Martin Gutierrez1, Robin Guo2, Giuseppe Giaccone3, Stephen V Liu4, Zhonglin Hao4, Christie Hilton5, James M Hinson6, Mark G Kris2, Everardus Otto Orlemans7, Alexander Drilon8. 1. John Theurer Cancer Center, Hackensack University Medical Center, Hackensack, NJ, USA. 2. Memorial Sloan Kettering Cancer Center, New York, NY, USA; Weill Cornell Medical Center, New York, NY, USA. 3. Weill Cornell Medical Center, New York, NY, USA. 4. Georgetown Lombardi Comprehensive Cancer Center, Washington, DC, USA. 5. West Penn Allegheny Oncology Network, Pittsburgh, PA, USA. 6. Unicorn Pharma Consulting, Nashville, TN, USA. 7. Esanex Inc, Indianapolis, IN, USA. 8. Memorial Sloan Kettering Cancer Center, New York, NY, USA; Weill Cornell Medical Center, New York, NY, USA. Electronic address: drilona@mskcc.org.
Abstract
OBJECTIVES: Single-agent heat shock protein 90 (HSP90) inhibition has demonstrated activity in oncogene-driven non-small cell and small cell lung cancers. SNX-5422 is an oral HSP90 inhibitor with increased activity in vitro with the addition of carboplatin and paclitaxel. Therefore, we conducted a phase 1, open-label, multicenter study to evaluate SNX-5422, carboplatin and paclitaxel followed by SNX-5422 maintenance in patients with advanced lung cancers. MATERIALS AND METHODS: In part 1 (3 + 3 dose escalation), SNX-5422 (50/75/100-mg/m2) was dosed every other day (qod) for 21 days (28-day cycle) for ≤4 cycles; carboplatin (AUC 5)-paclitaxel (175 mg/m2) was administered once every 3 weeks for ≤6 courses. In part 2 (maintenance), subjects who achieved at least stable disease in part 1 received 100 mg/m2 SNX-5422 monotherapy qod for 21 days (28-day cycle). RESULTS: Twenty-three patients with advanced non-small cell lung cancer (NSCLC, n = 20) and small cell lung cancer (SCLC, n = 3) were enrolled. The median age was 60 years and 61% (n = 14/23) had ≥1 prior treatment regimens. The maximum tolerated dose of SNX-5422 was 100 mg/m2 qod in combination with carboplatin-paclitaxel. The most common treatment-related grade 3/4 adverse events (part 1/part 2) were diarrhea (26%/15%) and nausea (9%/0%). In response-evaluable patients with NSCLC, 33% (6/18) had a partial response, 56% (10/18) stable disease, and 11% (2/18) progressive disease. Patients who remained on single-agent SNX-5422 maintenance therapy ≥2 months (n = 9) had cancers enriched for oncogenic drivers (n = 3 KRAS mutation, n = 1 EGFR exon 20 mutation, n = 1 HER2 mutation, and n = 1 RET fusion). CONCLUSIONS: The triplet combination of SNX-5422, carboplatin and paclitaxel followed by maintenance SNX-5422 therapy was well-tolerated and showed anti-tumor activity. Cancers for which disease control on single-agent SNX-5422 maintenance was observed were enriched for oncogene-driven NSCLCs.
OBJECTIVES: Single-agent heat shock protein 90 (HSP90) inhibition has demonstrated activity in oncogene-driven non-small cell and small cell lung cancers. SNX-5422 is an oral HSP90 inhibitor with increased activity in vitro with the addition of carboplatin and paclitaxel. Therefore, we conducted a phase 1, open-label, multicenter study to evaluate SNX-5422, carboplatin and paclitaxel followed by SNX-5422 maintenance in patients with advanced lung cancers. MATERIALS AND METHODS: In part 1 (3 + 3 dose escalation), SNX-5422 (50/75/100-mg/m2) was dosed every other day (qod) for 21 days (28-day cycle) for ≤4 cycles; carboplatin (AUC 5)-paclitaxel (175 mg/m2) was administered once every 3 weeks for ≤6 courses. In part 2 (maintenance), subjects who achieved at least stable disease in part 1 received 100 mg/m2 SNX-5422 monotherapy qod for 21 days (28-day cycle). RESULTS: Twenty-three patients with advanced non-small cell lung cancer (NSCLC, n = 20) and small cell lung cancer (SCLC, n = 3) were enrolled. The median age was 60 years and 61% (n = 14/23) had ≥1 prior treatment regimens. The maximum tolerated dose of SNX-5422 was 100 mg/m2 qod in combination with carboplatin-paclitaxel. The most common treatment-related grade 3/4 adverse events (part 1/part 2) were diarrhea (26%/15%) and nausea (9%/0%). In response-evaluable patients with NSCLC, 33% (6/18) had a partial response, 56% (10/18) stable disease, and 11% (2/18) progressive disease. Patients who remained on single-agent SNX-5422 maintenance therapy ≥2 months (n = 9) had cancers enriched for oncogenic drivers (n = 3 KRAS mutation, n = 1 EGFR exon 20 mutation, n = 1 HER2 mutation, and n = 1 RET fusion). CONCLUSIONS: The triplet combination of SNX-5422, carboplatin and paclitaxel followed by maintenance SNX-5422 therapy was well-tolerated and showed anti-tumor activity. Cancers for which disease control on single-agent SNX-5422 maintenance was observed were enriched for oncogene-driven NSCLCs.
Authors: Jeffrey R Infante; Glen J Weiss; Suzanne Jones; Raoul Tibes; Todd M Bauer; Johanna C Bendell; James M Hinson; Daniel D Von Hoff; Howard A Burris; Everardus O Orlemans; Ramesh K Ramanathan Journal: Eur J Cancer Date: 2014-09-25 Impact factor: 9.162
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Authors: Kenneth H Huang; James M Veal; R Patrick Fadden; John W Rice; Jeron Eaves; Jon-Paul Strachan; Amy F Barabasz; Briana E Foley; Thomas E Barta; Wei Ma; Melanie A Silinski; Mei Hu; Jeffrey M Partridge; Anisa Scott; Laura G DuBois; Tiffany Freed; Paul M Steed; Andy J Ommen; Emilie D Smith; Philip F Hughes; Angela R Woodward; Gunnar J Hanson; W Stephen McCall; Christopher J Markworth; Lindsay Hinkley; Matthew Jenks; Lifeng Geng; Meredith Lewis; James Otto; Bert Pronk; Katleen Verleysen; Steven E Hall Journal: J Med Chem Date: 2009-07-23 Impact factor: 7.446