Phase I study of sorafenib plus ifosfamide in patients with advanced soft tissue and bone sarcoma: A Spanish Group for Research on Sarcomas (GEIS) study.

Abstract

10024 Background: Sorafenib is a multi-kinase inhibitor of VEGFR, PDGFR and RAF that showed activity against some sarcoma subtypes. Preclinical studies suggest that the combination of sorafenib with cytotoxic agents could result in additive activity. Methods: Patients with advanced soft tissue or bone sarcoma, previously treated with doxorubicin, no prior ifosfamide, ECOG PS 0-2, and adequate hematological, renal and hepatic function, were enrolled in this phase I study to assess safety, tolerability, pharmacokinetics (PK), and to identify the dose limiting toxicity (DLT), maximum tolerated dose (MTD) and recommended dose (RD) of the combination of sorafenib and ifosfamide. A 3+3 dose escalation design with cohorts of 3-6 patients was used. Sorafenib was given po continuously. Ifosfamide was given iv over 4 hours on 3 consecutive days every 3 weeks. Dose levels 1, 2, 3 and 4 corresponded to sorafenib 200, 400, 400 and 400 mg, bid, plus ifosfamide 6, 6, 7.5 and 9 gr/m2, with concurrent administration of mesna 400, 400, 500 and 600 mg/m2 iv, at 0, 4 and 8 hours after ifosfamide administration. Results: Twelve patients were enrolled: median age 58 years (23-70); gender 6M: 6F; 3 lipo, 2 leio, 2 chondro, 5 other. The median number of cycles was 4. Patients were treated at 3 dose levels, the MTD was reached at level 3 and the RD was: sorafenib 400 mg bid and ifosfamide 6 g/m2, together with,esna 400 mg/m2. Three DLTs occurred, one at the second dose level and two at the third: fatigue grade 4, encephalopathy grade 3 and emesis grade 3. Other toxicities included rash, hand-foot syndrome, neutropenia, thrombocytopenia, anemia and deep vein thrombosis. Eight patients achieved stable disease lasting more than 5 months. Progression-free survival rate at 3 months was 64%. Concomitant treatment with sorafenib and ifosfamide showed no relevant effect on PK of both drugs. Conclusions: The combination of sorafenib and ifosfamide appears to be feasible and safe allowing the administration of active doses of both agents. A phase II study to assess the activity of this combination is ongoing. No significant financial relationships to disclose.