Safety and PK results from a phase Ib study of AL3818 (anlotinib) hydrochloride in subjects with ovarian, cervical, and endometrial cancers.

e17071 Background: AL3818 (anlotinib) hydrochloride is a multi-targeted receptor tyrosine kinase inhibitor with potential FGFR inhibition and anti-angiogenesis activity in gynecological cancers. A phase Ib dose verification study was conducted at a single U.S. center to evaluate the safety and tolerability of AL3818 and pharmacokinetic (PK) properties after oral administration of a single dose and at steady state after continuous dosing. The 12 mg dose has been used in multiple clinical trials in China for various indications including NSCLC and sarcoma. Methods: Patients with recurrent or persistent ovarian, cervical, endometrial or other uterine cancers refractory to standard therapies were eligible for enrollment in a 3+3 dose escalation design. The starting dose was 12 mg orally daily for 14 days on and 7 days off. Safety assessments included laboratory evaluations, physical exam, ECOG, vitals, ECG, and adverse events monitoring. Single and multi-dose PK were collected. Results: Three patients (1 with ovarian and 2 with endometrial) were enrolled and completed the initial 21-day safety evaluation period. AL3818 at 12mg/day was found to be safe and well tolerated with no dose-limiting toxicities reported in cycle 1. Only grade 1 and 2 treatment emergent adverse events were noted, including hypertension (htn), oral pain, epistaxis, pain, insomnia, headache, fatigue, tinnitus, sinus tachycardia, anorexia, fatigue, urinary tract infection and urinary frequency. No significant safety concerns were noted. After a single 12 mg dose, the average drug concentration peak time (Tmax) was 10 (4-24) hrs; the average max drug blood concentration (Cmax) was 9.60 (8.47-11.50) ng/mL. After multiple, continuous dosing, the average Tmax was 360 hrs (15 days); average Cmax was 63.80 (52.90-80.30) ng/mL. Because one subject experienced grade 2 htn and one subject experienced grade 3 htn on C2D2, the decision was made that the dose would not be escalated with further cohorts. Conclusions: The recommended phase II dose for AL3818 was determined to be 12 mg daily at 2 wks on/1 wk off regimen. Overall this drug was well tolerated. Blood pressure was manageable with anti-hypertensive medication. Clinical trial information: NCT02558348.