Phase I study of everolimus (E, RAD001) and ganitumab (G, AMG 479) in patients (pts) with advanced solid tumors.

Abstract

2529 Background: Synergism between IGF and mTOR inhibitors has been documented preclinically. We conducted a phase I study to determine the safety, recommended phase II dose (RP2D), pharmacokinetics (PK), pharmacodynamics (PD), and antitumor efficacy of E with G. Methods: Eligible pts had good organ function, ECOG PS 0-1. The study had a standard “3+3” design, using E 5 or 10 mg orally daily (QD), and G 12 mg/kg IV every 2 wks (Q2W) in 28 day cycles (C); an expansion cohort was added at MTD for further efficacy analysis. E was given as single agent during C1D1-7 with PKs on C1D1 and D7, and continuously after C1D16. G was started on C1D15 with single agent PK. PKs for both drugs at steady state were performed on C3D1. PDs (blood and serial tumor biopsies) for IGF and PI3K/Akt/mTOR pathways were performed at baseline, C1D7, C3D1 and time of progression. Results: 20 ptswere enrolled to date, M/F: 8/12, median age 55 yrs (24-70); PS: 0/1= 13/7. The table summarizes dose levels and DLTs. The most common toxicities were fatigue (5), diarrhea, mucositis, dysgeusia, anemia and thrombocytopenia (4 each), and rigors (3). Grade (Gr) 3 toxicities were: mucositis (3), anemia (2), thrombocytopenia (2), and diarrhea (1). Pts received a median of 3 cycles (0-9). One pt discontinued study on C1D9 due to intracerebral bleed and 1 pt withdrew consent on C1D15. Among 18 evaluable pts, none responded and 9 pts (50%) had SD with a median duration of 20 wks (range 11-35). Prolonged clinical benefit (SD ≥ 20 wks) was noted in refractory fibrolamellar HCC, neuroendocrine, GIST and urachal cancers. PKs showed no significant interaction between E and G. Baseline IGF-1R and PTEN expression, and IGF1 levels did not affect clinical benefit. pS6 downregulation and pAkt upregulation in paired tumor biopsies occurred in all (7/7) or most (6/7) samples evaluated, and did not correlate with efficacy. IGF1 and IGFBP3 levels increased on-treatment in 80-90% of pts. Conclusions: E+G is safe and the RP2D is E 10 mg QD + G 12 mg/kg Q2W. While on target pS6 reduction occured, the IGF1-R inhibition did not affect pAkt upregulation from mTOR blockade. Clinical trial information: NCT01122199. [Table: see text]