First-in-human phase I trial of the dual mTORC1 and mTORC2 inhibitor AZD2014 in solid tumors.

• DOI: 10.1200/jco.2012.30.15_suppl.3004
• Publication Date: 2020-03-11T15:10:19Z
• Authors: Udai Banerji; Emma Jane Dean; Michael Gonzalez; Alastair P Greystoke; Bristi Basu; Matthew Krebs; Martina Puglisi; Lynda Grinsted; Elisabeth Oelmann; Wendy Burke; Elizabeth Harrington; Stephen Green; Malcolm Ranson
• Keywords: Lethargy; Mucositis; Tolerability; Pharmacodynamics

3004 Background: AZD2014 is a potent, dual mTORC1/mTORC2 inhibitor with clear activity in vivo and vitro experimental models. Methods: This 2-part study consisted of "rolling six" dose escalation (Part A) expansion B) phases. Part A: 3–6 pts per cohort received an oral solution BD starting at 50 mg. A further 6 were treated below the MTD to changes pharmacodynamic (PD) biomarkers. B: additional dosed MTD, including group ER+/PR+ or HER2+ patients breast cancer. Primary endpoint: safety tolerability; secondary endpoints: pharmacokinetics (PK), PD efficacy. Biomarkers assessed: mTORC1: pS6 (S235/236) p4EBP1 (T37/46); mTORC2: pAKT (S473). Results: have been enroled this ongoing interim data are reported: A, n=23 (25 mg, n=6; n=8; 70 n=5; 100 n=4; all BD); B, n=27. The was mg BD. DLTs seen both (Gr 2 3 lethargy/fatigue, n=4/4) mucositis, Gr lethargy, n=2/4); no 25 most common AEs order incidence fatigue, stomatitis, decreased appetite, nausea diarrhea. Seven SAEs (nausea, vomiting, abdominal pain, mucositis) reported by considered ‘possibly related’ drug investigators. rapidly absorbed following single multiple doses short t 1/2 ~3 h. At (n=32), preliminary show geometric mean AUC ss =7.4 µg.h/ml C max =1.7 µg/ml. One pt acinar pancreatic cancer had RECIST partial response. reductions observed between 2–8 h platelet-rich plasma peripheral blood mononuclear cells respectively. Target modulation paired tumor biopsies MTD. Reduction phosphorylation S6 4EBP1 evident 8/10 3/9 reduced 3/6 evaluable biopsies. As opposed rapalogs, not upregulated any post-treatment Conclusions: for Further clinical evaluation now warranted based on safety, PK proof-of-mechanism data, as well its activity. Updated results will be presented.