Phase Ii Of Abtl0812, A Pro-Autophagic Drug, In Combination With Paclitaxel And Carboplatin (P/C) As First-Line Treatment In Advanced/Recurrent Endometrial Cancer

ABTL0812 induces cytotoxic autophagy-mediated cell death. It inhibits Akt/mTOR axis by upregulating TRIB3, an endogenous Akt inhibitor, and induces reticular (ER)-stress. Preclinical data in endometrial cancer (EC) indicated efficacy as a single agent and synergy with chemotherapy. A phase I of ABTL0812 with P/C confirmed the safety of the triple combination. A single-arm phase II study was designed where ABTL0812 was administered 1300 mg TID orally with P/C 175 mg/m2/ AUC5 D1 every 3 weeks, followed by ABTL0812 as a maintenance until disease progression or unacceptable toxicity. The study enrolled patients (pts) with advanced/recurrent EC except carcinosarcoma and leiomyosarcoma. Primary endpoint was overall response rate (ORR) by RECIST criteria v.1.1. Secondary endpoints were progression free survival (PFS), duration of response (DOR), safety and tolerability according to CTCAE v4.03 and pharmacokinetics (PK). Target modulation was assessed by two pharmacodynamic (PD) markers: TRIB3 and CHOP (an ER-stress biomarker) in blood. 42 pts received at least 1 dose of ABTL0812 and 34 were evaluable (median age: 67.9 years old; 15 advanced / 19 recurrent; 23 endometrioid / 2 serous / 2 clear cell / 7 not determined -ND; 3 grade-1, 7 grade-2, 9 grade-3 / 15 ND). ORR was 66% (95% CI: 46-80%), DOR was 7.8 months (6.3-10.8) and PFS was 10.2 months (7.1-11.4). Most frequent hematological adverse events (AEs) were neutropenia (all grades 23.8%, grade≥3 14.3%), anemia (21.4%, 2.4%) and thrombocytopenia (9.5%, 2.4%). Most frequent non-hematological AEs were nausea (47.6%, 2.4%), asthenia (45.2%, 0), vomiting (42.9%, 0), diarrhea (26.2%, 0), arthralgia and neurotoxicity (both 23.8%, 0). PK and PD analysis performed at 4 weeks showed that Cmax were 8.0/5.5 mg/L and t1/2 3.3/2.0 h for -/+-ABTL0812; TRIB3 and CHOP levels increased. The combination of ABTL0812+P/C shows promising results with an acceptable safety and tolerability profile. These outcomes look promising compared with historical controls and warrant further investigation. PK and PD profiles indicate sustained target modulation.