Lin-Chi Chen

Acute myeloid leukemia patients' clinical response to idasanutlin (RG7388) is associated with pre-treatment MDM2 protein expression in leukemic blasts.

In translational research described, we investigated biomarker expression by flow cytometry for MDM2 antagonist clinical response association in relapsed/refractory AML patients treated with idasanutlin-based therapy ( [Clinicaltrials.gov][1] identifier: [NCT01773408][2] ). As MDM2 targets p53 for

MDM2 antagonist clinical response association with a gene expression signature in acute myeloid leukaemia.

Acute myeloid leukaemia (AML) is uniquely sensitive to p53 activation 1, 2 as ≈90% of patients carry wild-type TP53 and frequent MDM2 overexpression.3 MDM2 blocks p53 transactivation and targets p53 for ubiquitin-dependent degradation.4, 5 Nutlins have been characterized as potent and selective small-molecule MDM2 antagonists.1, 6–8 RG7112 was the first such MDM2 antagonist to undergo clinical assessment in solid tumors and leukaemia trials.1, 2, 9 As not all patients with functional p53 will respond to MDM2 antagonists, diagnostic tools may identify patients likely to respond.

Abstract A082: A phase I study of the MDM2 antagonist RO6839921, a pegylated intravenous prodrug of idasanutlin, in patients with AML

Background: Activation of the p53 pathway by inhibiting MDM2 has been proposed as a novel strategy for cancer therapy. We previously reported the phase 1 results in solid tumor patients (pts) of RO6839921, a small-molecule pegylated IV prodrug of the MDM2 antagonist idasanutlin (active principle = AP), which was developed with the goal of reducing exposure variability to improve the therapeutic index. We report here on the safety, PK, PD, and activity in AML pts. Methods: This was an open-label phase I monotherapy study evaluating RO6839921 in R/R AML pts on a 5-day dosing schedule. Primary objectives were to identify dose-limiting toxicities (DLTs) and the maximum tolerated dose (MTD, DLT rate ≤ 33%). Secondary objectives were to assess PK, PD, and preliminary activity. Maximum escalation increments followed a Modified Fibonacci sequence. TP53 mutational status was assessed by next-generation sequencing from bone marrow samples. Serum MIC-1 (macrophage inhibitory cytokine-1), a p53 transcriptional target, was analyzed by Elecsys® ECL as a PD marker of p53 activation. Results: 26 DLT-evaluable pts were treated at doses between 120-300 mg AP. The MTD was 250 mg with DLTs reported at 250 mg (2/8 pts, 25%) and 300 mg (2/5 pts, 40%) (table). Related AEs ≥ G3 in >5% of pts included febrile neutropenia (3/26, 11.5%), epistaxis and platelet count decreased (both 2/26, 7.7%). Related AEs of all grades observed in > 20% pts were diarrhea, nausea, vomiting, decreased appetite, and fatigue. PK analyses showed rapid and near-complete conversion of prodrug to AP and dose-proportional exposure across the doses tested (table). Variability ranged from 30-47% (22-54% for idasanutlin). 11/26 pts had evidence of antileukemic activity (CR, CRi/MLFS, PR, HI/SD) for a disease control rate of 42%, with a composite CR rate of 7.7% (1 CR, 1 CRi/MLFS; 2/26); TP53 was evaluable in 24 pts; 21 (87.5%) were wild type and 3 mutant (12.5%). 10/11 pts with activity were wild type and 1 did not have a sample. p53 activation was demonstrated by MIC-1 induction in serum and was associated with AP exposure. Conclusions: RO6839921 shows a PK profile similar to idasanutlin. The MTD of 250 mg AP qd x 5 days has a manageable safety profile in R/R AML at ~25% of the idasanutlin dose identified for development in this population. Single-agent antileukemic activity is observed in 42% pts overall, including 4 of 8 pts (50%) at the MTD. NCT02098967. Citation Format: Karen Yee, Geoffrey Uy, Sarit Assouline, Carolyn D. Britten, Jianguo Zhi, Steven Blotner, William Pierceall, Brian Higgins, Lin-Chi Chen. A phase I study of the MDM2 antagonist RO6839921, a pegylated intravenous prodrug of idasanutlin, in patients with AML [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A082.

Phase 1 summary of plasma concentration–QTc analysis for idasanutlin, an MDM2 antagonist, in patients with advanced solid tumors and AML

PurposeIdasanutlin, a selective small-molecule MDM2 antagonist in phase 3 testing for refractory/relapsed AML, is a non-genotoxic oral p53 activator. The aim of this analysis is to examine the potential of idasanutlin to prolong the corrected QT (QTc) interval by evaluating the relationship between plasma idasanutlin concentration and QTc interval.MethodIntensive plasma concentration QTc interval data were collected at the same timepoints, from three idasanutlin (RO5503781) phase 1 studies in patients with solid tumors and AML. QTc data in absolute values and changes from baseline (Δ) were analyzed for a potential association with plasma idasanutlin concentrations with a linear mixed effect model. Categorical analysis was also performed.ResultsA total of 282 patients were exposed to idasanutlin and had at least one observation of QTc and idasanutlin plasma concentration. There was no apparent increase of QTcF or ΔQTcF in a wide idasanutlin plasma concentration range, even at concentrations exceeding the exposure matching the dose adopted in the ongoing phase 3 study (300-mg BID). Categorical analysis did not detect a potential signal of QT prolongation.ConclusionThe concentration–QTc analysis indicates that idasanutlin does not prolong the QT interval within the targeted concentration range currently in consideration for clinical development.

Abstract A156: Preclinical activity of MDM2 antagonist RO6839921, a pegylated prodrug for intravenous administration

The p53 tumor suppressor is a transcription factor that inhibits tumorigenesis by inducing cell cycle arrest or apoptosis in response to diverse stresses. In normal cells, p53 levels are tightly controlled by MDM2 which binds p53 and negatively regulates its activity and stability. MDM2 is overproduced in many human cancers, thereby impairing p53 function. Antagonists of p53-MDM2 interaction can enhance p53 activity and offer a novel approach to cancer therapy. The first potent and selective small-molecule inhibitors of p53-MDM2 binding, the nutlins, provided preclinical proof-of-concept for MDM2 antagonists as therapeutics for patients with tumors expressing wild-type p53. The nutlin family member idasanutlin (RG7388, RO5503781) is an oral small molecule inhibitor of MDM2 currently in clinical testing. Here we describe RO6839921, a pegylated prodrug formulated for intravenous administration. This IV MDM2 antagonist has been developed in order to improve variability in exposure seen with the oral compound, and to allow expansion into indications where patients cannot swallow or absorb the oral idasanutlin. RO6839921 is rapidly metabolized to the active principle (AP) idasanutlin which then binds selectively to the p53 site on the surface of the MDM2 molecule. In vitro testing with the AP shows high affinity with effective displacement of p53 from MDM2, leading to stabilization and accumulation of p53 protein and activation of the p53 pathway. Studies focused on in vivo investigation of activity of the prodrug RO6839921 since esterase cleavage is required to release the AP. The anti-tumor activity of RO6839921 was investigated in several sarcoma xenograft models including highly responsive wild-type (WT) p53, MDM2 overexpressing osteosarcoma models SJSA-1 and MHM. Sustained survival was seen in the WT p53 HT1080 fibrosarcoma model when combined with Doxil. Activity was also seen in the WT p53 MOLM-13 disseminated AML model alone and in combination with cytarabine, in the CRPC model 22rv1, and in the ER+ BCa model MCF-7. In these studies we see an increase in dose commensurate with exposure and activity (prodrug vs oral), less variability, and potentiated activity in combination with relevant therapeutics. Clinical studies with the oral AP (idasanutlin) have shown that p53 may be activated by this novel therapeutic strategy that releases p53 from MDM2 inhibition. In particular, patients with AML exhibit significant clinical activity (ASH 2014). In view of the existing unmet medical need in advanced cancers, and the promising activity seen with idasanutlin, RO6839921 is believed to be a promising agent that may offer new therapeutic options, and is therefore currently in clinical testing in both solid and hematologic malignancies. Citation Format: Brian Higgins, Christian Tovar, Kelli Glen, Aruna Railkar, Zoran Filipovic, Farooq Qureshi, Binh Vu, George Ehrlich, Dan Fishlock, Lin-Chi Chen, Steven Middleton, Gwen Nichols, Kathryn Packman, Lyubomir Vassilev. Preclinical activity of MDM2 antagonist RO6839921, a pegylated prodrug for intravenous administration. [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 A156.

Abstract 2835: MDM2 antagonist-based therapeutic response is discriminated by a 4-gene signature in acute myeloid leukemia patients

The activity of p53, a key tumor suppressor is tightly controlled by MDM2-mediated ubiquination and degradation. Nutlins, a class of small-molecule MDM2 antagonists, have been characterized as drivers of p53 re-activation. Acute myeloid leukemia (AML) is uniquely sensitive to p53 re-activation as ∼90% of cases have wild-type TP53 and frequent MDM2 overexpression to overcome mechanisms of oncogene addiction. Personalized theranostic strategies may distinguish patients likely to clinically benefit from MDM2-antagonist therapy. Association between MDM2 antagonist (RG7112) growth inhibition (IC50s) in 287 human cancer cell lines (Cell Lines for Oncology/Chugai Accumulative Tumor Encyclopedia), and pretreatment RNAseq profiling established a classifier comprising MDM2, XPC, BBC3, and CDKN2A. This signature significantly associated with cell-line efficacy to MDM2 antagonist (odds ratio = 2.53; P RG7112 treatment was assessed in a phase 1 dose escalation trial in relapsed/refractory AML patients (NO21279). Signature scores of AML patient blood specimens at baseline significantly associated with clinical response (PD In summary, we demonstrate that a biological classifier discriminates response broadly to MDM2-antagonist therapy. The level of evidence attained by cell line efficacy modeling and response assessments in trial NO21279 (with MDM2 antagonist RG7112) and now in trial NP28679 (with MDM2 antagonist RG7388) adds substantial weight to the validity of this panel. Citation Format: Hua Zhong, Gong Chen, Lori Jukofsky, David Geho, Sung Won Han, Fabian Birzele, Sabine Bader, Lucia Himmelein, James Cai, Zayed Albertyn, Mark Rothe, Laurent Essioux, Helmut Burtscher, Steven A. Middleton, Lin-Chi Chen, Markus Dangl, William E. Pierceall, Gwen Nichols. MDM2 antagonist-based therapeutic response is discriminated by a 4-gene signature in acute myeloid leukemia patients. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2835. doi:10.1158/1538-7445.AM2015-2835