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Solid tumors may benefit from new drug combination
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AACR 102nd Annual Meeting
ORLANDO, Fla. — The combination of a class 1 PI3 kinase inhibitor and a MEK 1/2 inhibitor was well tolerated in a cohort of patients with advanced solid tumors, according to findings presented here at the American Association for Cancer Research 102nd Annual Meeting.
Johanna Bendell, MD, director of gastrointestinal cancer research at the Sarah Cannon Research Institute in Nashville, Tenn., said the PI3K and RAS/RAF signaling pathways are both deregulated in multiple tumor types.
“We were interested in looking at blocking these pathways individually and together to decrease the expression and stop tumor growth,” Bendell said, noting that GDC-0941 is a novel, highly specific, class 1 PI3K inhibitor and GDC-0973 is a novel, selective, MEK1/2 inhibitor.
“Both drugs have demonstrated tolerability and pharmacokinetic properties in phase 1 trials,” Bendell said.
The current phase 1b dose-escalation study involved 27 patients with advanced solid tumors. Treatment regimens involved once-daily administration of GDC-0973 and GDC-0941 on a 21-day on, 7-day off schedule.
“We started at dose level 1, which was two dose levels down from the maximum tolerated dose level for GDC-0973 and two levels down from the highest dose we had reached at the time for GDC-0941,” she said. The dose escalation design involved increasing the doses of each single agent independently before increasing the doses of both agents together.
The researchers collected pharmacokinetic samples after the first and last combination doses during the first cycle. Serial FDG-PET scans were taken at baseline, cycle 1, steady state and cycle 2 through peak and trough drug concentrations, according to the study.
“Tumors were assessed every 8 weeks,” Bendell said. “At those points, archival tumor tissue collection also was conducted.”
Grade 3 lipase elevation without clinical symptoms was reported in one patient, as was grade 4 creatine phosphokinase elevation. Other adverse events reported included diarrhea, fatigue, nausea, rash, vomiting, decreased appetite and dysgeusia. Of those events, grade 3 or higher fatigue and rash occurred. The rest were grade 1 to 2.
“The toxicity profile indicates that the combination was fairly well tolerated by patients treated to date,” Bendell said. “The most common adverse events were grade 1-2. Grade 3 or higher events were consistent with those seen in PI3 kinase and MEK inhibitors given singly or with other compounds of the same class.”
Pharmacokinetic activity of the two drugs was not altered by the combination, according to preliminary analysis.
A partial metabolic response — defined as a decrease in mean percent change from baseline standardized uptake value of more than 20% — was observed at one or more time points in six of 15 patients with PET scan data available.
Five patients achieved decreases in Response Evaluation Criteria in Solid Tumors (RECIST) measurable target lesions, and three patients had prolonged stable disease for more than 6 months, according to the results.
“Due to these early signs of antitumor activity, we will continue to look into dose escalation for this combination,” Bendell said.
Dr. Bendell reports no financial disclosures.
For more information:
- Bendell J. #LB-89. Presented at: AACR 102nd Annual Meeting; April 2-6, 2011; Orlando, Fla.
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