Inhibiting Fatty Acid Synthase to Improve Efficacy of Neoadjuvant Chemotherapy

Cancer of the Breast Clinical Trial

Official title:

Inhibiting Fatty Acid Synthase to Improve Efficacy of Neoadjuvant Chemotherapy

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02595372
• Other study ID #: IUSCC-0555
• Status: Completed
• Phase: Phase 2
• Start date: November 12, 2015
• Est. completion date: March 1, 2021

Study information

• Verified date: December 2021
• Source: Indiana University
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 42
• Est. completion date: March 1, 2021
• Est. primary completion date: November 21, 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Breast Neoplasms
• Cancer of the Breast

Intervention

Drug:
• Omeprazole

Locations

Country	Name	City	State
United States	Franklin Square Medical Center	Baltimore	Maryland
United States	Indiana University Health North Hospital	Carmel	Indiana
United States	Ohio State University	Columbus	Ohio
United States	Indiana University Health Hospital	Indianapolis	Indiana
United States	Indiana University Health Melvin and Bren Simon Cancer Center	Indianapolis	Indiana
United States	Spring Mill Medical Center	Indianapolis	Indiana
United States	Georgetown University	Washington	District of Columbia
United States	Washington Hospital	Washington	District of Columbia
United States	Wake Forest Baptist Health	Winston-Salem	North Carolina

Sponsors (1)

Lead Sponsor	Collaborator
Kathy Miller

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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