A Phase 1, Open-label, Dose-escalation Study of SNX 5422 and Erlotinib in Subjects With Lung Adenocarcinoma With "Acquired Resistance" to Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors.
Heat shock protein 90 (Hsp90) chaperone proteins stabilize many client proteins including
mutant EGFR, and are also hypothesized to help maintain the malignant phenotype of mutant
EGFR in lung adenocarcinoma. Treatment of EGFR mutant cell lines with the Hsp90 inhibitor
geldanamycin results in cellular degradation, decreased levels of pAKT/cyclin D1, and
increased apoptosis. Furthermore, Hsp90 inhibitors hamper growth of tumors in nude mice with
gefitinib-resistant H1975-xenografts in vivo.
Clinical data showed that mono-therapy with some Hsp90 inhibitors provides stable disease
and some patients have partial remissions as best responses in heavily pre-treated non small
cell lung cancer patients.
SNX-5422 is a pro-drug of SNX-2112, a potent, highly selective, small-molecule inhibitor of
the molecular chaperone Hsp90. Inhibitors of the chaperone protein Hsp90 are of current
interest because of the central role that Hsp90 plays in the maturation and maintenance of
numerous proteins, for example HER2 and mutated EGFR, that are critical for tumor cell
viability and growth.
Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Number of patients with dose limiting toxicities
Number of patients with dose limiting toxicities defined as adverse events (AE) or laboratory abnormalities of Common Terminology Criteria for Adverse Events(CTCAE) version 4.03 ≥ Grade 3 that are not clearly related to disease progression
Day 28 of first dose cycle
United States: Food and Drug Administration
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