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Phase I study of the combination of temsirolimus and pazopanib in advanced solid tumors
Thomas J Semrad1, Courtney Eddings, Mrinal P Dutia
1Department of Internal Medicine, Division of Hematology/Oncology, University of California, Davis, Sacramento, California 95817, USA. thomas.semrad@ucdmc.ucdavis.edu
Abstract:
Inhibition of either vascular endothelial growth factor receptor or mammalian target of rapamycin (mTOR) signaling improves outcomes in patients with several advanced solid tumors. We conducted a phase I trial of temsirolimus with pazopanib to investigate the feasibility of simultaneous 'vertical inhibition' of vascular endothelial growth factor receptor and mTOR pathways. Patients with advanced solid tumors, no previous pazopanib or mTOR inhibitor, good performance status, and acceptable end-organ function were eligible. In a typical 3+3 escalation design starting at temsirolimus 15 mg by an intravenous infusion weekly and pazopanib 400 mg orally daily, we defined dose-limiting toxicity (DLT) as attributable grade 3 or higher nonhematologic adverse events in the first 28-day cycle and the maximum tolerable dose as the maximum dose level at which less than two patients experienced DLT. At the initial dose level, two patients had four DLTs (anorexia, fatigue, hyponatremia, and hypophosphatemia). After reduction to temsirolimus 10 mg intravenous infusion weekly and pazopanib 200 mg orally daily, one of three patients had DLT (fatigue) and the first patient in the subsequent expansion had dose-limiting hypophosphatemia. Attributable grade 3 or higher adverse events in more than one patient included leukopenia, neutropenia, fatigue, and hypophosphatemia. Tumor reduction not fulfilling the RECIST criteria for partial response was the best response in four of seven evaluable patients. The combination of temsirolimus and pazopanib was not feasible at clinically meaningful doses in this population because of constitutional and electrolyte disturbances.
Insights
The combination of temsirolimus and pazopanib showed significant toxicities, including constitutional and electrolyte disturbances, making it not feasible for advanced solid tumors. Further research into vertical inhibition strategies is warranted.
Area of Science:
- Oncology
- Pharmacology
Background:
- Vascular endothelial growth factor receptor (VEGFR) and mammalian target of rapamycin (mTOR) signaling pathways are crucial in advanced solid tumors.
- Inhibiting these pathways individually has shown therapeutic benefits.
Purpose of the Study:
- To investigate the feasibility of simultaneous "vertical inhibition" of VEGFR and mTOR pathways using temsirolimus and pazopanib.
- To determine the maximum tolerable dose (MTD) and dose-limiting toxicities (DLTs) of this combination therapy.
Main Methods:
- Phase I clinical trial with a 3+3 dose escalation design.
- Patients with advanced solid tumors received escalating doses of intravenous temsirolimus and oral pazopanib.
- Dose-limiting toxicity was defined as grade 3 or higher nonhematologic adverse events within the first 28-day cycle.
Main Results:
- The initial dose of temsirolimus 15 mg weekly and pazopanib 400 mg daily resulted in dose-limiting toxicities (anorexia, fatigue, hyponatremia, hypophosphatemia) in two patients.
- Reduced doses (temsirolimus 10 mg weekly, pazopanib 200 mg daily) also led to dose-limiting toxicities (fatigue, hypophosphatemia).
- Common grade 3 or higher adverse events included leukopenia, neutropenia, fatigue, and hypophosphatemia. Best response was tumor reduction not meeting RECIST criteria for partial response in 4/7 evaluable patients.
Conclusions:
- The combination of temsirolimus and pazopanib was not feasible at clinically meaningful doses due to severe constitutional and electrolyte disturbances.
- Simultaneous vertical inhibition of VEGFR and mTOR pathways with this specific combination requires further investigation at potentially lower doses or different schedules.
