title: Results of the Phase I Trial of RG7112, a Small-Molecule MDM2 Antagonist in Leukemia.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
authors.affiliation: The University of Texas MD Anderson Cancer Center, Houston, Texas. mandreef@mdanderson.org.
authors.forename: Michael
authors.initials: M
authors.lastname: Andreeff
authors.affiliation: The University of Texas Health Science Center at San Antonio, San Antonio, Texas.
authors.forename: Kevin R
authors.initials: KR
authors.lastname: Kelly
authors.affiliation: Princess Margaret Cancer Centre, Toronto, Ontario, Canada.
authors.forename: Karen
authors.initials: K
authors.lastname: Yee
authors.affiliation: McGill University, Montreal, Quebec, Canada.
authors.forename: Sarit
authors.initials: S
authors.lastname: Assouline
authors.affiliation: Cancer Institute of New Jersey/UMDNJ-Robert Wood Johnson Medical School, New Brunswick, New Jersey.
authors.forename: Roger
authors.initials: R
authors.lastname: Strair
authors.affiliation: City of Hope National Medical Center, Los Angeles, California.
authors.forename: Leslie
authors.initials: L
authors.lastname: Popplewell
authors.affiliation: St. James's Institute of Oncology, Leeds, United Kingdom.
authors.forename: David
authors.initials: D
authors.lastname: Bowen
authors.affiliation: University of Bologna, Bologna, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Martinelli
authors.affiliation: Beatson West of Scotland Cancer Centre, Glasgow, United Kingdom.
authors.forename: Mark W
authors.initials: MW
authors.lastname: Drummond
authors.affiliation: University of Oxford, Oxford, United Kingdom.
authors.forename: Paresh
authors.initials: P
authors.lastname: Vyas
authors.affiliation: City of Hope National Medical Center, Los Angeles, California.
authors.forename: Mark
authors.initials: M
authors.lastname: Kirschbaum
authors.affiliation: The University of Texas Health Science Center at San Antonio, San Antonio, Texas.
authors.forename: Swaminathan Padmanabhan
authors.initials: SP
authors.lastname: Iyer
authors.affiliation: The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Vivian
authors.initials: V
authors.lastname: Ruvolo
authors.affiliation: The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Graciela M Nogueras
authors.initials: GM
authors.lastname: González
authors.affiliation: The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Xuelin
authors.initials: X
authors.lastname: Huang
authors.affiliation: Roche Innovation Center New York, New York.
authors.forename: Gong
authors.initials: G
authors.lastname: Chen
authors.affiliation: FORMA Therapeutics, Boston, Massachusetts.
authors.forename: Bradford
authors.initials: B
authors.lastname: Graves
authors.affiliation: Roche Innovation Center New York, New York.
authors.forename: Steven
authors.initials: S
authors.lastname: Blotner
authors.affiliation: Roche Innovation Center New York, New York.
authors.forename: Peter
authors.initials: P
authors.lastname: Bridge
authors.affiliation: Roche Innovation Center New York, New York.
authors.forename: Lori
authors.initials: L
authors.lastname: Jukofsky
authors.affiliation: Roche Innovation Center New York, New York.
authors.forename: Steve
authors.initials: S
authors.lastname: Middleton
authors.affiliation: Roche Innovation Center New York, New York.
authors.forename: Monica
authors.initials: M
authors.lastname: Reckner
authors.affiliation: Roche Innovative Center Penzberg, Penzberg, Germany.
authors.forename: Ruediger
authors.initials: R
authors.lastname: Rueger
authors.affiliation: Roche Innovation Center New York, New York.
authors.forename: Jianguo
authors.initials: J
authors.lastname: Zhi
authors.affiliation: Roche Innovation Center New York, New York.
authors.forename: Gwen
authors.initials: G
authors.lastname: Nichols
authors.affiliation: The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Kensuke
authors.initials: K
authors.lastname: Kojima
mesh_terms: D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000627:therapeutic use* / Q000633:toxicity; D017209:Apoptosis; D004252:DNA Mutational Analysis; D004334:Drug Administration Schedule; D015870:Gene Expression; D006801:Humans; D048288:Imidazolines / Q000493:pharmacokinetics / Q000627:therapeutic use* / Q000633:toxicity; D007945:Leukemia, Lymphoid / Q000188:drug therapy* / Q000235:genetics; D020714:Maximum Tolerated Dose; D051736:Proto-Oncogene Proteins c-mdm2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D048288:Imidazolines; C579783:RG7112; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2