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1. Activation of Pyruvate Kinase-R with Etavopivat (FT-4202) Is Well Tolerated, Improves Anemia, and Decreases Intravascular Hemolysis in Patients with Sickle Cell Disease Treated for up to 12 Weeks

Author

Santosh L. Saraf, Patrick Kelly, Theodosia A. Kalfa, Marilyn J. Telen, Modupe Idowu, Patricia Schroeder, James Geib, Kimberly Cruz, R. Clark Brown, Sanjeev Forsyth, and Eric Q. Wu

Subjects
medicine.medical_specialty, business.industry, Anemia, Immunology, Cell, Cell Biology, Hematology, Disease, medicine.disease, Biochemistry, Gastroenterology, Intravascular hemolysis, medicine.anatomical_structure, Internal medicine, Medicine, In patient, business, Pyruvate kinase
Abstract

Etavopivat is a small molecule activator of erythrocyte pyruvate kinase (PKR), that increases PKR activity, resulting in decreased 2,3-DPG and increased ATP in red blood cells (RBCs) of healthy volunteers (HV) and patients (pts) with sickle cell disease (SCD) (Kalfa 2019, Brown 2020). Based on initial safety, pharmacokinetic (PK) and pharmacodynamic (PD) data for HVs and pts with SCD, we performed multiple-dose studies in pts with SCD (NCT03815695): 2-wk multiple ascending dose (MD) cohorts to identify the once daily etavopivat dose that provides maximum PD activity with an acceptable safety profile and a 12-wk open label (OL) study to further characterize the safety and clinical activity at the maximum PD dose. These data are presented here. In the completed MD cohorts, 20 pts with SCD were randomized 8:2 to receive etavopivat (300 mg, then 600 mg) or placebo (PBO) once daily for 2 wks. In the ongoing OL cohort, up to 20 pts will receive etavopivat 400 mg once daily for 12 wks. Safety assessments included adverse events (AEs), vital signs, electrocardiograms, and peripheral blood laboratory parameters. PK/PD blood sampling was performed for up to 72 h after last dose and at end of study visit. RBC function studies were performed to assess membrane deformability (Lorrca ®). Enrollment in the MD cohorts (n=17 HbSS, n=2 HbSβ+thalassemia, n=1 HbSC) is complete and data unblinded (n=8: 300 mg etavopivat; n=8: 600 mg etavopivat; n=4: PBO). As of July 13, 2021, 11 pts (n=10 HbSS, 1 HbSC) have been treated in the OL cohort: median treatment duration was 12 (range 1-12) wks, 6 pts completed 12 wks of treatment. In MD pts, etavopivat demonstrated dose-proportional PK with overlapping PD responses (decreased 2,3-DPG and increased ATP), confirming prior results in HVs that etavopivat 400 mg once daily provides near maximal PD activity. Etavopivat was well tolerated in both MD and OL cohorts. AEs were reported in 1 of 4 (25%) MD PBO pts, most were grade (gr) ≤3, with 1 gr 4 blood creatine phosphokinase (CPK) increase. 13 of 16 (81%) etavopivat-treated MD pts reported AEs, most were gr 1/2 and commonly (>2 pts) included sickle cell pain (n=6 [38%]), headache (n=5 [31%]), and nausea (n=3 [19%]). One pt had a serious AE (SAE) of gr 3 vaso-occlusive crisis (VOC) after completion of etavopivat (considered unrelated). In the OL cohort, AEs were reported in 7 of 11 (64%) pts who received at least 1 wk of etavopivat. AEs reported in >1 pt were headache and VOC (n=2 [18%] each). Most AEs were gr 1/2; one pt had SAEs of gr 3 acute chest syndrome and VOC (unrelated), one pt had an SAE of gr 3 deep vein thrombosis (possibly related), and one pt had an AE of gr 4 transient blood CPK increase (unrelated). Hematologic and hemolytic parameters were significantly improved at end of treatment in both MD and OL cohorts (Table 1); 11 of 15 (73%) evaluable MD pts achieved a Hb increase ≥1g/dL over baseline (mean 1.1 g/dL, P1g/dL Hb increase over baseline (mean 1.39 g/dL). Reductions in ARC, indirect bilirubin and LDH were also observed. Of 9 pts on etavopivat for at least 4 wks, 8 (89%) reported an increase in Hb >1g/dL, and the highest mean Hb increase was 1.81 g/dL during active treatment. Etavopivat-treated RBCs from MD pts (n=14) demonstrated improved functional health, including point of sickling and deformability. The improved deformability persisted up to 1 wk after etavopivat treatment in 36% of pts. Similar results were observed in the initial OL pts. Data on additional treated pts will be presented. Etavopivat 400 mg once daily for up to 12 wks was well-tolerated, with a safety profile consistent with underlying SCD. Increases in Hb >1 g/dL were observed in 89% of pts and maintained throughout 12 wks of treatment in the majority (83%) of pts. Increased Hb and a significant reduction in ARC indicated that etavopivat enhanced survival of sickle RBCs and significantly improved the severe anemia associated with SCD. These longer-living sickle RBCs have improved membrane health that may further reduce the risk of VOCs and end-organ damage. These results support further evaluation of etavopivat in the ongoing Phase 2/3 Hibiscus Study in pts with SCD (NCT04624659). Figure 1 Figure 1. Disclosures Brown: Imara: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Novo Nordisk: Consultancy; Forma Therapeutics: Research Funding; Pfizer: Research Funding; Global Blood Therapeutics: Consultancy, Research Funding. Saraf: Global Blood Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Research Funding. Idowu: Pfizer: Research Funding; Global Blood Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Forma Therapeutics, Inc.: Research Funding; Ironwood: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding. Kalfa: Agios Pharmaceuticals, Inc.: Other: Steering Committee, Research Funding; FORMA Therapeutics, Inc: Research Funding. Geib: Forma Therapeutics, Inc.: Current Employment, Current equity holder in publicly-traded company. Forsyth: Forma Therapeutics, Inc.: Current Employment, Current equity holder in publicly-traded company. Schroeder: Forma Therapeutics, Inc.: Current Employment, Current equity holder in publicly-traded company. Wu: Forma Therapeutics, Inc.: Current Employment, Current equity holder in publicly-traded company. Kelly: Forma Therapeutics, Inc.: Current Employment, Current equity holder in publicly-traded company. Telen: GlycoMimetics, Inc.: Consultancy; Novartis, Inc.: Other: Data Safety Monitoring Board; Forma Therapeutics, Inc.: Consultancy, Research Funding; CSL Behring, Inc.: Research Funding; Doris Duke Charitable Foundation: Research Funding; National Institutes of Health: Research Funding.

Published
2021

2. 31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016): part one

Author

Andreas Lundqvist, Vincent van Hoef, Xiaonan Zhang, Erik Wennerberg, Julie Lorent, Kristina Witt, Laia Masvidal Sanz, Shuo Liang, Shannon Murray, Ola Larsson, Rolf Kiessling, Yumeng Mao, John-William Sidhom, Catherine A. Bessell, Jonathan Havel, Jonathan Schneck, Timothy A. Chan, Eliot Sachsenmeier, David Woods, Anders Berglund, Rupal Ramakrishnan, Andressa Sodre, Jeffrey Weber, Roberta Zappasodi, Yanyun Li, Jingjing Qi, Philip Wong, Cynthia Sirard, Michael Postow, Walter Newman, Henry Koon, Vamsidhar Velcheti, Margaret K. Callahan, Jedd D. Wolchok, Taha Merghoub, Lawrence G. Lum, Minsig Choi, Archana Thakur, Abhinav Deol, Gregory Dyson, Anthony Shields, Cara Haymaker, Marc Uemura, Ravi Murthy, Marihella James, Daqing Wang, Julie Brevard, Catherine Monaghan, Suzanne Swann, James Geib, Mark Cornfeld, Srinivas Chunduru, Sudhir Agrawal, Cassian Yee, Jennifer Wargo, Sapna P. Patel, Rodabe Amaria, Hussein Tawbi, Isabella Glitza, Scott Woodman, Wen-Jen Hwu, Michael A. Davies, Patrick Hwu, Willem W. Overwijk, Chantale Bernatchez, Adi Diab, Erminia Massarelli, Neil H. Segal, Vincent Ribrag, Ignacio Melero, Tara C. Gangadhar, Walter Urba, Dirk Schadendorf, Robert L. Ferris, Roch Houot, Franck Morschhauser, Theodore Logan, Jason J. Luke, William Sharfman, Fabrice Barlesi, Patrick A. Ott, Laura Mansi, Shivaani Kummar, Gilles Salles, Cecilia Carpio, Roland Meier, Suba Krishnan, Dan McDonald, Matthew Maurer, Xuemin Gu, Jaclyn Neely, Satyendra Suryawanshi, Ronald Levy, Nikhil Khushalani, Jennifer Wu, Jinyu Zhang, Fahmin Basher, Mark Rubinstein, Mark Bucsek, Guanxi Qiao, Cameron MacDonald, Bonnie Hylander, Elizabeth Repasky, Shilpak Chatterjee, Anusara Daenthanasanmak, Paramita Chakraborty, Kyle Toth, Megan Meek, Elizabeth Garrett-Mayer, Michael Nishimura, Chrystal Paulos, Craig Beeson, Xuezhong Yu, Shikhar Mehrotra, Fei Zhao, Kathy Evans, Christine Xiao, Alisha Holtzhausen, Brent A. Hanks, Nicole Scharping, Ashley V. Menk, Rebecca Moreci, Ryan Whetstone, Rebekah Dadey, Simon Watkins, Robert Ferris, Greg M. Delgoffe, Jonathan Peled, Sean Devlin, Anna Staffas, Melissa Lumish, Kori Porosnicu Rodriguez, Katya Ahr, Miguel Perales, Sergio Giralt, Ying Taur, Eric Pamer, Marcel R. M. van den Brink, Robert Jenq, Nicola Annels, Hardev Pandha, Guy Simpson, Hugh Mostafid, Kevin Harrington, Alan Melcher, Mark Grose, Bronwyn Davies, Gough Au, Roberta Karpathy, Darren Shafren, Jacob Ricca, Dmitriy Zamarin, Luciana Batista, Florence Marliot, Angela Vasaturo, Sabrina Carpentier, Cécile Poggionovo, Véronique Frayssinet, Jacques Fieschi, Marc Van den Eynde, Franck Pagès, Jérôme Galon, Fabienne Hermitte, Sean G. Smith, Khue Nguyen, Sruthi Ravindranathan, Bhanu Koppolu, David Zaharoff, Gustavo Schvartsman, Roland Bassett, Jennifer L. McQuade, Lauren E. Haydu, Douglas Kline, Xiufen Chen, Dominick Fosco, Justin Kline, Abigail Overacre, Maria Chikina, Erin Brunazzi, Gulidanna Shayan, William Horne, Jay Kolls, Tullia C. Bruno, Creg Workman, Dario Vignali, Prasad S. Adusumilli, Ephraim A Ansa-Addo, Zihai Li, Andrew Gerry, Joseph P. Sanderson, Karen Howe, Roslin Docta, Qian Gao, Eleanor A. L. Bagg, Nicholas Tribble, Miguel Maroto, Gareth Betts, Natalie Bath, Luca Melchiori, Daniel E. Lowther, Indu Ramachandran, Gabor Kari, Samik Basu, Gwendolyn Binder-Scholl, Karen Chagin, Lini Pandite, Tom Holdich, Rafael Amado, Hua Zhang, John Glod, Donna Bernstein, Bent Jakobsen, Crystal Mackall, Ryan Wong, Jonathan D. Silk, Katherine Adams, Garth Hamilton, Alan D. Bennett, Sara Brett, Junping Jing, Adriano Quattrini, Manoj Saini, Guy Wiedermann, Joanna Brewer, MyLinh Duong, An Lu, Peter Chang, Aruna Mahendravada, Nicholas Shinners, Kevin Slawin, David M. Spencer, Aaron E. Foster, J. Henri Bayle, Cristina Bergamaschi, Sinnie Sin Man Ng, Bethany Nagy, Shawn Jensen, Xintao Hu, Candido Alicea, Bernard Fox, Barbara Felber, George Pavlakis, Jessica Chacon, Tori Yamamoto, Thomas Garrabrant, Luis Cortina, Daniel J. Powell, Marco Donia, Julie Westerlin Kjeldsen, Rikke Andersen, Marie Christine Wulff Westergaard, Valentina Bianchi, Mateusz Legut, Meriem Attaf, Garry Dolton, Barbara Szomolay, Sascha Ott, Rikke Lyngaa, Sine Reker Hadrup, Andrew Kelvin Sewell, Inge Marie Svane, Aaron Fan, Takumi Kumai, Esteban Celis, Ian Frank, Amanda Stramer, Michelle A. Blaskovich, Seth Wardell, Maria Fardis, James Bender, Michael T. Lotze, Stephanie L. Goff, Nikolaos Zacharakis, Yasmine Assadipour, Todd D. Prickett, Jared J. Gartner, Robert Somerville, Mary Black, Hui Xu, Harshini Chinnasamy, Isaac Kriley, Lily Lu, John Wunderlich, Paul F. Robbins, Steven Rosenberg, Steven A. Feldman, Kasia Trebska-McGowan, Parisa Malekzadeh, Eden Payabyab, Richard Sherry, Aishwarya Gokuldass, Charlene Kopits, Brian Rabinovich, Daniel S. Green, Olena Kamenyeva, Kathryn C. Zoon, Christina M. Annunziata, Joanne Hammill, Christopher Helsen, Craig Aarts, Jonathan Bramson, Yui Harada, Yoshikazu Yonemitsu, Kenneth Mwawasi, Galina Denisova, Rajanish Giri, Benjamin Jin, Tracy Campbell, Lindsey M. Draper, Sanja Stevanovic, Zhiya Yu, Bianca Weissbrich, Nicholas P. Restifo, Cornelia L. Trimble, Christian S. Hinrichs, Kwong Tsang, Massimo Fantini, James W. Hodge, Rika Fujii, Ingrid Fernando, Caroline Jochems, Christopher Heery, James Gulley, Patrick Soon-Shiong, Jeffrey Schlom, Weiqing Jing, Jill Gershan, Grace Blitzer, James Weber, Laura McOlash, Bryon D. Johnson, Simin Kiany, Huang Gangxiong, Eugenie S. Kleinerman, Michael Klichinsky, Marco Ruella, Olga Shestova, Saad Kenderian, Miriam Kim, John Scholler, Carl H. June, Saar Gill, Duane Moogk, Shi Zhong, Ivan Liadi, William Rittase, Victoria Fang, Janna Dougherty, Arianne Perez-Garcia, Iman Osman, Cheng Zhu, Navin Varadarajan, Alan Frey, Michelle Krogsgaard, Daniel Landi, Kristen Fousek, Malini Mukherjee, Ankita Shree, Sujith Joseph, Kevin Bielamowicz, Tiara Byrd, Nabil Ahmed, Meenakshi Hegde, Sylvia Lee, David Byrd, John Thompson, Shailender Bhatia, Scott Tykodi, Judy Delismon, Liz Chu, Siddiq Abdul-Alim, Arpy Ohanian, Anna Marie DeVito, Stanley Riddell, Kim Margolin, Isabelle Magalhaes, Jonas Mattsson, Michael Uhlin, Satoshi Nemoto, Patricio Pérez Villarroel, Ryosuke Nakagawa, James J. Mule, Adam W. Mailloux, Melinda Mata, Phuong Nguyen, Claudia Gerken, Christopher DeRenzo, Stephen Gottschalk, Mélissa Mathieu, Sandy Pelletier, John Stagg, Simon Turcotte, Nicholas Minutolo, Prannda Sharma, Andrew Tsourkas, Nadine Mockel-Tenbrinck, Daniela Mauer, Katharina Drechsel, Carola Barth, Katharina Freese, Ulrike Kolrep, Silke Schult, Mario Assenmacher, Andrew Kaiser, John Mullinax, MacLean Hall, Julie Le, Krithika Kodumudi, Erica Royster, Allison Richards, Ricardo Gonzalez, Amod Sarnaik, Shari Pilon-Thomas, Morten Nielsen, Anders Krarup-Hansen, Dorrit Hovgaard, Michael Mørk Petersen, Anand Chainsukh Loya, Niels Junker, Charlotte Rivas, Robin Parihar, Cliona M. Rooney, Haiying Qin, Sang Nguyen, Paul Su, Chad Burk, Brynn Duncan, Bong-Hyun Kim, M. Eric Kohler, Terry Fry, Arjun A. Rao, Noam Teyssier, Jacob Pfeil, Nikolaos Sgourakis, Sofie Salama, David Haussler, Sarah A. Richman, Selene Nunez-Cruz, Zack Gershenson, Zissimos Mourelatos, David Barrett, Stephan Grupp, Michael Milone, Alba Rodriguez-Garcia, Matthew K. Robinson, Gregory P. Adams, João Santos, Riikka Havunen, Mikko Siurala, Víctor Cervera-Carrascón, Suvi Parviainen, Marjukka Antilla, Akseli Hemminki, Jyothi Sethuraman, Laurelis Santiago, Jie Qing Chen, Zhimin Dai, Huizi Sha, Shu Su, Naiqing Ding, Baorui Liu, Anna Pasetto, Sarah R. Helman, Steven A. Rosenberg, Melissa Burgess, Hui Zhang, Tien Lee, Hans Klingemann, Paul Nghiem, John M. Kirkwood, John M. Rossi, Marika Sherman, Allen Xue, Yueh-wei Shen, Lynn Navale, James N. Kochenderfer, Adrian Bot, Anandaraman Veerapathran, Doris Wiener, Edmund K. Waller, Jian-Ming Li, Christopher Petersen, Bruce R. Blazar, Jingxia Li, Cynthia R. Giver, Ziming Wang, Steven K. Grossenbacher, Ian Sturgill, Robert J. Canter, William J. Murphy, Congcong Zhang, Michael C. Burger, Lukas Jennewein, Anja Waldmann, Michel Mittelbronn, Torsten Tonn, Joachim P. Steinbach, Winfried S. Wels, Jason B. Williams, Yuanyuan Zha, Thomas F. Gajewski, LaTerrica C. Williams, Giedre Krenciute, Mamta Kalra, Chrystal Louis, Gang Xin, David Schauder, Aimin Jiang, Nikhil Joshi, Weiguo Cui, Xue Zeng, Zeguo Zhao, Mohamad Hamieh, Justin Eyquem, Gertrude Gunset, Neil Bander, Michel Sadelain, David Askmyr, Milad Abolhalaj, Kristina Lundberg, Lennart Greiff, Malin Lindstedt, Helen K. Angell, Kyoung-Mee Kim, Seung-Tae Kim, Sung Kim, Alan D. Sharpe, Julia Ogden, Anna Davenport, Darren R. Hodgson, Carl Barrett, Jeeyun Lee, Elaine Kilgour, Jodi Hanson, Richard Caspell, Alexey Karulin, Paul Lehmann, Tameem Ansari, Annemarie Schiller, Srividya Sundararaman, Diana Roen, Mark Ayers, Diane Levitan, Gladys Arreaza, Fang Liu, Robin Mogg, Yung-Jue Bang, Bert O’Neil, Razvan Cristescu, Philip Friedlander, Karl Wassman, Chrisann Kyi, William Oh, Nina Bhardwaj, Svetlana Bornschlegl, Michael P. Gustafson, Dennis A. Gastineau, Ian F. Parney, Allan B. Dietz, Daniel Carvajal-Hausdorf, Nikita Mani, Kurt Schalper, David Rimm, Serena Chang, John Kurland, Christoph Matthias Ahlers, Maria Jure-Kunkel, Lewis Cohen, Holden Maecker, Holbrook Kohrt, Shuming Chen, George Crabill, Theresa Pritchard, Tracee McMiller, Drew Pardoll, Fan Pan, Suzanne Topalian, Patrick Danaher, Sarah Warren, Lucas Dennis, Andrew M. White, Leonard D’Amico, Melissa Geller, Mary L. Disis, Joseph Beechem, Kunle Odunsi, Steven Fling, Roshanak Derakhshandeh, Tonya J. Webb, Sigrid Dubois, Kevin Conlon, Bonita Bryant, Jennifer Hsu, Nancy Beltran, Jürgen Müller, Thomas Waldmann, Rebekka Duhen, Thomas Duhen, Lucas Thompson, Ryan Montler, Andrew Weinberg, Max Kates, Brandon Early, Erik Yusko, Taylor H. Schreiber, Trinity J. Bivalacqua, Jared Lunceford, Michael Nebozhyn, Erin Murphy, Andrey Loboda, David R. Kaufman, Andrew Albright, Jonathan Cheng, S. Peter Kang, Veena Shankaran, Sarina A. Piha-Paul, Jennifer Yearley, Tanguy Seiwert, Antoni Ribas, Terrill K. McClanahan, Xinwei Sher, Xiao Qiao Liu, Andrew Joe, Elizabeth Plimack, Alex Forrest-Hay, Cheryl A. Guyre, Kohei Narumiya, Marc Delcommenne, Heather A. Hirsch, Amit Deshpande, Jason Reeves, Jenny Shu, Tong Zi, Jennifer Michaelson, Debbie Law, Elizabeth Trehu, Sriram Sathyanaryanan, Brendan P. Hodkinson, Natalie A. Hutnick, Michael E. Schaffer, Michael Gormley, Tyler Hulett, Carmen Ballesteros-Merino, Christopher Dubay, Michael Afentoulis, Ashok Reddy, Larry David, Kumar Jayant, Swati Agrawal, Rajendra Agrawal, Ghayathri Jeyakumar, Seongho Kim, Heejin Kim, Cynthia Silski, Stacey Suisham, Elisabeth Heath, Ulka Vaishampayan, Natalie Vandeven, Natasja Nielsen Viller, Alison O’Connor, Hui Chen, Bolette Bossen, Eric Sievers, Robert Uger, Lisa Johnson, Hsiang-Fong Kao, Chin-Fu Hsiao, Shu-Chuan Lai, Chun-Wei Wang, Jenq-Yuh Ko, Pei-Jen Lou, Tsai-Jan Lee, Tsang-Wu Liu, Ruey-Long Hong, Staci J. Kearney, Joshua C. Black, Benjamin J. Landis, Sally Koegler, Brooke Hirsch, Roberto Gianani, Jeffrey Kim, Ming-Xiao He, Bingqing Zhang, Nan Su, Yuling Luo, Xiao-Jun Ma, Emily Park, Dae Won Kim, Domenico Copploa, Nishi Kothari, Young doo Chang, Richard Kim, Namyong Kim, Melvin Lye, Ee Wan, Hanna A. Knaus, Sofia Berglund, Hubert Hackl, Judith E. Karp, Ivana Gojo, Leo Luznik, Henoch S. Hong, Sven D. Koch, Birgit Scheel, Ulrike Gnad-Vogt, Karl-Josef Kallen, Volker Wiegand, Linus Backert, Oliver Kohlbacher, Ingmar Hoerr, Mariola Fotin-Mleczek, James M. Billingsley, Yoshinobu Koguchi, Valerie Conrad, William Miller, Iliana Gonzalez, Tomasz Poplonski, Tanisha Meeuwsen, Ana Howells-Ferreira, Rogan Rattray, Mary Campbell, Carlo Bifulco, Keith Bahjat, Brendan Curti, E-K Vetsika, G. Kallergi, Despoina Aggouraki, Z. Lyristi, P. Katsarlinos, Filippos Koinis, V. Georgoulias, Athanasios Kotsakis, Nathan T. Martin, Famke Aeffner, Logan Cerkovnik, Luke Pratte, Rebecca Kim, Joseph Krueger, Amaia Martínez-Usatorre, Camilla Jandus, Alena Donda, Laura Carretero-Iglesia, Daniel E. Speiser, Dietmar Zehn, Nathalie Rufer, Pedro Romero, Anshuman Panda, Janice Mehnert, Kim M. Hirshfield, Greg Riedlinger, Sherri Damare, Tracie Saunders, Levi Sokol, Mark Stein, Elizabeth Poplin, Lorna Rodriguez-Rodriguez, Ann Silk, Nancy Chan, Melissa Frankel, Michael Kane, Jyoti Malhotra, Joseph Aisner, Howard L. Kaufman, Siraj Ali, Jeffrey Ross, Eileen White, Gyan Bhanot, Shridar Ganesan, Anne Monette, Derek Bergeron, Amira Ben Amor, Liliane Meunier, Christine Caron, Antigoni Morou, Daniel Kaufmann, Moishe Liberman, Igor Jurisica, Anne-Marie Mes-Masson, Kamel Hamzaoui, Rejean Lapointe, Ann Mongan, Yuan-Chieh Ku, Warren Tom, Yongming Sun, Alex Pankov, Tim Looney, Janice Au-Young, Fiona Hyland, Jeff Conroy, Carl Morrison, Sean Glenn, Blake Burgher, He Ji, Mark Gardner, Angela R. Omilian, Wiam Bshara, Omilian Angela, Joseph M. Obeid, Gulsun Erdag, Mark E. Smolkin, Donna H. Deacon, James W. Patterson, Lieping Chen, Timothy N. Bullock, Craig L. Slingluff, John T. Loffredo, Raja Vuyyuru, Sophie Beyer, Vanessa M. Spires, Maxine Fox, Jon M. Ehrmann, Katrina A. Taylor, Alan J. Korman, Robert F. Graziano, David Page, Katherine Sanchez, Maritza Martel, Mariana Petaccia De Macedo, Yong Qin, Alex Reuben, Christine Spencer, Michele Guindani, Adriana Racolta, Brian Kelly, Tobin Jones, Nathan Polaske, Noah Theiss, Mark Robida, Jeffrey Meridew, Iva Habensus, Liping Zhang, Lidija Pestic-Dragovich, Lei Tang, Ryan J. Sullivan, Thomas Olencki, Thomas Hutson, Joanna Roder, Shauna Blackmon, Heinrich Roder, John Stewart, Asim Amin, Marc S. Ernstoff, Joseph I. Clark, Michael B. Atkins, Jeffrey Sosman, David F. McDermott, Harriet Kluger, Ruth Halaban, Mario Snzol, Senait Asmellash, Arni Steingrimsson, Chichung Wang, Kristin Roman, Amanda Clement, Sean Downing, Clifford Hoyt, Nathalie Harder, Guenter Schmidt, Ralf Schoenmeyer, Nicolas Brieu, Mehmet Yigitsoy, Gabriele Madonna, Gerardo Botti, Antonio Grimaldi, Paolo A. Ascierto, Ralf Huss, Maria Athelogou, Harald Hessel, Alexander Buchner, Christian Stief, Gerd Binnig, Thomas Kirchner, Shankar Sellappan, Sheeno Thyparambil, Sarit Schwartz, Fabiola Cecchi, Andrew Nguyen, Charles Vaske, Todd Hembrough, Jan Spacek, Michal Vocka, Eva Zavadova, Helena Skalova, Pavel Dundr, Lubos Petruzelka, Nicole Francis, Rau T. Tilman, Arndt Hartmann, Irena Netikova, Julia Stump, Amanda Tufman, Frank Berger, Michael Neuberger, Rudolf Hatz, Michael Lindner, Rachel E. Sanborn, John Handy, Rudolf M. Huber, Hauke Winter, Simone Reu, Cheng Sun, Weihua Xiao, Zhigang Tian, Kshitij Arora, Niyati Desai, Anupriya Kulkarni, Mihir Rajurkar, Miguel Rivera, Vikram Deshpande, David Ting, Katy Tsai, Adi Nosrati, Simone Goldinger, Omid Hamid, Alain Algazi, Paul Tumeh, Jimmy Hwang, Jacqueline Liu, Lawrence Chen, Reinhard Dummer, Michael Rosenblum, Adil Daud, Tsu-Shuen Tsao, Julia Ashworth-Sharpe, Donald Johnson, Srabani Bhaumik, Christopher Bieniarz, Joseph Couto, Michael Farrell, Mahsa Ghaffari, Antony Hubbard, Jerome Kosmeder, Cleo Lee, Erin Marner, Diana Uribe, Hongjun Zhang, Jian Zhang, Wenjun Zhang, Yifei Zhu, Larry Morrison, Takahiro Tsujikawa, Rohan N. Borkar, Vahid Azimi, Sushil Kumar, Guillaume Thibault, Motomi Mori, Edward El Rassi, Daniel R. Clayburgh, Molly F. Kulesz-Martin, Paul W. Flint, Lisa M. Coussens, Lisa Villabona, Giuseppe V. Masucci, Gary Geiss, Brian Birditt, Qian Mei, Alan Huang, Maribeth A. Eagan, Eduardo Ignacio, Nathan Elliott, Dwayne Dunaway, Jaemyeong Jung, Chris Merritt, Isaac Sprague, Philippa Webster, Yan Liang, Jessica Wenthe, Gunilla Enblad, Hannah Karlsson, Magnus Essand, Barbara Savoldo, Gianpietro Dotti, Martin Höglund, Malcolm K. Brenner, Hans Hagberg, Angelica Loskog, Matthew J. Bernett, Gregory L. Moore, Michael Hedvat, Christine Bonzon, Seung Chu, Rumana Rashid, Kendra N. Avery, Umesh Muchhal, John Desjarlais, Matthew Kraman, Katarzyna Kmiecik, Natalie Allen, Mustapha Faroudi, Carlo Zimarino, Mateusz Wydro, Jacqueline Doody, Sreesha P. Srinivasa, Nagaraja Govindappa, Praveen Reddy, Aparajita Dubey, Sankar Periyasamy, Madhukara Adekandi, Chaitali Dey, Mary Joy, Pieter Fokko van Loo, Henrike Veninga, Setareh Shamsili, Mark Throsby, Harry Dolstra, Lex Bakker, Ajjai Alva, Juergen Gschwendt, Yohann Loriot, Joaquim Bellmunt, Dai Feng, Christian Poehlein, Thomas Powles, Emmanuel S. Antonarakis, Charles G. Drake, Haiyan Wu, Johann De Bono, Rajat Bannerji, John Byrd, Gareth Gregory, Stephen Opat, Jake Shortt, Andrew J. Yee, Noopur Raje, Seth Thompson, Arun Balakumaran, Shaji Kumar, Brian I. Rini, Toni K. Choueiri, Mariangela Mariani, Laurence Albiges, John B. Haanen, James Larkin, Manuela Schmidinger, Domenico Magazzù, Alessandra di Pietro, Robert J. Motzer, Troels Holz Borch, Per Kongsted, Magnus Pedersen, Özcan Met, Karim Boudadi, Hao Wang, James Vasselli, Jan E. Baughman, Jon Wigginton, Rehab Abdallah, Ashley Ross, Jiwon Park, Steven Grossenbacher, Jesus I. Luna, Sita Withers, William Culp, Mingyi Chen, Arta Monjazeb, Michael S. Kent, Smita Chandran, David Danforth, James Yang, Christopher Klebanoff, Stephanie Goff, Biman Paria, Arvind Sabesan, Abhishek Srivastava, Udai Kammula, Jon Richards, Mark Faries, Robert H. I. Andtbacka, Luis A. Diaz, Dung T. Le, Takayuki Yoshino, Thierry André, Johanna Bendell, Minori Koshiji, Yayan Zhang, S Peter Kang, Bao Lam, Dirk Jäger, Todd M. Bauer, Judy S. Wang, Jean K. Lee, Gulam A. Manji, Ragini Kudchadkar, John S. Kauh, Shande Tang, Naomi Laing, Gerald Falchook, Edward B. Garon, Balazs Halmos, Hui Rina, Natasha Leighl, Sung Sook Lee, William Walsh, Konstanin Dragnev, Bilal Piperdi, Luis Paz-Ares Rodriguez, Nabeegha Shinwari, Ziewn Wei, Mary L Maas, Michael Deeds, Adam Armstrong, Tim Peterson, Sue Steinmetz, Thomas Herzog, Floor J. Backes, Larry Copeland, Maria Del Pilar Estevez Diz, Thomas W. Hare, Warner Huh, Byoung-Gie Kim, Kathleen M. Moore, Ana Oaknin, William Small, Krishnansu S. Tewari, Bradley J. Monk, Ashish M. Kamat, Kijoeng Nam, Maria De Santis, Robert Dreicer, Noah M. Hahn, Rodolfo Perini, Arlene Siefker-Radtke, Guru Sonpavde, Ronald de Wit, J. Alfred Witjes, Stephen Keefe, Dean Bajorin, Philippe Armand, John Kuruvilla, Craig Moskowitz, Mehdi Hamadani, Pier Luigi Zinzani, Sabine Chlosta, Nancy Bartlett, Rachel Sabado, Yvonne Saenger, Loging William, Michael Joseph Donovan, Erlinda Sacris, John Mandeli, Andres M. Salazar, John Powderly, Joshua Brody, John Nemunaitis, Leisha Emens, Amita Patnaik, Ian McCaffery, Richard Miller, Ginna Laport, Andrew L. Coveler, David C. Smith, Juneko E. Grilley-Olson, Sanjay Goel, Shyra J. Gardai, Che-Leung Law, Gary Means, Thomas Manley, Kristen A. Marrone, Gary Rosner, Valsamo Anagnostou, Joanne Riemer, Jessica Wakefield, Cynthia Zanhow, Stephen Baylin, Barbara Gitlitz, Julie Brahmer, Sabina Signoretti, Wenting Li, Charles Schloss, Jean-Marie Michot, Wei Ding, Beth Christian, Patricia Marinello, Margaret Shipp, Yana G. Najjar, null Lin, Lisa H. Butterfield, Ahmad A. Tarhini, Diwakar Davar, Hassane Zarour, Elizabeth Rush, Cindy Sander, Siqing Fu, Todd Bauer, Chris Molineaux, Mark K. Bennett, Keith W. Orford, Kyriakos P. Papadopoulos, Sukhmani K. Padda, Sumit A. Shah, A Dimitrios Colevas, Sujata Narayanan, George A. Fisher, Dana Supan, Heather A. Wakelee, Rhonda Aoki, Mark D. Pegram, Victor M. Villalobos, Jie Liu, Chris H. Takimoto, Mark Chao, Jens-Peter Volkmer, Ravindra Majeti, Irving L. Weissman, Branimir I. Sikic, Wendy Yu, Alison Conlin, Janet Ruzich, Stacy Lewis, Anupama Acheson, Kathleen Kemmer, Kelly Perlewitz, Nicole M. Moxon, Staci Mellinger, Heather McArthur, Trine Juhler-Nøttrup, Jayesh Desai, Ben Markman, Shahneen Sandhu, Hui Gan, Michael L. Friedlander, Ben Tran, Tarek Meniawy, Joanne Lundy, Duncan Colyer, Malaka Ameratunga, Christie Norris, Jason Yang, Kang Li, Lai Wang, Lusong Luo, Zhen Qin, Song Mu, Xuemei Tan, James Song, Michael Millward, Matthew H. G. Katz, Todd W. Bauer, Gauri R. Varadhachary, Nicolas Acquavella, Nipun Merchant, Gina Petroni, Osama E. Rahma, Mei Chen, Yang Song, Markus Puhlmann, Arun Khattri, Ryan Brisson, Christopher Harvey, Jatin Shah, Maria Victoria Mateos, Morio Matsumoto, Hilary Blacklock, Albert Oriol Rocafiguera, Hartmut Goldschmidt, Shinsuke Iida, Dina Ben Yehuda, Enrique Ocio, Paula Rodríguez-Otero, Sundar Jagannath, Sagar Lonial, Uma Kher, Jesus San-Miguel, Moacyr Ribeiro de Oliveira, Habte Yimer, Robert Rifkin, Fredrik Schjesvold, Razi Ghori, Anna Spreafico, Victor Lee, Roger K. C. Ngan, Ka Fai To, Myung Ju Ahn, Quan Sing Ng, Jin-Ching Lin, Ramona F. Swaby, Christine Gause, Sanatan Saraf, Anthony T. C. Chan, Elaine Lam, Nizar M. Tannir, Funda Meric-Bernstam, Matt Gross, Andy MacKinnon, Sam Whiting, Martin Voss, Evan Y. Yu, Mark R. Albertini, Erik A. Ranheim, Jacquelyn A. Hank, Cindy Zuleger, Thomas McFarland, Jennifer Collins, Erin Clements, Sharon Weber, Tracey Weigel, Heather Neuman, Greg Hartig, David Mahvi, MaryBeth Henry, Jacek Gan, Richard Yang, Lakeesha Carmichael, KyungMann Kim, Stephen D. Gillies, Paul M. Sondel, Vivek Subbiah, Lori Noffsinger, Kyle Hendricks, Marnix Bosch, Jay M. Lee, Mi-Heon Lee, Jonathan W. Goldman, Felicita E. Baratelli, Dorthe Schaue, Gerald Wang, Frances Rosen, Jane Yanagawa, Tonya C. Walser, Ying Q. Lin, Sharon Adams, Franco M. Marincola, Paul C. Tumeh, Fereidoun Abtin, Robert Suh, Karen Reckamp, William D. Wallace, Gang Zeng, David A. Elashoff, Sherven Sharma, Steven M. Dubinett, Anna C. Pavlick, Brian Gastman, Brent Hanks, Tibor Keler, Tom Davis, Laura A. Vitale, Elad Sharon, Chihiro Morishima, Martin Cheever, Christopher R. Heery, Joseph W. Kim, Elizabeth Lamping, Jennifer Marte, Sheri McMahon, Lisa Cordes, Farhad Fakhrejahani, Ravi Madan, Rachel Salazar, Maggie Zhang, Christoph Helwig, James L Gulley, Roger Li, John Amrhein, Zvi Cohen, Monique Champagne, Ashish Kamat, M. Angela Aznar, Sara Labiano, Angel Diaz-Lagares, Manel Esteller, Juan Sandoval, Susannah D. Barbee, David I. Bellovin, John C. Timmer, Nebiyu Wondyfraw, Susan Johnson, Johanna Park, Amanda Chen, Mikayel Mkrtichyan, Amir S. Razai, Kyle S. Jones, Chelsie Y. Hata, Denise Gonzalez, Quinn Deveraux, Brendan P. Eckelman, Luis Borges, Rukmini Bhardwaj, Raj K. Puri, Akiko Suzuki, Pamela Leland, Bharat H. Joshi, Todd Bartkowiak, Ashvin Jaiswal, Casey Ager, Midan Ai, Pratha Budhani, Renee Chin, David Hong, Michael Curran, William D. Hastings, Maria Pinzon-Ortiz, Masato Murakami, Jason R. Dobson, David Quinn, Joel P. Wagner, Xianhui Rong, Pamela Shaw, Ernesta Dammassa, Wei Guan, Glenn Dranoff, Alexander Cao, Ross B. Fulton, Steven Leonardo, Kathryn Fraser, Takashi O. Kangas, Nadine Ottoson, Nandita Bose, Richard D. Huhn, Jeremy Graff, Jamie Lowe, Keith Gorden, Mark Uhlik, Thomas O’Neill, Jenifer Widger, Andrea Crocker, Li-Zhen He, Jeffrey Weidlick, Karuna Sundarapandiyan, Venky Ramakrishna, James Storey, Lawrence J. Thomas, Joel Goldstein, Henry C. Marsh, Jamison Grailer, Julia Gilden, Pete Stecha, Denise Garvin, Jim Hartnett, Frank Fan, Mei Cong, Zhi-jie Jey Cheng, Marlon J. Hinner, Rachida-Siham Bel Aiba, Corinna Schlosser, Thomas Jaquin, Andrea Allersdorfer, Sven Berger, Alexander Wiedenmann, Gabriele Matschiner, Julia Schüler, Ulrich Moebius, Christine Rothe, Olwill A. Shane, Brendan Horton, Stefani Spranger, Dayson Moreira, Tomasz Adamus, Xingli Zhao, Piotr Swiderski, Sumanta Pal, Marcin Kortylewski, Alyssa Kosmides, Kevin Necochea, Kathleen M. Mahoney, Sachet A. Shukla, Nikolaos Patsoukis, Apoorvi Chaudhri, Hung Pham, Ping Hua, Xia Bu, Baogong Zhu, Nir Hacohen, Catherine J. Wu, Edward Fritsch, Vassiliki A. Boussiotis, Gordon J. Freeman, Amy E. Moran, Fanny Polesso, Lisa Lukaesko, Emelie Rådestad, Lars Egevad, Berit Sundberg, Lars Henningsohn, Victor Levitsky, William Rafelson, John L. Reagan, Loren Fast, Pottayil Sasikumar, Naremaddepalli Sudarshan, Raghuveer Ramachandra, Nagesh Gowda, Dodheri Samiulla, Talapaneni Chandrasekhar, Sreenivas Adurthi, Jiju Mani, Rashmi Nair, Amit Dhudashia, Nagaraj Gowda, Murali Ramachandra, Alexander Sankin, Benjamin Gartrell, Kerwin Cumberbatch, Hongying Huang, Joshua Stern, Mark Schoenberg, Xingxing Zang, Ryan Swanson, Michael Kornacker, Lawrence Evans, Erika Rickel, Martin Wolfson, Sandrine Valsesia-Wittmann, Tala Shekarian, François Simard, Rodrigo Nailo, Aurélie Dutour, Anne-Catherine Jallas, Christophe Caux, and Aurélien Marabelle

Subjects
Pharmacology, 0303 health sciences, Cancer Research, Side effect, business.industry, medicine.drug_class, Immunology, Phases of clinical research, Monoclonal antibody, Phase i study, Clinical trial, 03 medical and health sciences, 0302 clinical medicine, Oncology, Pharmacokinetics, 030220 oncology & carcinogenesis, Molecular Medicine, Immunology and Allergy, Medicine, In patient, Programmed death 1, business, 030304 developmental biology
Published
2016

3. Abstract 4062: Activation of innate and adaptive immunity using intratumoral tilsotolimod (IMO-2125) as monotherapy in patients with refractory solid tumors: a phase Ib study (ILLUMINATE-101)

Author

Shah Rahimian, Cara Haymaker, Adi Diab, Orla Maguire, Peter M. Anderson, Erkut Borazanci, Hani M. Babiker, James Geib, Vivek Subbiah, Chantale Bernatchez, Srinivas K. Chunduru, Hans Minderman, and Igor Puzanov

Subjects
0301 basic medicine, Cancer Research, Tumor microenvironment, business.industry, T cell, Melanoma, Ipilimumab, Dendritic cell, Acquired immune system, medicine.disease, Immune checkpoint, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, Immune system, medicine.anatomical_structure, Oncology, 030220 oncology & carcinogenesis, Cancer research, medicine, business, medicine.drug
Abstract

While checkpoint inhibitor therapy has transformed treatment of multiple tumor types, many patients remain refractory. Tilsotolimod, a toll-like receptor 9 agonist, has been shown in preclinical models to activate plasmacytoid dendritic cells and increase T cell infiltration to the tumor microenvironment. Preliminary results of a phase 1/2 study suggested that intratumoral injection of tilsotolimod in combination with ipilimumab may revive an immune response in patients with immune checkpoint inhibitor-resistant metastatic melanoma. To further explore the role of tilsotolimod in modulating the tumor immune microenvironment, we conducted a Phase Ib monotherapy trial (ILLUMINATE-101). Adults with histologically or cytologically confirmed diagnosis of cancer not amenable to curative therapies received intratumoral tilsotolimod in doses escalating from 8 mg to 32 mg into a single lesion at weeks 1, 2, 3, 5, 8, and 11. Objectives of the dose evaluation portion included characterizing safety and pharmacokinetics, and evaluating alterations in the tumor microenvironment. Blood samples and tumor biopsies of injected and distal lesions were obtained at baseline and on treatment. Immune analyses included evaluation using Nanostring and/or flow cytometry of activation of the type 1 interferon (IFN) pathway, IFN gamma levels, activation of dendritic cell subsets, and changes in T cell status. As of November 7, 2018, 41 patients have been enrolled, including 38 patients into the dose evaluation portion and 3 patients into a melanoma expansion cohort. No dose-limiting toxicities or treatment-related adverse events have been observed. Within 24 hours, fresh tumor biopsies showed significant increases in IFN gamma levels, activation of the type 1 IFN pathway, induction of an antigen processing gene signature (a measure of the MHC class I antigen presentation pathway), and maturation of dendritic cells as measured by expression of HLA-DR (MHC class II), compared to pretreatment biopsies. Of 25 evaluable patients who received at least 1 dose of tilsotolimod and had at least 1 post-baseline disease assessment, 12 (48%) had a RECIST v1.1 disease assessment of stable disease. For patients with at least one disease assessment following documentation of stable disease (n=8), duration of stable disease ranged from 0.53 to 4.2+ months, with 3 patients ongoing. These results demonstrate that single agent tilsotolimod was well tolerated and induced robust alterations in the tumor microenvironment. Citation Format: Hani M. Babiker, Vivek Subbiah, Orla Maguire, Shah Rahimian, Hans Minderman, Cara L. Haymaker, Chantale Bernatchez, Erkut Borazanci, James Geib, Srinivas K. Chunduru, Peter M. Anderson, Igor Puzanov, Adi Diab. Activation of innate and adaptive immunity using intratumoral tilsotolimod (IMO-2125) as monotherapy in patients with refractory solid tumors: a phase Ib study (ILLUMINATE-101) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4062.

Published
2019

4. Preliminary safety of deep/visceral (D/V) image guided (IG) intratumoral injection (ITI) of IMO-2125

Author

Ankit H Shah, James Geib, Hani M. Babiker, Vivek Subbiah, Gregory Woodhead, Rolf Hultsch, Adi Diab, Suzanne Swann, Charles Hennemeyer, Christopher Miller, Ravi Murthy, Melissa Catlett, Erkut Borazanci, and Shah Rahimian

Subjects
0301 basic medicine, 03 medical and health sciences, Cancer Research, 030104 developmental biology, 0302 clinical medicine, Oncology, business.industry, 030220 oncology & carcinogenesis, medicine.medical_treatment, Medicine, Immunotherapy, Nuclear medicine, business
Abstract

e15150Background: Patients without palpable lesions who are candidates for intratumoral immunotherapy may need D/V IG agent delivery. Novel immuno-oncology (I-O) agents requiring ITI highlight the ...

Published
2018

5. Abstract 5652: Translational evidence of reactivated innate and adaptive immunity with intratumoral IMO-2125 in combination with systemic checkpoint inhibitors from a Phase I/II study in patients with anti-PD-1 refractory metastatic melanoma

Author

James Geib, Hussein Abdul-Hassan Tawbi, Srinivas K. Chunduru, Scott E. Woodman, Rodabe N. Amaria, Wen-Jen Hwu, Daqing Wang, Patrick Hwu, Willem Overwjik, Suzanne Swann, Marc Uemura, Julie Brevard, Cassian Yee, Isabella C. Glitza, Chantale Bernatchez, Jennifer A. Wargo, Michael A. Davies, Mark Cornfeld, Marihella James, Ravi Murthy, Sudhir Agrawal, Cara Haymaker, Sapna Pradyuman Patel, and Adi Diab

Subjects
Cancer Research, Tumor microenvironment, Myeloid, business.industry, T cell, Ipilimumab, Pembrolizumab, Gene signature, Acquired immune system, 030207 dermatology & venereal diseases, 03 medical and health sciences, 0302 clinical medicine, medicine.anatomical_structure, Immune system, Oncology, 030220 oncology & carcinogenesis, Immunology, medicine, Cancer research, business, medicine.drug
Abstract

Background: While checkpoint inhibitor (CPI) therapy has transformed metastatic melanoma (MM) treatment, many patients remain refractory. We reasoned that combining CPI with an agent that activates antigen presenting cells and improves T-cell priming may result in improved response. Our approach is to modulate the tumor microenvironment through image-guided intratumoral (i.t.) injection of the TLR9 agonist, IMO-2125, in combination with either ipilimumab (ipi) or pembrolizumab (pembro). We hypothesize that this will result in dendritic cell (DC) activation and induction of tumor-specific CD8+T-cells which will synergize with ipilimumab or pembrolizumab to overcome immune-escape. Based on this rationale we initiated a phase I/II clinical trial. Study Design/Methods: Adults with refractory MM that have had prior PD-1 blockade therapy (with or without a BRAF inhibitor) are eligible. IMO-2125, in doses escalating from 4mg to 32mg, is given i.t. weeks 1, 2, 3, 5, 8, and 11 along with standard doses of ipilimumab or pembrolizumab. Primary endpoints are safety, tumor response, and PK. Multiple biopsies are obtained in both the injected and distant tumor pre- and on-treatment. Immune analyses include DC subsets and their activation status as well as T cell activation, function and proliferation. T-cell repertoire diversity is evaluated by high-throughput CDR3 sequencing and changes in gene expression signatures are assessed by nanoString. Changes in circulating cytokines are also being assessed during therapy. Results: Enrollment is proceeding on both the IMO-ipilimumab and IMO-pembrolizumab dose-escalation arms of the trial. Safety is acceptable with no DLT recorded to date. Durable clinical responses (including 1 CR) have been observed with IMO-ipilimumab in patients who were refractory to PD-1 inhibitor. Fresh tumor biopsies show maturation (upregulation of HLA-DR) of the myeloid DC1 subset (CD1c+CD303-), upregulation of PD-L1 by malignant cells, as well as an IFNα response gene signature in the IMO-2125 injected tumor lesion 24 hrs post-treatment compared to pre-treatment biopsy. On-treatment biopsy results show a higher expression of CD56+ and Ki67+ effector CD8+ T-cells in responding patients. Initial CDR3 sequencing demonstrates increased diversity in the injected lesions of all patients assessed and expansion of top clones present in the distant lesion in a responding patient. Plasma analysis showed an increase in IFNγ levels in the plasma of responding patients. Conclusions: These results demonstrate that IMO-2125 with a checkpoint inhibitor is a viable strategy to revive the immune response in tumors that are refractory to PD-1 inhibitors. Further clinical evaluation of both the IMO-ipilimumab and IMO-pembrolizumab combination is planned in a Phase 2 expansion of the current trial. Citation Format: Cara Haymaker, Marc Uemura, Ravi Murthy, Marihella James, Daqing Wang, Julie Brevard, Suzanne Swann, James Geib, Mark Cornfeld, Srinivas Chunduru, Sudhir Agrawal, Cassian Yee, Jennifer Wargo, Rodabe Amaria, Sapna Patel, Hussein Tawbi, Isabella Glitza, Scott Woodman, Wen-Jen Hwu, Michael A. Davies, Patrick Hwu, Willem Overwjik, Chantale Bernatchez, Adi Diab. Translational evidence of reactivated innate and adaptive immunity with intratumoral IMO-2125 in combination with systemic checkpoint inhibitors from a Phase I/II study in patients with anti-PD-1 refractory metastatic melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5652. doi:10.1158/1538-7445.AM2017-5652

Published
2017

6. Eltrombopag increases platelet numbers in thrombocytopenic patients with HCV infection and cirrhosis, allowing for effective antiviral therapy

Author

Rita Patwardhan, Mitchell L. Shiffman, Kwang Hyub Han, Pei-Jer Chen, Dickens Theodore, Yasser Mostafa Kamel, Fiona Campbell, James Geib, Nezam H. Afdhal, Geoffrey Dusheiko, Edoardo G. Giannini, Sorin Rugină, Fred Poordad, Aftab Mohsin, Ghias Un Nabi Tayyab, Andres Brainsky, E.J. Lawitz, Maribel Rodriguez-Torres, Sandra Y. Vasey, and Igor G. Bakulin

Subjects
Adult, Liver Cirrhosis, Male, medicine.medical_specialty, Cirrhosis, Adolescent, Eltrombopag, Alpha interferon, Interferon alpha-2, Placebo, Chronic liver disease, Gastroenterology, Antiviral Agents, Benzoates, Drug Administration Schedule, Maintenance Chemotherapy, Polyethylene Glycols, chemistry.chemical_compound, Young Adult, Maintenance therapy, Internal medicine, Hematologic Agents, Ribavirin, medicine, Humans, Aged, Hepatitis, Aged, 80 and over, Hepatology, business.industry, Platelet Count, Interferon-alpha, Induction Chemotherapy, Hepatitis C, Chronic, Middle Aged, medicine.disease, Thrombocytopenia, Recombinant Proteins, Intention to Treat Analysis, Hydrazines, Treatment Outcome, chemistry, Immunology, Pyrazoles, Female, business, Follow-Up Studies
Abstract

Thrombocytopenia is common among patients with hepatitis C virus (HCV) infection and advanced fibrosis or cirrhosis, limiting initiation and dose of peginterferon-alfa (PEG) and ribavirin (RBV) therapy. The phase 3 randomized, controlled studies, Eltrombopag to Initiate and Maintain Interferon Antiviral Treatment to Benefit Subjects with Hepatitis C-Related Liver Disease (ENABLE)-1 and ENABLE-2, investigated the ability of eltrombopag to increase the number of platelets in patients, thereby allowing them to receive initiation or maintenance therapy with PEG and RBV.Patients with HCV infection and thrombocytopenia (platelet count75,000/μL) who participated in ENABLE-1 (n = 715) or ENABLE-2 (n = 805), from approximately 150 centers in 23 countries, received open-label eltrombopag (25-100 mg/day) for 9 weeks or fewer. Patients whose platelet counts reached the predefined minimal threshold for the initiation of PEG and RBV therapy (95% from ENABLE-1 and 94% from ENABLE-2) entered the antiviral treatment phase, and were assigned randomly (2:1) to groups that received eltrombopag or placebo along with antiviral therapy (24 or 48 weeks, depending on HCV genotype). The primary end point was sustained virologic response (SVR) 24 weeks after completion of antiviral therapy.More patients who received eltrombopag than placebo achieved SVRs (ENABLE-1: eltrombopag, 23%; placebo, 14%; P = .0064; ENABLE-2: eltrombopag, 19%; placebo, 13%; P = .0202). PEG was administered at higher doses, with fewer dose reductions, in the eltrombopag groups of each study compared with the placebo groups. More patients who received eltrombopag than placebo maintained platelet counts of 50,000/μL or higher throughout antiviral treatment (ENABLE-1, 69% vs 15%; ENABLE-2, 81% vs 23%). Adverse events were similar between groups, with the exception of hepatic decompensation (both studies: eltrombopag, 10%; placebo, 5%) and thromboembolic events, which were more common in the eltrombopag group of ENABLE-2.Eltrombopag increases platelet numbers in thrombocytopenic patients with HCV and advanced fibrosis and cirrhosis, allowing otherwise ineligible or marginal patients to begin and maintain antiviral therapy, leading to significantly increased rates of SVR. Clinical trial no: NCT00516321, NCT00529568.

Published
2013

7. Ertapenem monotherapy versus combination therapy with ceftriaxone plus metronidazole for treatment of complicated intra-abdominal infections in adults

Author

Gail L. Woods, James M Hassett, James Geib, Ben Adeyi, Hedy Teppler, Alvaro Fernandez, and Albert E Yellin

Subjects
Microbiology (medical), Adult, Ertapenem, Male, medicine.medical_specialty, Combination therapy, Adolescent, Lactams, beta-Lactams, chemistry.chemical_compound, Pharmacotherapy, Anti-Infective Agents, Double-Blind Method, Internal medicine, Metronidazole, Abdomen, polycyclic compounds, medicine, Humans, Pharmacology (medical), Adverse effect, Antibacterial agent, Aged, business.industry, Ceftriaxone, General Medicine, Bacterial Infections, Middle Aged, Surgery, Anti-Bacterial Agents, body regions, Ciprofloxacin, Infectious Diseases, chemistry, Injections, Intravenous, Drug Therapy, Combination, Female, business, medicine.drug
Abstract

The efficacy and safety of intravenous (IV) ertapenem, 1 and 1.5 g once a day, for treatment of adults with complicated intra-abdominal infection were compared with those of IV ceftriaxone 2 g once a day plus IV metronidazole 500 mg every 8 h. After at least 3 days of IV therapy and satisfactory clinical response, patients could be switched to oral ciprofloxacin plus metronidazole. Fifty-nine patients were randomized to receive ertapenem 1 g and 51 to receive ertapenem 1.5 g; 55 patients were randomized to each comparator group. At the test of cure, 4-6 weeks post therapy, in the 1 g cohort, 84% (26/31) of patients treated with ertapenem and 85% (35/41) with comparator therapy had a favourable clinical and microbiological assessment. Success rates in the 1.5 g cohort were 83% (22/29) and 77% (24/31) in the ertapenem and comparator groups, respectively. Drug-related adverse events were generally similar in both treatment groups. Ertapenem 1 or 1.5 g once a day followed by optional oral therapy appeared similar to combined therapy with ceftriaxone plus metronidazole with the same optional oral switch for treatment of complicated intra-abdominal infections in adults. Although not compared directly in a randomized fashion, the efficacy and safety profiles of ertapenem 1 and 1.5 g appeared comparable. Ertapenem was generally well tolerated and had an overall safety profile similar to ceftriaxone plus metronidazole.

Published
2002

8. 60 RESULTS OF ENABLE 2, A PHASE 3, MULTICENTER STUDY OF ELTROMBOPAG AND PEGINTERFERON ALFA-2B TREATMENT IN PATIENTS WITH HEPATITIS C AND THROMBOCYTOPENIA

Author

Y. Mostafa Kamel, Pei-Jer Chen, Rita Patwardhan, Fiona Campbell, Mitchell L. Shiffman, Sandra Y. Vasey, Dickens Theodore, K.-H. Han, Maribel Rodriguez-Torres, E.J. Lawitz, James Geib, G.M. Dusheiko, Sorin Rugină, A. Streinu-Cercel, Nezam H. Afdhal, Edoardo G. Giannini, Fred Poordad, and Andres Brainsky

Subjects
medicine.medical_specialty, Hepatology, business.industry, Eltrombopag, Hepatitis C, medicine.disease, Gastroenterology, chemistry.chemical_compound, chemistry, Multicenter study, Internal medicine, medicine, Peginterferon alfa-2b, In patient, business, medicine.drug
Published
2012

9. Final Results of Open-Label Treatment with Eltrombopag During ENABLE 1: A Study of Eltrombopag As An Adjunct for Antiviral Treatment of Hepatitis C Virus Associated with Thrombocytopenia

Author

Edoardo G. Giannini, Pei-Jer Chen, Nezam H. Afdhal, Rita Patwardhan, Sandra Y. Vasey, Fiona Campbell, Andres Brainsky, Geoffrey Dusheiko, Kwang Hyub Han, Dickens Theodore, James Geib, and Yasser Mostafa Kamel

Subjects
medicine.medical_specialty, business.industry, Ribavirin, Hepatitis C virus, OPEN LABEL TREATMENT, Immunology, Eltrombopag, Cell Biology, Hematology, Hepatitis C, Placebo, medicine.disease, medicine.disease_cause, Off-label use, Biochemistry, Discontinuation, chemistry.chemical_compound, chemistry, Internal medicine, medicine, business
Abstract

Abstract 2232 Introduction: Thrombocytopenia (TCP) is a common complication of cirrhosis in patients with hepatitis C virus (HCV) infections (Louie et al 2011); the presence of TCP impairs the ability to initiate peginterferon alpha (PEG) therapy and necessitates PEG dose reduction or discontinuation, thus reducing the potential for sustained virologic response (SVR). Eltrombopag, an oral, nonpeptide thrombopoietin receptor agonist approved for the treatment of chronic immune thrombocytopenia, increases platelet counts in patients with TCP due to HCV-related cirrhosis (McHutchison et al 2007). ENABLE 1 was a phase 3, multicenter, two-part study of eltrombopag for the treatment of HCV-associated TCP. Part 1 involved open-label, pre-antiviral treatment with eltrombopag. Patients achieving platelet counts ≥90,000/μL were randomized in Part 2 to receive eltrombopag or placebo in combination with antiviral therapy (PEG-2a plus ribavirin). Aim: To assess the safety and efficacy of eltrombopag during the open-label, pre-antiviral treatment phase (Part 1) of ENABLE 1 in patients with cirrhosis. Methods: Patients with chronic HCV and a baseline platelet count 200,000/μL. No thromboembolic events were observed during open-label treatment. Conclusions: Eltrombopag was generally well-tolerated and resulted in sustained increase in platelet counts during the open-label, pre-antiviral treatment phase. Platelet count increases were seen as early as 2 weeks following initiation of treatment. The vast majority of patients (97%) achieved platelet count increases to ≥90,000/μL, the threshold for initiating PEG-2a plus ribavirin therapy, and most did so within 4 weeks of initiating eltrombopag treatment. Disclosures: Dusheiko: GlaxoSmithKline: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding; Merck: Consultancy, Honoraria, Research Funding. Off Label Use: Eltrombopag, inteferon and Ribavirin; eltrombopag is a thrombopoetin receptor agonist. Its efficacy and safety in raising platelet counts in hepatitis C positive patients (most with cirrhosis) and thrombocyotopaenia was studied in this protocol. Afdhal:Merck: Consultancy, Honoraria, Research Funding; Vertex: Consultancy, Honoraria, Research Funding; Idenix: Consultancy, Honoraria, Research Funding; GlaxoSmithKline: Consultancy, Honoraria, Research Funding; Springbank: Consultancy, Honoraria, Research Funding; Gilead: Consultancy, Honoraria, Research Funding; Pharmasett: Consultancy, Honoraria, Research Funding; Abbott: Consultancy, Honoraria, Research Funding. Giannini:GlaxoSmithKline: Consultancy, Speakers Bureau; Hoffman-LaRoche: Consultancy, Speakers Bureau. Chen:Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Mostafa Kamel:GlaxoSmithKline: Employment, Equity Ownership. Brainsky:GlaxoSmithKline: Employment, Equity Ownership. Geib:GlaxoSmithKline: Employment. Vasey:GlaxoSmithKline: Employment. Patwardhan:GlaxoSmithKline: Employment, company shares. Campbell:GlaxoSmithKline: Employment, Equity Ownership. Theodore:GlaxoSmithKline: Employment, Equity Ownership, Patents & Royalties.

Published
2011

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