Jivani, Manoj A.

TPS7569 Background: Progress in genome technology allows analysis of previously completed trials to identify patients subgroups potentially benefiting from therapy. Enzastaurin is a potent inhibitor of protein kinase C beta (PKC- b) and suppresses the phosphoinositide 3-kinase (PI3K)/AKT pathway. The safety and efficacy of Enzastaurin has been tested in more than 60 clinical trials including 2 major studies in DLBCL: (1) PRELUDE (A phase III maintenance trial of Enzastaurin vs Placebo, N=758) ( Crump, 2016), and (2) S028 (A randomized phase II study of Enzastaurin/R-CHOP vs R-CHOP in frontline intermediate/high-risk DLBCL, N=101) ( Hainsworth, 2016). DNA samples extracted from blood of patients from PRELUDE were retrospectively genotyped using whole genome SNP arrays. From the genome wide screening a novel genetic biomarker, DGM1, was identified showing high correlation with response to Enzastaurin treatment ( Luo, ASH 2018). Importantly, these findings were replicated in the phase II S028 study. In the S028 study the hazard ratio (HR) for OS in high-risk (IPI ≥ 3) DGM1 positive (+) patients who received Enzastaurin/R-CHOP was 0.28 (0.1-0.81) when compared to subjects who received R-CHOP, a benefit favoring Enzastaurin (p=0.018). These data suggest that addition of Enzastaurin to R-CHOP may significantly improve outcome in frontline high-risk DGM1 (+) DLBCL. The ENGINE study was initiated to validate this finding in a prospective study. Methods: Adult patients must have untreated CD20+ DLBCL, IPI ≥ 3. Patients are randomized 1:1 to Enzastaurin/R-CHOP or Placebo/R-CHOP for 6 cycles during combination phase. Each subject’s treatment assignment will be unblinded after response assessment at the end of the combination phase. Subjects randomized to the investigational arm who have a complete or partial response will have the option to continue in the single agent phase to receive Enzastaurin for up to 2 additional years. The study intends to enroll approximately 235 patients with primary endpoint of OS in DGM1 (+) patients. The study is ongoing with 51 sites open in the US and China. As of 22 Jan 2019, 70 patients have been randomized. Clinical trial information: NCT03263026.

Background: Progress in genome technology allows analysis of previously completed trials to identify subgroups potentially benefiting from therapy. Enzastaurin is a potent inhibitor of protein kinase C beta (PKC-β) and suppresses the phosphoinositide 3-kinase (PI3K)/AKT pathway. The safety and efficacy of Enzastaurin has been tested in more than 60 clinical trials including 2 major studies in DLBCL: (1) PRELUDE (A phase III maintenance trial of Enzastaurin vs Placebo, N=758) (Crump, 2016), and (2) S028 (A randomized phase II study of Enzastaurin/R-CHOP vs R-CHOP in frontline intermediate/high-risk DLBCL, N=101) (Hainsworth, 2016). DNA samples extracted from blood of patients from PRELUDE were retrospectively genotyped using whole genome SNP arrays. From the genome wide screening a novel genetic biomarker, DGM1, was identified showing high correlation with response to Enzastaurin treatment (Luo, ASH 2018). Importantly, these findings were replicated in the phase II S028 study. In the S028 study the hazard ratio (HR) for OS in high-risk (IPI ≥ 3) DGM1 positive (+) patients who received Enzastaurin/R-CHOP was 0.28 (0.1-0.81) when compared to subjects who received R-CHOP, a benefit favoring Enzastaurin (p=0.018). These data suggest that addition of Enzastaurin to R-CHOP may significantly improve outcome in frontline high-risk DGM1 (+) DLBCL. The ENGINE study was initiated to validate this finding in a prospective study. Study Design and Methods: Adult patients must have untreated CD20+ DLBCL, IPI ≥ 3. Patients are randomized 1:1 to Enzastaurin/R-CHOP or Placebo/R-CHOP for 6 cycles during combination phase. Each subject's treatment assignment will be unblinded after response assessment at the end of the combination phase. Subjects randomized to the investigational arm who have a complete or partial response will have the option to continue in the single agent phase to receive Enzastaurin for up to 2 additional years. The study intends to enroll approximately 235 patients with primary endpoint of OS in DGM1 (+) patients. The study is ongoing with 57 sites open in the US and China. As of 20 July 2019, 128 patients have been randomized. Clinical trial information: NCT03263026. Disclosures Nowakowski: Genentech, Inc.: Research Funding; Curis: Research Funding; Bayer: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; F. Hoffmann-La Roche Ltd: Research Funding; Selvita: Membership on an entity's Board of Directors or advisory committees; NanoString: Research Funding; MorphoSys: Consultancy, Research Funding. Brody:Acerta Pharma: Research Funding; Merck: Research Funding; Celldex Therapeutics: Research Funding; Genentech: Research Funding; Oncovir, Inc.: Research Funding; BMS: Research Funding; Kite Pharma: Research Funding. Lue:Kymera Therapeutics: Honoraria; Astex Pharmaceuticals: Honoraria. Luo:Denovo Biopharma LLC: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties. Zhang:Denovo Biopharma LLC: Employment. Han:Denovo Biopharma LLC: Employment. Jivani:TRACON Pharmaceuticals, Inc.: Other: Stock; Denovo Biopharma LLC: Employment. Liu:Denovo Biopharma LLC: Employment. Li:Denovo Biopharma LLC: Employment. Sun:Novartis: Other: Stock; Denovo Biopharma LLC: Employment.

11546 Background: TRC105, an endoglin-targeting monoclonal antibody with anti-angiogenic and anti-tumor activity, is being evaluated in multiple diseases. Here we report on pharmacodynamic and prognostic biomarkers in patients (pts) treated with both TRC105 and anti-VEGF agents. Methods: Plasma samples were collected from pts on three phase 2 trials combining TRC105 with an anti-VEGF agent: axitinib in metastatic renal cell carcinoma (mRCC), pazopanib in advanced soft tissue sarcoma, and bevacizumab in glioblastoma (GBM). Baseline and on-treatment levels of 22 soluble protein biomarkers were assessed. Results: Soluble endoglin markedly increased after TRC105 treatment in all pts ( p< 0.001) as previously reported. BMP9 (a ligand for endoglin) and TGFβR3 (a type III TGFβ receptor) decreased in sarcoma pts at Cycle 2 Day 1 (C2D1) and generally remained below baseline throughout the course of treatment (BMP9, p= 0.004; TGFβR3, p= 0.003). Although TGFβR3 was decreased at C2D1 in mRCC (p = 0.030), no clear patterns were observed over time. Overall BMP9 levels did not change in response to therapy in either mRCC or GBM. Osteopontin (OPN) levels, a downstream effector of TGFβ signaling, were increased in sarcoma pts [ p= 0.002 at C2D15, p< 0.001 at C4D1 and end of study (EOS)]; however, in mRCC ( p= 0.010) and GBM ( p= 0.003), OPN was only elevated at EOS. Increases in PlGF and VEGFD, and decreases in VEGFR2 were observed across all studies, as previously noted for VEGF inhibitors. In the mRCC trial, 5 of 18 pts exhibited a ≥30% tumor reduction. Lower OPN ( p= 0.026) and higher TGFβR3 ( p= 0.003) levels at baseline correlated with radiographic response to treatment. In the sarcoma trial, 6 of 19 pts responded (CHOI criteria) in which lower baseline levels of ICAM1 ( p= 0.018) and TSP2 ( p= 0.042) correlated with stable disease. Conclusions: In these trials, increases of soluble endoglin in response to TRC105 were observed, independent of the presence of any specific VEGF inhibitor. Differential regulation of BMP9, TGFβR3, and OPN suggests potential disease-specific modulation of key TGFβ signaling molecules in response to dual therapy. Baseline levels of OPN and TGFβR3 showed potential prognostic value in mRCC. Confirmation in larger trials is needed.