HER2+ breast cancer (HER2+ BC) is an aggressive type of breast cancer that claims the lives of over 120,000women annually worldwide. Current treatments for HER2+ BC rely on chemotherapy in combination withtrastuzumab, pertuzumab, and trastuzumab-emtansine (TD-M1), which target the HER2 receptor on cancercells. While initially responsive to these treatments, HER2+ breast cancer eventually progress.. Beyond thesetherapies there are limited options recognized to have a significant clinical benefit with therapies such asLapatinib (a chemotherapy drug) demonstrating a benefit in time to progression, but not in overall survival.Although these therapies have resulted in higher response rates, longer time to progression and increasedsurvival in some patients with metastatic disease, they are plagued by drug-related toxicities that have long-term adverse effects that severely impact the quality of life of patients. Considering these limitations, HER2+BC poses a major clinical challenge, and developing new agents that are effective and safe is a critical unmetneed. Veana Therapeutics has developed a novel proprietary clinical drug candidate, a-TEA-Lysine (a-TEA-Lys) that kills cancer but not normal cells in a fashion that stimulates anti-tumor immunity. In pre-clinicalstudies, we demonstrated that a-TEA-Lys is safe and efficacious in causing regression of establishedHER2/neu-expressing tumors. Veana has conducted a first-in-human dose escalation trial of a-TEA-Lys inpatients with multiple types of advanced cancer. At the doses tested, a-TEA-Lys was safe, well tolerated andstopped tumor from growing (stable disease) in 12 of 17 patients (70%). The safety profile of a-TEA-Lys,coupled with its pro-apoptotic and immune-stimulating properties, make it an ideal candidate to combine withHER2-specific antibody to eliminate tumors. The goal of this application is to conduct proof-of-concept pre-clinical studies to determine the optimum dosing schedule of a-TEA and anti-HER2/neu combination therapythat will yield the best therapeutic outcome while limiting toxicity. We will pursue three specific aims to achievethis goal: Aim 1: Determine the schedule of a-TEA-Lys/anti-HER2/neu combination therapy that will elicitlasting tumor regression in a well-described pre-clinical model of HER2/neu+ breast cancer. Aim 2: Identifysurrogate immunologic biomarkers of effective a-TEA-Lys/anti-HER2/neu combination therapy. Aim 3:Compare the antitumor activity and toxicity profile of a-TEA/anti-HER2/neu treatment with that ofpaclitaxel/anti-HER2/neu and lapatinib/anti-HER2/neu treatments. We will assess tumor growth and survival,and perform hematological analysis, complete necropsy and examination of tissues and organs of treatedanimals. Completion of the studies and realization of the milestones will lay the groundwork for a Phase II grantapplication to evaluate safety and tolerability of a-TEA plus trastuzumab in a first-in-human combination trial inpatients with HER2+ BC. Demonstration of efficacy in subsequent Phase II/III trials could lead to FDA-approvalpaving the way for commercialization of a-TEA as a companion drug with trastuzumab for treating HER2+ BC. PROJECT NARRATIVE
Intensive combination chemotherapy, which is standard of care for HER-2 positive breast cancer patients is
associated with significant toxicity and morbidity. This project will assess the efficacy and toxicity profile of a-
TEA lysine salt, a novel proprietary drug candidate in combination with trastuzumab (anti-HER2) for the
treatment of HER2+ breast cancer. The minimal toxicity coupled with the immune adjuvant activity of a-TEA-Lys
position it strongly as an attractive alternative for HER2+ breast cancer patients that are ineligible for treatment
with current drugs due to safety concerns. Immunologic Adjuvants ; Immunoactivators ; Immunoadjuvants ; Immunological Adjuvant ; Immunopotentiators ; Immunostimulants ; immune adjuvant ; Animals ; Antibodies ; Antigens ; immunogen ; Autopsy ; necropsy ; postmortem ; Blood Chemical Analysis ; Blood Chemical Analyses ; blood chemistry ; malignant breast neoplasm ; Breast Cancer ; malignant breast tumor ; Malignant Neoplasms ; Cancers ; Malignant Tumor ; malignancy ; neoplasm/cancer ; Combined Modality Therapy ; Multimodal Therapy ; Multimodal Treatment ; combination therapy ; combined modality treatment ; combined treatment ; multi-modal therapy ; multi-modal treatment ; Complete Blood Count ; Cessation of life ; Death ; Disease ; Disorder ; Combination Drug Therapy ; Polychemotherapy ; combination chemotherapy ; combination pharmacotherapy ; combined drug therapy ; Pharmaceutical Preparations ; Drugs ; Medication ; Pharmaceutic Preparations ; drug/agent ; Goals ; Hematology ; Immunity ; Natural Killer Cells ; Cytotoxic cell ; K lymphocyte ; NK Cells ; Lead ; Pb element ; heavy metal Pb ; heavy metal lead ; Lysine ; L-Lysine ; Mitochondria ; mitochondrial ; Morbidity - disease rate ; Morbidity ; Neoplasm Metastasis ; Metastasis ; Metastasize ; Metastatic Lesion ; Metastatic Mass ; Metastatic Neoplasm ; Metastatic Tumor ; Secondary Neoplasm ; Secondary Tumor ; cancer metastasis ; tumor cell metastasis ; Patients ; Production ; Quality of life ; QOL ; Safety ; Signal Transduction ; Cell Communication and Signaling ; Cell Signaling ; Intracellular Communication and Signaling ; Signal Transduction Systems ; Signaling ; biological signal transduction ; Sodium Chloride ; salt ; T-Lymphocyte ; T-Cells ; thymus derived lymphocyte ; Testing ; Time ; Tissues ; Body Tissues ; Woman ; cytokine ; Surrogate Markers ; surrogate bio-markers ; surrogate biomarkers ; Schedule ; Paclitaxel ; Anzatax ; Asotax ; Bristaxol ; Paclitaxel (Taxol) ; Praxel ; Taxol ; Taxol A ; Taxol Konzentrat ; Immunologic Markers ; Immune Markers ; immune-based biomarkers ; immunological biomarkers ; immunological markers ; Organ ; improved ; Clinical ; Phase ; Oxidative Stress ; CD8-Positive T-Lymphocytes ; CD8 Cell ; CD8 T cells ; CD8 lymphocyte ; CD8+ T cell ; CD8+ T-Lymphocyte ; CD8-Positive Lymphocytes ; T8 Cells ; T8 Lymphocytes ; ERBB2 gene ; ERBB2 ; HER -2 ; HER-2 ; HER2 ; HER2 Genes ; HER2/neu ; NEU Oncogene ; NEU protein ; Oncogene ErbB2 ; TKR1 ; c-erbB-2 ; c-erbB-2 Genes ; c-erbB-2 Proto-Oncogenes ; erbB-2 Genes ; herstatin ; neu Genes ; Collaborations ; Therapeutic ; Therapeutic Agents ; Malignant Cell ; cancer cell ; Companions ; Immunes ; Immune ; Treatment Period ; treatment days ; treatment duration ; Tumor Cell ; neoplastic cell ; Receptor Protein ; receptor ; tumor growth ; Toxicities ; Toxic effect ; Stable Disease ; novel ; Anti-ERB-2 ; Anti-HER2/c-erbB2 Monoclonal Antibody ; Anti-c-ERB-2 ; Anti-c-erbB2 Monoclonal Antibody ; Anti-erbB-2 ; Anti-erbB2 Monoclonal Antibody ; Anti-p185-HER2 ; HER2 Monoclonal Antibody ; Herceptin ; MoAb HER2 ; c-erb-2 Monoclonal Antibody ; rhuMAb HER2 ; Trastuzumab ; Position ; Positioning Attribute ; Property ; response ; Advanced Cancer ; Advanced Malignant Neoplasm ; Adverse effects ; Early-Stage Clinical Trials ; Phase 1 Clinical Trials ; phase I protocol ; Phase I Clinical Trials ; T-Cell Proliferation ; Natural Killer Cell Activation ; NK Cell Activation ; T-Cell Activation ; Cross Presentation ; rhuMAb2C4 ; Pertuzumab ; Dose ; lapatinib ; Grant Proposals ; Applications Grants ; Preclinical Models ; Pre-Clinical Model ; Apoptotic ; Cancer Center ; New Agents ; therapy outcome ; therapeutic outcome ; Phase II/III Trial ; Phase 2/3 trial ; Tumor Immunity ; anti-tumor immunity ; antitumor immunity ; cancer immunity ; Immunomodulators ; IMiD ; Immune modulatory therapeutic ; immune modulating agents ; immune modulating drug ; immune modulating therapeutics ; immune modulators ; immune modulatory agents ; immune modulatory drugs ; immunomodulating agents ; immunomodulatory agents ; immunomodulatory drugs ; immunomodulatory therapeutics ; preclinical study ; pre-clinical study ; Treatment Efficacy ; intervention efficacy ; therapeutic efficacy ; therapy efficacy ; Coupled ; chemotherapy ; novel therapeutics ; new drug treatments ; new drugs ; new therapeutics ; new therapy ; next generation therapeutics ; novel drug treatments ; novel drugs ; novel therapy ; commercialization ; tumor ; standard of care ; preclinical evaluation ; pre-clinical evaluation ; drug candidate ; Breast Cancer Patient ; Breast Tumor Patient ; Metastatic breast cancer ; immunogenic cell death ; immunogenic apoptosis ; anti-tumor immune response ; antitumor immune response ; first-in-human ; first in man ; aggressive breast cancer ;
