Phase II study of PX-866 in recurrent glioblastoma.

Abstract

BACKGROUND:

Glioblastoma (GBM) is the most aggressive malignancy of the central nervous system in adults. Increased activity of the phosphatidylinositol-3-OH kinase (PI3K) signal transduction pathway is common. We performed a phase II study using PX-866, an oral PI3K inhibitor, in participants with recurrent GBM.

METHODS:

Patients with histologically confirmed GBM at first recurrence were given oral PX-866 at a dose of 8 mg daily. An MRI and clinical exam were done every 8 weeks. Tissue was analyzed for potential predictive markers.

RESULTS:

Thirty-three participants (12 female) were enrolled. Median age was 56 years (range 35-78y). Eastern Cooperative Oncology Group performance status was 0-1 in 29 participants and 2 in the remainder. Median number of cycles was 1 (range 1-8). All participants have discontinued therapy: 27 for disease progression and 6 for toxicity (5 liver enzymes and 1 allergic reaction). Four participants had treatment-related serious adverse events (1 liver enzyme, 1 diarrhea, 2 venous thromboembolism). Other adverse effects included fatigue, diarrhea, nausea, vomiting, and lymphopenia. Twenty-four participants had a response of progression (73%), 1 had partial response (3%, and 8 (24%) had stable disease (median, 6.3 months; range, 3.1-16.8 months). Median 6-month progression-free survival was 17%. None of the associations between stable disease and PTEN, PIK3CA, PIK3R1, or EGFRvIII status were statistically significant.

CONCLUSIONS:

PX-866 was relatively well tolerated. Overall response rate was low, and the study did not meet its primary endpoint; however, 21% of participants obtained durable stable disease. This study also failed to identify a statistically significant association between clinical outcome and relevant biomarkers in patients with available tissue.

• Authors: Marshall W Pitz, Elizabeth A Eisenhauer, Mary V MacNeil, Brian Thiessen, Jacob C Easaw, David R Macdonald, David D Eisenstat, Ankineedu S Kakumanu, Muhammad Salim, Haji Chalchal, Jeremy Squire, Ming Sound Tsao, Suzanne Kamel-Reid, Shantanu Banerji, Dongsheng Tu, Jean Powers, Diana F Hausman, Warren P Mason
• Journal: Neuro-oncology (Neuro Oncol) Vol. 17 Issue 9 Pg. 1270-4 (Sep 2015) ISSN: 1523-5866 [Electronic] England
• PMID: 25605819 (Publication Type: Clinical Trial, Phase II, Journal Article, Multicenter Study, Research Support, Non-U.S. Gov't)
• Copyright: © The Author(s) 2015. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: [email protected].

Chemical References

• Antineoplastic Agents
• Gonanes
• PX-866
• Phosphoinositide-3 Kinase Inhibitors

Topics

• Administration, Oral
• Adult
• Aged
• Antineoplastic Agents (therapeutic use)
• Brain Neoplasms (drug therapy, pathology, radiotherapy)
• Female
• Glioblastoma (drug therapy, pathology, radiotherapy)
• Gonanes (administration & dosage, therapeutic use)
• Humans
• Male
• Middle Aged
• Phosphoinositide-3 Kinase Inhibitors
• Treatment Outcome