BACKGROUND: Patients with glioblastoma (GBM) inevitably develop recurrent or progressive disease after initial multimodal treatment and have a median survival of 6-9 months from time of progression. To date, there is no accepted standard treatment for GBM relapse or progression. Patupilone (EPO906) is a novel natural microtubule-stabilizing cytotoxic agent that crosses the blood-brain barrier and has been found to have preclinical activity in glioma models. METHODS: This is a single-institution, early-phase I/II trial of GBM patients with tumor progression who qualified for second surgery with the goal of evaluating efficacy and safety of the single-agent patupilone (10 mg/m(2), every 3 weeks). Patients received patupilone 1 week prior to second surgery and every 3 weeks thereafter until tumor progression or toxicity. Primary end points were progression-free survival (PFS) and overall survival (OS) at 6 months as well as patupilone concentration in tumor tissue. Secondary end points were toxicity, patupilone concentration in plasma and translational analyses for predictive biomarkers. RESULTS: Nine patients with a mean age of 54.6 ± 8.6 years were recruited between June 2008 and April 2010. Median survival and 1-year OS after second surgery were 11 months (95% CI, 5-17 months) and 45% (95% CI, 14-76), respectively. Median PFS was 1.5 months (95% CI, 1.3-1.7 months) and PFS6 was 22% (95% CI, 0-46), with 2 patients remaining recurrence-free at 9.75 and 22 months. At the time of surgery, the concentration of patupilone in tumor tissue was 30 times higher than in the plasma. Tumor response was not predictable by the tested biomarkers. Treatment was generally well tolerated with no hematological, but cumulative, though reversible sensory neuropathy grade ≤3 was seen in 2 patients (22%) at 8 months and grade 4 diarrhea in the 2nd patient (11%). Non-patupilone-related peri-operative complications occurred in 2 patients resulting in discontinuation of patupilone therapy. There were no neurocognitive changes 3 months after surgery compared to baseline. CONCLUSIONS: In recurrent GBM, patupilone can be given safely pre- and postoperatively. The drug accumulates in the tumor tissue. The treatment results in long-term PFS in some patients. Patupilone represents a valuable novel compound which deserves further evaluation in combination with radiation therapy in patients with GBM.
BACKGROUND:Patients with glioblastoma (GBM) inevitably develop recurrent or progressive disease after initial multimodal treatment and have a median survival of 6-9 months from time of progression. To date, there is no accepted standard treatment for GBM relapse or progression. Patupilone (EPO906) is a novel natural microtubule-stabilizing cytotoxic agent that crosses the blood-brain barrier and has been found to have preclinical activity in glioma models. METHODS: This is a single-institution, early-phase I/II trial of GBM patients with tumor progression who qualified for second surgery with the goal of evaluating efficacy and safety of the single-agent patupilone (10 mg/m(2), every 3 weeks). Patients received patupilone 1 week prior to second surgery and every 3 weeks thereafter until tumor progression or toxicity. Primary end points were progression-free survival (PFS) and overall survival (OS) at 6 months as well as patupilone concentration in tumor tissue. Secondary end points were toxicity, patupilone concentration in plasma and translational analyses for predictive biomarkers. RESULTS: Nine patients with a mean age of 54.6 ± 8.6 years were recruited between June 2008 and April 2010. Median survival and 1-year OS after second surgery were 11 months (95% CI, 5-17 months) and 45% (95% CI, 14-76), respectively. Median PFS was 1.5 months (95% CI, 1.3-1.7 months) and PFS6 was 22% (95% CI, 0-46), with 2 patients remaining recurrence-free at 9.75 and 22 months. At the time of surgery, the concentration of patupilone in tumor tissue was 30 times higher than in the plasma. Tumor response was not predictable by the tested biomarkers. Treatment was generally well tolerated with no hematological, but cumulative, though reversible sensory neuropathy grade ≤3 was seen in 2 patients (22%) at 8 months and grade 4 diarrhea in the 2nd patient (11%). Non-patupilone-related peri-operative complications occurred in 2 patients resulting in discontinuation of patupilone therapy. There were no neurocognitive changes 3 months after surgery compared to baseline. CONCLUSIONS: In recurrent GBM, patupilone can be given safely pre- and postoperatively. The drug accumulates in the tumor tissue. The treatment results in long-term PFS in some patients. Patupilone represents a valuable novel compound which deserves further evaluation in combination with radiation therapy in patients with GBM.
Authors: Philippe Diaz; Eric Horne; Cong Xu; Ernest Hamel; Michael Wagenbach; Ravil R Petrov; Benjamin Uhlenbruck; Brian Haas; Parvinder Hothi; Linda Wordeman; Rick Gussio; Nephi Stella Journal: Eur J Med Chem Date: 2018-09-11 Impact factor: 6.514
Authors: Lakshmi Nayak; Lisa M DeAngelis; H Ian Robins; Ramaswamy Govindan; Shirish Gadgeel; Karen Kelly; James R Rigas; David M Peereboom; Steven S Rosenfeld; Alona Muzikansky; Ming Zheng; Patrick Urban; Lauren E Abrey; Antonio Omuro; Patrick Y Wen Journal: Cancer Date: 2015-08-26 Impact factor: 6.860
Authors: David M Peereboom; Conleth Murphy; Manmeet S Ahluwalia; Alison Conlin; April Eichler; Catherine Van Poznak; Joseph Baar; Paul Elson; Andrew D Seidman Journal: Neuro Oncol Date: 2014-01-26 Impact factor: 12.300
Authors: Y Otani; T Ichikawa; K Kurozumi; S Inoue; J Ishida; T Oka; T Shimizu; Y Tomita; Y Hattori; A Uneda; Y Matsumoto; H Michiue; I Date Journal: Oncogene Date: 2017-10-23 Impact factor: 9.867
Authors: S Y Moorcraft; I Chau; C Peckitt; D Cunningham; S Rao; K L Yim; A Walther; C G C A Jackson; G Stamp; J Webb; G Smith; A Gillbanks; C Swanton Journal: Invest New Drugs Date: 2013-06-26 Impact factor: 3.850