OBJECTIVE: To evaluate clinical activity and safety of retaspimycin hydrochloride (IPI-504) in patients with castration-resistant prostate cancer (CRPC). METHODS: A single-arm trial was conducted in 2 cohorts: group 1, chemotherapy naive; group 2, docetaxel-treated. IPI-504 was administered intravenously at 400 mg/m2 on days 1, 4, 8, and 11 of a 21-day cycle. Trial expansion was planned if ≥1 prostate-specific antigen (PSA) or radiographic response was noted per cohort. Pharmacokinetic samples were collected after the first dose; safety was assessed throughout. RESULTS: A total of 19 patients were enrolled (4 in group 1; 15 in group 2), with a median age of 66 years (range 49-78). Group 2 had received a median of 2 previous chemotherapy regimens. All group 2 patients had bone metastases; 66% had measurable soft tissue or visceral metastases. One group 1 patient remained on-trial for 9 cycles; his PSA level declined 48% from baseline. No PSA response was observed in the other patients. Adverse events reported in >25% of the study population included nausea (47%), diarrhea (42%), fatigue (32%), anorexia (26%), and arthralgia (26%). Two patients in group 2 died on-trial, involving study drug-related events of hepatic failure and ketoacidosis, respectively. CONCLUSION: Heat shock protein 90 inhibition with IPI-504 administered as a single agent had a minimal effect on the PSA level or tumor burden and was associated with unacceptable toxicity in several patients. Therefore, additional evaluation in CRPC patients is not warranted. IPI-504 is being investigated at less-intensive doses and schedules in other tumor types.
OBJECTIVE: To evaluate clinical activity and safety of retaspimycin hydrochloride (IPI-504) in patients with castration-resistant prostate cancer (CRPC). METHODS: A single-arm trial was conducted in 2 cohorts: group 1, chemotherapy naive; group 2, docetaxel-treated. IPI-504 was administered intravenously at 400 mg/m2 on days 1, 4, 8, and 11 of a 21-day cycle. Trial expansion was planned if ≥1 prostate-specific antigen (PSA) or radiographic response was noted per cohort. Pharmacokinetic samples were collected after the first dose; safety was assessed throughout. RESULTS: A total of 19 patients were enrolled (4 in group 1; 15 in group 2), with a median age of 66 years (range 49-78). Group 2 had received a median of 2 previous chemotherapy regimens. All group 2 patients had bone metastases; 66% had measurable soft tissue or visceral metastases. One group 1 patient remained on-trial for 9 cycles; his PSA level declined 48% from baseline. No PSA response was observed in the other patients. Adverse events reported in >25% of the study population included nausea (47%), diarrhea (42%), fatigue (32%), anorexia (26%), and arthralgia (26%). Two patients in group 2 died on-trial, involving study drug-related events of hepatic failure and ketoacidosis, respectively. CONCLUSION:Heat shock protein 90 inhibition with IPI-504 administered as a single agent had a minimal effect on the PSA level or tumor burden and was associated with unacceptable toxicity in several patients. Therefore, additional evaluation in CRPC patients is not warranted. IPI-504 is being investigated at less-intensive doses and schedules in other tumor types.
Authors: Barry S Taylor; Nikolaus Schultz; Haley Hieronymus; Anuradha Gopalan; Yonghong Xiao; Brett S Carver; Vivek K Arora; Poorvi Kaushik; Ethan Cerami; Boris Reva; Yevgeniy Antipin; Nicholas Mitsiades; Thomas Landers; Igor Dolgalev; John E Major; Manda Wilson; Nicholas D Socci; Alex E Lash; Adriana Heguy; James A Eastham; Howard I Scher; Victor E Reuter; Peter T Scardino; Chris Sander; Charles L Sawyers; William L Gerald Journal: Cancer Cell Date: 2010-06-24 Impact factor: 31.743
Authors: David B Solit; Fuzhong F Zheng; Maria Drobnjak; Pamela N Münster; Brian Higgins; David Verbel; Glenn Heller; William Tong; Carlos Cordon-Cardo; David B Agus; Howard I Scher; Neal Rosen Journal: Clin Cancer Res Date: 2002-05 Impact factor: 12.531
Authors: G J Bubley; M Carducci; W Dahut; N Dawson; D Daliani; M Eisenberger; W D Figg; B Freidlin; S Halabi; G Hudes; M Hussain; R Kaplan; C Myers; W Oh; D P Petrylak; E Reed; B Roth; O Sartor; H Scher; J Simons; V Sinibaldi; E J Small; M R Smith; D L Trump; G Wilding Journal: J Clin Oncol Date: 1999-11 Impact factor: 44.544
Authors: J Li; C Yen; D Liaw; K Podsypanina; S Bose; S I Wang; J Puc; C Miliaresis; L Rodgers; R McCombie; S H Bigner; B C Giovanella; M Ittmann; B Tycko; H Hibshoosh; M H Wigler; R Parsons Journal: Science Date: 1997-03-28 Impact factor: 47.728
Authors: Ramesh K Ramanathan; Donald L Trump; Julie L Eiseman; Chandra P Belani; Sanjiv S Agarwala; Eleanor G Zuhowski; Jing Lan; Douglas M Potter; S Percy Ivy; Sakkaraiappan Ramalingam; Adam M Brufsky; Michael K K Wong; Susan Tutchko; Merrill J Egorin Journal: Clin Cancer Res Date: 2005-05-01 Impact factor: 12.531
Authors: Victoria A Johnson; Erinprit K Singh; Lidia A Nazarova; Leslie D Alexander; Shelli R McAlpine Journal: Curr Top Med Chem Date: 2010 Impact factor: 3.295
Authors: Giovanna Speranza; Larry Anderson; Alice P Chen; Khanh Do; Michelle Eugeni; Marcie Weil; Larry Rubinstein; Eva Majerova; Jerry Collins; Yvonne Horneffer; Lamin Juwara; Jennifer Zlott; Rachel Bishop; Barbara A Conley; Howard Streicher; Joseph Tomaszewski; James H Doroshow; Shivaani Kummar Journal: Invest New Drugs Date: 2017-08-12 Impact factor: 3.850
Authors: Tomoko Smyth; Kim H T Paraiso; Keisha Hearn; Ana M Rodriguez-Lopez; Joanne M Munck; H Eirik Haarberg; Vernon K Sondak; Neil T Thompson; Mohammad Azab; John F Lyons; Keiran S M Smalley; Nicola G Wallis Journal: Mol Cancer Ther Date: 2014-10-27 Impact factor: 6.261
Authors: Buddhini Samarasinghe; Christina T K Wales; Frederick R Taylor; Aaron T Jacobs Journal: Biochem Pharmacol Date: 2013-11-28 Impact factor: 5.858