PURPOSE: Six-transmembrane epithelial antigen of the prostate 1 (STEAP1) is highly expressed in prostate cancers. DSTP3086S is a humanized immunoglobulin G1 anti-STEAP1 monoclonal antibody linked to the potent antimitotic agent monomethyl auristatin E. This study evaluated the safety and activity of DSTP3086S in patients with metastatic castration-resistant prostate cancer. METHODS: Patients were enrolled in a 3 + 3 dose escalation study to evaluate DSTP3086S (0.3 to 2.8 mg/kg intravenously) given once every 3 weeks followed by cohort expansion at the recommended phase II dose or weekly (0.8 to 1.0 mg/kg). RESULTS: Seventy-seven patients were given DSTP3086S once every 3 weeks, and seven were treated weekly. Two patients in the once-every-3-weeks dose escalation had dose-limiting grade 3 transaminitis. Grade 3 hyperglycemia and grade 4 hypophosphatemia were dose-limiting toxicities in one patient treated at 1.0 mg/kg weekly. Initial cohort expansion evaluated dosing at 2.8 mg/kg once every 3 weeks (n = 10), but frequent dose reductions led to testing of 2.4 mg/kg (n = 39) in the expansion phase. Common related adverse events (> 20%) across doses (once every 3 weeks) were fatigue, peripheral neuropathy, nausea, constipation, anorexia, diarrhea, and vomiting. DSTP3086S pharmacokinetics were linear. Among 62 patients who received > 2 mg/kg DSTP3086S once every 3 weeks, 11 (18%) demonstrated a ≥ 50% decline in prostate-specific antigen; two (6%) of 36 with measurable disease at baseline achieved a radiographic partial response; and of 27 patients with informative unfavorable baseline circulating tumor cells ≥ 5/7.5 mL of blood, 16 (59%) showed conversions to favorable circulating tumor cells < 5. No prostate-specific antigen or RECIST responses were seen with weekly dosing. CONCLUSION: DSTP3086S has acceptable safety at the recommended phase II dose level of 2.4 mg/kg once every 3 weeks. Antitumor activity at doses between 2.25 and 2.8 mg/kg once every 3 weeks supports the potential benefit of treating STEAP1-expressing metastatic castration-resistant prostate cancer with an STEAP1-targeting antibody-drug conjugate.
PURPOSE:Six-transmembrane epithelial antigen of the prostate 1 (STEAP1) is highly expressed in prostate cancers. DSTP3086S is a humanized immunoglobulin G1 anti-STEAP1 monoclonal antibody linked to the potent antimitotic agent monomethyl auristatin E. This study evaluated the safety and activity of DSTP3086S in patients with metastatic castration-resistant prostate cancer. METHODS:Patients were enrolled in a 3 + 3 dose escalation study to evaluate DSTP3086S (0.3 to 2.8 mg/kg intravenously) given once every 3 weeks followed by cohort expansion at the recommended phase II dose or weekly (0.8 to 1.0 mg/kg). RESULTS: Seventy-seven patients were given DSTP3086S once every 3 weeks, and seven were treated weekly. Two patients in the once-every-3-weeks dose escalation had dose-limiting grade 3 transaminitis. Grade 3 hyperglycemia and grade 4 hypophosphatemia were dose-limiting toxicities in one patient treated at 1.0 mg/kg weekly. Initial cohort expansion evaluated dosing at 2.8 mg/kg once every 3 weeks (n = 10), but frequent dose reductions led to testing of 2.4 mg/kg (n = 39) in the expansion phase. Common related adverse events (> 20%) across doses (once every 3 weeks) were fatigue, peripheral neuropathy, nausea, constipation, anorexia, diarrhea, and vomiting. DSTP3086S pharmacokinetics were linear. Among 62 patients who received > 2 mg/kg DSTP3086S once every 3 weeks, 11 (18%) demonstrated a ≥ 50% decline in prostate-specific antigen; two (6%) of 36 with measurable disease at baseline achieved a radiographic partial response; and of 27 patients with informative unfavorable baseline circulating tumor cells ≥ 5/7.5 mL of blood, 16 (59%) showed conversions to favorable circulating tumor cells < 5. No prostate-specific antigen or RECIST responses were seen with weekly dosing. CONCLUSION:DSTP3086S has acceptable safety at the recommended phase II dose level of 2.4 mg/kg once every 3 weeks. Antitumor activity at doses between 2.25 and 2.8 mg/kg once every 3 weeks supports the potential benefit of treating STEAP1-expressing metastatic castration-resistant prostate cancer with an STEAP1-targeting antibody-drug conjugate.
Authors: Glenn Heller; Robert McCormack; Thian Kheoh; Arturo Molina; Matthew R Smith; Robert Dreicer; Fred Saad; Ronald de Wit; Dana T Aftab; Mohammad Hirmand; Ana Limon; Karim Fizazi; Martin Fleisher; Johann S de Bono; Howard I Scher Journal: J Clin Oncol Date: 2017-12-22 Impact factor: 44.544
Authors: R S Hubert; I Vivanco; E Chen; S Rastegar; K Leong; S C Mitchell; R Madraswala; Y Zhou; J Kuo; A B Raitano; A Jakobovits; D C Saffran; D E Afar Journal: Proc Natl Acad Sci U S A Date: 1999-12-07 Impact factor: 11.205
Authors: Ajay K Gopal; Radhakrishnan Ramchandren; Owen A O'Connor; Robert B Berryman; Ranjana H Advani; Robert Chen; Scott E Smith; Maureen Cooper; Achim Rothe; Jeffrey V Matous; Laurie E Grove; Jasmine Zain Journal: Blood Date: 2012-04-17 Impact factor: 22.113
Authors: Charles J Ryan; Matthew R Smith; Karim Fizazi; Fred Saad; Peter F A Mulders; Cora N Sternberg; Kurt Miller; Christopher J Logothetis; Neal D Shore; Eric J Small; Joan Carles; Thomas W Flaig; Mary-Ellen Taplin; Celestia S Higano; Paul de Souza; Johann S de Bono; Thomas W Griffin; Peter De Porre; Margaret K Yu; Youn C Park; Jinhui Li; Thian Kheoh; Vahid Naini; Arturo Molina; Dana E Rathkopf Journal: Lancet Oncol Date: 2015-01-16 Impact factor: 41.316
Authors: Howard I Scher; Xiaoyu Jia; Johann S de Bono; Martin Fleisher; Kenneth J Pienta; Derek Raghavan; Glenn Heller Journal: Lancet Oncol Date: 2009-02-11 Impact factor: 41.316
Authors: C Parker; S Nilsson; D Heinrich; S I Helle; J M O'Sullivan; S D Fosså; A Chodacki; P Wiechno; J Logue; M Seke; A Widmark; D C Johannessen; P Hoskin; D Bottomley; N D James; A Solberg; I Syndikus; J Kliment; S Wedel; S Boehmer; M Dall'Oglio; L Franzén; R Coleman; N J Vogelzang; C G O'Bryan-Tear; K Staudacher; J Garcia-Vargas; M Shan; Ø S Bruland; O Sartor Journal: N Engl J Med Date: 2013-07-18 Impact factor: 91.245
Authors: Howard I Scher; Susan Halabi; Ian Tannock; Michael Morris; Cora N Sternberg; Michael A Carducci; Mario A Eisenberger; Celestia Higano; Glenn J Bubley; Robert Dreicer; Daniel Petrylak; Philip Kantoff; Ethan Basch; William Kevin Kelly; William D Figg; Eric J Small; Tomasz M Beer; George Wilding; Alison Martin; Maha Hussain Journal: J Clin Oncol Date: 2008-03-01 Impact factor: 44.544
Authors: Colin D Weekes; Laetitia E Lamberts; Mitesh J Borad; Johannes Voortman; Robert R McWilliams; Jennifer R Diamond; Elisabeth G E de Vries; Henk M Verheul; Christopher H Lieu; George P Kim; Yulei Wang; Suzie J Scales; Divya Samineni; Flavia Brunstein; YounJeong Choi; Daniel J Maslyar; Gerardo Colon-Otero Journal: Mol Cancer Ther Date: 2016-01-28 Impact factor: 6.261
Authors: Joseph A O'Donoghue; Daniel C Danila; Neeta Pandit-Taskar; Volkan Beylergil; Sarah M Cheal; Stephen E Fleming; Josef J Fox; Shutian Ruan; Pat B Zanzonico; Govind Ragupathi; Serge K Lyashchenko; Simon P Williams; Howard I Scher; Bernard M Fine; John L Humm; Steven M Larson; Michael J Morris; Jorge A Carrasquillo Journal: Mol Pharm Date: 2019-05-31 Impact factor: 4.939
Authors: Tanya B Dorff; Vivek Narayan; Stephen J Forman; Peter D Zang; Joseph A Fraietta; Carl H June; Naomi B Haas; Saul J Priceman Journal: Clin Cancer Res Date: 2022-02-15 Impact factor: 13.801
Authors: Mahasha P J Perera; Patrick B Thomas; Gail P Risbridger; Renea Taylor; Arun Azad; Michael S Hofman; Elizabeth D Williams; Ian Vela Journal: Cancers (Basel) Date: 2022-01-20 Impact factor: 6.639