title: Phase I dose-escalation trial of checkpoint kinase 1 inhibitor MK-8776 as monotherapy and in combination with gemcitabine in patients with advanced solid tumors.
abstract: OBJECTIVE
  We determined the safety, pharmacokinetics, pharmacodynamics, and recommended phase II dose of MK-8776 (SCH 900776), a potent, selective checkpoint kinase 1 (Chk1) inhibitor, as monotherapy and in combination with gemcitabine in a first-in-human phase I clinical trial in patients with advanced solid tumor malignancies.
  
  
  METHODS
  Forty-three patients were treated by intravenous infusion with MK-8776 at seven dose levels ranging from 10 to 150 mg/m(2) as monotherapy and then in combination with gemcitabine 800 mg/m(2) (part A, n = 26) or gemcitabine 1,000 mg/m(2) (part B, n = 17). Forty percent of patients had three or more prior treatment regimens, and one third of patients had previously received gemcitabine.
  
  
  RESULTS
  As monotherapy, MK-8776 was well tolerated, with QTc prolongation (19%), nausea (16%), fatigue (14%), and constipation (14%) as the most frequent adverse effects. Combination therapy demonstrated a higher frequency of adverse effects, predominantly fatigue (63%), nausea (44%), decreased appetite (37%), thrombocytopenia (32%), and neutropenia (24%), as well as dose-related, transient QTc prolongation (17%). The median number of doses of MK-8776 administered was five doses, with relative dose-intensity of 0.96. Bioactivity was assessed by γ-H2AX ex vivo assay. Of 30 patients evaluable for response, two showed partial response, and 13 exhibited stable disease.
  
  
  CONCLUSIONS
  MK-8776 was well tolerated as monotherapy and in combination with gemcitabine. Early evidence of clinical efficacy was observed. The recommended phase II dose is MK-8776 200 mg plus gemcitabine 1,000 mg/m(2) on days 1 and 8 of a 21-day cycle.
authors.affiliation: Adil I. Daud, Michelle T. Ashworth, Alan P. Venook, Jennifer A. Grabowsky, and Pamela N. Munster, University of California, San Francisco, San Francisco; Jonathan W. Goldman and Lee S. Rosen, University of California, Los Angeles, Santa Monica, CA; Jonathan Strosberg and Gregory Springett, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL; David Mendelson, Pinnacle Oncology Hematology, Scottsdale, AZ; and Sabine Loechner, Frances Shanahan, David Parry, Stuart Shumway, Tomoko Freshwater, Christopher Sorge, Soonmo Peter Kang, and Randi Isaacs, Merck, Whitehouse Station, NJ. adaud@medicine.ucsf.edu.
authors.forename: Adil I
authors.initials: AI
authors.lastname: Daud
authors.affiliation: Adil I. Daud, Michelle T. Ashworth, Alan P. Venook, Jennifer A. Grabowsky, and Pamela N. Munster, University of California, San Francisco, San Francisco; Jonathan W. Goldman and Lee S. Rosen, University of California, Los Angeles, Santa Monica, CA; Jonathan Strosberg and Gregory Springett, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL; David Mendelson, Pinnacle Oncology Hematology, Scottsdale, AZ; and Sabine Loechner, Frances Shanahan, David Parry, Stuart Shumway, Tomoko Freshwater, Christopher Sorge, Soonmo Peter Kang, and Randi Isaacs, Merck, Whitehouse Station, NJ.
authors.forename: Michelle T
authors.initials: MT
authors.lastname: Ashworth
authors.affiliation: Adil I. Daud, Michelle T. Ashworth, Alan P. Venook, Jennifer A. Grabowsky, and Pamela N. Munster, University of California, San Francisco, San Francisco; Jonathan W. Goldman and Lee S. Rosen, University of California, Los Angeles, Santa Monica, CA; Jonathan Strosberg and Gregory Springett, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL; David Mendelson, Pinnacle Oncology Hematology, Scottsdale, AZ; and Sabine Loechner, Frances Shanahan, David Parry, Stuart Shumway, Tomoko Freshwater, Christopher Sorge, Soonmo Peter Kang, and Randi Isaacs, Merck, Whitehouse Station, NJ.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Strosberg
authors.affiliation: Adil I. Daud, Michelle T. Ashworth, Alan P. Venook, Jennifer A. Grabowsky, and Pamela N. Munster, University of California, San Francisco, San Francisco; Jonathan W. Goldman and Lee S. Rosen, University of California, Los Angeles, Santa Monica, CA; Jonathan Strosberg and Gregory Springett, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL; David Mendelson, Pinnacle Oncology Hematology, Scottsdale, AZ; and Sabine Loechner, Frances Shanahan, David Parry, Stuart Shumway, Tomoko Freshwater, Christopher Sorge, Soonmo Peter Kang, and Randi Isaacs, Merck, Whitehouse Station, NJ.
authors.forename: Jonathan W
authors.initials: JW
authors.lastname: Goldman
authors.affiliation: Adil I. Daud, Michelle T. Ashworth, Alan P. Venook, Jennifer A. Grabowsky, and Pamela N. Munster, University of California, San Francisco, San Francisco; Jonathan W. Goldman and Lee S. Rosen, University of California, Los Angeles, Santa Monica, CA; Jonathan Strosberg and Gregory Springett, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL; David Mendelson, Pinnacle Oncology Hematology, Scottsdale, AZ; and Sabine Loechner, Frances Shanahan, David Parry, Stuart Shumway, Tomoko Freshwater, Christopher Sorge, Soonmo Peter Kang, and Randi Isaacs, Merck, Whitehouse Station, NJ.
authors.forename: David
authors.initials: D
authors.lastname: Mendelson
authors.affiliation: Adil I. Daud, Michelle T. Ashworth, Alan P. Venook, Jennifer A. Grabowsky, and Pamela N. Munster, University of California, San Francisco, San Francisco; Jonathan W. Goldman and Lee S. Rosen, University of California, Los Angeles, Santa Monica, CA; Jonathan Strosberg and Gregory Springett, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL; David Mendelson, Pinnacle Oncology Hematology, Scottsdale, AZ; and Sabine Loechner, Frances Shanahan, David Parry, Stuart Shumway, Tomoko Freshwater, Christopher Sorge, Soonmo Peter Kang, and Randi Isaacs, Merck, Whitehouse Station, NJ.
authors.forename: Gregory
authors.initials: G
authors.lastname: Springett
authors.affiliation: Adil I. Daud, Michelle T. Ashworth, Alan P. Venook, Jennifer A. Grabowsky, and Pamela N. Munster, University of California, San Francisco, San Francisco; Jonathan W. Goldman and Lee S. Rosen, University of California, Los Angeles, Santa Monica, CA; Jonathan Strosberg and Gregory Springett, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL; David Mendelson, Pinnacle Oncology Hematology, Scottsdale, AZ; and Sabine Loechner, Frances Shanahan, David Parry, Stuart Shumway, Tomoko Freshwater, Christopher Sorge, Soonmo Peter Kang, and Randi Isaacs, Merck, Whitehouse Station, NJ.
authors.forename: Alan P
authors.initials: AP
authors.lastname: Venook
authors.affiliation: Adil I. Daud, Michelle T. Ashworth, Alan P. Venook, Jennifer A. Grabowsky, and Pamela N. Munster, University of California, San Francisco, San Francisco; Jonathan W. Goldman and Lee S. Rosen, University of California, Los Angeles, Santa Monica, CA; Jonathan Strosberg and Gregory Springett, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL; David Mendelson, Pinnacle Oncology Hematology, Scottsdale, AZ; and Sabine Loechner, Frances Shanahan, David Parry, Stuart Shumway, Tomoko Freshwater, Christopher Sorge, Soonmo Peter Kang, and Randi Isaacs, Merck, Whitehouse Station, NJ.
authors.forename: Sabine
authors.initials: S
authors.lastname: Loechner
authors.affiliation: Adil I. Daud, Michelle T. Ashworth, Alan P. Venook, Jennifer A. Grabowsky, and Pamela N. Munster, University of California, San Francisco, San Francisco; Jonathan W. Goldman and Lee S. Rosen, University of California, Los Angeles, Santa Monica, CA; Jonathan Strosberg and Gregory Springett, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL; David Mendelson, Pinnacle Oncology Hematology, Scottsdale, AZ; and Sabine Loechner, Frances Shanahan, David Parry, Stuart Shumway, Tomoko Freshwater, Christopher Sorge, Soonmo Peter Kang, and Randi Isaacs, Merck, Whitehouse Station, NJ.
authors.forename: Lee S
authors.initials: LS
authors.lastname: Rosen
authors.affiliation: Adil I. Daud, Michelle T. Ashworth, Alan P. Venook, Jennifer A. Grabowsky, and Pamela N. Munster, University of California, San Francisco, San Francisco; Jonathan W. Goldman and Lee S. Rosen, University of California, Los Angeles, Santa Monica, CA; Jonathan Strosberg and Gregory Springett, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL; David Mendelson, Pinnacle Oncology Hematology, Scottsdale, AZ; and Sabine Loechner, Frances Shanahan, David Parry, Stuart Shumway, Tomoko Freshwater, Christopher Sorge, Soonmo Peter Kang, and Randi Isaacs, Merck, Whitehouse Station, NJ.
authors.forename: Frances
authors.initials: F
authors.lastname: Shanahan
authors.affiliation: Adil I. Daud, Michelle T. Ashworth, Alan P. Venook, Jennifer A. Grabowsky, and Pamela N. Munster, University of California, San Francisco, San Francisco; Jonathan W. Goldman and Lee S. Rosen, University of California, Los Angeles, Santa Monica, CA; Jonathan Strosberg and Gregory Springett, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL; David Mendelson, Pinnacle Oncology Hematology, Scottsdale, AZ; and Sabine Loechner, Frances Shanahan, David Parry, Stuart Shumway, Tomoko Freshwater, Christopher Sorge, Soonmo Peter Kang, and Randi Isaacs, Merck, Whitehouse Station, NJ.
authors.forename: David
authors.initials: D
authors.lastname: Parry
authors.affiliation: Adil I. Daud, Michelle T. Ashworth, Alan P. Venook, Jennifer A. Grabowsky, and Pamela N. Munster, University of California, San Francisco, San Francisco; Jonathan W. Goldman and Lee S. Rosen, University of California, Los Angeles, Santa Monica, CA; Jonathan Strosberg and Gregory Springett, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL; David Mendelson, Pinnacle Oncology Hematology, Scottsdale, AZ; and Sabine Loechner, Frances Shanahan, David Parry, Stuart Shumway, Tomoko Freshwater, Christopher Sorge, Soonmo Peter Kang, and Randi Isaacs, Merck, Whitehouse Station, NJ.
authors.forename: Stuart
authors.initials: S
authors.lastname: Shumway
authors.affiliation: Adil I. Daud, Michelle T. Ashworth, Alan P. Venook, Jennifer A. Grabowsky, and Pamela N. Munster, University of California, San Francisco, San Francisco; Jonathan W. Goldman and Lee S. Rosen, University of California, Los Angeles, Santa Monica, CA; Jonathan Strosberg and Gregory Springett, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL; David Mendelson, Pinnacle Oncology Hematology, Scottsdale, AZ; and Sabine Loechner, Frances Shanahan, David Parry, Stuart Shumway, Tomoko Freshwater, Christopher Sorge, Soonmo Peter Kang, and Randi Isaacs, Merck, Whitehouse Station, NJ.
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Grabowsky
authors.affiliation: Adil I. Daud, Michelle T. Ashworth, Alan P. Venook, Jennifer A. Grabowsky, and Pamela N. Munster, University of California, San Francisco, San Francisco; Jonathan W. Goldman and Lee S. Rosen, University of California, Los Angeles, Santa Monica, CA; Jonathan Strosberg and Gregory Springett, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL; David Mendelson, Pinnacle Oncology Hematology, Scottsdale, AZ; and Sabine Loechner, Frances Shanahan, David Parry, Stuart Shumway, Tomoko Freshwater, Christopher Sorge, Soonmo Peter Kang, and Randi Isaacs, Merck, Whitehouse Station, NJ.
authors.forename: Tomoko
authors.initials: T
authors.lastname: Freshwater
authors.affiliation: Adil I. Daud, Michelle T. Ashworth, Alan P. Venook, Jennifer A. Grabowsky, and Pamela N. Munster, University of California, San Francisco, San Francisco; Jonathan W. Goldman and Lee S. Rosen, University of California, Los Angeles, Santa Monica, CA; Jonathan Strosberg and Gregory Springett, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL; David Mendelson, Pinnacle Oncology Hematology, Scottsdale, AZ; and Sabine Loechner, Frances Shanahan, David Parry, Stuart Shumway, Tomoko Freshwater, Christopher Sorge, Soonmo Peter Kang, and Randi Isaacs, Merck, Whitehouse Station, NJ.
authors.forename: Christopher
authors.initials: C
authors.lastname: Sorge
authors.affiliation: Adil I. Daud, Michelle T. Ashworth, Alan P. Venook, Jennifer A. Grabowsky, and Pamela N. Munster, University of California, San Francisco, San Francisco; Jonathan W. Goldman and Lee S. Rosen, University of California, Los Angeles, Santa Monica, CA; Jonathan Strosberg and Gregory Springett, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL; David Mendelson, Pinnacle Oncology Hematology, Scottsdale, AZ; and Sabine Loechner, Frances Shanahan, David Parry, Stuart Shumway, Tomoko Freshwater, Christopher Sorge, Soonmo Peter Kang, and Randi Isaacs, Merck, Whitehouse Station, NJ.
authors.forename: Soonmo Peter
authors.initials: SP
authors.lastname: Kang
authors.affiliation: Adil I. Daud, Michelle T. Ashworth, Alan P. Venook, Jennifer A. Grabowsky, and Pamela N. Munster, University of California, San Francisco, San Francisco; Jonathan W. Goldman and Lee S. Rosen, University of California, Los Angeles, Santa Monica, CA; Jonathan Strosberg and Gregory Springett, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL; David Mendelson, Pinnacle Oncology Hematology, Scottsdale, AZ; and Sabine Loechner, Frances Shanahan, David Parry, Stuart Shumway, Tomoko Freshwater, Christopher Sorge, Soonmo Peter Kang, and Randi Isaacs, Merck, Whitehouse Station, NJ.
authors.forename: Randi
authors.initials: R
authors.lastname: Isaacs
authors.affiliation: Adil I. Daud, Michelle T. Ashworth, Alan P. Venook, Jennifer A. Grabowsky, and Pamela N. Munster, University of California, San Francisco, San Francisco; Jonathan W. Goldman and Lee S. Rosen, University of California, Los Angeles, Santa Monica, CA; Jonathan Strosberg and Gregory Springett, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL; David Mendelson, Pinnacle Oncology Hematology, Scottsdale, AZ; and Sabine Loechner, Frances Shanahan, David Parry, Stuart Shumway, Tomoko Freshwater, Christopher Sorge, Soonmo Peter Kang, and Randi Isaacs, Merck, Whitehouse Station, NJ.
authors.forename: Pamela N
authors.initials: PN
authors.lastname: Munster
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000627:therapeutic use; D000071877:Checkpoint Kinase 1; D015331:Cohort Studies; D003561:Cytarabine / Q000008:administration & dosage; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D005260:Female; D006657:Histones / Q000378:metabolism; D006801:Humans; D007262:Infusions, Intravenous; D020014:K562 Cells; D008297:Male; D008545:Melanoma / Q000188:drug therapy; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use; D011494:Protein Kinases / Q000378:metabolism*; D011720:Pyrazoles / Q000008:administration & dosage* / Q000627:therapeutic use*; D011743:Pyrimidines / Q000008:administration & dosage* / Q000627:therapeutic use*; D012509:Sarcoma / Q000188:drug therapy; D013997:Time Factors; D000093542:Gemcitabine
chemical_list: D000970:Antineoplastic Agents; C468783:H2AX protein, human; D006657:Histones; C559815:MK-8776; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011743:Pyrimidines; D003561:Cytarabine; D003841:Deoxycytidine; D011494:Protein Kinases; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1; D000093542:Gemcitabine