Cancer of the Breast
Conditions
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.
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.
Interventions
DRUGOmeprazole
Sponsors
Kathy Miller
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
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) 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 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. | 42 |
| Total | 42 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 6 |
| Overall Study | Disease Progression | 1 |
| Overall Study | Physician Decision | 2 |
Baseline characteristics
| Characteristic | High Dose Omeprazole Treatment |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 6 Participants |
| Age, Categorical Between 18 and 65 years | 36 Participants |
| Age, Continuous | 52.6 years STANDARD_DEVIATION 10.5 |
| Eastern Cooperative Oncology Group (ECOG) Performance Status 0-Fully active | 36 Participants |
| Eastern Cooperative Oncology Group (ECOG) Performance Status 1-Restricted in physically strenuous activity | 6 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 3 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 38 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 14 Participants |
| Race (NIH/OMB) More than one race | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 3 Participants |
| Race (NIH/OMB) White | 24 Participants |
| Sex: Female, Male Female | 42 Participants |
| Sex: Female, Male Male | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 42 |
| other Total, other adverse events | 37 / 42 |
| serious Total, serious adverse events | 5 / 42 |
Outcome results
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.
Time frame: Up to 6 months
Population: Patients who had surgery and positive FASN expression
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| High Dose Omeprazole Treatment | Percentage of Patients With Pathological Complete Response (pCR) in Patients Who Have Fatty Acid Synthase (FASN) Expression | 72.4 percentage of participants |
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.
Time frame: baseline and after 4-7 days
Population: Patients with FASN activity evaluated at baseline and after 4-7 days of treatment.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| High Dose Omeprazole Treatment | FASN Activity at Baseline and After 4-7 Days of Omeprazole Treatment | Baseline | 2.1 ng/mg | Standard Deviation 1.61 |
| High Dose Omeprazole Treatment | FASN Activity at Baseline and After 4-7 Days of Omeprazole Treatment | After 4-7 days | 1.3 ng/mg | Standard Deviation 0.93 |
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.
Time frame: baseline and after 4-7 days
Population: Patients with FASN positivity expression at both baseline and after 4-7 days of treatment.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| High Dose Omeprazole Treatment | FASN Positivity Expression at Baseline and After 4-7 Days of Omeprazole Treatment | Baseline | 53.9 percentage of positivity | Standard Deviation 23.6 |
| High Dose Omeprazole Treatment | FASN Positivity Expression at Baseline and After 4-7 Days of Omeprazole Treatment | After 4-7 days | 41.7 percentage of positivity | Standard Deviation 30.7 |
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.
Time frame: up to 8 months
Population: Patients who received treatment
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| High Dose Omeprazole Treatment | Number of Patients With Treatment Related Adverse Events Grade 3 or Above | 0 Participants |
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.
Time frame: Up to 6 months
Population: Patients who received surgery
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| High Dose Omeprazole Treatment | Percentage of Patients With Pathological Complete Response (pCR) in All Patients | 74.4 percentage of participants |
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.
Time frame: up to 1 week
Population: Patients with FASN positivity results at either baseline or after 4-7 days of treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| High Dose Omeprazole Treatment | Percent of Patients With FASN Expression | 93.3 percentage of participants |