Enrollment of the first patient in a Phase I/II trial of PX-866 in combination with the chimeric monoclonal antibody cetuximab (Erbitux?, ImClone LLC/Bristol-Myers Squibb Company) started today. PX-866 is a small molecule compound designed to inhibit the activity of phosphatidylinositol-3-kinase (PI-3K), a component of an important cell survival signaling pathway is activated in many types of human cancer. Aberrant activation and regulation of PI-3K is implicated in a large proportion of human cancers, where it leads to increased proliferation and inhibition of apoptosis.

Oncothyreon , a seattle based biotechnology company, develops PX-866. Results from a single-agent Phase I open-label, dose escalation study of PX-866 in patients with advanced metastatic cancer presented at the American Society of Clinical Oncology (ASCO) earlier this year demonstrated that PX-866 was well tolerated using both an intermittent and continuous (daily) dosing schedule.

Additional data from the Phase I trial presented at the 22nd EORTC/NCI/AACR Symposium on “Molecular Targets and Cancer Therapeutics” in Berlin, Germany, on November 18, 2010 demonstrated positive results. The results were presented by Antonio Jimeno, M.D., Ph.D., of the University of Colorado Cancer Center, Aurora, Colorado.

The highlighted were from the continuous dosing arm of the single-agent, Phase I open-label, dose escalation study of PX-866 in patients with advanced solid tumors who had failed or were intolerant of standard therapy. In the continuous dosing arm, patients received oral doses of 8 mg or 10 mg of PX-866 once daily. Eight of 19 evaluable patients (42%) achieved stable disease as their best response. Three patients remained on study, including one patient with prostate cancer who has been on therapy for more than 10 months.

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“It is promising to see evidence of long-term disease control and tolerance of a continuous dosing treatment regimen in this early stage trial involving advanced cancer patients who had failed multiple prior therapies,” noted Dr. Jimeno. “We look forward to further clinical evaluation of this novel, irreversible PI-3K inhibitor in the recently initiated Phase I/II trial of PX-866 and docetaxel as well as in additional clinical trials.”

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PX-866 was well tolerated in this trial, with the majority of adverse events mild to moderate in severity. The most common adverse events included diarrhea, nausea, vomiting, fatigue and reversible elevation of liver enzymes. There were no significant adverse hematologic events and no increase in adverse events noted in patients receiving more than two cycles of treatment. Pharmacokinetic analysis confirmed that PX-866 is rapidly metabolized to a more potent derivative.

PX-866 in combination with cetuximab
The primary objective of the Phase I dose-escalation portion of the trial is to determine the maximum tolerated or recommended daily dose of PX-866 to be given in combination with the standard dose of cetuximab administered weekly to patients with either progressive metastatic colorectal carcinoma (CRC) or progressive, recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN).

The Phase II portion is designed as a screening trial and will be an open-label, randomized evaluation of the antitumor activity and safety of PX-866 administered at the maximum tolerated or recommended dose in combination with cetuximab, versus cetuximab alone, in two groups of patients not previously treated with cetuximab. Group 1 will enroll patients with metastatic CRC who have a history of progression or recurrence following prior treatment with irinotecan and oxaliplatin containing regimens or who are intolerant of irinotecan. Patients with CRC and Kras mutations are excluded from the trial. Group 2 will enroll patients with progressive, recurrent or metastatic SCCHN. The two groups will be randomized and evaluated independently.

The primary endpoint of the Phase I portion of the trial is safety, and will enroll up to a total of 18 patients at three different dose levels of PX-866 in combination with cetuximab. Up to 144 patients may be enrolled in the Phase II portion of the study, including 72 (36 per arm) in each group. The primary endpoint of the Phase II portion is objective response rate based on RECIST criteria. Secondary endpoints include progression free and overall survival, duration of response and disease control rate.

“We are delighted to have initiated this second of four planned Phase I/II and Phase II trials of PX-866,” said Robert L. Kirkman, M.D., President and CEO of Oncothyreon. “As previously indicated, we are committed to a broad PhaseII development program for PX-866, in combination with other agents, as a single agent, and in multiple tumor types, to maximize our opportunity to demonstrate the utility of this novel, irreversible PI-3K inhibitor.”

Development program
Oncothyreon has initiated a Phase I/II trial of PX-866 in combination with docetaxel and plans to begin three additional Phase I/II and Phase II trials of PX-866 in multiple tumor types, either in combination with another targeted agent or as a single agent.

The ongoing Phase I/II combination trial includes a dose escalation of PX-866 in combination with docetaxel administered at the standard dose of 75 mg/m2 in patients with advanced cancer for which docetaxel is considered standard of care. Once the recommended dose of PX-866 in combination with docetaxel is established, the PhaseII portion will consist of two independent arms examining PX-866 in combination with docetaxel in second or third line non-small cell lung cancer and in second or third line squamous cell carcinoma of the head and neck.

For more information:
– Jimeno A, Herbst RS, Falchook GS, Messersmith WA, Hecker S, Peterson S, et al. Final results from a phase I, dose-escalation study of PX-866, an irreversible, pan-isoform inhibitor of PI3 kinase. J Clin Oncol 28:15s, 2010 (suppl; abstr 3089)
– Koul D, Shen R, Kim YW, Kondo Y, Lu Y, et al. Cellular and in vivo activity of a novel PI3K inhibitor, PX-866, against human glioblastoma. Neuro Oncol. 2010 Jun;12(6):559-69. Epub 2010 Feb 15.
– Gwak HS, Shingu T, Chumbalkar V, Hwang YH, Dejournett R, Combined action of the dinuclear platinum compound BBR3610 with the PI3-K inhibitor PX-866 in glioblastoma. Int J Cancer. 2010 Apr 15. [Epub ahead of print]

Clinical trials
PX-866 and Cetuximab
Phase I Trial of Oral PX-866
A Study of PX-866 in Patients With Glioblastoma Multiforme at Time of First Relapse or Progression
Study of PX-866 and Docetaxel in Solid Tumors

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