Mammalian target of rapamycin (mTOR) regulates cellular processes important for progression of human cancer. RAD001 (everolimus), an mTORC1 (mTOR/raptor) inhibitor, has broad antitumor activity in preclinical models and cancer patients. Although most tumor lines are RAD001 sensitive, some are not. Selective mTORC1 inhibition can elicit increased AKT S473 phosphorylation, involving insulin receptor substrate 1, which is suggested to potentially attenuate effects on tumor cell proliferation and viability. Rictor may also play a role because rictor kinase complexes (including mTOR/rictor) regulate AKT S473 phosphorylation. The role of raptor and rictor in the in vitro response of human cancer cells to RAD001 was investigated. Using a large panel of cell lines representing different tumor histotypes, the basal phosphorylation of AKT S473 and some AKT substrates was found to correlate with the antiproliferative response to RAD001. In contrast, increased AKT S473 phosphorylation induced by RAD001 did not correlate. Similar increases in AKT phosphorylation occurred following raptor depletion using siRNA. Strikingly, rictor down-regulation attenuated AKT S473 phosphorylation induced by mTORC1 inhibition. Further analyses showed no relationship between modulation of AKT phosphorylation on S473 and T308 and AKTsubstrate phosphorylation patterns. Using a dual pan-class I phosphatidylinositol 3-kinase/mTOR catalytic inhibitor (NVP-BEZ235), currently in phase I trials, concomitant targeting of these kinases inhibited AKT S473 phosphorylation, eliciting more profound cellular responses than mTORC1 inhibition alone. However, reduced cell viability could not be predicted from biochemical or cellular responses to mTORC1 inhibitors. These data could have implications for the clinical application of phosphatidylinositol 3-kinase/mTOR inhibitors.

Background: NVP-HDM201 is a selective inhibitor of the p53-HDM2 interaction and has demonstrated potent single-agent activity in various in vitro and in vivo tumor models, dependent on wild-type (wt) TP53. This study aims to determine the optimal dose and schedule of NVP-HDM201 for treating patients (pts) with TP53 wt tumors for further clinical study. Here we focus on pts with advanced, TP53 wt acute leukemias. Methods: In this multicenter, open-label, dose-finding, Phase I study, pts with advanced, TP53 wt tumors who had relapsed or refractory acute myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL) were treated with single-agent oral NVP-HDM201. Four treatment regimens were explored: two high-dose intermittent regimens (reg), Reg 1A and 1B (1A: Day 1 of a 3-week [wk] cycle; 1B: Days 1 and 8 of a 4-wk cycle) and two low-dose extended regimens, Reg 2A and 2C (2A: once daily for the first 2 wks of a 4-wk cycle; 2C: once daily for the first wk of a 4-wk cycle). Results: As of Dec 07, 2016, a total of 37 pts, comprising 35 pts with AML and 2 pts with ALL, had been enrolled in the study (Reg 1A n=16; Reg 1B n=6; Reg 2A n=7; Reg 2C n=8); treatment is ongoing in 3 pts (2 in Reg 1B and 1 in Reg 2C). The most common Grade 3/4 adverse events (AEs) suspected to be treatment-related (occurring in ≥25% of pts; Reg 1A; Reg 1B; Reg 2A; Reg 2C) were thrombocytopenia (50%; 50%; 29%; 50%), tumor lysis syndrome (TLS; 44%; 0; 14%; 13%), neutropenia (38%; 17%; 0; 25%), anemia (25%; 33%; 29%; 38%), febrile neutropenia (25%; 33%; 29%; 38%), and decreased white blood cell count (0; 0; 14%; 25%). Six dose-limiting toxicities (DLTs) were observed in 4 pts at 400 mg in Reg 1A: G4 hypophosphatemia (n=2), G3 infection (n=1), G3 chronic graft versus host disease (n=1), G3 stomatitis (n=1), and G4 subarachnoid hemorrhage (n=1). One DLT each occurred in Reg 1B (G4 acute kidney injury at 150 mg) and Reg 2C (G4 TLS at 45 mg). Importantly, there were no dose-limiting gastrointestinal (GI) toxicities. NVP-HDM201 also showed approximate dose-proportional pharmacokinetics (PK) and pharmacodynamics. Investigator-assessed overall response rate (CR + CRi + PR) for all pts with AML who had ≥1 post-baseline assessment (n=34) was 20.6% (95% confidence interval: 8.7-37.9%). There were 3 CRs (2 in Reg 1A; 1 in Reg 2C) and 4 CRis (1 in Reg 1B; 3 in Reg 2C). CRs/CRis were observed in pts receiving a cumulative dose of 250 mg within the first wk of treatment. Conclusions: Across all regimens, the AEs reported were overall expected and manageable, with no dose-limiting GI toxicities. The recommended dose for expansion (RDE) was declared as 45 mg in Reg 2C, based on the manageable safety profile, therapeutically relevant exposures determined by PK modeling, and meaningful antitumor activity seen at this dose level of NVP-HDM201. RDE determination for Reg 1A and Reg 1B is ongoing. Preliminary anti-leukemic activity is promising in these pts and warrants further study of this agent in AML. Citation Format: Eytan Stein, Joerg Chromik, Daniel J. DeAngelo, Manik Chatterjee, Richard Noppeney, Filip de Vos, Hironobu Minami, Sébastien Jeay, Christophe Meille, Ensar Halilovic, Luisa Mariconti, Matthieu Klopfenstein, Nelson Guerreiro, Rajkumar Radhakrishnan, Emil T. Kuriakose, Cecilia Carpio. Phase I dose- and regimen-finding study of NVP-HDM201 in pts with advanced TP53 wt acute leukemias [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 CT152. doi:10.1158/1538-7445.AM2017-CT152

Background: NVP-HDM201 is a selective inhibitor of the p53-HDM2 interaction, and has demonstrated potent single-agent activity in various in vitro and in vivo tumor models dependent on wild-type (wt) TP53. This study aims to determine the optimal dose and schedule of NVP-HDM201 for treating patients (pts) with TP53 wt tumors for further clinical study. Here we report results from pts with solid tumors. Methods: In this multicenter, open-label, Phase I, ongoing study, pts with advanced TP53 wt tumors progressing on standard therapy or for whom no standard therapy exists were treated with single-agent oral NVP-HDM201. Four treatment regimens of NVP-HDM201 are explored: two high-dose intermittent regimens, Regimen (Reg) 1A (single dose [SD] on Day 1 in a 3-week [wk] cycle) and Reg 1B (SD on Days 1 and 8 in a 4-wk cycle); and two low-dose extended regimens, Reg 2A (SD every day for first 2 wks in a 4-wk cycle) and Reg 2C (SD every day for first wk in a 4-wk cycle). Results: As of the data cut-off (Sep 19, 2016), 85 pts received NVP-HDM201 (Reg 1A n=26; Reg 1B n=20; Reg 2A n=20; Reg 2C n=19); 13% were still receiving treatment. Common Grade 3/4 adverse events (AEs) suspected to be treatment related (Reg 1A; Reg 1B; Reg 2A; Reg 2C) included neutropenia (23%; 25%; 15%; 5%), thrombocytopenia (23%; 10%; 20%; 11%), and anemia (12%; 0%; 20%; 16%); the first two were dose limiting in 4 pts (2; 1; 0; 1). Gastrointestinal toxicity was predominantly low grade, and not dose limiting; the most common treatment-related AE reported was nausea (62%; 60%; 40%; 42%). Median duration of exposure across all regimens was 8.5 weeks (range: 2-86 weeks). Partial responses were observed in 2 (2%) pts (1 in Reg 1A and 1 in Reg 1B). Stable disease was achieved by 29 (34%) pts (8 in Reg 1A, and 7 each in Reg 1B, Reg 2A and Reg 2C). Furthermore, the average plasma concentration per cycle reached with Reg 1A/Reg 1B was closer to the predicted preclinical target efficacious levels required for tumor regression compared with Reg 2A/Reg 2C, and is associated with the observed clinical activity. NVP-HDM201 showed approximate dose-proportional pharmacokinetics, and exposure correlated with blood concentrations of the GDF-15 biomarker on day 1. Conclusions: NVP-HDM201 demonstrated a manageable safety profile and clinical activity in a heavily pretreated population. Dose-limiting toxicities consisted primarily of neutropenia and thrombocytopenia. Reg 1B was chosen for the expansion phase as it achieved the most favorable therapeutic index: the lowest incidence of Grade 3/4 thrombocytopenia while achieving therapeutically relevant exposures. The recommended dose for expansion was declared as 120 mg NVP-HDM201 and the expansion phase is enrolling. To enhance the safety and efficacy of NVP-HDM201, a separate cohort combining NVP-HDM201 with eltrombopag to mitigate thrombocytopenia is being investigated and will be reported. Citation Format: David M. Hyman, Manik Chatterjee, Filip de Vos, Chia-Chi Lin, Cristina Suárez, David Tai, Philippe Cassier, Noboru Yamamoto, Vincent A. de Weger, Sébastien Jeay, Christophe Meille, Ensar Halilovic, Luisa Mariconti, Matthieu Klopfenstein, Nelson Guerreiro, Rajkumar Radhakrishnan, Emil T. Kuriakose, Sebastian Bauer. Optimizing the therapeutic index of HDM2 inhibition: Results from a dose- and regimen-finding Phase I study of NVP-HDM201 in pts with TP53 wt advanced tumors [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 CT150. doi:10.1158/1538-7445.AM2017-CT150

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Background: NVP-HDM201 is a selective inhibitor of the p53-HDM2 interaction, demonstrating potent preclinical activity, and is currently in Phase I clinical development. As delayed thrombocytopenia is the primary dose-limiting toxicity (DLT) of NVP-HDM201 treatment, reducing the incidence, severity, and duration of thrombocytopenia is critical to maximizing the therapeutic effect. Using data from the ongoing Phase I study of NVP-HDM201 in patients (pts) with TP53 wild-type (wt) tumors, a mechanism-based pharmacokinetic/pharmacodynamic (PK/PD) model describing drug-induced longitudinal platelet changes and tumor growth kinetics was developed to complement the clinical data in guiding dose escalation decisions and selection of an optimal dosing regimen for NVP-HDM201. Methods: In the ongoing Phase I study of NVP-HDM201 in pts with advanced TP53 wt solid and hematologic tumors, 4 oral treatment regimens of NVP-HDM201 are being explored: Regimen (Reg) 1A (single dose [SD] on Day 1 every 3 weeks [wks]); Reg 1B (SD on Days 1 and 8 every 4 wks); Reg 2A (SD daily on Days 1-14 every 4 wks); Reg 2C (SD daily on Days 1-7 every 4 wks). Population PK and PK/PD models of thrombocytopenia and GDF-15 (a transcriptional target of activated p53) were developed based on data from 85 pts with solid tumors. The PK/PD relationship for plasma GDF-15 was quantitatively integrated into a thrombocytopenia model to explore the link between cellular drug potency on platelets and stimulation of plasma GDF-15 levels. In addition, a PK/PD model of tumor growth kinetics was explored. Results: As of the data cut-off (September 19, 2016), 85 pts with solid tumors have been enrolled in the study (Reg 1A/1B; Reg 2A/2C: 46; 39) and treatment is ongoing in 11 (13%) pts. Thrombocytopenia and neutropenia were the main DLTs observed. The PK/PD model accurately reproduced the platelet time course after NVP-HDM201 administration and was used to guide dose escalation and regimen/dose selection for expansion phase. Model simulations predicted Reg 1B to achieve target exposures while having the lowest rate and duration of thrombocytopenia, as observed subsequently during dose escalation. Interestingly, greater induction of circulating GDF-15 was associated with greater platelet count reduction, suggesting GDF-15 might be a possible early indicator of delayed thrombocytopenia. Conclusions: The PK/PD model performed well as a reliable predictor of regimen-dependent hematologic toxicity, and was a valuable tool in guiding decisions around dose escalation dose/regimen selection for expansion during the Phase I study. This work provided an integrated quantitative understanding of regimen-dependent thrombocytopenia, PD modulation using the GDF-15 biomarker, and efficacy. The model continues to be developed as a platform for optimizing dose/schedule in ongoing and future clinical studies with NVP-HDM201. Citation Format: Christophe Meille, Nelson Guerreiro, Astrid Jullion, Sebastian Bauer, Manik Chatterjee, Filip de Vos, Chia-Chi Lin, Cristina Suárez Rodríguez, David Tai, Philippe Cassier, Noboru Yamamoto, Vincent A. de Weger, Matthieu Klopfenstein, Luisa Mariconti, Emil T. Kuriakose, David M. Hyman. Optimization of the dose and schedule of an HDM2 inhibitor NVP-HDM201 in a first-in-human Phase I study using a mechanism-based PK/PD model [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 CT154. doi:10.1158/1538-7445.AM2017-CT154