A phase II trial of tamoxifen and bortezomib in patients with recurrent malignant gliomas.
NF-kB inhibition by bortezomib enhances tamoxifen-induced apoptosis in preclinical glioma models. We conducted a single institution, phase II trial to evaluate efficacy and safety of high dose tamoxifen with bortezomib in adults with recurrent malignant gliomas. The primary endpoint was radiographic response. Concurrent enzyme inducing anticonvulsants and grade ≥2 peripheral neuropathy were exclusion criteria. Patients received tamoxifen (120 mg PO twice daily) and bortezomib (1.3 mg/m2 IV on days 3, 6, 10, 13, 24, 27, 31, and 34) per 6-week cycles. We enrolled 42 patients with anaplastic gliomas (AGs, n = 12) and glioblastomas (GBMs, n = 30), 32 males and 10 females. Median age was 38 years (range 22-65) and 48 years (range 19-68) for AGs and GBMs, respectively. median karnofsky performance status was 90% (range 70-100) for AGs and 80% (range 60-100) for GBMs. Median prior therapies was 3, ranging 1-7. Grade ≥3 toxicities included lymphopenia (4/42), hypophosphatemia (3/42), thromobocytopenia (2/42), and 1/42 with hyponatremia, headache, dyspnea, or DVT. One patient withdrew consent, two were removed for toxicity, and all others discontinued for progression. Among 40 patients evaluable for response, only one achieved stable disease for 3 months; all others progressed rapidly. For AGs and GBMs respectively, median progression-free survival was 5.9 and 5.7 weeks and median overall survival was 25.6 and 14.7 weeks. The study was closed due to poor accrual and therapeutic futility. Combination tamoxifen and bortezomib has no activity in recurrent malignant gliomas. Poor penetration across blood brain barrier of bortezomib likely limited efficacy.
Division of Neuro-Oncology, Neurological Institute of New York, Columbia University College of Physicians and Surgeons, 710 West 168th Street, NI 9-017, New York, NY, 10032, USA. yo2240@cumc.columbia.edu.
Yazmín
Y
Odia
Division of Neuro-Oncology, Neurological Institute of New York, Columbia University College of Physicians and Surgeons, 710 West 168th Street, NI 9-017, New York, NY, 10032, USA.
Teri N
TN
Kreisl
Division of Neuro-oncology, Penn State Milton S. Hershey Medical Center, Hershey, PA, USA.
Dawit
D
Aregawi
University of Maryland School of Medicine, Baltimore, MD, USA.
Ellen K
EK
Innis
Division of Neuro-Oncology, Director of the Brain Tumor Center, New York-Presbyterian Hospital/Weill Cornell Medical Center, New York, NY, USA.
Howard A
HA
Fine
D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D000069286:Bortezomib / Q000627:therapeutic use*; D001932:Brain Neoplasms / Q000188:drug therapy*; D018450:Disease Progression; D018572:Disease-Free Survival; D004305:Dose-Response Relationship, Drug; D005260:Female; D005500:Follow-Up Studies; D005910:Glioma / Q000188:drug therapy*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy; D012189:Retrospective Studies; D013629:Tamoxifen / Q000627:therapeutic use*; D016896:Treatment Outcome; D055815:Young Adult
D000970:Antineoplastic Agents; D013629:Tamoxifen; D000069286:Bortezomib
Bortezomib; Glioblastoma; Glioma; Tamoxifen