Initial results from a phase II trial of motesanib diphosphate (AMG 706) in patients with differentiated thyroid cancer (DTC)

Abstract

6017 Background: This phase 2 study evaluated the safety and efficacy of AMG 706, an oral, investigational multikinase (MKI) inhibitor with antiangiogenic and direct antitumor activity achieved by selectively targeting VEGF, PDGF, and Kit receptors and RET, in pts with advanced DTC or medullary thyroid cancer (MTC). Presented here are results from the DTC stratum. Methods: This was a multicenter, phase 2, open-label, single-arm study of pts with advanced thyroid cancer stratified by DTC or MTC (planned n=80 each). The primary endpoint was objective tumor response per modified RECIST by independent central review. Secondary DTC endpoints were duration of response and progression-free survival (PFS). Pts = 18 yrs with progressive, 131I-resistant disease, ECOG 0–2, and no prior treatment with VEGFr MKIs received AMG 706 125mg QD until disease progression or unacceptable toxicity. Assessments included tumor response (q8w), pharmacokinetics (PK), and safety. Results: 93 pts with DTC were enrolled and received at least 1 dose of AMG 706. DTC subtypes were: papillary, 58%; Hürthle cell, 18%; follicular, 16%; other, 8%. Median (range) age was 62 (36–81) yrs. 20% of pts had prior chemotherapy; 96% had prior 131I therapy. With median follow-up of 32 wks, objective tumor response (CR or PR) rate (95% CI) was 12% (6.1, 20.2); SD, n=64 (69%; durable SD =24 wks, 24%); PD, n=7 (8%). Median (95% CI) time to response was 103 (53, 161) days; median PFS was 276 (221, not estimable) days. 85% of pts were alive >8 months after starting therapy. All pts (100%) had some treatment- emergent adverse events (AE): grade 3, 55%; grade 4, 10%; grade 5, 5% (all grade 5 were deemed unrelated to AMG 706). Common AEs included diarrhea (70%; 11% grade 3), fatigue (58%; 5% grade 3), hypertension (49%; 22% grade 3), headache (43%; 4% grade 3), nausea (40%; 2% grade 3), and hypothyroidism and/or increased TSH (17%; no grade 3); none of these were grade 4 or 5. 6% of pts had cholecystitis. PK results showed that AMG 706 PK at 125mg QD was comparable to data obtained in other monotherapy studies at the same dose level. Conclusions: In this study of pts with advanced 131I-resistant DTC, AMG 706 showed encouraging antitumor activity and had tolerable and manageable toxicities. Further investigation is warranted. No significant financial relationships to disclose.