Context
The study continues to evaluate safety, PK, activity and pharmacodynamics of GDC-0919 at a continuous dosing schedule (BID 28/28) to enable greater
flexibility in future dosing regimens. GDC-0919 also is being evaluated in a Phase Ib study in combination with atezolizumab (PD-L1 inhibitor) in patients with
recurrent or advanced solid tumors.
Design
Per the abstract, this open-label, single center, Phase Ia study with a 3+3 design assesses safety, pharmacokinetics (PK), pharmacodynamics (PD), and
preliminary anti-tumor activity of GDC-0919 in patients (pts) with recurrent/advanced solid tumors. GDC-0919 is administered at doses 50¨C800mg BID on a
21 days on/7 days off schedule, for up to 12 months. PK parameters and PD markers (plasma Kyn: Trp ratio) were evaluated after single and multiple doses.
Tumor assessments are performed every 2 cycles (RECIST v1.1 and immune related response criteria [irRC]).
Results
The data showed an acceptable safety profile, disease stabilization and preliminary evidence of peripheral pharmacodynamic modulation. GDC-0919 was
well tolerated up to 800 mg BID (twice daily) on a 21/28 day cycle. Thirty seven percent of patients available for tumor assessments (7/17) achieved stable
disease. The MTD was not reached. Single and multiple dose exposure from 50 to 800 mg of GDC-0919 increased in approximately dose-proportional
manner, and higher doses of GDC-0919 modulated plasma Kynurenine in a manner consistent with the half-life of GDC-0919.
Per the abstract, as of March 26, 2015, 19 pts were treated and 3 remained active (16 pts discontinued treatment due to progressive disease). Pts received a
median of 3 cycles (range 1¨C11) of GDC-0919 and remained 77 days on treatment (range 13¨C289 days). Preliminary PK results up to 600mg BID suggest that
GDC-0919 is rapidly absorbed and demonstrates dose proportional increases in exposure, with a half-life supportive of BID dosing. Best RECIST responses
among 16 pts with on-treatment tumor assessments were 7 (44%) stable disease (SD, lasting ¡Ý4 cycles in 4 pts) and 9 (56%) progressive disease. irRC and
PD marker data are pending.
Most Common Adverse Events
The most common adverse events related to GDC-0919 were lower grade and included pruritus or itching (37%), fatigue, (26%) and decreased appetite
(21%). Per the abstract, one DLT of Grade 4 lower gastrointestinal hemorrhage was reported at 800mg in 69 yo male w/mRCC with extensive GI serosal
metastasis (the only Grade ¡Ý3 AE assessed as related to GDC-0919). Adverse events (AEs) regardless of causality and reported in ¡Ý4 pts were fatigue (9 pts,
47%), cough, decreased appetite, and nausea (8 pts, 42% each), pruritis (7 pts, 37%), vomiting (6 pts, 32%), increased AST (5 pts, 26%), and hypokalemia
and dyspnea (4 pts, 21% each). Grade ¡Ý3 AEs regardless of causality occurred in 11 pts (58%), and those in ¡Ý2 pts were neoplasm progression (3 pts, 16%)
and increased AST (2 pts, 10.5%). Grade 3 AST elevations coincided with progression of liver metastases (2 pts, 10%) and were reported as unrelated; a 3rd
pt with Grade 2 AST/ALT elevations at Cycle 2 Day 1 was assessed as related to GDC-0919. No AEs led to treatment discontinuation.
Conclusion
Per the abstract, GDC-0919 has been well tolerated up to 800mg BID on 21 days on/7 days off. PK was linear and dose-proportional. Prolonged SD was reported in 4 patients. Updated results will be presented. ·µ»ØСľ³æ²é¿´¸ü¶à