Patupilone (epothilone B) for recurrent glioblastoma: clinical outcome and translational analysis of a single-institution phase I/II trial.
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.
Department of Radiation Oncology, University Hospital Zürich, Zürich, Switzerland.
Christoph
C
Oehler
Karl
K
Frei
Elisabeth J
EJ
Rushing
Paul M J
PM
McSheehy
Dirk
D
Weber
Peter R
PR
Allegrini
Dorothea
D
Weniger
Urs M
UM
Lütolf
Alexander
A
Knuth
Yasuhiro
Y
Yonekawa
Krisztina
K
Barath
Angela
A
Broggini-Tenzer
Martin
M
Pruschy
Silvia
S
Hofer
D000368:Aged; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000097:blood / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D001932:Brain Neoplasms / Q000188:drug therapy / Q000401:mortality / Q000473:pathology / Q000601:surgery; D016543:Central Nervous System Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology / Q000601:surgery; D003131:Combined Modality Therapy; D034261:Epothilones / Q000009:adverse effects / Q000097:blood / Q000627:therapeutic use*; D005909:Glioblastoma / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology / Q000601:surgery; D006801:Humans; D019394:Ki-67 Antigen / Q000032:analysis; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy / Q000401:mortality; D016896:Treatment Outcome; D014404:Tubulin / Q000032:analysis
D000970:Antineoplastic Agents; D034261:Epothilones; D019394:Ki-67 Antigen; D014404:Tubulin; C093788:epothilone B