SORAVE trial: Phase I sorafenib and everolimus in solid tumors

TPS170 Background: Clinical efficacy of the multikinase inhibitor sorafenib is mainly based on its antiangiogenic properties mediated by VEGFR inhibition. The mTOR inhibitor everolimus also exerts antiangiogenic effects; additionally it may induce antiproliferative effects on the tumor cells by blocking the PI3K/AKT pathway. Treatment with both drugs simultaneously thus may enhance antitumor effects by combining (I) two differently acting antiangiogenic agents and (II) antiangiogenic and antitumor cell activity. This phase I study aims at demonstrating the safety of combination therapy with these two agents in patients suffering from relapsed solid tumors. Besides pharmacokinetic (PK) analyses for sorafenib and everolimus dynamic FDG-PET is used as pharmacodynamic parameter. A descriptive analysis of response is intended to gain first insight into efficacy of this treatment. Methods: A maximum of 24 patients with relapsed solid tumors is planned to be recruited for defining the MTD of everolimus in a cumulative 3+3 dose escalating scheme with 2.5-10 mg everolimus od. This treatment is combined with fixed dose sorafenib 400 mg bid after a two weeks run-in interval with everolimus monotherapy. Further 12 patients will be included in an extension phase treated with the MTD. Individual and population PK analysis will be based on the measurement of serum concentrations of both substances. FDG-PET will be performed before as well as 5 and 14 days after start of therapy. A comparison of standard uptake values (SUV) of glucose in target lesions with baseline imaging values serves for early assessment of pharmacodynamic response to therapy. After a period of 8 weeks of combination therapy response will be assessed by CT scan and comparison of previously defined target lesions with baseline findings according to RECIST criteria. Patients without clinical or radiological signs of progressive disease will continue treatment. An outcome analysis will measure RR, TTP, PFR, and OS. FDG-PET, clinical findings, and outcome parameters will be incorporated in a PK/pharmacodynamic model to optimize the treatment schedule. Currently 6 patients have been enrolled in this study with ovarian cancer (2), colorectal carcinoma (2), SCLC (1), and pancreatic cancer (1). Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Novartis Bayer, Novartis Bayer, Novartis