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3016 Background: BI 907828, a highly potent and orally administered MDM2-p53 antagonist, showed antitumor efficacy in vivo, especially in TP53 wild-type MDM2-amplified de-differentiated liposarcoma (DDLPS) patient-derived xenografts and syngeneic models. Methods: NCT03449381 is a phase I study of BI 907828 in pts with solid tumors. The objectives of the dose-escalation part were to determine the maximum tolerated dose (MTD) based on the frequency of pts with dose-limiting toxicities (DLTs) during cycle 1, determine the recommended dose for expansion, and evaluate the safety and tolerability of two dosing schedules: BI 907828 given on day 1 of 21-day cycles (Arm A) or days 1 and 8 of 28-day cycles (Arm B). Dose escalation was guided by a Bayesian logistic regression model. The secondary objectives include pharmacokinetics (PK), pharmacodynamics and antitumor activity. Results: At January 15, 2021, 54 pts with advanced solid tumors (median of 2 lines of prior systemic therapies; range 0–11) were treated with BI 907828 (Arm A, 29 pts, dose range 10–80 mg; Arm B, 25 pts, dose range 5–60 mg). In Arm A, 5 pts experienced DLTs in cycle 1, including one Grade (Gr) 3 Nausea and one Gr 3 Thrombocytopenia at 45 mg, one Gr 3 Enterocolitis at 60 mg, and one Gr 4 Neutropenia and one Gr 4 Thrombocytopenia at 80 mg. In Arm B, 3 DLTs were reported: one Gr 4 Thrombocytopenia at 45 mg, one Gr 4 Neutropenia associated with Gr 4 Thrombocytopenia, and one Gr 3 Neutropenia at 60 mg. The most common Gr 3/4 treatment-related adverse events (AEs) were Thrombocytopenia (28.6%), Neutropenia (10.7%) and Nausea (10.7%) in Arm A, and Thrombocytopenia (16.6%) and Neutropenia (12.5%) in Arm B. Preliminary PK data indicate that BI 907828 reaches Tmax at 4–6 h. Mean plasma exposures (Cmax and AUC0-inf) increased with dose. The geometric mean (gMean) Clearance/F was 5–19 mL/min and the gMean apparent volume of distribution was 23–57 L. The gMean half-lives estimated after the 1st dose were 26–55 h. Inter-patient variability in exposure was moderate. An increase in the target engagement biomarker GDF-15 in plasma was observed. The mean fold-change from baseline ranged from 8 to 49. Antitumor activity was seen in both schedules. In Arm A, a confirmed PR was seen in 2 pts with MDM2-amplified LPS (one PR lasted > 2 years) and SD in 17 pts. In Arm B, 2 pts had PR (one confirmed in MDM2-amplified LPS and one not yet confirmed in MDM2-amplified pancreatic adenocarcinoma) and 14 had SD. Of note, 5 of 10 pts with DDLPS were progression-free for ≥9 months. Conclusions: BI 907828 showed a manageable safety profile, favorable PK properties and early signs of efficacy, especially in MDM2-amplified tumors. With both dosing regimens, DLTs were Neutropenia and Thrombocytopenia. Non-hematologic AEs, mainly gastrointestinal, were mostly low-grade and not dose-limiting. The MTD of 60 mg in Arm A (day 1 of 21-day cycles) and 45 mg in Arm B (days 1 and 8 of 28-day cycles) are awaiting confirmation. Clinical trial information: NCT03449381.

11542 Background: APG-115 is a potent, small-molecule MDM2 inhibitor and immune modulator with promising antitumor activities in various tumors, especially those wild-type TP53 with MDM2 amplification ( TP53wt+MDM2 amp). To better delineate safety, optimal dosage, and potential target population, we report updated results. Methods: Patients with advanced liposarcoma and other solid tumors received APG-115 (100-200 mg) orally every other day for 21 days of a 28-day cycle. The primary endpoints were safety and tolerability. Efficacy (assessed by RECIST v1.1), pharmacokinetics (PK) and pharmacodynamics (PD) have also been analyzed. Results: Enrollment of this Phase I study (CTR20170975) was completed. As of January 7, 2020, 21 patients (14 liposarcomas, 2 synovial sarcomas, 2 adenoid cystic carcinomas, 1 chondrosarcoma, 1 osteosarcoma, 1 rhabdomyosarcoma) were treated in 3 dose levels of APG-115: 100 mg (n = 11), 150 mg (n = 8) and 200 mg (n = 2). The median number of cycles of APG-115 was 2 (0; 6). Two DLTs were observed at 200 mg, thrombocytopenia and febrile neutropenia. The most common treatment-emergent adverse events (TEAEs) (≥20%) included leukopenia, thrombocytopenia, neutropenia, anemia, increased blood creatinine, hypercholesterolemia, hypertriglyceridemia, hypoalbuminemia, vomiting, and nausea. The incidence of TEAEs was much lower at 100 mg. Serious AEs occurred in 5 patients (23.8%) which were assessed as possibly drug related by investigators. In 20 efficacy-evaluable patients, there was 1 patient with a partial response, 12 patients with stable disease, and 7 patients with progressive disease, yielding a disease control rate (CR, PR, SD) of 61.9%. Among the 13 patients (9 liposarcomas) who benefited, 11 had TP53wt and 7 had TP53wt+MDM2 amp, including one liposarcoma patient (150 mg) who had a PR, she was kept-up over 10 months, even though the treatment was discontinued for over 5 months, indicating the host immune modulatory effects of APG-115. Another patient with liposarcoma (100 mg, TP53wt+MDM2 amp) had 28.5% tumor shrinkage at cycle 4 and remained on treatment. PK results showed an approximately dose-proportional increase in exposure on Day 1. PK-PD analyses showed the serum macrophage inhibitory cytokine-1 (MIC-1) increased with increased APG-115 exposure. Conclusions: The phase I data have demonstrated that APG-115 monotherapy was well tolerated, with minimal toxicity at 100mg (RP2D), and conferred encouraging anti-tumor activities in patients with liposarcomas. Clinical trial information: CTR20170975 .

3124 Background: APG-115 is a novel and orally active small-molecule MDM2 inhibitor. APG-115 alone or in combination with chemotherapeutic, targeted or IO agents have shown potent antitumor activities in multiple human xenograft tumor models and human cancer patient derived xenograft (PDX) models. Methods: The patients with advanced solid tumors were enrolled in this study in China (CTR20170975). The study objectives were to assess safety, pharmacokinetics (PK), pharmacodynamics (PD) and antitumor activity of APG-115. The patients received APG-115 (ranging 100–200 mg) orally QOD for first 21 days of a 28-day-cycle, until disease progression. Antitumor response assessment was performed every 8 weeks per RECIST v1.1. Archived tumor tissues were collected for analyses of MDM2 and TP53 before treatment. Results: As cut-off on Jan 4 2019, total 13 patients (9 soft tissue sarcomas (STSs), 2 adenoid cystic carcinomas (ACCs) and 2 osteosarcomas) were treated in 3 cohorts of APG-115 (100mg, 150mg, 200mg). The median number of prior systemic anticancer therapies was 2 (range 0-4). Two DLTs were observed in one patient at 200mg including thrombocytopenia and febrile neutropenia. The most common TEAEs (≥50% of pts) included: anemia, thrombocytopenia, vomiting, hypercholesterolaemia, and leukopenia. SAEs occurred in 7 patients (54%), four of which were treatment related. The most common Grade 3 or 4 TRAEs were anemia (38.5%), thrombocytopenia (38.5%), leukopenia (30.8%), and neutropenia (23.1%). One partial response was observed in a liposarcoma patient with MDM2-amplification and TP53-wild type at the 150mg cohort, 5 patients (3 STSs, 2 ACCs) had SD as the best overall response. PK analyses indicated an approximately dose proportional increase in Cmax and AUC0-t following a single or multiple oral administration across dose levels. Preliminary PD data showed that serum MIC-1 increase was exposure dependent within the dose range tested. Conclusions: Preliminary data suggested that APG-115 had promising anti-tumor activity in treatment of patients with MDM2-amplification and TP53-WT liposarcoma. Safety profile and PD effect were consistent with other MDM2 inhibitors. Dosing regimen optimization are ongoing. Clinical trial information: CTR20170975.

TPS3166 Background: Inactivation of tumor protein 53 (TP53) is a central mechanism of tumors to promote survival and proliferation. The murine double minute 2 ( MDM2) oncogene is the primary cellular negative regulator of TP53. Small molecule inhibitors of the MDM2-p53 interaction are currently being evaluated in clinical trials as new anti-cancer drugs, and clinical data published to date support the rationale to target MDM2-amplified tumors. BI 907828 is a potent MDM2-p53 antagonist that has shown efficacy in mouse models of human cancer. Methods: NCT03449381 is a Phase 1a/1b, open-label, multicenter, dose-escalation trial of BI 907828 in patients aged ≥18 years with advanced/metastatic solid tumors. Primary objectives of the Phase 1a (dose-escalation) part are to determine: the maximum tolerated dose (MTD) of BI 907828 based on dose-limiting toxicities (DLTs) during the first treatment cycle; the recommended dose for expansion (RDE); safety and tolerability. Patients in Arm A will receive one dose of BI 907828 every 21 days, and patients in Arm B one dose on Days 1 and 8, every 28 days. Secondary objectives include pharmacokinetics (PK), pharmacodynamics (PD) [GDF-15 induction in plasma], and preliminary anti-tumor activity. Primary endpoints are the number of patients with DLTs during the first treatment cycle, and the MTD. Phase 1a will include ≈50 evaluable patients with locally advanced or metastatic solid tumors with either a known TP53 wild type (wt) status or unknown TP53 status, regardless of MDM2 amplification status at the time of study entry. The main objectives of Phase 1b (expansion cohorts) are to assess efficacy, safety, and PK profiles at the RDE, and to determine the recommended dose for Phase 2. The primary endpoint is objective response, where best response is determined according to RECIST v1.1, or RANO criteria for patients with glioblastoma. Phase 1b will include up to 150 evaluable patients with TP53 wt tumors, assigned to four different cohorts, including non-squamous NSCLC, soft tissue sarcoma, glioblastoma, urothelial carcinoma, and solid tumors with brain metastases. As of 8th February 2019, 11 patients have been enrolled. Clinical trial information: NCT03449381.