A phase I study of a novel MDM2 antagonist APG-115 in patients with advanced solid tumors.

Abstract

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.

Targeted modulation of E3 ligases using engineered ubiquitin variants

“…This study suggested that MDM2 catalytic inhibitors can reactivate p53, while maintaining p53 at the basal level to reduce cytotoxicity. Currently, two small-molecule compounds, APG-115 and CGM097, are in clinical trial stages to address this opportunity [75,76]. CGM097 is designed to mimic three key hydrophobic interactions made by MDM2-binding pocket and P53 while making other stabilizing interactions [77] resulting in it being 4 times as potent as Nutlin-3A with lower toxicity [78].…”

“…Using the UbV platform, inhibitors were engineered to target and inhibit (SCF) E3 ligases by preventing Cul1 binding to the Skp1-F-Box complex, instead of binding to the known Ub-binding site [75] (Fig. 4F).…”

“…Furthermore, due to the multi‐subunit nature and similarities among all F‐Boxes, it is difficult to create small‐molecule inhibitors that display high specificity. Using the UbV platform, inhibitors were engineered to target and inhibit (SCF) E3 ligases by preventing Cul1 binding to the Skp1‐F‐Box complex, instead of binding to the known Ub‐binding site [75] (Fig. 4F).…”

Revolutionizing the landscape of colorectal cancer treatment: The potential role of immune checkpoint inhibitors

“…BI‐907828 safety and pharmacokinetics are currently being tested in a Phase Ia/Ib clinical trial in patients with advanced/metastatic solid malignancies regardless to MDM2 expression status (NCT03449381) 53 . A phase I study was initiated to test APG‐115 safety and pharmacokinetics in patients with advanced solid malignancies and the preliminary data indicated that APG‐115 is well tolerated (NCT02935907) 54 . The antitumor activity of a combination of APG‐115 with pembrolizumab is under testing in a Phase I/II clinical trial in patients with advanced/metastatic solid tumors (NCT03611868).…”

Design, Synthesis, and Antitumor Activity of a Series of Novel 4-(Aromatic Sulfonyl)-1-oxa-4-azaspiro[4.5]deca-6,9-dien-8-ones

“…In addition, the inclusion of a spiro ring structure is one of the important strategies for drug development in recent years [ 17 , 18 ]. Some antitumor compounds with a spiro ring moiety such as SAR405838, DS-3032b, and APG-115 are undergoing clinical trials ( Figure 1 ) [ 19 , 20 , 21 ]. Spirodienone derivatives of hybridized quinone and spiro scaffolds have a wide range of biological activities [ 22 ].…”