Phase I trial of RAD001 (everolimus) plus sunitinib in patients with metastatic renal cell carcinoma
Authors: Kroog G. S. , Feldman D. R. , Kondagunta G. V. , Ginsberg M. S. , Fischer P. M. , Trinos M. J. , Patil S. , Ishill N. M. , Motzer R. J. 
Published: August 2020

5037^

Background: RAD001 (everolimus) and sunitinib (SUTENT) both have activity in metastatic renal cell carcinoma (mRCC). Combining RAD001 and sunitinib may increase antitumor efficacy by maximizing inhibition of HIF-dependent signaling. The safety and maximum tolerated dose (MTD) of sunitinib in combination with RAD001 was assessed in this phase I trial. Methods:Cohorts of 3–6 patients (pts) with mRCC received sunitinib at 37.5 or 50 mg daily for 4 weeks (wks) followed by 2 wks off with RAD001 administered either daily (2.5 or 5 mg) or weekly (20 or 30 mg). Predetermined dose-limiting toxicities (DLTs) were assessed in the first 6-wk cycle. Serum levels of RAD001 and sunitinib were measured for pts on weekly RAD001. Results: Of 20 pts (median age 62; 13 clear cell (cc) and 7 non-cc RCC) enrolled, 19 are evaluable for DLT including 3 in cohort 1 (2.5 mg RAD001 daily/ 37. 5 mg sunitinib), 2 in cohort 2 (5 mg RAD001 daily/ 37. 5 mg sunitinib), 5 in cohort 3 (20 mg RAD001 weekly/ 37. 5 mg sunitinib; 1 pt too early to evaluate), 6 in cohort 4 (30 mg RAD001 weekly/ 37. 5 mg sunitinib), and 3 in cohort 5 (30 mg RAD001 weekly/ 50 mg sunitinib). On daily RAD001 dosing, 2/2 patients on 5 mg/day experienced grade (G) 3 DLT (thrombocytopenia and mucositis; vomiting). On weekly RAD001 dosing, 2/3 patients on cohort 5 experienced G3 DLT (mucositis; thrombocytopenia with bleeding). 1/6 patients on cohort 4 experienced G3 DLT (febrile neutropenia and mucositis). Therefore, the MTD was cohort 4. However, with chronic treatment, only 1/6 pts at cohort 4 tolerated treatment beyond 4 cycles. Toxicities observed with chronic dosing include: G3 strep viridans endocarditis, G3 gastrointestinal hemorrhage with G4 anemia, and G4 pulmonary embolism. Therefore, we treated 3 more pts at cohort 3. All 6 pts remaining on study, including 2 dose reduced from other cohorts, are on 20 mg RAD001 weekly/ 37. 5 mg sunitinib. 3/5 pts with confirmed partial responses have non-cc RCC (2 chromophobe; 1 papillary). RAD001 blood levels (Cmax and AUC) at 20–30 mg/week were comparable to those seen at 50–70 mg/week in a single agent study. Conclusions: The combination of 20 mg RAD001 weekly/ 37. 5 mg sunitinib is recommended for phase II and shows responses in non-cc RCC.

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