Abstract CT145: A phase I open-label study to evaluate the effect of olaratumab on the pharmacokinetics (PK) of doxorubicin (Dox) in patients with advanced soft tissue sarcoma (STS)

Olaratumab (Olara), a fully human monoclonal antibody that selectively binds human platelet-derived growth factor receptor alpha and blocks ligand binding, shows encouraging efficacy in combination with Dox in STS. Patients with metastatic or locally advanced STS not amenable to treatment with surgery or curative radiotherapy, aged ?18 years with an ECOG PS of 0-2 and documented LVE fraction ?50% were included. The primary objective was to assess the effect of Olara on the PK of Dox. Secondary objectives were to further characterize the PK and safety profiles of Olara alone and in combination with Dox. Drug-drug interaction (DDI) was assessed in 21-day cycles, where patients received each drug alone (Cycle 1) then in combination (Cycle 2). In Cycles 3-8, patients with clinical benefit could continue treatment with Olara+Dox. 15-mg/kg Olara was given IV over ∼60 min; 75-mg/m2 Dox was given IV over ∼15 min. Overall, 25 patients (10 male and 15 female, aged 27-83 years) received at least one dose of study drug; as planned, 15 patients were evaluable for PK and DDI assessment. The AUC and Cmax for Dox were similar with or without Olara; the 90% CIs for the ratios of geometric LS means for AUC were within the standard no-effect boundary (0.8, 1.25); the 90% CI for Cmax was only slightly out of the boundary but with a Cmax ratio close to unity (0.984). After the first infusion of Olara alone (Cycle 1, Day 10), a mean Olara Cmax of 293μg/mL was achieved at ∼2h post start of infusion, with a mean t1/2 of ∼157h. The mean Olara CL was 0.0259L/h. After the second infusion (Cycle 2, Day 1, Olara+Dox), Olara serum concentration had a median tmax of ∼2.8h post start of infusion, and the mean Cmax was higher (393μg/mL), due to the residual Olara serum concentrations from cycle 1. The mean t1/2 (∼131h) and CL (0.0218L/h) were, however, similar to those obtained after the first infusion. These Olara PK results are consistent with those previously reported. No deaths occurred. The most common treatment-emergent AE reported during the study were nausea (48%) and fatigue (44%). One Grade 4 IRR was observed; there was no evidence of QT prolongation. IV infusion of Olara did not have a clinically relevant effect on systemic exposure to Dox when both agents were given in combination. The PK of Olara alone and with Dox was consistent with previously reported data. Olara+Dox had an acceptable safety profile Citation Format: Victor Villalobos, Mark Agulnik, Seth M. Pollack, Daniel A. Rushing, Arun Singh, Brian A. Van Tine, Chukwuemeka Okereke, Wee Teck Ng, Damien M. Cronier. A phase I open-label study to evaluate the effect of olaratumab on the pharmacokinetics (PK) of doxorubicin (Dox) in patients with advanced soft tissue sarcoma (STS). [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr CT145.