BACKGROUND: The current study was conducted to assess the maximum tolerated dose (MTD), safety, pharmacokinetics, and preliminary antitumor effect of everolimus, a mammalian target of rapamycin inhibitor, in combination with sorafenib, a tyrosine kinase inhibitor, in patients with metastatic clear cell renal cell carcinoma. METHODS: Sequential cohorts of patients received escalating doses of everolimus and sorafenib in 28-day cycles in the absence of a dose-limiting toxicity (DLT) or disease progression were examined. RESULTS: Twenty patients with a median age of 65 years received therapy in 3 cohorts. Dose level 1 was comprised of everolimus at a dose of 2.5 mg daily and sorafenib at a dose of 400 mg twice daily (6 patients), dose level 2 was comprised of everolimus at a dose of 5 mg daily and sorafenib at a dose of 400 mg twice daily (8 patients), and dose level 3 was comprised of everolimus at a dose of 10 mg daily and sorafenib at a dose of 200 mg twice daily (6 patients). DLTs included grade 4 (according to National Cancer Institute Common Terminology Criteria for Adverse Events [version 3.0]) hyperuricemia with grade 2 gout and grade 3 lipase associated with grade 2 pancreatitis at dose level 2, and grade 3 rash in 2 patients at dose level 3. Dose level 2 (everolimus at a dose of 5 mg daily and sorafenib at a dose of 400 mg twice daily) was established as the maximum tolerated dose. Treatment-related adverse events occurring in >20% of patients included diarrhea, hand-foot syndrome, hypertension, hypophosphatemia, hypothyroidism, and rash. Five of 20 patients achieved Response Evaluation Criteria In Solid Tumors (RECIST)-defined partial responses, all of which occurred in patients without a history of prior systemic therapy. Seven of 8 patients treated at dose level 2 experienced a partial response or stable disease. Pharmacokinetic analysis revealed no interaction between everolimus and sorafenib. CONCLUSIONS: The combination of everolimus and sorafenib was associated with acceptable toxicity and evidence of antitumor activity in previously untreated patients with metastatic renal cell carcinoma.
BACKGROUND: The current study was conducted to assess the maximum tolerated dose (MTD), safety, pharmacokinetics, and preliminary antitumor effect of everolimus, a mammalian target of rapamycin inhibitor, in combination with sorafenib, a tyrosine kinase inhibitor, in patients with metastatic clear cell renal cell carcinoma. METHODS: Sequential cohorts of patients received escalating doses of everolimus and sorafenib in 28-day cycles in the absence of a dose-limiting toxicity (DLT) or disease progression were examined. RESULTS: Twenty patients with a median age of 65 years received therapy in 3 cohorts. Dose level 1 was comprised of everolimus at a dose of 2.5 mg daily and sorafenib at a dose of 400 mg twice daily (6 patients), dose level 2 was comprised of everolimus at a dose of 5 mg daily and sorafenib at a dose of 400 mg twice daily (8 patients), and dose level 3 was comprised of everolimus at a dose of 10 mg daily and sorafenib at a dose of 200 mg twice daily (6 patients). DLTs included grade 4 (according to National Cancer Institute Common Terminology Criteria for Adverse Events [version 3.0]) hyperuricemia with grade 2 gout and grade 3 lipase associated with grade 2 pancreatitis at dose level 2, and grade 3 rash in 2 patients at dose level 3. Dose level 2 (everolimus at a dose of 5 mg daily and sorafenib at a dose of 400 mg twice daily) was established as the maximum tolerated dose. Treatment-related adverse events occurring in >20% of patients included diarrhea, hand-foot syndrome, hypertension, hypophosphatemia, hypothyroidism, and rash. Five of 20 patients achieved Response Evaluation Criteria In Solid Tumors (RECIST)-defined partial responses, all of which occurred in patients without a history of prior systemic therapy. Seven of 8 patients treated at dose level 2 experienced a partial response or stable disease. Pharmacokinetic analysis revealed no interaction between everolimus and sorafenib. CONCLUSIONS: The combination of everolimus and sorafenib was associated with acceptable toxicity and evidence of antitumor activity in previously untreated patients with metastatic renal cell carcinoma.
Authors: Rhonda L Bitting; Patrick Healy; Patricia A Creel; James Turnbull; Karla Morris; Sarah Yenser Wood; Herbert I Hurwitz; Mark D Starr; Andrew B Nixon; Andrew J Armstrong; Daniel J George Journal: Clin Genitourin Cancer Date: 2013-11-14 Impact factor: 2.872
Authors: Joshua E Logan; Edward N Rampersaud; Geoffrey A Sonn; Karim Chamie; Arie S Belldegrun; Allan J Pantuck; Dennis J Slamon; Fairooz F Kabbinavar Journal: Rev Urol Date: 2012
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Authors: Jennifer A Chan; Robert J Mayer; Nadine Jackson; Paige Malinowski; Eileen Regan; Matthew H Kulke Journal: Cancer Chemother Pharmacol Date: 2013-03-09 Impact factor: 3.333