Inhibiting Fatty Acid Synthase to Improve Efficacy of Neoadjuvant Chemotherapy

In preliminary laboratory science studies, the investigators show that proton pump inhibitors (PPIs) effectively inhibit human fatty acid synthase (FASN) and breast cancer cell survival. A preliminary retrospective study shows that PPI usage in breast cancer patients during chemotherapy significantly improved overall survival. The impact was most striking in patients with triple negative breast cancer (TNBC). Thus, PPIs may be repositioned as safe and effective breast cancer drugs to enhance the effect of chemotherapy.

Many of the hurdles that slow progress from target, to lead compound, to investigational agent, to standard therapy are not barriers for the PPIs. The PPIs are FDA-approved, chronically used, and well tolerated so the investigators can move quickly from the laboratory to a proof of concept clinical trial. Incorporating the PPIs into standard care will require more than the investigators propose here, but the investigators have already plotted the additional steps needed to truly impact patient care. If successful, the data gathered in this proposal will lend support to and guide development of a definitive randomized trial.

Study Overview

• Status: Completed
• Conditions: Cancer of the Breast
• Intervention / Treatment: Drug: Omeprazole

Detailed Description

Primary Objective

• Estimate the rate of pathologic complete response (pCR) in patients with triple negative breast cancer and FASN expression treated with standard neoadjuvant chemotherapy (NAC) in combination with high dose omeprazole.

Secondary Objectives

• Quantify the number of patients with newly diagnosed TNBC with tumors that express FASN.
• Estimate the rate of pCR in patients with triple negative breast cancer (irrespective of FASN status) treated with standard NAC in combination with high dose omeprazole.
• Describe the safety of incorporating high dose omeprazole with standard NAC.
• Estimate the biologic activity of high dose omeprazole in modulating FASN expression and activity.

This is a single arm Phase II study. Patients should begin therapy within 7 working days of study entry. Patients will be treated with omeprazole 80 mg orally twice a day (BID) beginning 4-7 days prior to chemotherapy and continuing until surgery. After the brief period of omeprazole monotherapy, patients will begin standard neoadjuvant chemotherapy with doxorubicin (60 mg/m2) and cyclophosphamide (600 mg/m2) for 4 cycles followed by paclitaxel (80 mg/m2) weekly x 12. Doxorubicin and cyclophosphamide (AC) may be administered on a classical every 3 week or dose dense every 2 week (with growth factor support) schedule at the treating physician's discretion. Routine incorporation of carboplatin is not recommended, however use of carboplatin (AUC 6 on week 1, 4, 7, and 10) with paclitaxel is allowed at the treating investigator's discretion. Chemotherapy will be adjusted based on toxicity according to standard treatment guidelines. Patients with overt disease progression during AC should move immediately to paclitaxel therapy. Patients with disease progression during paclitaxel should proceed immediately to surgery.

• Study Type: Interventional
• Enrollment (Actual): 42
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • District of Columbia
    • Washington, District of Columbia, United States, 20007
      • Georgetown University
    • Washington, District of Columbia, United States, 20010
      • Washington Hospital
  • Indiana
    • Carmel, Indiana, United States, 46032
      • Indiana University Health North Hospital
    • Indianapolis, Indiana, United States, 46202
      • Indiana University Health Melvin and Bren Simon Cancer Center
    • Indianapolis, Indiana, United States, 46290
      • Spring Mill Medical Center
    • Indianapolis, Indiana, United States, 46202
      • Indiana University Health Hospital
  • Maryland
    • Baltimore, Maryland, United States, 21237
      • Franklin Square Medical Center
  • North Carolina
    • Winston-Salem, North Carolina, United States, 27157
      • Wake Forest Baptist Health
  • Ohio
    • Columbus, Ohio, United States, 43210
      • Ohio State University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria

1. Newly diagnosed triple negative breast cancer (TNBC) clinical stage Ic, II, or III

   • ER and PR < 10%

   • HER2 negative based on one of the following:

     • IHC 0 or 1+
     • IHC 2+ and FISH negative
     • IHC 2+ and FISH equivocal and no indication for HER2 targeted therapy based on the treating investigators discretion (i.e., HER2: CEP17 ratio < 2.0 or HER2 total copy number <6)
2. Planned neoadjuvant treatment with anthracycline and taxane containing chemotherapy
3. ≥ 18 years old at the time of informed consent
4. ECOG Performance Status 0-1
5. Ability to provide written informed consent and HIPAA authorization

6. Women of childbearing potential definition must have a negative pregnancy test within 14 days of registration. All women (regardless of sexual orientation, having undergone a tubal ligation, or remaining celibate by choice) are considered to have childbearing potential unless they meet one of the following criteria:

   • Prior hysterectomy or bilateral oophorectomy;
   • Has not had menses at any time in the preceding 24 consecutive months

7. Adequate organ function for anthracycline and taxane based therapy

   • LVEF > LLN based on cardiac ECHO or MUGA
   • Hgb > 8.5
   • ANC > 1,000
   • Platelets > 100,000
   • Creatinine < 1.5
   • T. bili < 1.3
   • AST < 2.5 x ULN

Exclusion Criteria

1. Use of prescription PPIs within 12 months prior to study entry [Dexlansoprazole (Dexilant), Pantoprazole (Protonix), Rabeprazole (Aciphex), Esomeprazole (Nexium), Lansoprazole (Prevacid), Omeprazole (Prilosec, Zegerid)]
2. Use of OTC PPIs within 6 months prior to study entry [Esomeprazole (Nexium), Lansoprazole (Prevacid), Omeprazole (Prilosec, Zegerid)]
3. Use of Orlistat or any other known FASN inhibitor within 6 months prior to study entry
4. Nursing mothers are excluded
5. Known hypersensitivity to any component of the formulation or substituted benzimidazoles
6. Prior osteoporotic fracture

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: High dose omeprazole treatment; Patients will be treated with omeprazole 80 mg orally BID beginning 4-7 days prior to chemotherapy and continuing until surgery.	Drug: Omeprazole

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Patients With Pathological Complete Response (pCR) in Patients Who Have Fatty Acid Synthase (FASN) Expression	pCR is defined as no invasive disease in the breast of axilla at the time of definitive surgery. A patient is considered to have FASN expression if the positivity was >= 15% at the baseline or after 4-7 days of Omeprazole monotherapy. FASN expression is evaluated using immunohistochemistry in core biopsy samples. The percent of patients with FASN expression that have pCR will be calculated with an exact 95% confidence interval.	Up to 6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Patients With Pathological Complete Response (pCR) in All Patients	pCR is defined as no invasive disease in the breast or axilla at the time of definitive surgery. The percentage of patients who achieve pCR along with exact 95% confidence intervals were calculated.	Up to 6 months
Percent of Patients With FASN Expression	FASN expression was evaluated using immunohistochemistry in core biopsy samples. FASN expression was determined if the positivity was >= 15%. The percent of patients who had FASN expression and the exact 95% confidence intervals were calculated.	up to 1 week
FASN Positivity Expression at Baseline and After 4-7 Days of Omeprazole Treatment	The mean and standard deviation of FASN positivity expression determined at baseline and after 4-7 days of Omeprazole treatment. FASN expression is evaluated using immunohistochemistry in core biopsy samples.	baseline and after 4-7 days
FASN Activity at Baseline and After 4-7 Days of Omeprazole Treatment	The mean and standard deviation of FASN activity determined at baseline and after 4-7 days of Omeprazole treatment. FASN activity was evaluated using immunohistochemistry in core biopsy samples.	baseline and after 4-7 days
Number of Patients With Treatment Related Adverse Events Grade 3 or Above	Number of unique patients who had an Omeprazole treatment related (possible, probable or definite) adverse event with grade >= 3.	up to 8 months

Collaborators and Investigators

• Sponsor: Kathy Miller
• Investigators: Principal Investigator: Kathy Miller, MD, Professor of Medicine, Ballve' Lantero Scholar

Study record dates

Study Major Dates

• Study Start (Actual): November 12, 2015
• Primary Completion (Actual): November 21, 2019
• Study Completion (Actual): March 1, 2021

Study Registration Dates

• First Submitted: November 2, 2015
• First Submitted That Met QC Criteria: November 2, 2015
• First Posted (Estimate): November 3, 2015

Study Record Updates

• Last Update Posted (Actual): December 15, 2021
• Last Update Submitted That Met QC Criteria: December 13, 2021
• Last Verified: December 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Skin Diseases; Neoplasms; Neoplasms by Site; Breast Diseases; Breast Neoplasms; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Gastrointestinal Agents; Anti-Ulcer Agents; Proton Pump Inhibitors; Omeprazole
• Other Study ID Numbers: IUSCC-0555

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes