Phase I study of the combination of temsirolimus and pazopanib in advanced solid tumors

Abstract

Objectives Inhibition of either vascular endothelial growth factor receptor (VEGFR) 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 VEGFR and mTOR pathways. Methods Patients with advanced solid tumors, no prior 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 intravenous (IV) infusion weekly and pazopanib 400 mg orally daily, we defined dose-limiting toxicity (DLT) as attributable grade 3 or higher non-hematologic adverse events in the first 28-day cycle and the maximum tolerable dose as the maximum dose level at which less than 2 patients experienced DLT. Results At the initial dose level, 2 patients had 4 DLTs (anorexia, fatigue, hyponatremia, hypophosphatemia). After reduction to temsirolimus 10 mg IV weekly and pazopanib 200 mg orally daily, 1 of 3 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 meeting RECIST criteria for partial response was the best response in 4 of 7 evaluable patients. Conclusions The combination of temsirolimus and pazopanib was not feasible at clinically meaningful doses in this population due to constitutional and electrolyte disturbances.

Dosingde novocombinations of two targeted drugs: Towards a customized precision medicine approach to advanced cancers

“… a The five studies where no safe dose was found or study was aborted early due to unacceptable toxicity were excluded from this table and include: bevacizumab and sorafenib [ 28 , 29 ], pazopanib and temsirolimus [ 27 ], bevacizumab and everolimus [ 31 ], and bevacizumab and temsirolimus [ 32 ] b First drug had the dose percentage closest to the FDA-approved/RP2D/MTD dose c In these cases, the combinations were same class (small molecule inhibitors) with non-overlapping targets (sorafenib at 100% with everolimus at 25%, and imatinib at 100% with everolimus at 25%) [ 12 – 14 ]. d Sunitinib was at 75% and everolimus at 29% [ 20 ] e Rapamycin was at 93% and bevacizumab was at 50% [ 19 ] f Bevacizumab with vatalinib [ 26 ] and bevacizumab with telatinib [ 25 ] each included an anti-VEGF antibody and a small molecule VEGFR inhibitor (both at 10% and 50%, respectively) g Sorafenib was at 50% and temsirolimus at 40% [ 23 ]; however the combination of pazopanib and temsirolimus was above the FDA-approved/RP2D/MTD at an additive dose percentage of 65% (albeit with no acute or irreversible side effects and with the nonspecific side effect of fatigue as dose limiting in one patient).…”

“… a The five studies where no safe dose was found or study was aborted early due to unacceptable toxicity were excluded from this table and include: bevacizumab and sorafenib [ 28 , 29 ], pazopanib and temsirolimus [ 27 ], bevacizumab and everolimus [ 31 ], and bevacizumab and temsirolimus [ 32 ] …”

A phase I trial of ANG1/2-Tie2 inhibitor trebaninib (AMG386) and temsirolimus in advanced solid tumors (PJC008/NCI♯9041)

“…Temsirolimus has also been combined with oral tyrosine kinase inhibitors with anti-angiogenic effects. The combinations of temsirolimus with pazopanib were intolerable due to significant fatigue, leukopenia and electrolyte disturbances [ 26 ]. In the phase 1 study of temsirolimus with sunitinib, DLTs observed included rash, thrombocytopenia, stomatitis, diarrhea and stomatitis, and the combination was also found to be intolerable [ 27 ].…”

The mTOR pathway in obesity driven gastrointestinal cancers: Potential targets and clinical trials

“…This combination was shown to be tolerable and had modest clinical activity however recent phase I trials combining mTOR inhibitors with anti-angiogenic TKIs have shown conflicting results. A phase I study of the combination of temsirolimus and pazopanib (a pan-VEGF receptor inhibitor) in advanced solid tumours including CRC showed high levels of grade 3 and higher toxicities as doses far less than the approved dose of each drug as a single agent [128] . Overlapping mTOR inhibitor and VEGFR TKI toxicities could account for the unfeasibility of this combination and further research is required to understand these potential interactions and evaluate alternate treatment strategies to circumvent these toxicities.…”