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11542Background: Olaratumab (O) is an antibody against platelet-derived growth factor receptor alpha. In a randomized phase 2 study, O in combination with doxorubicin (dox) demonstrated a significa...

TPS524 Background: Olaratumab is a human IgG1 monoclonal antibody that specifically binds human platelet-derived growth factor receptor (PDGFR)-α and blocks PDGF-mediated signaling pathways. Increased PDGFRα expression is observed in pancreatic cancer tissue, and has been suggested to play a role in the mesenchymal transition of pancreatic cancer. An ongoing trial designed to evaluate the safety and efficacy of olaratumab in combination with nab-paclitaxel/gemcitabine (nPG) in patients with unresectable metastatic pancreatic cancer not previously treated for metastatic disease is currently being conducted. Methods: JGDP (NCT03086369) is a global Phase 1b/Phase 2 study being conducted to evaluate the safety and efficacy of olaratumab in combination with nPG as first-line therapy in patients with Stage IV pancreatic cancer (ECOG PS ≤1). In the Phase 1b portion of the study, patients will receive intravenous (iv) olaratumab following a 3+3 dose escalation scheme at two different schedules: on Days 1, 8 and 15 at doses of 15 mg/kg and 20 mg/kg, or on Days 1 and 15 at 20 mg/kg and 25 mg/kg. Olaratumab will be given in combination with nPG (125 mg/m2 iv/1000 mg/m2 iv) on Days 1, 8, and 15 of a 28-day cycle. After the maximum tolerated dose has been identified, additional patients will be enrolled in a cohort expansion to confirm the safety of the combination prior to proceeding to the Phase 2 portion of the study. In the Phase 2 study, approximately 162 patients will be randomized at a 1:1 ratio to receive olaratumab at the recommended Phase 2 dose regimen or placebo, both in combination with nPG (125 mg/m2 iv/1000 mg/m2 iv). Treatment will continue until disease progression or other discontinuation criteria are met. The primary end point of the Phase 2 study is overall survival; a 2-sided α level of 0.20 will be applied. Assuming OS HR = 0.67, there is ≥80% power to show a significant difference in OS between study arms. Secondary end points include progression free survival, duration of response, objective response rate, patient-reported outcomes, and safety. As of September 2017, enrollment for the Phase 1b study is currently ongoing. Clinical trial information: NCT03086369.

8026 Background: LY2835219, a novel cell cycle inhibitor selective for the cyclin-dependent kinases CDK4 and CDK6 (CDK4/6), has shown antitumor activity in human NSCLC xenograft models. Importantly...

534 Background: Cyclin-dependent kinases 4 and 6 (CDK4/6) act with D-type cyclins to enable cell proliferation. LY2835219, a small molecule inhibitor of CDK4/6, has shown antitumor activity in xeno...

2500 Background: Cyclin dependent kinases 4 and 6 (CDK4/6) act with D-type cyclins to inactivate the retinoblastoma (Rb) tumor suppressor protein and enable cell cycle progression from G1 to S phase. LY2835219 is a selective inhibitor of CDK4/6 that shows antitumor activity in preclinical models of human cancer and also distributes efficiently to the brain. We performed a phase 1 study to evaluate safety, pharmacokinetics, pharmacodynamics, and antitumor activity of LY2835219. Methods: 3+3 dose escalation was followed by expansions in 5 tumor types (brain metastases permitted): non-small cell lung cancer (NSCLC), glioblastoma, breast cancer, melanoma, and colorectal cancer. LY2835219 was taken orally every 12 or 24 hours (in escalation) and every 12 hours (in expansions) on days 1-28 of a 28-day cycle. Results: 55 patients (pts) received LY2835219. In escalation, 33 pts received LY2835219 on 1 of 2 schedules: 50, 100, 150, 225 mg every 24 hours (Q24H) or 75, 100, 150, 200, 275 mg every 12 hours (Q12H). On the Q24H schedule, the maximum tolerated dose (MTD) was not identified. On the Q12H schedule, the MTD was 200mg Q12H with dose limiting toxicity of G3 fatigue at 200 mg (1/6 evaluable pts) and 275 mg (2/3 evaluable pts). At 200mg Q12H, the mean Cmax and AUC0-24hr at steady state were 285 ng/mL and 5502 ng-hr/ml, respectively. In skin, LY2835219 induced pharmacodynamic inhibition of both Rb phosphorylation and topoisomerase IIα expression. In the ongoing expansions, 22 pts have received LY2835219. Across the study, the most common related adverse events were diarrhea (52%, including 5% G3), nausea (30%, 4% G3), fatigue (21%, 7% G3), vomiting (18%, 2% G3), and neutropenia (16%, 7% G3). 15 pts have reached ≥4 cycles for stable disease or better with 3 pts achieving 8, 16, and 26 cycles. One pt with ovarian cancer had a durable CA-125 response with >50% decrease for 16 cycles. One pt with KRAS mutant NSCLC had a 27% decrease by RECIST. One pt with CDKN2A-/- NRAS mutant melanoma had a confirmed partial response. Early clinical activity has been observed in ovarian cancer, NSCLC, breast cancer, and melanoma. Conclusions: LY2835219 shows acceptable safety and early clinical activity as a single agent for patients with advanced cancer. Clinical trial information: NCT01394016.

8012 Background: LY2127399 (LY) is a human mAb that neutralizes membrane-bound and soluble B cell activating factor (BAFF). LY has activity in xenograft models of multiple myeloma (MM) and is being...