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3126 Background: APG-115 is a potent and orally active small-molecule MDM2 protein inhibitor. Binding to MDM2 protein, APG-115 restores p53 tumor suppressive function via induction of apoptosis in tumor cells retaining wild-type p53. In addition, enhanced antitumor activity was demonstrated in the syngeneic tumor models after APG-115 combined with PD-1 blockade. Methods: This Phase I study (APG-115-US-001) was designed to enroll the patients with advanced solid tumors in US (NCT02935907). Study objectives included to assess safety, dose limited toxicity (DLT), pharmacokinetics (PK), pharmacodynamics (PD), and antitumor activity (assessed every 8 weeks per RECIST v1.1). The patients received APG-115 orally every other day (QOD) at the designated dose (ranging from 10 to 300 mg) for first 21 days of a 28-day cycle, until disease progression. Results: Up until Jan 4 2019, total 28 patients were treated with APG-115 at various doses (one patient at 10mg, 20mg and 50mg, respectively; 14 patients at 100mg, 6 patients at 200mg, and 5 patients at 300mg). The median number of prior systemic anticancer therapies was 4 (range 0-15). The DLTs were observed during cycle 1, including one grade 2 thrombocytopenia at 200mg, one grade 3 thrombocytopenia at 300mg, and one grade 3 fatigue at 100mg and 300mg respectively. The most common AEs (reported in ≥10% of pts) included: fatigue, nausea, vomiting, diarrhea, decreased appetite, dehydration, neutrophil count decreased, white blood cell count decreased, pain in extremity, thrombocytopenia. The most common Grade 3 or 4 treatment related AEs were fatigue (10.7%), and thrombocytopenia (10.7%). Six patients had stable disease (SD) after two cycle treatments, two of them are continuing in this study. PK analyses indicated that exposure (Cmax and AUC) generally increases with the increase of dose level from 20 mg to 300 mg. Conclusions: APG-115 was well tolerated and had manageable adverse events. The MTD/RP2D of APG-115 monotherapy with oral administration, QOD for 21 days of a 28-day cycle for treatment of patients with advanced solid tumors was determined as 100 mg. Further evaluation of APG-115 in combination with pembrolizumab in patients with advanced solid tumors is ongoing. Clinical trial information: NCT02935907.

3125 Background: APG-1387 is a novel, bivalent small molecule IAP (inhibitor of apoptosis proteins) inhibitor. It has shown strong antitumor activities in multiple human xenograft cancer models. APG-1387 also acts as host immune modulator, supporting the notion that APG-1387 in combination with anti-PD1 antibody for cancer therapy. Methods: This study consists of two parts (NCT03386526). Part 1 is the dose escalation study of APG-1387 including a mPC (metastatic pancreatic cancer) cohort expansion. Part 2 is the dose escalation and cohort expansion study of APG-1387 in combination with pembrolizumab. APG-1387 is administrated IV for 30 minutes once weekly in a 21-day-cycle. Pembrolizumab is administrated at 200mg IV on day1 of a 21-day-cycle. The study objectives are to assess the safety, pharmacokinetics (PK), pharmacodynamics (PD), and efficacy (assessed per RECIST v1.1 every 6 weeks). Results: Through Jan 4, 2019, total 23 patients had been treated in 4 cohorts of APG-1387 (20mg, 30mg, 45mg, 60mg). Two DLTs were observed at 60mg including lipase increase and Bell’s palsy, MTD was determined as 45mg. Nineteen of 23 patients experienced at least 1 TEAE. The most common TEAEs were nausea (21.7%), fatigue (17.4%), decreased appetite (13.0%), and abdominal pain (13.0%). Three grade 3 TEAEs including elevated bilirubin, lipase increase, and shortness of breath were documented at 45mg and 60mg. Three out of six mPC patients (one at 60mg, two at 45mg) achieved SD, one of them at 45mg has been treated > 5 cycles with confirmed SD (-18%). Two patients, who were treated with APG-1387 at 20mg in combination with pembrolizumab, had no DLT observed during the first cycle. Preliminary PK data of APG-1387 showed a dose proportionality in exposure (Cmax and AUC) over the dose range of 20-60 mg. Conclusions: APG-1387 was well tolerated and had manageable adverse events. The potential effects of APG-1387 alone or in combination with pembrolizumab deserve further exploration in patients with advanced solid tumors, especially in the mPC patients. Clinical trial information: NCT03386526.

LY3022859 is an anti-TGFβRII IgG1 monoclonal antibody that inhibits receptor-mediated signaling activation. The primary objective of this phase I study was to determine a phase II dose in patients with advanced solid tumors. Secondary objectives were to assess safety and pharmacokinetics (PK). LY3022859 was infused intravenously (IV) at 1.25 mg/kg over 1 h every 2 weeks (Q2W) (cohort 1A) and at flat doses of 12.5 mg (cohort 1B) and 25 mg (cohort 2) over 3 h Q2W. Fourteen patients were enrolled in cohorts 1A (n = 2), 1B (n = 5), and 2 (n = 7). DLTs were experienced by both patients in cohort 1A (infusion-related reaction) and 2 patients in cohort 2 (cytokine release syndrome and infusion-related reaction). No MTD was determined. At the 25 mg dose level (cohort 2), after fifth infusion, LY3022859 had a short t1/2 (4.37-7.80 h) and rapid clearance (CLss, 0.412 L/h). Exposure increased twofold (from 28.5 to 60.2 μg·h/mL) with increase in dose from 12.5 to 25 mg. No accumulation was observed after repeat administration. The MTD for LY3022859 was not determined. Dose escalation beyond 25 mg was considered unsafe due to worsening symptoms (uncontrolled cytokine release) despite prophylaxis (corticosteroids and antihistamines). clinicaltrials.gov Identifier: NCT01646203.

2594Background: We have developed a unique strategy to tactically reduce on-target platelet toxicity with APG-1252, a novel dual Bcl-2/Bcl-xL inhibitor, while maintaining strong in vivo antitumor a...