Jianguo Zhi

Effect of the MDM2 antagonist RG7112 on the P53 pathway in patients with MDM2-amplified, well-differentiated or dedifferentiated liposarcoma: an exploratory proof-of-mechanism study

BACKGROUND We report a proof-of-mechanism study of RG7112, a small-molecule MDM2 antagonist, in patients with chemotherapy-naive primary or relapsed well-differentiated or dedifferentiated MDM2-amplified liposarcoma who were eligible for resection. METHODS Patients with well-differentiated or dedifferentiated liposarcoma were enrolled at four centres in France. Patients received up to three 28-day neoadjuvant treatment cycles of RG7112 1440 mg/m(2) per day for 10 days. If a patient progressed at any point after the first cycle, the lesion was resected or, if unresectable, an end-of-study biopsy was done. The primary endpoint was to assess markers of RG7112-dependent MDM2 inhibition and P53 pathway activation (P53, P21, MDM2, Ki-67, macrophage inhibitory cytokine-1 [MIC-1], and apoptosis). All analyses were per protocol. This trial is registered with EudraCT, number 2009-015522-10. RESULTS Between June 3, and Dec 14, 2010, 20 patients were enrolled and completed pretreatment and day 8 biopsies. 18 of 20 patients had TP53 wild-type tumours and two carried missense TP53 mutations. 14 of 17 assessed patients had MDM2 gene amplification. Compared with baseline, P53 and P21 concentrations, assessed by immunohistochemistry, had increased by a median of 4·86 times (IQR 4·38-7·97; p=0·0001) and 3·48 times (2·05-4·09; p=0·0001), respectively, at day 8 (give or take 2 days). At the same timepoint, relative MDM2 mRNA expression had increased by a median of 3·03 times (1·23-4·93; p=0·003) that at baseline. The median change from baseline for Ki-67-positive tumour cells was -5·05% (IQR -12·55 to 0·05; p=0·01). Drug exposure correlated with blood concentrations of MIC-1 (p<0·0001) and haematological toxicity. One patient had a confirmed partial response and 14 had stable disease. All patients experienced at least one adverse event, mostly nausea (14 patients), vomiting (11 patients), asthenia (nine patients), diarrhoea (nine patients), and thrombocytopenia (eight patients). There were 12 serious adverse events in eight patients, the most common of which were neutropenia (six patients) and thrombocytopenia (three patients). DISCUSSION MDM2 inhibition activates the P53 pathway and decreases cell proliferation in MDM2-amplified liposarcoma. This study suggests that it is feasible to undertake neoadjuvant biopsy-driven biomarker studies in liposarcoma. FUNDING F Hoffmann-La Roche.

Investigating the effect of autoinduction in cynomolgus monkeys of a novel anticancer MDM2 antagonist, idasanutlin, and relevance to humans

Abstract 1. Idasanutlin (RG7388) is a potent p53-MDM2 antagonist currently in clinical development for treatment of cancer. The purpose of the present studies was to investigate the cause of marked decrease in plasma exposure after repeated oral administration of RG7388 in monkeys and whether the autoinduction observed in monkeys is relevant to humans. 2. In monkey liver and intestinal microsomes collected after repeated oral administration of RG7388 to monkeys, significantly increased activities of homologue CYP3A8 were observed (ex vivo). Investigation using a physiologically based pharmacokinetic (PBPK) model suggested that the loss of exposure was primarily due to induction of metabolism in the gut of monkeys. 3. Studies in monkey and human primary hepatocytes showed that CYP3A induction by RG7388 only occurred in monkey hepatocytes but not in human hepatocytes, which suggests the observed CYP3A induction is monkey specific. 4. The human PK data obtained from the first cohorts confirmed the lack of relevant induction as predicted by the human hepatocytes and the PBPK modelling based on no induction in humans.

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.

An apparent clinical pharmacokinetic drug–drug interaction between bevacizumab and the anti-placental growth factor monoclonal antibody RO5323441 via a target-trapping mechanism

PurposeRO5323441 is a humanized anti-placental growth factor (PlGF) monoclonal antibody that has shown preclinical activity in several cancer models. The objective of this analysis is to examine the pharmacokinetic (PK) results from four Phase I studies that have been conducted with RO5323441 (n = 61) and to report an apparent drug–drug interaction observed when RO5323441 was administered in combination with bevacizumab.MethodsThe four Phase I studies were a multiple-ascending dose study in 23 patients with solid tumors (Study 1), an open-label study in seven patients with colorectal/ovarian cancer (Study 2), a sorafenib combination study in nine patients with hepatocellular carcinoma (Study 3), and a bevacizumab combination study in 22 patients with recurrent glioblastoma (Study 4). A two-compartment linear population PK model was developed from these four studies to characterize the PK of RO5323441 in patients with cancer.ResultsThe PK properties of RO5323441 were similar in the first three studies. However, substantially higher RO5323441 exposures were observed in Study 4 when RO5323441 was administered in combination with bevacizumab. A linear two-compartmental population PK model indicated that the co-administration of bevacizumab would decrease the clearance of RO5323441 by 53%. Clinical data suggested that the decrease in RO5323441 clearance was inversely associated with bevacizumab exposure.ConclusionsThe exact reason for the increase in RO5323441 exposure following bevacizumab co-administration is not currently known. One possibility is a drug–drug interaction via a target-trapping mechanism that is mediated by the vascular endothelial growth factor receptor-1 (VEGFR-1).

Abstract LB-201: Clinical pharmacology characterization of RG7112, an MDM2 antagonist, in patients with advanced solid tumors.

MDM2 is overproduced as a mechanism to impair p53 function in many cancers. By reactivating p53, antagonists of p53-MDM2 interaction could offer a novel approach to treatment of solid tumors and leukemias. RG7112, the first potent and selective small-molecule MDM2 antagonist in clinical testing, is an oral p53 activator and is currently in phase I. To optimize its dose and schedule, a number of clinical pharmacology characteristics were explored in this multi-center trial in patients (pts) with advanced solid tumors. In Part I, the impact of high-energy/high-fat meal and formulation (crystalline versus amorphous) was examined in cross-over design. In Part II, schedule optimization (4 schedules of drug adm under fasting condition and 1 cohort with liquid supplementation) was investigated in parallel, dose escalation design. Clinical endpoints were PK/PD and safety/tolerability including platelet reduction (a potential target-mediated hematological toxicity indicator). A total of 76 pts (42F and 34M, mean age 60 yr) participated in the study. In their first-cycle treatment, 36 pts received weekly x3 (26 with food/formulation evaluation), 15 pts daily x5, 6 pts daily x20, and 19 pts daily x3 (3 with food evaluation) doses; daily doses ranged from 500-4500 mg. The most commonly reported AEs (> 20%) were GI-related. Twelve pts have reported 21 SAEs, of which, 4 events in 2 pts (1 pt with G4 thrombocytopenia, anemia, and neutropenia; 1 pt with G3 delirium) were related to study treatment. A high-energy (∼1000 kcal)/high-fat (∼60 g) meal and a reduced energy (∼500 kcal)/fat (∼30 g) liquid supplementation both enhanced overall bioavailability (BA) of tested formulations by 2-fold, with inter-pt variability reduced by half. At steady-state, amorphous formulation also reduced PK variability by half from the crystalline formulation. High-dose consecutive daily dosing for 5 and 3 d yielded highest drug concentrations on the last day of treatment. On the other hand, both weekly and low-dose/long-duration (20-day) schedules yielded lower peak concentrations (note that the per-cycle exposure was comparable to, or higher than, high-dose 5x and 3x daily schedules). Serum profiles of MIC-1, a secreted protein that is strongly induced by activated p53, showed similar patterns to the PK when the clinical pharmacology conditions were varied. The first-cycle platelet profiles indicate that the weekly schedule didn9t cause platelet reduction, while the daily schedules showed a trend of dose- and length-dependent platelet reduction with daily x 5 at high doses being the most pronounced (1 pt resulted in G-4 thrombocytopenia). In conclusion, RG7112 is well tolerated with or without food in the therapeutically relevant dose range, food enhanced BA with reduced variability, and high-dose consecutive daily for 3-5 d is superior in yielding sufficiently high PK exposure and PD effects potentially required for cancer treatment efficacy. Citation Format: Amita Patnaik, Anthony Tolcher, Muralidhar Beeram, John Nemunaitis, Glen Weiss, Gwen Nichols, Steven Middleton, Nenad Sarapa, Anna Beryozkina, Jianguo Zhi. Clinical pharmacology characterization of RG7112, an MDM2 antagonist, in patients with advanced solid tumors. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-201. doi:10.1158/1538-7445.AM2013-LB-201