Inhibiting Fatty Acid Synthase to Improve Efficacy of Neoadjuvant Chemotherapy

• Sponsor: Kathy Miller (Other)
• Overall Status: Completed
• CT.gov ID: NCT02595372
• Collaborator: (none)
• Enrollment: 42
• Locations: 9
• Arm: 1
• Actual Duration (Months): 63.6
• Patients Per Site: 4.7
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief 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.

Condition or Disease	Intervention/Treatment	Phase
Cancer of the Breast	Drug: Omeprazole	Phase 2

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 Design

• Study Type: Interventional
• Actual Enrollment: 42 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Inhibiting Fatty Acid Synthase to Improve Efficacy of Neoadjuvant Chemotherapy
• Actual Study Start Date: Nov 12, 2015
• Actual Primary Completion Date: Nov 21, 2019
• Actual Study Completion Date: Mar 1, 2021

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures

1. Percentage of Patients With Pathological Complete Response (pCR) in Patients Who Have Fatty Acid Synthase (FASN) Expression [Up to 6 months]

   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.

Secondary Outcome Measures

1. Percentage of Patients With Pathological Complete Response (pCR) in All Patients [Up to 6 months]

   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.

2. Percent of Patients With FASN Expression [up to 1 week]

   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.

3. FASN Positivity Expression at Baseline and After 4-7 Days of Omeprazole Treatment [baseline and after 4-7 days]

   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.

4. FASN Activity at Baseline and After 4-7 Days of Omeprazole Treatment [baseline and after 4-7 days]

   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.

5. Number of Patients With Treatment Related Adverse Events Grade 3 or Above [up to 8 months]

   Number of unique patients who had an Omeprazole treatment related (possible, probable or definite) adverse event with grade >= 3.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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)

1. Planned neoadjuvant treatment with anthracycline and taxane containing chemotherapy

2. ≥ 18 years old at the time of informed consent

3. ECOG Performance Status 0-1

4. Ability to provide written informed consent and HIPAA authorization

5. 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

1. 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

• 1. 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Georgetown University	Washington	District of Columbia	United States	20007
2	Washington Hospital	Washington	District of Columbia	United States	20010
3	Indiana University Health North Hospital	Carmel	Indiana	United States	46032
4	Indiana University Health Hospital	Indianapolis	Indiana	United States	46202
5	Indiana University Health Melvin and Bren Simon Cancer Center	Indianapolis	Indiana	United States	46202
6	Spring Mill Medical Center	Indianapolis	Indiana	United States	46290
7	Franklin Square Medical Center	Baltimore	Maryland	United States	21237
8	Wake Forest Baptist Health	Winston-Salem	North Carolina	United States	27157
9	Ohio State University	Columbus	Ohio	United States	43210

Sponsors and Collaborators

• Kathy Miller

Investigators

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

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Apr 3, 2020

More Information

Publications

None provided.

• Responsible Party: Kathy Miller, Professor of Medicine, Ballve' Lantero Scholar, Indiana University School of Medicine
• ClinicalTrials.gov Identifier: NCT02595372
• Other Study ID Numbers: IUSCC-0555
• First Posted: Nov 3, 2015
• Last Update Posted: Dec 15, 2021
• Last Verified: Dec 1, 2021

• Studies a U.S. FDA-regulated Drug Product: Yes
• Additional relevant MeSH terms: Breast Neoplasms; Omeprazole

Study Results

Participant Flow

Arm/Group Title	High Dose Omeprazole Treatment
Arm/Group Description	Patients will be treated with omeprazole 80 mg orally BID beginning 4-7 days prior to chemotherapy and continuing until surgery.
Period Title: Overall Study
STARTED	42
COMPLETED	33
NOT COMPLETED	9

Baseline Characteristics

Arm/Group Title	High Dose Omeprazole Treatment
Arm/Group Description	Patients will be treated with omeprazole 80 mg orally BID beginning 4-7 days prior to chemotherapy and continuing until surgery.
Overall Participants	42
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	36 85.7%
>=65 years	6 14.3%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	52.6 (10.50)
Sex: Female, Male (Count of Participants)
Female	42 100%
Male	0 0%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	3 7.1%
Not Hispanic or Latino	38 90.5%
Unknown or Not Reported	1 2.4%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	0 0%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	14 33.3%
White	24 57.1%
More than one race	1 2.4%
Unknown or Not Reported	3 7.1%
Eastern Cooperative Oncology Group (ECOG) Performance Status (Count of Participants)
0-Fully active	36 85.7%
1-Restricted in physically strenuous activity	6 14.3%

Outcome Measures

1. Primary Outcome

Title	Percentage of Patients With Pathological Complete Response (pCR) in Patients Who Have Fatty Acid Synthase (FASN) Expression
Description	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.
Time Frame	Up to 6 months

Outcome Measure Data

Analysis Population Description

Patients who had surgery and positive FASN expression

Arm/Group Title	High Dose Omeprazole Treatment
Arm/Group Description	Patients will be treated with omeprazole 80 mg orally BID beginning 4-7 days prior to chemotherapy and continuing until surgery.
Measure Participants	29
Number (95% Confidence Interval) [percentage of participants]	72.4 172.4%

2. Secondary Outcome

Title	Percentage of Patients With Pathological Complete Response (pCR) in All Patients
Description	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.
Time Frame	Up to 6 months

Outcome Measure Data

Analysis Population Description

Patients who received surgery

Arm/Group Title	High Dose Omeprazole Treatment
Arm/Group Description	Patients will be treated with omeprazole 80 mg orally BID beginning 4-7 days prior to chemotherapy and continuing until surgery.
Measure Participants	39
Number (95% Confidence Interval) [percentage of participants]	74.4 177.1%

3. Secondary Outcome

Title	Percent of Patients With FASN Expression
Description	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.
Time Frame	up to 1 week

Outcome Measure Data

Analysis Population Description

Patients with FASN positivity results at either baseline or after 4-7 days of treatment.

Arm/Group Title	High Dose Omeprazole Treatment
Arm/Group Description	Patients will be treated with omeprazole 80 mg orally BID beginning 4-7 days prior to chemotherapy and continuing until surgery.
Measure Participants	30
Number (95% Confidence Interval) [percentage of participants]	93.3 222.1%

4. Secondary Outcome

Title	FASN Positivity Expression at Baseline and After 4-7 Days of Omeprazole Treatment
Description	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.
Time Frame	baseline and after 4-7 days

Outcome Measure Data

Analysis Population Description

Patients with FASN positivity expression at both baseline and after 4-7 days of treatment.

Arm/Group Title	High Dose Omeprazole Treatment
Arm/Group Description	Patients will be treated with omeprazole 80 mg orally BID beginning 4-7 days prior to chemotherapy and continuing until surgery.
Measure Participants	24
Baseline	53.9 (23.6)
After 4-7 days	41.7 (30.7)

5. Secondary Outcome

Title	FASN Activity at Baseline and After 4-7 Days of Omeprazole Treatment
Description	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.
Time Frame	baseline and after 4-7 days

Outcome Measure Data

Analysis Population Description

Patients with FASN activity evaluated at baseline and after 4-7 days of treatment.

Arm/Group Title	High Dose Omeprazole Treatment
Arm/Group Description	Patients will be treated with omeprazole 80 mg orally BID beginning 4-7 days prior to chemotherapy and continuing until surgery.
Measure Participants	12
Baseline	2.1 (1.61)
After 4-7 days	1.3 (0.93)

6. Secondary Outcome

Title	Number of Patients With Treatment Related Adverse Events Grade 3 or Above
Description	Number of unique patients who had an Omeprazole treatment related (possible, probable or definite) adverse event with grade >= 3.
Time Frame	up to 8 months

Outcome Measure Data

Analysis Population Description

Patients who received treatment

Arm/Group Title	High Dose Omeprazole Treatment
Arm/Group Description	Patients will be treated with omeprazole 80 mg orally BID beginning 4-7 days prior to chemotherapy and continuing until surgery.
Measure Participants	42
Count of Participants [Participants]	0 0%

Adverse Events

Time Frame	Up to 8 months
Arm/Group Title	High Dose Omeprazole Treatment
Arm/Group Description	Patients will be treated with omeprazole 80 mg orally BID beginning 4-7 days prior to chemotherapy and continuing until surgery.
All Cause Mortality
	High Dose Omeprazole Treatment
	Affected / at Risk (%)	# Events
Total	0/42 (0%)
Serious Adverse Events
	High Dose Omeprazole Treatment
	Affected / at Risk (%)	# Events
Total	5/42 (11.9%)
Blood and lymphatic system disorders
Febrile neutropenia	3/42 (7.1%)
Gastrointestinal disorders
Constipation	1/42 (2.4%)
Investigations
Neutrophil count decreased	1/42 (2.4%)
White blood cell decreased	1/42 (2.4%)
Respiratory, thoracic and mediastinal disorders
Cough	1/42 (2.4%)
Other (Not Including Serious) Adverse Events
	High Dose Omeprazole Treatment
	Affected / at Risk (%)	# Events
Total	37/42 (88.1%)
Blood and lymphatic system disorders
Anemia	13/42 (31%)
Gastrointestinal disorders
Constipation	10/42 (23.8%)
Diarrhea	11/42 (26.2%)
Dry mouth	4/42 (9.5%)
Dyspepsia	4/42 (9.5%)
Mucositis oral	10/42 (23.8%)
Nausea	14/42 (33.3%)
Vomiting	7/42 (16.7%)
General disorders
Edema limbs	3/42 (7.1%)
Fatigue	16/42 (38.1%)
Pain	6/42 (14.3%)
Infections and infestations
Urinary tract infection	4/42 (9.5%)
Investigations
Alanine aminotransferase increased	5/42 (11.9%)
Lymphocyte count decreased	10/42 (23.8%)
Neutrophil count decreased	8/42 (19%)
Platelet count decreased	3/42 (7.1%)
Weight loss	3/42 (7.1%)
White blood cell decreased	7/42 (16.7%)
Metabolism and nutrition disorders
Anorexia	9/42 (21.4%)
Hyperglycemia	3/42 (7.1%)
Hypertriglyceridemia	3/42 (7.1%)
Hypokalemia	6/42 (14.3%)
Hypomagnesemia	4/42 (9.5%)
Musculoskeletal and connective tissue disorders
Back pain	6/42 (14.3%)
Myalgia	4/42 (9.5%)
Pain in extremity	5/42 (11.9%)
Nervous system disorders
Dizziness	3/42 (7.1%)
Dysgeusia	4/42 (9.5%)
Headache	8/42 (19%)
Peripheral motor neuropathy	4/42 (9.5%)
Peripheral sensory neuropathy	16/42 (38.1%)
Psychiatric disorders
Anxiety	4/42 (9.5%)
Insomnia	9/42 (21.4%)
Respiratory, thoracic and mediastinal disorders
Cough	11/42 (26.2%)
Dyspnea	7/42 (16.7%)
Skin and subcutaneous tissue disorders
Alopecia	13/42 (31%)
Pruritus	7/42 (16.7%)
Skin and subcutaneous tissue disorders - Other	3/42 (7.1%)
Skin hyperpigmentation	5/42 (11.9%)
Vascular disorders
Hot flashes	4/42 (9.5%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.