Clinical Data
Phase 1/2 Combination Trials*
PX-866 is currently being evaluated in Phase 1/2 trials evaluating PX-866 in combination with docetaxel (Taxotere®) and PX-866 in combination with cetuximab (Erbitux®). Preliminary data from the Phase 1 dose-escalation portions of these trials was presented at the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics in November 2011 (View press release | View posters).
PX-866 in Combination with Docetaxel
As presented at the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics, the Phase 1 portion of the Phase 1/2 trial of PX-866 in combination with the chemotherapeutic agent docetaxel enrolled 43 patients with advanced cancer for whom docetaxel was considered standard of care. Patients were treated at three different dose levels of PX-866 administered daily in combination with the standard dose of docetaxel (75 mg/m2) administered once every three weeks. No dose-limiting toxicities were identified, and the recommended Phase 2 daily dose of PX-866 to be given in combination with docetaxel was determined to be the same as the single agent daily maximum tolerated dose of 8 mg. The combination of PX-866 and docetaxel was generally well-tolerated, with the most adverse events being Grade 1/2 in severity. The safety profile for combination treatment was consistent with that for either drug administered alone. Combination treatment had no impact on the pharmacokinetic profile of either drug.
In 28 patients evaluable for response, best response was stable disease in 21 patients, and progressive disease in seven patients, for a disease control rate of 75 percent. Eight patients have received seven or more cycles of treatment, and 20 patients were reported to be still active on study. The most common reason for discontinuing therapy has been progressive disease. A trend to increased time on study was seen in patients with a mutation in their PIK3CA gene compared to patients without such a mutation.
PX-866 in Combination with Cetuximab
As presented at the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics, The Phase 1 portion of the Phase 1/2 trial of PX-866 in combination with cetuximab enrolled 11 patients with either incurable metastatic colorectal carcinoma or incurable progressive, recurrent or metastatic squamous cell carcinoma of the head and neck treated at two different daily dose levels of PX-866 plus the standard weekly dose of cetuximab. No dose-limiting toxicities were identified and the recommended daily dose of PX-866 in combination with cetuximab was determined to be the same as the single agent daily maximum tolerated dose of 8 mg. The combination of PX-866 and cetuximab was generally well-tolerated, with the majority of adverse events Grade 1/2 in severity. PX-866 had no impact on the pharmacokinetic profile of cetuximab as compared to historical data.
Eight patients were evaluable for response per protocol, and four patients had a confirmed partial response, three patients had stable disease and one patient had progressive disease, for a disease control rate of 88 percent. Five of the eight evaluable patients had received prior treatment with an EGFR inhibitor. Among these patients, the best response was one partial response, three stable disease and one progressive disease. The median number of cycles (21 days each) received by all patients was six (range 1-13).
*For additional information regarding clinical data on PX-866, please visit our Publications & Presentations page.
Phase 1 single agent dose escalation study*
PX-866 has been evaluated as a single agent in a Phase 1 dose-escalation study in patients with advanced solid tumors. Two dosing schedules were studied, an intermittent schedule, and a continuous schedule. Patients could receive repeated cycles of treatment until development of progressive disease or unacceptable toxicity. Study endpoints included safety, pharmacokinetics, pharmacodynamics, and tumor response. Preliminary results from this study have been presented at several scientific conferences, including the 22nd EORTC/NCI/AACR Symposium on "Molecular Targets and Cancer Therapeutics," in November 2010. (View press release | View poster), the American Society of Clinical Oncology Annual Meeting in June 2010 (View press release | View poster).
The patient population treated in this study was typical of an early Phase 1 dose-escalation study, with a median age of 61. Patients were heterogeneous with regard to tumor type and had been heavily pretreated, having received a median of 4 prior systemic therapeutic regimens for metastatic disease.
The maximum tolerated dose of PX-866 was 12 mg in the intermittent schedule and 8 mg in the continuous schedule. Pharmacokinetic analysis confirmed that PX-866 is rapidly metabolized to a more potent derivative, consistent with preclinical data. Pharmacodynamic analysis demonstrated inhibition of the PI-3K pathway as assessed by changes in phosphorylation status of downstream kinases. Treatment with PX-866 was associated with prolonged disease stabilization, particularly when given on the continuous dosing schedule, including in patients with disease progression at the time of study entry. Overall, PX-866 was well-tolerated using either the intermittent or continuous dosing schedule. There was no significant increase in adverse events noted in patients receiving more than two cycles of treatment in either arm of the trial. The most common adverse events were mild to moderate in severity, and included diarrhea, nausea, vomiting, fatigue and reversible elevation of liver enzymes.
*For additional information regarding clinical data on PX-866, please visit our Publications & Presentations page.
PX-866 Preclinical Results*
Preclinical data on PX-866 were presented at the American Association of Cancer Research 102nd Annual Conference in April 2011. (View press release | View poster) Data presented at the meeting concerned the efficacy of PX-866 alone or in combination with either docetaxel or cetuximab in direct patient human tumor xenograft models (DPTM) of squamous cell carcinoma of the head and neck (SCCHN) developed by Dr. Antonio Jimeno's laboratory at University of Colorado School of Medicine. These models maintain the histology of the tumor and are particularly suited to preclinical evaluation of novel cancer therapeutics. PX-866 was equal or superior to docetaxel in slowing tumor growth in two of four DPTM and equal or superior to cetuximab in each of four DPTM. The combination of PX-866 plus docetaxel was superior to single agent therapy in three of four DPTM, while the combination with cetuximab was superior to single agent therapy in two of four DPTM.
Preclinical data on PX-866 were also presented at the American Association of Cancer Research (AACR) Special Conference "Targeting PI3K/mTOR Signaling" in February 2011. (View press release | View poster ) Results presented at the meeting demonstrate that the primary metabolite of PX-866, 17-OH PX-866, has improved potency compared to the already potent parent compound against the alpha and beta isoforms of PI3K, as well as improved potency against forms of PI3K alpha that contain activating mutations. In addition, the effect of PX-866 and its metabolite as an irreversible PI3K inhibitor was demonstrated using biochemical and cellular assays.
*For additional information regarding clinical data on PX-866, please visit our Publications & Presentations page.
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