K N Chi1, E Y Yu2, C Jacobs3, J Bazov4, C Kollmannsberger5, C S Higano2, S D Mukherjee6, M E Gleave4, P S Stewart3, S J Hotte6. 1. Department of Medical Oncology, British Columbia Cancer Agency, Vancouver Department of Urologic Sciences, Vancouver Prostate Center, University of British Columbia, Vancouver, Canada kchi@bccancer.bc.ca. 2. University of Washington, Fred Hutchinson Cancer Research Center, Seattle. 3. Clinical Development, OncoGenex Pharmaceuticals, Inc., Bothell, USA. 4. Department of Urologic Sciences, Vancouver Prostate Center, University of British Columbia, Vancouver, Canada. 5. Department of Medical Oncology, British Columbia Cancer Agency, Vancouver. 6. Department of Medical Oncology, Juravinski Cancer Centre, Hamilton, Canada.
Abstract
BACKGROUND: Heat shock protein 27 (Hsp27) is a chaperone protein that regulates cell survival via androgen receptor and other signaling pathways, thereby mediating cancer progression. Apatorsen (OGX-427) is a 2'-methoxyethyl-modified antisense oligonucleotide that inhibits Hsp27 expression. This study evaluated the safety profile and recommended phase II dosing of apatorsen in patients with advanced cancer. PATIENTS AND METHODS: Patients with castration-resistant prostate (CRPC), breast, ovary, lung, or bladder cancer were enrolled to this phase I dose-escalation study. Apatorsen was administered i.v. weekly in 21-day cycles following 3 loading doses and over 5 dose levels (200-1000 mg). Apatorsen plasma concentrations, circulating tumor cells (CTCs) and CTC Hsp27 expression, and serum Hsp27 levels were evaluated. RESULTS: Forty-two patients were accrued, of which 52% had CRPC. Patients were heavily pretreated, with 57% having had ≥3 prior chemotherapy regimens. During the loading dose/cycle 1 and overall study period, 93% and 100% of patients (N = 42) experienced treatment-related adverse events, respectively; most were grade 1-2 and included chills, pruritus, flushing, prolonged aPTT, lymphopenia, and anemia. One patient experienced a dose-limiting toxicity at the 600 mg dose level (intracranial hemorrhage in a previously undiagnosed brain metastasis). A maximum tolerated dose was not defined. Apatorsen Cmax increased proportionally with dose. Decreases in tumor markers and declines in CTCs were observed, with a prostate-specific antigen decline >%50% occurring in 10% of patients with CRPC; 29/39 assessable patients (74%) had reductions from ≥5 CTC/7.5 ml at baseline to <5 CTC/7.5 ml post-treatment. Twelve patients had stable measurable disease as best response. CONCLUSIONS: Apatorsen was tolerated at the highest dose evaluated (1000 mg). Single-agent activity was suggested by changes in tumor markers, CTC, and stable measurable disease. Phase II studies evaluating apatorsen are underway. CLINICALTRIALSGOV ID: NCT00487786.
BACKGROUND:Heat shock protein 27 (Hsp27) is a chaperone protein that regulates cell survival via androgen receptor and other signaling pathways, thereby mediating cancer progression. Apatorsen (OGX-427) is a 2'-methoxyethyl-modified antisense oligonucleotide that inhibits Hsp27 expression. This study evaluated the safety profile and recommended phase II dosing of apatorsen in patients with advanced cancer. PATIENTS AND METHODS: Patients with castration-resistant prostate (CRPC), breast, ovary, lung, or bladder cancer were enrolled to this phase I dose-escalation study. Apatorsen was administered i.v. weekly in 21-day cycles following 3 loading doses and over 5 dose levels (200-1000 mg). Apatorsen plasma concentrations, circulating tumor cells (CTCs) and CTC Hsp27 expression, and serum Hsp27 levels were evaluated. RESULTS: Forty-two patients were accrued, of which 52% had CRPC. Patients were heavily pretreated, with 57% having had ≥3 prior chemotherapy regimens. During the loading dose/cycle 1 and overall study period, 93% and 100% of patients (N = 42) experienced treatment-related adverse events, respectively; most were grade 1-2 and included chills, pruritus, flushing, prolonged aPTT, lymphopenia, and anemia. One patient experienced a dose-limiting toxicity at the 600 mg dose level (intracranial hemorrhage in a previously undiagnosed brain metastasis). A maximum tolerated dose was not defined. Apatorsen Cmax increased proportionally with dose. Decreases in tumor markers and declines in CTCs were observed, with a prostate-specific antigen decline >%50% occurring in 10% of patients with CRPC; 29/39 assessable patients (74%) had reductions from ≥5 CTC/7.5 ml at baseline to <5 CTC/7.5 ml post-treatment. Twelve patients had stable measurable disease as best response. CONCLUSIONS:Apatorsen was tolerated at the highest dose evaluated (1000 mg). Single-agent activity was suggested by changes in tumor markers, CTC, and stable measurable disease. Phase II studies evaluating apatorsen are underway. CLINICALTRIALSGOV ID: NCT00487786.
Authors: David R Spigel; Dianna L Shipley; David M Waterhouse; Suzanne F Jones; Patrick J Ward; Kent C Shih; Brian Hemphill; Michael McCleod; Robert C Whorf; Ray D Page; Joseph Stilwill; Tarek Mekhail; Cindy Jacobs; Howard A Burris; John D Hainsworth Journal: Oncologist Date: 2019-08-16
Authors: Margaret M Centenera; Luke A Selth; Esmaeil Ebrahimie; Lisa M Butler; Wayne D Tilley Journal: Cold Spring Harb Perspect Med Date: 2018-12-03 Impact factor: 6.915
Authors: Jessica Kho; P Chi Pham; Suhyeon Kwon; Alana Y Huang; Joel P Rivers; Huixin Wang; Heath Ecroyd; W Alexander Donald; Shelli R McAlpine Journal: ACS Med Chem Lett Date: 2021-05-03 Impact factor: 4.345
Authors: Andrew H Ko; Patrick B Murphy; James D Peyton; Dianna L Shipley; Ahmed Al-Hazzouri; Francisco A Rodriguez; Mark S Womack; Henry Q Xiong; David M Waterhouse; Margaret A Tempero; Shuangli Guo; Cassie M Lane; Chris Earwood; Laura M DeBusk; Johanna C Bendell Journal: Oncologist Date: 2017-09-21