Safety and Efficacy of SNX-5422 in Human Epidermal Growth Factor Receptor 2 (HER2) Positive Cancers

Study Overview
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Brief Summary
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Hsp90 is a chemical in the body that is involved in the promotion of cancer. SNX-5422 is an experimental drug that blocks Hsp90

Detailed Description
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Heat shock protein 90 (Hsp90) chaperone proteins stabilize well over 200 different known client proteins helping them to fold correctly as they take up their rightful positions in the cell. Hsp90 has a special fondness for oncoproteins whose structures shift according to functional state. Among Hsp90's clients, a surprising number are well recognized targets in oncology, including human epidermal growth factor receptor 2 (HER2). SNX-5422 is a pro-drug of SNX-2112, a potent, highly selective, small-molecule inhibitor of the molecular chaperone heat shock protein 90 (Hsp90). Treatment of HER2-positive cell lines such as BT-474 with the Hsp90 inhibitor SNX-2112 results in cellular degradation, decreased levels of phospho-AKT/cyclin D1, and increased apoptosis. Furthermore, treatment with SNX-5542 caused tumor regression, including remission in a HER2-overexpressing breast cancer xenograft model. SNX-5422 has demonstrated significant antitumor activity in mouse xenograft models of various human malignancies, including breast (BT474, MX-1), lung (H1975, H1650, EBC-1), colon (HT29), prostate (PC3), and melanoma (A375) with multiple oral dosing regimens.

Official Title
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A Single Arm, Phase 1/2 Study of SNX-5422 in Subjects With Selected HER2 Positive Cancers.

Conditions
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Cancer

Intervention / Treatment
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* Drug: SNX-5422


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Males or non-pregnant, non-breastfeeding females . Confirmed diagnosis of locally advanced or metastatic breast, esophagogastric, urothelial, or non-small cell lung cancer. Histological or cytological confirmed carcinoma with HER2 amplification (IHC 3+ or FISH+ (>2 HER2:CEP17)). Subjects with advanced or metastatic breast cancer must have received no more than 5 prior lines of anticancer therapy, including trastuzumab (but excluding hormonal treatments). Subjects with advanced or metastatic HER2 positive esophagogastric cancer must have received no more than 5 prior lines of anticancer therapy, including trastuzumab. Subjects with advanced or metastatic, urothelial carcinoma or non-small cell lung cancer must have received at least one, but no more than 5 prior lines of anticancer therapy. Measurable disease using Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. Life expectancy of at least 3 months. Karnofsky performance score ≥70. Adequate baseline laboratory assessments Recovered from toxicities of previous anticancer therapy, with the exception of CTCAE grade 1 sensory neuropathy. Exclusion Criteria: Subjects with symptomatic central nervous system (CNS) metastases who are neurologically unstable Prior treatment with any Hsp90 inhibitor. Surgery, radiotherapy, or lesion ablative procedure to the only area of measurable disease. Major surgery within 4 weeks prior to first dose of SNX-5422. Treatment with chronic immunosuppressants (e.g., cyclosporine following transplantation). The need for treatment with medications with clinically-relevant metabolism by the cytochrome P450 (CYP) 3A4 isoenzyme within 3 hours before or after administration of SNX-5422. Screening ECG QTc interval ≥470 msec for females, ≥450 msec for males. At increased risk for developing prolonged QT interval Patients with chronic diarrhea or with grade 2 or greater diarrhea despite maximal medical management. Gastrointestinal diseases or conditions that could affect drug absorption, including gastric bypass. Gastrointestinal diseases that could alter the assessment of safety, including irritable bowel syndrome, ulcerative colitis, Crohn's disease, or hemorrhagic coloproctitis. History of documented adrenal dysfunction not due to malignancy. Known seropositive for human immunodeficiency virus (HIV) or hepatitis C virus (HCV). History of chronic liver disease. Active hepatitis A or B. Current alcohol dependence or drug abuse. Treatment with other anticancer drugs within 28 days or 5 half-lives of anticancer therapy (whichever is shorter), and treatment with any other investigational agent is prohibited from 30 days prior to the first dose of SNX-5422 and throughout the study Glaucoma, retinitis pigmentosa, macular degeneration, or any retinal changes detected by ophthalmological examination. Other serious concurrent illness or medical condition. Psychological, social, familial, or geographical reasons that would hinder or prevent compliance with the requirements of the protocol or compromise the informed consent process.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: SNX-5422<br>Open-label administration of SNX-5422 capsules to total 100 mg/m2 every other day for 21 days (total = 11 doses), out of a 28-day treatment cycle. Subjects will continue treatment on a 28-day cycle at the discretion of the principal investigator based on safety. | Drug: SNX-5422<br>* Capsule(s) dosed every other day for 21 days (total = 11 doses), out of a 28-day treatment cycle.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate | The effect of SNX-5422 on tumor progression. Objective tumor responses (complete remissions plus partial remissions) and clinical benefit rate (complete remissions plus partial remissions plus stable disease at 6 months) will be listed by subject. Tumor measurements made using Response Evaluation Criteria in Solid Tumors (RECIST). | Up to 24 months from last patient entry | 
| Progression Free Survival | Time on treatment with at worst stable disease. | Every 3 months until 24 months after the last subject has been enrolled | 
| Overall Survival | Time from start of treatment that patients remain alive. | Every 3 months until 24 months after the last subject has been enrolled | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in Vital Signs, Physical Examination or Clinical Laboratory From Baseline | Descriptive summaries of vital signs, physical examination and clinical laboratory changes will be presented by treatment received. | Day 28 of each cycle | 
| Ophthalmologic Changes From Baseline | Ophthalmologic assessments will be presented by cohort, study visit and dose. Number of subjects experiencing clinically relevant changes from baseline in any of these examinations will be presented using descriptive summary | Screening, end of Cycle 1, final visit | 
| Adverse Events by Severity and Relationship to Treatment | Number of patients experiencing adverse events by highest recorded severity and relationship to study tretament | Every 28 day cycle | 
| Number of Patients With Adverse Events | Number of patients experiencing treatment emergent adverse events. | Day 28 of each cycle | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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SNX-5422, HER2 positive cancer