,
however controlled animal studies have shown that the drug poses a risk to the fetus.
Women of child bearing potential must have a negative pregnancy test within the 14
days prior to beginning ritonavir or for controls, date of surgery.

- Known positive HIV status or on medications for HIV

- Diagnosis of diabetes due to potential problems with insulin resistance and

- Any pre-existing gastrointestinal complaints including nausea, abdominal pain and/or
diarrhea which in the opinion of the investigator will mimic or worsen the expected
GI toxicity associated with ritonavir.

- Known hypersensitivity to ritonavir or any of the tablet ingredients

- Co-administration of ritonavir is contraindicated with any of the drugs listed in
Appendix III - 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.

- Appendix IV - Incompatible Drugs list those agents that would interfere with the
interpretation of data from the trial and patients who cannot discontinue these drugs
at least two days before the 1st dose of ritonavir to two days after the last dose
are also ineligible.

Type of Study:


Study Design:

Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Diagnostic

Outcome Measure:

Inhibition of intratumoral Akt pathway markers (pGSK3 α/β, pPRAS40, pFKHR/FKHRL1, or p-p70S6K phosphorylation)

Outcome Time Frame:

Pre and Post Treatment

Safety Issue:


Principal Investigator

David A. Potter, M.D., Ph.D.

Investigator Role:

Principal Investigator

Investigator Affiliation:

Masonic Cancer Center, University of Minnesota


United States: Food and Drug Administration

Study ID:




Start Date:

May 2010

Completion Date:

October 2013

Related Keywords:

  • Breast Cancer
  • 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
  • Breast Neoplasms



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