Safety and Pharmacology Study of SNX-5422 in Subjects With Refractory Hematological Malignancies

SNX-5422 is a prodrug for SNX-2112. Correlation has been observed between Hsp90 client
protein level changes and functional effects in cells in in vitro studies of SNX-2112,
supporting inhibition of Hsp90 as the mechanism of action for this compound. SNX-5422 has
demonstrated significant antitumor activity in mouse xenograft models of human tumors,
including breast (BT474, MX-1), colon (HT29), prostate (PC3), and melanoma (A375) with
multiple oral dosing regimens. Pharmacokinetic (PK) studies in mice, rats, and dogs have
shown high bioavailability of SNX-2112 following oral administration of SNX 5422. In mouse
xenograft studies, SNX-2112 was selectively retained in tumor tissue compared with other
tissues. This study will employ critical risk management features including the use of the
NCI Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03, which provides a
scale for consistently grading the severity of AEs, toxicity criteria analyses for dose
escalation, frequent laboratory and clinical observations, correlation of AEs with plasma
concentrations of SNX-5422 and SNX-2112, monitoring of the QTc interval at appropriate time
points, and a conservative dose-escalation scheme.

Inclusion Criteria:

- Males or non-pregnant, non-breastfeeding females 18 years-of-age or older with
histologically confirmed non-Hodgkins lymphoma, without known or clinically suspected
CNS involvement, that is refractory to available therapy or for which there is no
available therapy.

- No more than 4 prior lines of systemic anti-cancer therapy and no prior bone marrow
transplant or stem cell transplant within 12 months of dosing, and no prior
allogeneic transplant.

- Karnofsky performance score ≥60

- Life expectancy of at least 3 months.

- Adequate baseline laboratory assessments

Exclusion Criteria:

- Currently receiving anticancer therapy or have received anticancer therapy within the
past 28 days or 5 half-lives of the anticancer therapy

- 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

- At increased risk for developing prolonged QT interval, including hypokalemia or
hypomagnesemia, unless corrected to within normal limits prior to first dose of SNX-•
Chronic diarrhea.

- 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.

- Seropositive for human immunodeficiency virus (HIV) or hepatitis C virus (HCV).

- History of chronic liver disease