A phase II study of clinical activity of SCH 717454 (robatumumab) in patients with relapsed osteosarcoma and Ewing sarcoma

Peter M. Anderson; Stefan S. Bielack; Richard G. Gorlick; Keith Skubitz; Najat C. Daw; Cynthia E. Herzog; Odd R. Monge; Alvaro Lassaletta; Erica Boldrini; Zsuzanna Pápai; Joseph Rubino; Kumudu Pathiraja; Darcy A. Hille; Mark Ayers; Siu Long Yao; Michael Nebozhyn; Brian Lu; David Mauro

doi:10.1002/pbc.26087

A phase II study of clinical activity of SCH 717454 (robatumumab) in patients with relapsed osteosarcoma and Ewing sarcoma

Peter M. Anderson, Stefan S. Bielack, Richard G. Gorlick, Keith Skubitz, Najat C. Daw, Cynthia E. Herzog, Odd R. Monge, Alvaro Lassaletta, Erica Boldrini, Zsuzanna Pápai, Joseph Rubino, Kumudu Pathiraja, Darcy A. Hille, Mark Ayers, Siu Long Yao, Michael Nebozhyn, Brian Lu, David Mauro

Medicine - Hematology, Oncology, Transplant

Research output: Contribution to journal › Article › peer-review

71 Scopus citations

Abstract

Background: Robatumumab (19D12; MK-7454 otherwise known as SCH717454) is a fully human antibody that binds to and inhibits insulin-like growth factor receptor-1 (IGF-1R). This multiinstitutional study (P04720) determined the safety and clinical efficacy of robatumumab in three separate patient groups with resectable osteosarcoma metastases (Group 1), unresectable osteosarcoma metastases (Group 2), and Ewing sarcoma metastases (Group 3). Procedure: Robatumumab infusions were administered every 2 weeks and were well tolerated with minimal toxicity. Centrally reviewed response data were available for 144 patients. Results: Low disease burden was important for osteosarcoma response: three of 31 patients had complete response or partial response (PR) by Response Evaluation Criteria in Solid Tumors (RECIST) in resectable patients (Group 1) versus zero of 29 in unresectable patients (Group 2); median overall survival was 20 months in Group 1 versus 8.2 months in Group 2. In centrally reviewed patients with Ewing sarcoma with PET-CT data (N = 84/115), there were six PR, 23 stable disease, and 55 progression of disease by RECIST at 2 months. Patients with Ewing sarcoma had a median overall survival of 6.9 months. However, responding patients with Ewing sarcoma were allowed to continue on treatment after study closure. A minority of patients with metastatic Ewing sarcoma showed clinical responses and have remained healthy after receiving 25-115 doses of robatumumab with remissions of >4 years duration (N = 6). Conclusions: These findings show that although the IGF-1R remains an attractive treatment target, additional research is needed to identify responders and/or means to achieve durable remissions in order to successfully exploit IGF-1R signal blockade in Ewing sarcoma (clinicaltrials.gov: NCT00617890).

Original language	English (US)
Pages (from-to)	1761-1770
Number of pages	10
Journal	Pediatric Blood and Cancer
Volume	63
Issue number	10
DOIs	https://doi.org/10.1002/pbc.26087
State	Published - Oct 1 2016

Bibliographical note

Funding Information:
Merck & Co., Inc. provided financial support for this study. The authors acknowledge the numerous investigators and research staff that participated in this study. Dr. Anderson thanks Dr. Winston Huh and Laura Salvador, PA-C at MD Anderson for guidance and assistance in the conduct of the study. The authors acknowledge the contributions of Dr. Amy O. Johnson-Levonas, Merck & Co., Inc. for her assistance with the analyses, writing, and editing the paper. The authors also wish to thank Kristen Lewis and Sheila Erespe of Merck & Co., Inc. for assistance with preparing portions of manuscript for publication. All authors are responsible for the work described in this paper; involved in at least one of the following: conception, design, acquisition, analysis, statistical analysis, and interpretation of data, and drafting the manuscript and/or revising/reviewing the manuscript for important intellectual content; and provided final approval of the version to be published. All authors agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. A. Lassaletta reports consulting honoraria for Takeda and clinical trial payments from Merck & Co., Inc. S. S. Bielack reports payment to his institution from Schering Plough Corp. for the conduct of the study and personal fees from Celgene, Chugai, Bayer, Clinigen, and Lilly. N. C. Daw reports funding from Schering Plough Corp. for the conduct of the study. K. Skubitz reports grants from Merck and Co., Inc. and Schering Plough Corp. for the conduct of the study, as well as consulting fees for Amgen, Ariad/Merck, Novartis, Johnson & Johnson, Pfizer/Schering-Plough, Systems Medicine, and Seattle Genetics; stock ownership in Johnson & Johnson; research funding received from Amgen, Novartis, GSK, Ariad/Merck, Celgene, Cell Therapeutics, Systems Medicine, Infinity, Schering-Plough Corp., Bayer, Pfizer, and Daiichi; and provided expert testimony on the role of bisphosphonates in osteonecrosis of the jaw. R. G. Gorlick reports stock options with Oncolytics, Inc. and meeting travel support from Bayer Inc. J. Rubino, K. Pathiraja, D. A. Hille, M. Ayers, S.-L. Yao, M. Nebozhyn, B. Lu, and D. Mauro are former or current employees of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., and may own stock or stock options in the company. B. Lu reports current employment at Celgene. P. M. Anderson, C. Herzog, E. Boldrini, O. R. Monge, and Z. Papai have nothing to disclose. P.M. Anderson, MD Anderson Cancer Center, Houston, TX; M. Arico, Ospedale dei Bambini, Palermo, Italy; S.S. Bielack, Klinikum Stuttgart–Olgahospital, Stuttgart, Germany; M.E. Blackstein, Mount Sinai Hospital, Toronto, Canada; S.M. Blaney, Baylor College of Medicine, Houston, TX; E. Boldrini, Barretos Cancer Center, Barretos, Brazil; B. Bui, Institut Bergonie, Bordeaux, France; P. Chastagner, Children University Hospital, Cedex, France; S.P. Chawla, Sarcoma Oncology Center, Santa Monica, CA; Q. Chu, Cross Cancer Institute, Alberta, Canada; N.C. Daw, currently at MD Anderson Cancer Center, Houston, TX, previously at St. Jude Children's Research Hospital, Memphis, TN; T.N. Dechow, Onkologie Ravensburg, Ravensburg, Germany; J. Desai, Royal Melbourne Hospital, Parkville, Australia; U. Dirksen, University Children's Hospital-Muenster, Muenster, Germany; C. Favre, University or Pisa, Pisa, Italy; C. Forscher, Cedars-Sinai Medical Center, Los Angeles, CA; J.C. Gentet, Timone Hospital, Marseille, France; B. Geoerger, Institut Gustave Roussy, Villejuif, France; S. Gill, University of Cambridge, Hinxton, United Kingdom; R.G. Gorlick, Montefiore Medical Center, Bronx, NY; K.S. Hall, The Norwegian Radium Hospital, Oslo, Norway; C. Herzog, MD Anderson Cancer Center, Houston, TX; L. Hjorth, St. Anna Children's Hospital and Research Institute, Vienna, Austria; D. Hughes, MD Anderson Cancer Center, Houston, TX; L.E. Ju'arez-Villegas, Hospital Infantil de México Federico Gomez, Gomez, México; H. Katzenstein, Emory University, Atlanta, GA; T. Klingebiel, Children's Hospital of Frankfurt University Hospital, Frankfurt, Germany; A. Lassaletta, Hospital Infantil Universitario Niño Jesus, Madrid, Spain; E. Leculee Thebaud, Service d'Oncologie Pédiatrique, Lille, France; C.L. Stragliotto, Karolinska University Hospital, Stockholm, Sweden; D.M. Loeb, Johns Hopkins University/Sidney Kimmel Cancer Center, Baltimore, MD; A. Lunardi Brunetto, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil; L. Madero Lopez, Hospital Infantil Universitario Niño Jesus, Madrid, Spain; P. Marec-Berard, University of Lyon, Lyon, France; S. Martin-Algarra, University of Navarra, Pamplona, Spain; W.H. Meyer, University of Oklahoma, Oklahoma City, OK; P.A. Meyers, Memorial Sloan Kettering Cancer Center, New York, NY; M.M. Milhem, University of Iowa, Iowa City, IA; R.E.M. Miller, Alfred I DuPont Hospital for Children, Wilmington, DE; O.R. Monge, Haukeland University Hospital, Bergen, Norway; H. Pacquement, Institut Curie, Paris, France; Z. Papai, Military Hospital-State Health Centre Budapest; B.-K. Park, National Cancer Center, Goyang-si, Korea; A.S. Petrilli, Instituto de Oncologia Pediatrica, Sao Paulo, Brazil; A. Rey, Institut Gustave Roussy, Villejuif, France; E. Rodler, University of Washington Medical Center, Seattle, WA; E.M. Rubin, Children's Hospital of Orange County, Orange, CA; C. Sandoval, New York Medical College, Valhalla, NY; C.L. Schwartz, Rhode Island Hospital, Providence, RI; J.J. Seo, Asan Medical Center and University of Ulsan College of Medicine, Seoul, Korea; K. Skubitz, University of Minnesota, Minneapolis, MN; K. Stine, Arkansas Children's Hospital, Little Rock, AR; H.A.H. Tawbi, University of Pittsburg Cancer Institute, Pittsburgh, PA; W.T.A. van der Graaf, Institute of Cancer Research, Sutton, United Kingdom; M. Villarroel, Children's Hospital, Santiago, Chile; J. Whelan, University College Hospital, London, United Kingdom; C.-C. Yen, National Yang-Ming University School of Medicine, Taipei, Taiwan; D.S. Ziegler, Sydney Childrens Hospital, Randwick, Australia.

Publisher Copyright:
© 2016 The Authors and Merck & Co., Inc. Pediatric Blood & Cancer, published by Wiley Periodicals, Inc.

Keywords

Antibody therapy of cancer
Bone sarcoma
Ewing sarcoma
Osteosarcoma
Resistance
Tumor growth factor

PubMed: MeSH publication types

Journal Article
Clinical Trial, Phase II
Multicenter Study

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1002/pbc.26087

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Cite this

Anderson, P. M., Bielack, S. S., Gorlick, R. G., Skubitz, K., Daw, N. C., Herzog, C. E., Monge, O. R., Lassaletta, A., Boldrini, E., Pápai, Z., Rubino, J., Pathiraja, K., Hille, D. A., Ayers, M., Yao, S. L., Nebozhyn, M., Lu, B., & Mauro, D. (2016). A phase II study of clinical activity of SCH 717454 (robatumumab) in patients with relapsed osteosarcoma and Ewing sarcoma. Pediatric Blood and Cancer, 63(10), 1761-1770. https://doi.org/10.1002/pbc.26087

Anderson, PM, Bielack, SS, Gorlick, RG, Skubitz, K, Daw, NC, Herzog, CE, Monge, OR, Lassaletta, A, Boldrini, E, Pápai, Z, Rubino, J, Pathiraja, K, Hille, DA, Ayers, M, Yao, SL, Nebozhyn, M, Lu, B & Mauro, D 2016, 'A phase II study of clinical activity of SCH 717454 (robatumumab) in patients with relapsed osteosarcoma and Ewing sarcoma', Pediatric Blood and Cancer, vol. 63, no. 10, pp. 1761-1770. https://doi.org/10.1002/pbc.26087

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title = "A phase II study of clinical activity of SCH 717454 (robatumumab) in patients with relapsed osteosarcoma and Ewing sarcoma",

abstract = "Background: Robatumumab (19D12; MK-7454 otherwise known as SCH717454) is a fully human antibody that binds to and inhibits insulin-like growth factor receptor-1 (IGF-1R). This multiinstitutional study (P04720) determined the safety and clinical efficacy of robatumumab in three separate patient groups with resectable osteosarcoma metastases (Group 1), unresectable osteosarcoma metastases (Group 2), and Ewing sarcoma metastases (Group 3). Procedure: Robatumumab infusions were administered every 2 weeks and were well tolerated with minimal toxicity. Centrally reviewed response data were available for 144 patients. Results: Low disease burden was important for osteosarcoma response: three of 31 patients had complete response or partial response (PR) by Response Evaluation Criteria in Solid Tumors (RECIST) in resectable patients (Group 1) versus zero of 29 in unresectable patients (Group 2); median overall survival was 20 months in Group 1 versus 8.2 months in Group 2. In centrally reviewed patients with Ewing sarcoma with PET-CT data (N = 84/115), there were six PR, 23 stable disease, and 55 progression of disease by RECIST at 2 months. Patients with Ewing sarcoma had a median overall survival of 6.9 months. However, responding patients with Ewing sarcoma were allowed to continue on treatment after study closure. A minority of patients with metastatic Ewing sarcoma showed clinical responses and have remained healthy after receiving 25-115 doses of robatumumab with remissions of >4 years duration (N = 6). Conclusions: These findings show that although the IGF-1R remains an attractive treatment target, additional research is needed to identify responders and/or means to achieve durable remissions in order to successfully exploit IGF-1R signal blockade in Ewing sarcoma (clinicaltrials.gov: NCT00617890).",

keywords = "Antibody therapy of cancer, Bone sarcoma, Ewing sarcoma, Osteosarcoma, Resistance, Tumor growth factor",

author = "Anderson, {Peter M.} and Bielack, {Stefan S.} and Gorlick, {Richard G.} and Keith Skubitz and Daw, {Najat C.} and Herzog, {Cynthia E.} and Monge, {Odd R.} and Alvaro Lassaletta and Erica Boldrini and Zsuzanna P{\'a}pai and Joseph Rubino and Kumudu Pathiraja and Hille, {Darcy A.} and Mark Ayers and Yao, {Siu Long} and Michael Nebozhyn and Brian Lu and David Mauro",

note = "Funding Information: Merck & Co., Inc. provided financial support for this study. The authors acknowledge the numerous investigators and research staff that participated in this study. Dr. Anderson thanks Dr. Winston Huh and Laura Salvador, PA-C at MD Anderson for guidance and assistance in the conduct of the study. The authors acknowledge the contributions of Dr. Amy O. Johnson-Levonas, Merck & Co., Inc. for her assistance with the analyses, writing, and editing the paper. The authors also wish to thank Kristen Lewis and Sheila Erespe of Merck & Co., Inc. for assistance with preparing portions of manuscript for publication. All authors are responsible for the work described in this paper; involved in at least one of the following: conception, design, acquisition, analysis, statistical analysis, and interpretation of data, and drafting the manuscript and/or revising/reviewing the manuscript for important intellectual content; and provided final approval of the version to be published. All authors agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. A. Lassaletta reports consulting honoraria for Takeda and clinical trial payments from Merck & Co., Inc. S. S. Bielack reports payment to his institution from Schering Plough Corp. for the conduct of the study and personal fees from Celgene, Chugai, Bayer, Clinigen, and Lilly. N. C. Daw reports funding from Schering Plough Corp. for the conduct of the study. K. Skubitz reports grants from Merck and Co., Inc. and Schering Plough Corp. for the conduct of the study, as well as consulting fees for Amgen, Ariad/Merck, Novartis, Johnson & Johnson, Pfizer/Schering-Plough, Systems Medicine, and Seattle Genetics; stock ownership in Johnson & Johnson; research funding received from Amgen, Novartis, GSK, Ariad/Merck, Celgene, Cell Therapeutics, Systems Medicine, Infinity, Schering-Plough Corp., Bayer, Pfizer, and Daiichi; and provided expert testimony on the role of bisphosphonates in osteonecrosis of the jaw. R. G. Gorlick reports stock options with Oncolytics, Inc. and meeting travel support from Bayer Inc. J. Rubino, K. Pathiraja, D. A. Hille, M. Ayers, S.-L. Yao, M. Nebozhyn, B. Lu, and D. Mauro are former or current employees of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., and may own stock or stock options in the company. B. Lu reports current employment at Celgene. P. M. Anderson, C. Herzog, E. Boldrini, O. R. Monge, and Z. Papai have nothing to disclose. P.M. Anderson, MD Anderson Cancer Center, Houston, TX; M. Arico, Ospedale dei Bambini, Palermo, Italy; S.S. Bielack, Klinikum Stuttgart–Olgahospital, Stuttgart, Germany; M.E. Blackstein, Mount Sinai Hospital, Toronto, Canada; S.M. Blaney, Baylor College of Medicine, Houston, TX; E. Boldrini, Barretos Cancer Center, Barretos, Brazil; B. Bui, Institut Bergonie, Bordeaux, France; P. Chastagner, Children University Hospital, Cedex, France; S.P. Chawla, Sarcoma Oncology Center, Santa Monica, CA; Q. Chu, Cross Cancer Institute, Alberta, Canada; N.C. Daw, currently at MD Anderson Cancer Center, Houston, TX, previously at St. Jude Children's Research Hospital, Memphis, TN; T.N. Dechow, Onkologie Ravensburg, Ravensburg, Germany; J. Desai, Royal Melbourne Hospital, Parkville, Australia; U. Dirksen, University Children's Hospital-Muenster, Muenster, Germany; C. Favre, University or Pisa, Pisa, Italy; C. Forscher, Cedars-Sinai Medical Center, Los Angeles, CA; J.C. Gentet, Timone Hospital, Marseille, France; B. Geoerger, Institut Gustave Roussy, Villejuif, France; S. Gill, University of Cambridge, Hinxton, United Kingdom; R.G. Gorlick, Montefiore Medical Center, Bronx, NY; K.S. Hall, The Norwegian Radium Hospital, Oslo, Norway; C. Herzog, MD Anderson Cancer Center, Houston, TX; L. Hjorth, St. Anna Children's Hospital and Research Institute, Vienna, Austria; D. Hughes, MD Anderson Cancer Center, Houston, TX; L.E. Ju'arez-Villegas, Hospital Infantil de M{\'e}xico Federico Gomez, Gomez, M{\'e}xico; H. Katzenstein, Emory University, Atlanta, GA; T. Klingebiel, Children's Hospital of Frankfurt University Hospital, Frankfurt, Germany; A. Lassaletta, Hospital Infantil Universitario Ni{\~n}o Jesus, Madrid, Spain; E. Leculee Thebaud, Service d'Oncologie P{\'e}diatrique, Lille, France; C.L. Stragliotto, Karolinska University Hospital, Stockholm, Sweden; D.M. Loeb, Johns Hopkins University/Sidney Kimmel Cancer Center, Baltimore, MD; A. Lunardi Brunetto, Hospital de Cl{\'i}nicas de Porto Alegre, Porto Alegre, Brazil; L. Madero Lopez, Hospital Infantil Universitario Ni{\~n}o Jesus, Madrid, Spain; P. Marec-Berard, University of Lyon, Lyon, France; S. Martin-Algarra, University of Navarra, Pamplona, Spain; W.H. Meyer, University of Oklahoma, Oklahoma City, OK; P.A. Meyers, Memorial Sloan Kettering Cancer Center, New York, NY; M.M. Milhem, University of Iowa, Iowa City, IA; R.E.M. Miller, Alfred I DuPont Hospital for Children, Wilmington, DE; O.R. Monge, Haukeland University Hospital, Bergen, Norway; H. Pacquement, Institut Curie, Paris, France; Z. Papai, Military Hospital-State Health Centre Budapest; B.-K. Park, National Cancer Center, Goyang-si, Korea; A.S. Petrilli, Instituto de Oncologia Pediatrica, Sao Paulo, Brazil; A. Rey, Institut Gustave Roussy, Villejuif, France; E. Rodler, University of Washington Medical Center, Seattle, WA; E.M. Rubin, Children's Hospital of Orange County, Orange, CA; C. Sandoval, New York Medical College, Valhalla, NY; C.L. Schwartz, Rhode Island Hospital, Providence, RI; J.J. Seo, Asan Medical Center and University of Ulsan College of Medicine, Seoul, Korea; K. Skubitz, University of Minnesota, Minneapolis, MN; K. Stine, Arkansas Children's Hospital, Little Rock, AR; H.A.H. Tawbi, University of Pittsburg Cancer Institute, Pittsburgh, PA; W.T.A. van der Graaf, Institute of Cancer Research, Sutton, United Kingdom; M. Villarroel, Children's Hospital, Santiago, Chile; J. Whelan, University College Hospital, London, United Kingdom; C.-C. Yen, National Yang-Ming University School of Medicine, Taipei, Taiwan; D.S. Ziegler, Sydney Childrens Hospital, Randwick, Australia. Publisher Copyright: {\textcopyright} 2016 The Authors and Merck & Co., Inc. Pediatric Blood & Cancer, published by Wiley Periodicals, Inc.",

year = "2016",

month = oct,

day = "1",

doi = "10.1002/pbc.26087",

language = "English (US)",

volume = "63",

pages = "1761--1770",

journal = "Pediatric Blood and Cancer",

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TY - JOUR

T1 - A phase II study of clinical activity of SCH 717454 (robatumumab) in patients with relapsed osteosarcoma and Ewing sarcoma

AU - Anderson, Peter M.

AU - Bielack, Stefan S.

AU - Gorlick, Richard G.

AU - Skubitz, Keith

AU - Daw, Najat C.

AU - Herzog, Cynthia E.

AU - Monge, Odd R.

AU - Lassaletta, Alvaro

AU - Boldrini, Erica

AU - Pápai, Zsuzanna

AU - Rubino, Joseph

AU - Pathiraja, Kumudu

AU - Hille, Darcy A.

AU - Ayers, Mark

AU - Yao, Siu Long

AU - Nebozhyn, Michael

AU - Lu, Brian

AU - Mauro, David

N1 - Funding Information: Merck & Co., Inc. provided financial support for this study. The authors acknowledge the numerous investigators and research staff that participated in this study. Dr. Anderson thanks Dr. Winston Huh and Laura Salvador, PA-C at MD Anderson for guidance and assistance in the conduct of the study. The authors acknowledge the contributions of Dr. Amy O. Johnson-Levonas, Merck & Co., Inc. for her assistance with the analyses, writing, and editing the paper. The authors also wish to thank Kristen Lewis and Sheila Erespe of Merck & Co., Inc. for assistance with preparing portions of manuscript for publication. All authors are responsible for the work described in this paper; involved in at least one of the following: conception, design, acquisition, analysis, statistical analysis, and interpretation of data, and drafting the manuscript and/or revising/reviewing the manuscript for important intellectual content; and provided final approval of the version to be published. All authors agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. A. Lassaletta reports consulting honoraria for Takeda and clinical trial payments from Merck & Co., Inc. S. S. Bielack reports payment to his institution from Schering Plough Corp. for the conduct of the study and personal fees from Celgene, Chugai, Bayer, Clinigen, and Lilly. N. C. Daw reports funding from Schering Plough Corp. for the conduct of the study. K. Skubitz reports grants from Merck and Co., Inc. and Schering Plough Corp. for the conduct of the study, as well as consulting fees for Amgen, Ariad/Merck, Novartis, Johnson & Johnson, Pfizer/Schering-Plough, Systems Medicine, and Seattle Genetics; stock ownership in Johnson & Johnson; research funding received from Amgen, Novartis, GSK, Ariad/Merck, Celgene, Cell Therapeutics, Systems Medicine, Infinity, Schering-Plough Corp., Bayer, Pfizer, and Daiichi; and provided expert testimony on the role of bisphosphonates in osteonecrosis of the jaw. R. G. Gorlick reports stock options with Oncolytics, Inc. and meeting travel support from Bayer Inc. J. Rubino, K. Pathiraja, D. A. Hille, M. Ayers, S.-L. Yao, M. Nebozhyn, B. Lu, and D. Mauro are former or current employees of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., and may own stock or stock options in the company. B. Lu reports current employment at Celgene. P. M. Anderson, C. Herzog, E. Boldrini, O. R. Monge, and Z. Papai have nothing to disclose. P.M. Anderson, MD Anderson Cancer Center, Houston, TX; M. Arico, Ospedale dei Bambini, Palermo, Italy; S.S. Bielack, Klinikum Stuttgart–Olgahospital, Stuttgart, Germany; M.E. Blackstein, Mount Sinai Hospital, Toronto, Canada; S.M. Blaney, Baylor College of Medicine, Houston, TX; E. Boldrini, Barretos Cancer Center, Barretos, Brazil; B. Bui, Institut Bergonie, Bordeaux, France; P. Chastagner, Children University Hospital, Cedex, France; S.P. Chawla, Sarcoma Oncology Center, Santa Monica, CA; Q. Chu, Cross Cancer Institute, Alberta, Canada; N.C. Daw, currently at MD Anderson Cancer Center, Houston, TX, previously at St. Jude Children's Research Hospital, Memphis, TN; T.N. Dechow, Onkologie Ravensburg, Ravensburg, Germany; J. Desai, Royal Melbourne Hospital, Parkville, Australia; U. Dirksen, University Children's Hospital-Muenster, Muenster, Germany; C. Favre, University or Pisa, Pisa, Italy; C. Forscher, Cedars-Sinai Medical Center, Los Angeles, CA; J.C. Gentet, Timone Hospital, Marseille, France; B. Geoerger, Institut Gustave Roussy, Villejuif, France; S. Gill, University of Cambridge, Hinxton, United Kingdom; R.G. Gorlick, Montefiore Medical Center, Bronx, NY; K.S. Hall, The Norwegian Radium Hospital, Oslo, Norway; C. Herzog, MD Anderson Cancer Center, Houston, TX; L. Hjorth, St. Anna Children's Hospital and Research Institute, Vienna, Austria; D. Hughes, MD Anderson Cancer Center, Houston, TX; L.E. Ju'arez-Villegas, Hospital Infantil de México Federico Gomez, Gomez, México; H. Katzenstein, Emory University, Atlanta, GA; T. Klingebiel, Children's Hospital of Frankfurt University Hospital, Frankfurt, Germany; A. Lassaletta, Hospital Infantil Universitario Niño Jesus, Madrid, Spain; E. Leculee Thebaud, Service d'Oncologie Pédiatrique, Lille, France; C.L. Stragliotto, Karolinska University Hospital, Stockholm, Sweden; D.M. Loeb, Johns Hopkins University/Sidney Kimmel Cancer Center, Baltimore, MD; A. Lunardi Brunetto, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil; L. Madero Lopez, Hospital Infantil Universitario Niño Jesus, Madrid, Spain; P. Marec-Berard, University of Lyon, Lyon, France; S. Martin-Algarra, University of Navarra, Pamplona, Spain; W.H. Meyer, University of Oklahoma, Oklahoma City, OK; P.A. Meyers, Memorial Sloan Kettering Cancer Center, New York, NY; M.M. Milhem, University of Iowa, Iowa City, IA; R.E.M. Miller, Alfred I DuPont Hospital for Children, Wilmington, DE; O.R. Monge, Haukeland University Hospital, Bergen, Norway; H. Pacquement, Institut Curie, Paris, France; Z. Papai, Military Hospital-State Health Centre Budapest; B.-K. Park, National Cancer Center, Goyang-si, Korea; A.S. Petrilli, Instituto de Oncologia Pediatrica, Sao Paulo, Brazil; A. Rey, Institut Gustave Roussy, Villejuif, France; E. Rodler, University of Washington Medical Center, Seattle, WA; E.M. Rubin, Children's Hospital of Orange County, Orange, CA; C. Sandoval, New York Medical College, Valhalla, NY; C.L. Schwartz, Rhode Island Hospital, Providence, RI; J.J. Seo, Asan Medical Center and University of Ulsan College of Medicine, Seoul, Korea; K. Skubitz, University of Minnesota, Minneapolis, MN; K. Stine, Arkansas Children's Hospital, Little Rock, AR; H.A.H. Tawbi, University of Pittsburg Cancer Institute, Pittsburgh, PA; W.T.A. van der Graaf, Institute of Cancer Research, Sutton, United Kingdom; M. Villarroel, Children's Hospital, Santiago, Chile; J. Whelan, University College Hospital, London, United Kingdom; C.-C. Yen, National Yang-Ming University School of Medicine, Taipei, Taiwan; D.S. Ziegler, Sydney Childrens Hospital, Randwick, Australia. Publisher Copyright: © 2016 The Authors and Merck & Co., Inc. Pediatric Blood & Cancer, published by Wiley Periodicals, Inc.

PY - 2016/10/1

Y1 - 2016/10/1

N2 - Background: Robatumumab (19D12; MK-7454 otherwise known as SCH717454) is a fully human antibody that binds to and inhibits insulin-like growth factor receptor-1 (IGF-1R). This multiinstitutional study (P04720) determined the safety and clinical efficacy of robatumumab in three separate patient groups with resectable osteosarcoma metastases (Group 1), unresectable osteosarcoma metastases (Group 2), and Ewing sarcoma metastases (Group 3). Procedure: Robatumumab infusions were administered every 2 weeks and were well tolerated with minimal toxicity. Centrally reviewed response data were available for 144 patients. Results: Low disease burden was important for osteosarcoma response: three of 31 patients had complete response or partial response (PR) by Response Evaluation Criteria in Solid Tumors (RECIST) in resectable patients (Group 1) versus zero of 29 in unresectable patients (Group 2); median overall survival was 20 months in Group 1 versus 8.2 months in Group 2. In centrally reviewed patients with Ewing sarcoma with PET-CT data (N = 84/115), there were six PR, 23 stable disease, and 55 progression of disease by RECIST at 2 months. Patients with Ewing sarcoma had a median overall survival of 6.9 months. However, responding patients with Ewing sarcoma were allowed to continue on treatment after study closure. A minority of patients with metastatic Ewing sarcoma showed clinical responses and have remained healthy after receiving 25-115 doses of robatumumab with remissions of >4 years duration (N = 6). Conclusions: These findings show that although the IGF-1R remains an attractive treatment target, additional research is needed to identify responders and/or means to achieve durable remissions in order to successfully exploit IGF-1R signal blockade in Ewing sarcoma (clinicaltrials.gov: NCT00617890).

AB - Background: Robatumumab (19D12; MK-7454 otherwise known as SCH717454) is a fully human antibody that binds to and inhibits insulin-like growth factor receptor-1 (IGF-1R). This multiinstitutional study (P04720) determined the safety and clinical efficacy of robatumumab in three separate patient groups with resectable osteosarcoma metastases (Group 1), unresectable osteosarcoma metastases (Group 2), and Ewing sarcoma metastases (Group 3). Procedure: Robatumumab infusions were administered every 2 weeks and were well tolerated with minimal toxicity. Centrally reviewed response data were available for 144 patients. Results: Low disease burden was important for osteosarcoma response: three of 31 patients had complete response or partial response (PR) by Response Evaluation Criteria in Solid Tumors (RECIST) in resectable patients (Group 1) versus zero of 29 in unresectable patients (Group 2); median overall survival was 20 months in Group 1 versus 8.2 months in Group 2. In centrally reviewed patients with Ewing sarcoma with PET-CT data (N = 84/115), there were six PR, 23 stable disease, and 55 progression of disease by RECIST at 2 months. Patients with Ewing sarcoma had a median overall survival of 6.9 months. However, responding patients with Ewing sarcoma were allowed to continue on treatment after study closure. A minority of patients with metastatic Ewing sarcoma showed clinical responses and have remained healthy after receiving 25-115 doses of robatumumab with remissions of >4 years duration (N = 6). Conclusions: These findings show that although the IGF-1R remains an attractive treatment target, additional research is needed to identify responders and/or means to achieve durable remissions in order to successfully exploit IGF-1R signal blockade in Ewing sarcoma (clinicaltrials.gov: NCT00617890).

KW - Antibody therapy of cancer

KW - Bone sarcoma

KW - Ewing sarcoma

KW - Osteosarcoma

KW - Resistance

KW - Tumor growth factor

UR - http://www.scopus.com/inward/record.url?scp=84978175092&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84978175092&partnerID=8YFLogxK

U2 - 10.1002/pbc.26087

DO - 10.1002/pbc.26087

M3 - Article

C2 - 27362300

AN - SCOPUS:84983349062

SN - 1545-5009

VL - 63

SP - 1761

EP - 1770

JO - Pediatric Blood and Cancer

JF - Pediatric Blood and Cancer

IS - 10

ER -

A phase II study of clinical activity of SCH 717454 (robatumumab) in patients with relapsed osteosarcoma and Ewing sarcoma

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