Details

Autor(en) / Beteiligte

• Schiff, David
• Jaeckle, Kurt A.
• Anderson, S. Keith
• Galanis, Evanthia
• Giannini, Caterina
• Buckner, Jan C.
• Stella, Phillip
• Flynn, Patrick J.
• Erickson, Bradley J.
• Schwerkoske, John F.
• Kaluza, Vesna
• Twohy, Erin
• Dancey, Janet
• Wright, John
• Sarkaria, Jann N.

Titel

Phase 1/2 trial of temsirolimus and sorafenib in the treatment of patients with recurrent glioblastoma: North Central Cancer Treatment Group Study/Alliance N0572

Ist Teil von

• Cancer, 2018-04, Vol.124 (7), p.1455-1463

Ort / Verlag

United States: Wiley Subscription Services, Inc

Erscheinungsjahr

2018

Quelle

MEDLINE

Beschreibungen/Notizen

• BACKGROUND Mitogen‐activated protein kinase (MAPK) activation and mammalian target of rapamycin (mTOR)‐dependent signaling are hallmarks of glioblastoma. In the current study, the authors conducted a phase 1/2 study of sorafenib (an inhibitor of Raf kinase and vascular endothelial growth factor receptor 2 [VEGFR‐2]) and the mTOR inhibitor temsirolimus in patients with recurrent glioblastoma. METHODS Patients with recurrent glioblastoma who developed disease progression after surgery or radiotherapy plus temozolomide and with ≤2 prior chemotherapy regimens were eligible. The phase 1 endpoint was the maximum tolerated dose (MTD), using a cohorts‐of‐3 design. The 2‐stage phase 2 study included separate arms for VEGF inhibitor (VEGFi)–naive patients and patients who progressed after prior VEGFi. RESULTS The MTD was sorafenib at a dose of 200 mg twice daily and temsirolimus at a dose of 20 mg weekly. In the first 41 evaluable patients who were treated at the phase 2 dose, there were 7 who were free of disease progression at 6 months (progression‐free survival at 6 months [PFS6]) in the VEGFi‐naive group (17.1%); this finding met the prestudy threshold of success. In the prior VEGFi group, only 4 of the first 41 evaluable patients treated at the phase 2 dose achieved PFS6 (9.8%), and this did not meet the prestudy threshold for success. The median PFS for the 2 groups was 2.6 months and 1.9 months, respectively. The median overall survival for the 2 groups was 6.3 months and 3.9 months, respectively. At least 1 adverse event of grade ≥3 was observed in 75.5% of the VEGFi‐naive patients and in 73.9% of the prior VEGFi patients. CONCLUSIONS The limited activity of sorafenib and temsirolimus at the dose and schedule used in the current study was observed with considerable toxicity of grade ≥3. Significant dose reductions that were required in this treatment combination compared with tolerated single‐agent doses may have contributed to the lack of efficacy. Cancer 2018;124:1455‐63. © 2018 American Cancer Society. This phase 1/2 clinical trial tests the simultaneous blockade of the critical phosphatidylinositide 3′‐kinase (PI3K)/akt/mammalian target of rapamycin (mTOR) and mitogen‐activated protein kinase pathways with sorafenib and temsirolimus in cohorts of patients with recurrent glioblastoma who are both naive to and resistant to bevacizumab. The combination appears to be associated with synergistic toxicity and fails to demonstrate promising activity, highlighting the challenges in simultaneous pathway blockade with combinations of targeted agents.