Safety and Pharmacology of SNX-5422 Plus Everolimus in Subjects With Neuroendocrine Tumors

Heat shock protein 90 (Hsp90) plays a central role in the maturation and maintenance of
numerous proteins, for example HER2 and mutated EGFR, that are critical for tumor cell
viability and growth; 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). Hsp90 has
been found to be expressed in 95% of subjects with pancreatic neuroendocrine tumors.

This study will determine the MTD of SNX-5422 when given in combination with everolimus in
patients with neuroendocrine tumors.The clinical starting dose of 50 mg/m2 qod for SNX-5422
in combination with daily everolimus is 50% of the SNX-5422 qod mono-therapy MTD. The choice
to continue once every other day SNX-5422 dosing is based on the safety and efficacy profiles
from prior studies, so that drug holidays are interspersed into weekly dosing. The planned
subsequent dose levels are 75% and 100% of the SNX-5422 qod mono-therapy MTD.

Inclusion Criteria:

- Males or non-pregnant, non-breastfeeding females 18 years-of-age or older.

- Archived neuroendocrine tumor sample or biopsy sample (will also be used for genetic
testing).

- Pathologic evidence of chemo-resistant Small Cell Lung cancer (relapse <90 days after
1st line), chemo-sensitive Small Cell Lung Cancer (relapse >90 days after first line),
locally advanced metastatic neuroendocrine tumor of gastro-entero, pancreatic,
pulmonary (other than Small Cell Lung) or thymic origin, or advanced renal cell
carcinoma for which everolimus is indicated.

- Measurable (RECIST) indicator lesion not previously irradiated.

- Life expectancy of at least 3 months.

- No more than 4 prior lines of systemic anti-cancer therapy.

- Karnofsky performance score ≥70.

- Adequate baseline laboratory assessments, including

- Absolute neutrophil count (ANC) ≥1.5 x 109/L.

- WBC >3000/microliter

- Platelet count of ≥100 x 109/L.

- Total bilirubin level ≤1.5 times institutional upper limit of normal (ULN),
alanine aminotransferase or aspartate aminotransferase ≤2 x ULN

- Hemoglobin ≥9 mg/dL.

- Creatinine <1.5 X upper limit of normal or estimated plasma creatinine clearance
of ≥40 mL/min

- Signed informed consent form

- Recovered from toxicities of previous anticancer therapy

- Subjects with reproductive capability must agree to practice adequate contraception
methods.

Exclusion Criteria:

- Subjects in whom everolimus is contraindicated.

- Subjects with clinically significant interstitial lung disease, or obstructive disease
without sufficient reserve

- Carcinoid with hormone related symptoms

- Neuroendocrine cancer of the thyroid or thymus.

- Rare pancreatic neuroendocrine cancers such as, insulinomas, glucagonomas,
gastrinomas.

- Prior treatment with any Hsp90 inhibitor.

- Prior failed treatment with mTOR inhibitors

- CNS metastases that are symptomatic and /or requiring escalating doses of steroids.

- Major surgery or significant traumatic injury within 4 weeks of starting study
treatment.

- Conventional chemotherapy or radiation within 4 weeks.

- Palliative radiation within 2 weeks.

- 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, including hypokalemia or
hypomagnesemia, unless corrected to within normal limits prior to first dose of
SNX-5422; congenital long QT syndrome or a history of torsade de pointes; currently
receiving anti-arrhythmics or other medications that may be associated with QT
prolongation.

- Patients with chronic diarrhea or with Grade 2 or greater diarrhea despite appropriate
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.

- Use of an investigational treatment from 30 days prior to the first dose of SNX-5422
and during 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.