Introduction: Somatic mutations in the metabolic enzymes isocitrate dehydrogenase (IDH) 1 and 2 occur in a spectrum of solid and hematologic malignancies. Mutant IDH1/2 in cancer cells results in the neomorphic production of the oncometabolite, D-2-hydroxyglutarate (2-HG), which impairs cellular differentiation via an epigenetic mechanism. AG-120 is a first-in-class, oral, potent, reversible and selective inhibitor of mutated IDH1 protein. We report preliminary results from the ongoing, first-in-human, phase 1, open-label, single-arm study of AG-120 (NCT02073994). Aims: Key objectives are to evaluate the safety, tolerability, and maximum tolerated dose (MTD), pharmacokinetics (PK), pharmacodynamics (PD), and preliminary clinical activity. Key exploratory objectives include an analysis of tumor tissue samples in non-glioma subjects and magnetic resonance imagining/spectroscopy (MRI/MRS) in glioma subjects, pre and on AG-120 treatment. Methods: Patients with advanced, IDH1-mutant solid tumors, including glioma, who have recurred or progressed following standard therapy, or who have not responded to standard therapy, are eligible to receive continuous, single-agent, oral AG-120 dosed daily in 28-day cycles. Informed consent is obtained prior to entry. Sequential dose cohorts are being enrolled, with expansion cohorts planned. Blood and tumor biopsies are collected for PK/PD assessment. Objective responses are investigator assessed using either RECIST or RANO criteria for subjects with solid tumors and gliomas, respectively. Results: As of 1 July 2015, 55 patients (glioma: 20, non-glioma: 35) were treated with AG-120. Median age was 54 years (range, 23-88) and median number of prior systemic regimens 3 (range, 1-6). Doses administered were 100 mg BID (n = 4), 300 mg QD (n = 9), 400 mg QD (n = 5), 500 mg QD (n = 17), 600 mg QD (n = 5), 800 mg QD (n = 6), 900 mg QD (n = 4), and 1200 mg QD (n = 5). Median treatment duration was 1.9 months (range, 0.1-12.5). The MTD was not reached. PK analyses showed high plasma exposure and drug accumulation following oral administration and a mean half-life of 73.1 ± 66.6 hr. Overall, treatment was well tolerated: 49 patients experienced treatment-emergent adverse events (AEs), regardless of causality. Most frequently occurring AEs (%) were nausea (21.8), diarrhea (16.4), vomiting (14.5), anemia (12.7), and abdominal pain (10.9). There were no treatment-related serious AEs. Summary/Conclusion: AG-120 is a first-in-class, oral, potent, selective inhibitor of mutant IDH1 in development for solid and liquid tumors. Updated safety and clinical activity, as well as exploratory PD analyses will be presented. Future development plans for AG-120 in solid tumors will also be highlighted. Citation Format: Howard Burris, Ingo Mellinghoff, Elizabeth Maher, Patrick Wen, Murali Beeram, Mehdi Touat, Jason Faris, Nilofer Azad, Timothy Cloughesy, Lia Gore, Jonathan Trent, Daniel Von Hoff, Meredith Goldwasser, Bin Fan, Sam Agresta. The first reported results of AG-120, a first-in-class, potent inhibitor of the IDH1 mutant protein, in a Phase I study of patients with advanced IDH1-mutant solid tumors, including gliomas. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr PL04-05.

Introduction FASN inhibition causes selective disruption of palmitate biosynthesis that, in tumor cells, leads to apoptosis. TVB-2640 is an oral, first-in-class, small molecule reversible inhibitor of FASN that demonstrated in vivo antitumor effects. We previously reported the results of dose escalation and now present evidence of activity in patients (pts) treated in the dose expansion cohorts. Methods This fully enrolled multicenter phase I trial included pts with advanced solid tumors. TVB-2640 was given PO once daily at the MTD (100 mg/m2) as monotherapy (mono) or in combination (combo) with weekly IV paclitaxel (80 mg/m2). Results The most common related AEs observed in both groups (mono, N=44, combo, N=43) included alopecia (41%), palmar-plantar erythrodysesthesia (PPE) (47%), and decreased appetite (13%). Additional common AEs in the mono group included dry skin (19%) and in the combo group included nausea (28%). Gr3 related AEs included decreased appetite (8%) and PPE (9%); all other related AEs were ≤ Gr2. All related AEs were reversible on dose interruption. No enhancement of paclitaxel toxicity was observed with TVB-2640. Pneumonitis in the combo arm was observed uncommonly (9%), but the contribution of TVB-2640 to this effect is uncertain. Pharmacokinetic analyses showed that TVB-2640 had a similar half-life whether given alone or in combo with paclitaxel. Clearance rates were similar on days 1 and 8 (or day 15 for combo). Multiple pharmacodynamic markers demonstrated potent inhibition of FASN and lipogenesis in pts. With respect to clinical activity, overall, 5 confirmed RECIST partial responses (cPR) were seen. Among pts with NSCLC, 18 of 31 were KRASmut, and KRASmut pts achieved longer progression-free survival on TVB-2640 monotherapy, with 60% of KRASmut pts vs. 0% of KRASwt pts on study > 12 wks. Among 18 KRASmut pts, 11 achieved prolonged SD (≥16 wks), including 6 mono pts (SD=19-46 wks) and 5 combo pts (SD=23-54 wks), whereas no KRASwt pts achieved prolonged SD. One NSCLC combo pt achieved cPR at wk 12 and remained on study for 39 wks. Of 14 breast cancer pts, 3 pts achieved cPR and 8 pts achieved prolonged SD (≥16 wks), despite extensive previous treatment, including taxane resistance. One ongoing breast cancer pt with SD, entering her 78th wk of treatment, discontinued paclitaxel at wk 35 and remains on monotherapy . One pt with peritoneal carcinoma (combo) achieved cPR and a 58% decrease in CA125. Reductions in CA125 were seen in 5 out of 12 ovarian cancer pts, who were typically heavily pretreated and taxane-resistant. Summary TVB-2640 demonstrated antitumor activity, including objective responses when combined with weekly paclitaxel, as well as prolonged SD as monotherapy or in combination with paclitaxel. Further studies are planned to evaluate the efficacy of TVB-2640 in NSCLC and breast cancer pts. Citation Format: Gerald Falchook, Manish Patel, Jeffrey Infante, Hendrik-Tobias Arkenau, Emma Dean, Andrew Brenner, Erkut Borazanci, Juanita Lopez, Kathleen Moore, Peter Schmid, Arthur Frankel, Suzanne Jones, William McCulloch, George Kemble, Howard Burris. First in human study of the first-in-class fatty acid synthase (FASN) inhibitor TVB-2640 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT153. doi:10.1158/1538-7445.AM2017-CT153

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