Phase 1 of ABTL0812, a proautophagic drug, in combination with paclitaxel and carboplatin at first-line in advanced endometrial cancer and squamous cell lung carcinoma

Publications

Phase 1 of ABTL0812, a proautophagic drug, in combination with paclitaxel and carboplatin at first-line in advanced endometrial cancer and squamous cell lung carcinoma

Author(s): Lorena Farinas-Madrid, Purificación Estévez-García, Jose Alejandro Perez-Fidalgo, Joaquim Bosch-Barrera, Teresa Moran, Ernest Nadal, Victor Rodriguez Freixinos, Elisa Calvo, Alejandro Falcon, Paloma Martín-Martorell, Marisol Huerta Alvaro, Maria Pilar Barretina-Ginesta, Margarita Romeo, Marta Gil-Martin, Elena Garralda, Jordi Rodon, Jose M. Lizcano, Carles Domenech, Jose Alberto Alfon, Ana Oaknin; Vall d’Hebron University Hospital Institute of Oncology (VHIO), Barcelona, Spain; Unidad de Tumores Ginecológicos y Genitourinarios, Servicio de Oncologia Médica, Hospital Universitario Virgen del Rocío, Seville, Spain; INCLIVA Research Institute and Hospital Clínico Universitario de Valencia, Valencia, Spain; Institut Catala d'Oncologia, Universitary Hospital Dr. Josep Trueta, Girona, Spain; Institut Català d'Oncologia, Hospital Germans Trias i Pujol, Badalona, Spain; Institut Català d’Oncologia, L’Hospitalet, Barcelona, Spain; Vall d'Hebron Institut of Oncology, Barcelona, Spain; Servicio de Oncologia Médica, Hospital Universitario Virgen del Rocío, Seville, Spain; Medical Oncology Department. Hospital Universitario Virgen del Rocío, Seville, Spain; Hospital Clinic Universitario de Valencia, Valencia, Spain; Oncología Médica, Hospital Universitario de Valencia, Valencia, Spain; Medical Oncology Department, Catalan Institute of Oncology, Girona, Spain; Medical Oncology Department, Institut Català d’Oncologia (ICO) Badalona, B-ARGO, Badalona, Spain; Institut Català d'Oncologia-ICO L’Hospitalet, Barcelona, Spain; Hospital Universitari Vall d’Hebron, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain; Institut de Neurociencies, Universitat Autonoma de Barcelona, Bellaterra, Barcelona, Spain; Ability Pharmaceuticals, Barcelona, Spain; Ability Pharmaceuticals SL, Cerdanyola Del Valles, Spain; Vall d’Hebron University Hospital, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain

Meeting: 2019 ASCO Annual Meeting - Abstract No: 3089 - Poster Board Number: Poster Session (Board 81) - Citation: J Clin Oncol 37, 2019 (suppl; abstr 3089)

Abstract:

Background: ABTL0812 is a novel anti-cancer agent that induces a strong autophagy-mediated cell death by a dual mechanism. It inhibits the Akt/mTOR axis by upregulating TRIB3, an endogenous Akt inhibitor, and induces reticular (ER)-stress. Preclinical data in squamous non-small cell lung carcinoma (Sq-NSCLC) and endometrial cancer (EC) has indicated drug efficacy as a single agent and potentiation of chemotherapy. Methods: A phase 1 clinical study was designed where ABTL0812 was administered orally in combination with 175 mg/m²paclitaxel/carboplatin AUC5 D1 every 3 weeks (P/C), and posterior ABTL0812 as a maintenance therapy until disease progression or unacceptable toxicity. The study included first-line patients (pts) with advanced Sq-NSCLC or advanced/recurrent EC. The design included a 3+3 de-escalation trial followed by an expansion cohort, where the starting dose of ABTL0812 was 1300 mg tid and if at least 2 pts experienced a DLT, the dose level would be de-escalated to 1000 mg tid. Safety and tolerability were the primary endpoints and preliminary efficacy according to RECIST v1.1 criteria and pharmacodynamic biomarkers (TRIB3 and CHOP an ER-stress biomarker, by qPCR in whole blood) were the secondary endpoints. Results: 16 EC and 5 Sq-NSCLC pts were enrolled. One DLT, a grade 4 neutropenia, appeared in the first cohort of 6 pts and no de-escalation was applied. Fourteen pts were included in an expansion cohort with the same dose level (1300 mg tid), and 1 DLT, a grade 3 febrile neutropenia, was observed. Therefore, the dose of 1300 mg tid was selected as RP2D in combination with P/C. Most frequent grades 2-4 AEs were neutrophil count decreased (n = 9, 43%), nausea (n = 5, 24%), fatigue (n = 4, 19%), followed by anemia, vomiting, dyspepsia, platelet count decreased, arthralgia and neurotoxicity (n = 2, 10% each). Seventeen pts (13 EC and 4 Sq-NSCLC) who completed at least two treatment cycles were evaluable for efficacy; 1 CR (EC), 8 PR (7 EC and 1 Sq-NSCLC), 7 SD (5 EC and 2 Sq-NSCLC) and 1 PD (Sq-NSCLC) were observed. Pharmacodynamic biomarkers showed increased TRIB3 and CHOP levels. Conclusions: The combination of ABTL0812+P/C was safe and tolerated, efficacy signals were observed, and biomarker modulation confirmed drug activity. The triple combination is currently being evaluated in both indications in a Phase 2 study. Clinical trial information: NCT03366480