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

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.

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.