Clinical Trials /

Inhibiting Fatty Acid Synthase to Improve Efficacy of Neoadjuvant Chemotherapy

NCT02595372

Description:

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.

Related Conditions:
  • Breast Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Inhibiting Fatty Acid Synthase to Improve Efficacy of <span class="go-doc-concept go-doc-intervention">Neoadjuvant Chemotherapy</span>

Title

  • Brief Title: Inhibiting Fatty Acid Synthase to Improve Efficacy of Neoadjuvant Chemotherapy
  • Official Title: Inhibiting Fatty Acid Synthase to Improve Efficacy of Neoadjuvant Chemotherapy
  • Clinical Trial IDs

    NCT ID: NCT02595372

    ORG ID: IUSCC-0555

    Trial Conditions

    Cancer of the Breast

    Trial Interventions

    Drug Synonyms Arms
    Omeprazole High dose omeprazole treatment

    Trial Purpose

    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.

    Trial Arms

    Name Type Description Interventions
    High dose omeprazole treatment Experimental Patients will be treated with omeprazole 80 mg orally BID beginning 4-7 days prior to chemotherapy and continuing until surgery. Omeprazole

    Eligibility Criteria

    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

    Minimum Eligible Age: 18 Years

    Maximum Eligible Age: N/A

    Eligible Gender: Both

    Primary Outcome Measures

    Pathological complete recovery (pCR)

    Secondary Outcome Measures

    FASN expression

    FASN downstream target genes

    FASN activity

    Safety of incorporating high dose omeprazole with standard neoadjuvant chemotherapy (treatment related adverse events per NCI CTC version 4.0)

    Trial Keywords