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Featured researches published by Steven Blotner.


Clinical Cancer Research | 2016

Results of the Phase I Trial of RG7112, a Small-Molecule MDM2 Antagonist in Leukemia.

Michael Andreeff; Kevin R. Kelly; Karen Yee; Sarit Assouline; Roger Strair; Leslie Popplewell; David G. Bowen; Giovanni Martinelli; Mark W. Drummond; Paresh Vyas; Mark Kirschbaum; Swaminathan Padmanabhan Iyer; Vivian Ruvolo; Graciela Nogueras Gonzalez; Xuelin Huang; Gong Chen; Bradford Graves; Steven Blotner; Peter Bridge; Lori Jukofsky; Steve Middleton; Monica Reckner; Ruediger Rueger; Jianguo Zhi; Gwen Nichols; Kensuke Kojima

Purpose: RG7112 is a small-molecule MDM2 antagonist. MDM2 is a negative regulator of the tumor suppressor p53 and frequently overexpressed in leukemias. Thus, a phase I study of RG7112 in patients with hematologic malignancies was conducted. Experimental Design: Primary study objectives included determination of the dose and safety profile of RG7112. Secondary objectives included evaluation of pharmacokinetics; pharmacodynamics, such as TP53-mutation status and MDM2 expression; and preliminary clinical activity. Patients were divided into two cohorts: Stratum A [relapsed/refractory acute myeloid leukemia (AML; except acute promyelocytic leukemia), acute lymphoblastic leukemia, and chronic myelogenous leukemia] and Stratum B (relapsed/refractory chronic lymphocytic leukemia/small cell lymphocytic leukemia; CLL/sCLL). Some Stratum A patients were treated at the MTD to assess clinical activity. Results: RG7112 was administered to 116 patients (96 patients in Stratum A and 20 patients in Stratum B). All patients experienced at least 1 adverse event, and 3 dose-limiting toxicities were reported. Pharmacokinetic analysis indicated that twice-daily dosing enhanced daily exposure. Antileukemia activity was observed in the 30 patients with AML assessed at the MTD, including 5 patients who met International Working Group (IWG) criteria for response. Exploratory analysis revealed TP53 mutations in 14% of Stratum A patients and in 40% of Stratum B patients. Two patients with TP53 mutations exhibited clinical activity. p53 target genes were induced only in TP53 wild-type leukemic cells. Baseline expression levels of MDM2 correlated positively with clinical response. Conclusions: RG7112 demonstrated clinical activity against relapsed/refractory AML and CLL/sCLL. MDM2 inhibition resulted in p53 stabilization and transcriptional activation of p53-target genes. We provide proof-of-concept that MDM2 inhibition restores p53 function and generates clinical responses in hematologic malignancies. Clin Cancer Res; 22(4); 868–76. ©2015 AACR.


Haematologica | 2016

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

Bernhard Reis; Lori Jukofsky; Gong Chen; Giovanni Martinelli; Hua Zhong; W. Venus So; Michael Dickinson; Mark W. Drummond; Sarit Assouline; Maneja Hashemyan; Michel Theron; Steven Blotner; Je-Hwan Lee; Margaret Kasner; Sung-Soo Yoon; Ruediger Rueger; Karen Seiter; Steven Middleton; Kevin R. Kelly; Norbert Vey; Karen Yee; Gwen Nichols; Lin-Chi Chen; William E. Pierceall

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


Clinical Pharmacokinectics | 2012

Impact of Low-Dose Ritonavir on Danoprevir Pharmacokinetics

Micaela B. Reddy; Yuan Chen; Joshua Haznedar; Jennifer Fretland; Steven Blotner; Patrick F. Smith; Jonathan Q. Tran

Background and ObjectiveDanoprevir, a potent, selective inhibitor of the hepatitis C virus (HCV) NS3/4A protease, is metabolized by cytochrome P450 (CYP) Clinical studies in HCV patients have shown a potential need for a high danoprevir daily dose and/or dosing frequency. Ritonavir, an HIV-1 protease inhibitor (PI) and potent CYP3 A inhibitor, is used as a pharmacokinetic enhancer at subtherapeutic doses in combination with other HIV PIs. Coadministering danoprevir with ritonavir as a pharmacokinetic enhancer could allow reduced danoprevir doses and/or dosing frequency. Here we evaluate the impact of ritonavir on danoprevir pharmacokinetics.MethodsThe effects of low-dose ritonavir on danoprevir pharmacokinetics were simulated using Simcyp, a population-based simulator. Following results from this drug-drug interaction (DDI) model, a crossover study was performed in healthy volunteers to investigate the effects of acute and repeat dosing of low-dose ritonavir on danoprevir single-dose pharmacokinetics. Volunteers received a single oral dose of danoprevir 100 mg in a fixed sequence as follows: alone, and on the first day and the last day of 10-day dosing with ritonavir 100 mg every 12 hours.ResultsThe initial DDI model predicted that following multiple dosing of ritonavir 100 mg every 12 hours for 10 days, the danoprevir area under the plasma concentration-time curve (AUC) from time zero to 24 hours and maximum plasma drug concentration (Cmax) would increase by about 3.9- and 3.2-fold, respectively. The clinical results at day 10 of ritonavir dosing showed that the plasma drug concentration at 12 hours postdose, AUC from time zero to infinity and Cmax of danoprevir increased by approximately 42-fold, 5.5-fold and 3.2-fold, respectively, compared with danoprevir alone. The DDI model was refined with the clinical data and sensitivity analyses were performed to better understand factors impacting the ritonavir-danoprevir interaction.ConclusionDDI model simulations predicted that danoprevir exposures could be successfully enhanced with ritonavir coadministration, and that a clinical study confirming this result was warranted. The clinical results demonstrate that low-dose ritonavir enhances the pharmacokinetic profile of low-dose danoprevir such that overall danoprevir exposures can be reduced while sustaining danoprevir trough concentrations.


Clinical pharmacology in drug development | 2017

Effect of Food and Esomeprazole on the Pharmacokinetics of Alectinib, a Highly Selective ALK Inhibitor, in Healthy Subjects

Peter N. Morcos; Elena Guerini; Neil Parrott; Georgina Dall; Steven Blotner; Katrijn Bogman; Carolina Sturm; Bogdana Balas; Meret Martin-Facklam; Alex Phipps

Alectinib, an anaplastic lymphoma kinase (ALK) inhibitor, is approved for treatment of patients with ALK+ non–small cell lung cancer who have progressed, on or are intolerant to, crizotinib. This study assessed the effect of a high‐fat meal and the proton pump inhibitor, esomeprazole, on the pharmacokinetics (PK) of alectinib. This was an open‐label, 2‐group study in healthy subjects. In group 1 (n = 18), subjects were randomly assigned to a 2‐treatment (A, fasted conditions; B, following a high‐fat meal), 2‐sequence (AB or BA) crossover assessment, separated by a 10‐day washout. In group 2 (n = 24), subjects were enrolled in a 2‐period, fixed‐sequence crossover assessment to evaluate the effect of esomeprazole. PK parameters were evaluated for alectinib, its major similarly active metabolite, M4, and the combined exposure of alectinib and M4. Administration of alectinib following a high‐fat meal substantially increased the combined exposure of alectinib and M4 to 331% (90%CI, 279%–393%) and 311% (90%CI, 273%–355%) for Cmax and AUC0–∞, respectively, versus fasted conditions. Coadministration of esomeprazole had no clinically relevant effect on the combined exposure of alectinib and M4. Alectinib should be administered under fed conditions to maximize its bioavailability, whereas no restrictions are required with antisecretory agents.


Clinical Trials | 2018

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

Karen Yee; Geoffrey L. Uy; Sarit Assouline; Carolyn D. Britten; Jianguo Zhi; Steven Blotner; William E. Pierceall; Brian Higgins; Lin-Chi Chen

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.


Cancer Chemotherapy and Pharmacology | 2018

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

Steven Blotner; Lin-Chi Chen; Cristiano Ferlini; Jianguo Zhi

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.


Clinical Gastroenterology and Hepatology | 2006

Chronic Hepatitis C in Patients With Persistently Normal Alanine Transaminase Levels

Mitchell L. Shiffman; M. Diago; Albert Tran; Paul J. Pockros; Robert Reindollar; Daniele Prati; Maribel Rodriguez–Torres; Pilar Lardelli; Steven Blotner; Stefan Zeuzem


Journal of Hepatology | 2006

Viral and metabolic factors influencing alanine aminotransferase activity in patients with chronic hepatitis C

Daniele Prati; Mitchell L. Shiffman; M. Diago; Edward Gane; K. Rajender Reddy; Paul J. Pockros; Patrizia Farci; Christopher B. O'Brien; Pilar Lardelli; Steven Blotner; Stefan Zeuzem


Blood | 2012

Results of the Phase 1 Trial of RG7112, a Small-Molecule MDM2 Antagonist, in Acute Leukemia

Michael Andreeff; Kevin R. Kelly; Karen Yee; Sarit Assouline; Roger Strair; Leslie Popplewell; David G. Bowen; Giovanni Martinelli; Mark W. Drummond; Paresh Vyas; Mark Kirschbaum; Swaminathan Padmanabhan Iyer; Kensuke Kojima; David Geho; Steven Blotner; Suzanne Cheng; Lyubomir T. Vassilev; Meichun Ding; Jianguo Zhi; Steven Middleton; Gwen Nichols


Journal of Nutrition | 2001

Short-Term Orlistat Treatment Does Not Affect Mineral Balance and Bone Turnover in Obese Men

Daniel G. Pace; Steven Blotner; Roberto Guerciolini

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Kevin R. Kelly

University of Southern California

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Karen Yee

Princess Margaret Cancer Centre

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