SBIR-STTR Award

Oral mucositis has a significant impact on patient quality of life and outcomes during cancer therapy as well as having a significant pharmacoeconomic cost. There are no currently approved drugs to treat oral mucositis in patients with non-hematological malignancies, including head and neck cancer (HNC). Soligenix is developing a new compound, SGX942, a modulator of the innate defense system, which binds to the p62 protein. p62 is a key adaptor protein that functions downstream of key sensing receptors of the innate defense system. Preclinical studies with SGX942 revealed a significant reduction in both duration and peak intensity of oral mucositis in both a fractionated radiation-induced hamster model of oral mucositis and a chemotherapy- induced mouse model of oral (tongue) mucositis: there was ~50% reduction in the duration of severe mucositis. Efficacy was dose responsive and optimal at 25 mg/kg dosed every third day during fractionated radiation therapy. Based on the preclinical findings, we hypothesize that SGX942 will be a safe and effective therapy for chemotherapy and radiation induced mucositis, allowing for better long-term cancer-related outcomes. Therefore, SGX942 warrants further clinical investigation. A placebo-controlled Phase 1 study in 84 healthy volunteers has been completed under a clinical trial application (CTA) filed with Health Canada, demonstrating that single intravenous (IV) doses of SGX942 were well tolerated up to the maximum tested (8 mg/kg) and daily IV doses were well tolerated up to the maximum tested (6.5 mg/kg for 7 days). No adverse events or toxicities were reported. On February 20, 2013, Soligenix submitted an investigational new drug application (IND) that included the clinical protocol for Study IDR-OM-01 entitled, 'A Phase 2, Double-Blind, Randomized, Placebo-Controlled, Dose-Ranging, Multicenter Study of SGX942 for the Attenuation of Oral Mucositis in Patients Being Treated with Concomitant Chemoradiation for the Treatment of Squamous Cell Carcinoma of the Head and Neck.' The IND completed the 30-day review period on March 22, 2013 and is now effective. The proposal requests funding to support the conduct of the Phase 2 clinical study IDR-OM-01. Approximately 75 patients will be enrolled at 15-25 clinical centers in the US with recently diagnosed cancers of the oral cavity and pharynx who are planned to receive chemoradiation treatment (CRT) into 3 treatment groups (1:1:1) including placebo, SGX942 1.5 mg/kg and SGX942 6.0 mg/kg. The study is designed to include 50 experimental (SGX942) subjects and 25 control (placebo) subjects. This is an exploratory study to enable estimation of patient responses for future studies and to establish proof of concept. Specific Aim 1. Evaluate the efficacy of SGX942 compared to placebo in attenuating the onset of severe oral mucositis in patients receiving CRT for the treatment of HNC. Specific Aim 2. Evaluate the safety of SGX942 in patients receiving CRT for the treatment of HNC.

Thesaurus Terms:
Absence Of Pain Sensation;Adaptor Signaling Protein;Adverse Effects;Adverse Event;Attenuated;Attenuation;Bacterial Infections;Base;Binding (Molecular Function);Canada;Cancer Diagnosis;Cancer Therapy;Cell Death;Chemoradiation;Chemotherapy;Cisplatin;Clinical;Clinical Protocols;Clinical Research;Clinical Trials;Cost;Data;Design;Development;Dose;Dose-Limiting;Double-Blind Method;Effective Therapy;Enrollment;Follow-Up;Funding;Future;Gastrointestinal Tract Structure;Hamsters;Head And Neck Cancer;Head And Neck Cancer Patient;Head And Neck Squamous Cell Carcinoma;Health;Healthy Volunteer;Immune System;Infection;Inflammation;Intensity-Modulated Radiotherapy;Intravenous;Investigational New Drug Application;Keratinocyte Growth Factor;Lead;Lesion;Link;Malignant Neoplasms;Modeling;Mouse Model;Mucositis;Mucous Membrane;Multicenter Studies;Narcotics;Oral;Oral Cavity;Oral Mucositis;Outcome;Pain;Parenteral Nutrition;Patients;Pharmaceutical Economics;Pharmaceutical Preparations;Pharyngeal Structure;Phase;Phase 1 Study;Placebo Control;Placebos;Positioning Attribute;Pre-Clinical;Preclinical Study;Process;Programs;Protein Function;Proteins;Protocols Documentation;Public Health Relevance;Quality Of Life;Radiation;Radiation Therapy;Randomized;Receptor;Reporting;Request For Proposals;Research Personnel;Response;Safety;Sepsis;Site;Small Business Innovation Research Grant;Solid Neoplasm;Symptoms;System;Testing;Tongue;Toxic Effect;Treatment Cost;Treatment Outcome;Tumor;Ulcer;World Health Organization;

This proposal supports the conduct of the clinical study IDR-OM-02 entitled, “A Pivotal, Double-Blind, Randomized, Placebo-Controlled, Multinational Study of SGX942 (Dusquetide) for the Attenuation of Oral Mucositis in Patients Being Treated with Concomitant Chemoradiation for the Treatment of Squamous Cell Carcinoma of the Head and Neck”. This trial is designed to confirm the positive findings seen in the SBIR Phase I (R43DE024032) supported study IDR-OM-01 entitled “A Phase 2, Double-Blind, Randomized, Placebo-Controlled, Dose-Ranging, Multicenter Study of SGX942 for the Attenuation of Oral Mucositis in Patients Being Treated with Concomitant Chemoradiation for the Treatment of Squamous Cell Carcinoma of the Head and Neck”. Oral mucositis (OM) is a serious and debilitating condition and currently an unmet medical need for patients and physicians. It has a significant impact on patient quality of life and outcomes during cancer therapy as well as having a significant pharmacoeconomic cost. There are no currently approved drugs to treat OM in patients with non-hematological malignancies, including head and neck cancer (HNC). Severe OM (i.e., WHO grades 3 or 4) is the most clinically important form as they have the potential to result in alterations to a patient's cancer therapy. OM has been linked to the dysregulation of the innate defense system, resulting in an inflammatory cascade, which amplifies damage to the mucosal lining leading to clinically overt mucositis. Dusquetide (the active pharmaceutical ingredient in SGX942) is an Innate Defense Regulator (IDR), which binds to the p62 protein, a key adaptor protein which functions downstream of most innate immune receptors. SGX942 has received Fast Track Designation from the FDA validating it has demonstrated the potential to address this unmet medical need. SGX942 can address both acute trauma and acute infections, and SGX942 may have some independent direct anti-tumor activity via its activity in the innate immune system. This Phase II proposal seeks to conduct a study to confirm that SGX942 (1.5 mg/kg dusquetide) is an efficacious therapy for chemoradiation therapy (CRT) induced severe OM in patients with HNC, allowing for better long-term cancer-related outcomes. If successful, results from this study will support marketing authorization applications worldwide, including a New Drug Application (NDA) submission to the FDA. The Specific Aims of this proposal are: Specific Aim 1. Confirm the efficacy of 1.5 mg/kg SGX942 compared to placebo in reducing the duration of severe oral mucositis (SOM) in patients receiving CRT for their oral cavity or oropharyngeal squamous cell carcinoma. Specific Aim 2. Confirm the safety of this immunomodulator in HNC patients including the lack of interference with chemoradiation treatment outcomes (tumor progression and mortality) and the lack of an increased infection rate with 1.5 mg/kg SGX942 treatment compared to placebo.

Public Health Relevance Statement:
8. Project Narrative Oral mucositis (OM) is a serious condition that almost always occurs in patients with head and neck cancer (HNC) undergoing chemoradiation therapy (CRT) and can lead to infection, sepsis, the need for parenteral nutrition and narcotic analgesia. Severe OM can limit the doses and duration of cancer treatment (i.e., CRT), leading to sub-optimal treatment outcomes including reduced survival. The primary objective of this Phase II application, is to build upon the positive results obtained in the Phase I SBIR and confirm the efficacy of SGX942 (1.5 mg/kg dusquetide) as a treatment for severe OM in HNC patients, and if successful, support the submission of worldwide marketing authorization applications (e.g., a New Drug Application submission to the FDA).

Project Terms:
Absence of pain sensation; Acute; Adaptor Signaling Protein; Address; Adverse effects; Anti-inflammatory; Anti-Inflammatory Agents; Area Under Curve; attenuation; Authorization documentation; Bacterial Infections; base; Binding; Cancer Patient; cancer therapy; Cell Death; chemoradiation; chemotherapy; Clinical; Clinical Data; Clinical Research; cohort; cost; Data; design; Dose; Double-Blind Method; Eating; Enrollment; Europe; follow-up; Funding; Gastrointestinal tract structure; GTF2H1 gene; Head and Neck Cancer; head and neck cancer patient; Head and Neck Squamous Cell Carcinoma; Hematologic Neoplasms; High Dose Chemotherapy; high risk; Immune; Immune system; Immunologic Receptors; Immunomodulators; Incidence; Infection; Inflammation; Inflammatory; Innate Immune Response; Innate Immune System; Intravenous infusion procedures; Lead; Lesion; Link; Malignant Neoplasms; Marketing; Medical; Modeling; Molecular; mortality; mouth squamous cell carcinoma; Mucositis; Mucous Membrane; Multicenter Studies; Narcotics; Non-Hematologic Malignancy; novel therapeutics; Oral cavity; oral mucositis; Oropharyngeal; Oropharyngeal Squamous Cell Carcinoma; Outcome; Pain; Parenteral Nutrition; pathogen; Patients; Pattern; Pharmaceutical Economics; Pharmaceutical Preparations; Pharmacodynamics; Pharmacologic Substance; Phase; Physicians; Placebo Control; Placebos; preclinical study; programs; Quality of life; Radiation; Radiation therapy; Randomized; Request for Proposals; Resolution; response; Safety; Sepsis; Small Business Innovation Research Grant; Solid Neoplasm; Symptoms; System; Tissues; Trauma; Treatment Cost; treatment group; Treatment outcome; trend; tumor; tumor progression; Ulcer; United States; World Health Organization