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1. A phase II study of tivozanib in patients with metastatic and nonresectable soft-tissue sarcomas

Author

B. T. Rhodes, Claudia Roxana Vintilescu, Lauren Nye, Ricardo Costa, Alfred Rademaker, Scott H. Okuno, Mohammed M. Milhem, B. C. Prunder, Steven I. Robinson, Rasima Cehic, Mark Agulnik, D. Daniels, Ariel Polish, Thomas McFarland, B.A. Van Tine, Keith M. Skubitz, Susan Abbinanti, and Catherine Humphreys

Subjects
Adult, Male, 0301 basic medicine, Oncology, medicine.medical_specialty, Pathology, Tivozanib, medicine.drug_class, Population, Phases of clinical research, Antineoplastic Agents, Enzyme-Linked Immunosorbent Assay, Soft Tissue Neoplasms, Kaplan-Meier Estimate, Disease-Free Survival, Tyrosine-kinase inhibitor, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, medicine, Clinical endpoint, Humans, Progression-free survival, Child, education, Aged, Aged, 80 and over, education.field_of_study, Surrogate endpoint, business.industry, Phenylurea Compounds, Sarcoma, Original Articles, Hematology, Middle Aged, medicine.disease, Immunohistochemistry, Receptors, Vascular Endothelial Growth Factor, 030104 developmental biology, 030220 oncology & carcinogenesis, Quinolines, Female, business, medicine.drug
Abstract

Background Soft tissue sarcomas (STSs) overexpress vascular endothelial growth factors (VEGF) and VEGF-receptors (VEGFR) activation have been associated with tumor aggressiveness. Tivozanib is a potent small molecule tyrosine kinase inhibitor against VEGFR1-3, with activity against PDGFRα/β and cKIT. The primary endpoint of this study was progression free survival (PFS) rate at 16 weeks. Secondary end points were overall survival (OS), response rate, safety and correlative studies. Patients and methods A Simon two-stage phase II trial was performed using tivozanib given orally at 1.5 mg daily, 3 week on 1 week off on a 28 day cycle until disease progression or intolerable toxicity. Results Fifty-eight patients were enrolled and treated with tivozanib. Leiomyosarcoma was the most common STS histological type in our cohort (47%) and 27 patients (46%) had received at least 3 lines of therapy prior to study entry. Up to 24 patients (41%) had prior VEGF targeted therapies. Partial response and stable disease were observed in 2 (3.6%) and 30 (54.5%) patients. The 16 week PFS rate was 36.4% [95% confidence interval (CI) 23.7–49.1] and a median PFS of 3.5 months (95% CI 1.8–3). Median OS observed was 12.2 months (95% CI 8.1–16.8). The most frequent all grade toxicities were fatigue (48.3%), hypertension (43.1%), nausea (31%) and diarrhea (27.6%). The most common grade three toxicity was hypertension (22.4%). Correlative studies demonstrate no correlation between the expression of VEGFR 1, 2 or 3, PDGFRα/β or FGF, and activity of tivozanib. Conclusion Tivozanib was well tolerated and showed antitumor activity with a promising median PFS and PFS rate at 4 months in a heavily pretreated population of metastatic STSs. Our results support further studies to assess the clinical efficacy of tivozanib in STS. Clinical Trial Number NCT01782313

Published
2017
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2. Phase I study to evaluate toxicity and feasibility of intratumoral injection of α-gal glycolipids in patients with advanced melanoma

Author

Cindy L. Zuleger, Alan J. Bridges, Heather B. Neuman, Michael A. Newton, Giles F. Whalen, Uri Galili, Erin Clements, Mary Beth Henry, Jennifer Collins, Thomas McFarland, Mark R. Albertini, Jacquelyn A. Hank, Paul M. Sondel, Erik A. Ranheim, and Sharon M. Weber

Subjects
Adult, Male, 0301 basic medicine, Cancer Research, Pathology, medicine.medical_specialty, Necrosis, medicine.medical_treatment, Immunology, Tumor Cell Necrosis, Injections, Intralesional, Article, Metastasis, 03 medical and health sciences, 0302 clinical medicine, Antigen, medicine, Humans, Immunology and Allergy, Melanoma, Aged, business.industry, Immunotherapy, Middle Aged, medicine.disease, carbohydrates (lipids), 030104 developmental biology, Oncology, 030220 oncology & carcinogenesis, Toxicity, Feasibility Studies, Female, Tumor necrosis factor alpha, Glycolipids, medicine.symptom, business
Abstract

Effective uptake of tumor cell-derived antigens by antigen-presenting cells is achieved pre-clinically by in situ labeling of tumor with α-gal glycolipids that bind the naturally occurring anti-Gal antibody. We evaluated toxicity and feasibility of intratumoral injections of α-gal glycolipids as an autologous tumor antigen-targeted immunotherapy in melanoma patients (pts). Pts with unresectable metastatic melanoma, at least one cutaneous, subcutaneous, or palpable lymph node metastasis, and serum anti-Gal titer ≥1:50 were eligible for two intratumoral α-gal glycolipid injections given 4 weeks apart (cohort I: 0.1 mg/injection; cohort II: 1.0 mg/injection; cohort III: 10 mg/injection). Monitoring included blood for clinical, autoimmune, and immunological analyses and core tumor biopsies. Treatment outcome was determined 8 weeks after the first α-gal glycolipid injection. Nine pts received two intratumoral injections of α-gal glycolipids (3 pts/cohort). Injection-site toxicity was mild, and no systemic toxicity or autoimmunity could be attributed to the therapy. Two pts had stable disease by RECIST lasting 8 and 7 months. Tumor nodule biopsies revealed minimal to no change in inflammatory infiltrate between pre- and post-treatment biopsies except for 1 pt (cohort III) with a post-treatment inflammatory infiltrate. Two and four weeks post-injection, treated nodules in 5 of 9 pts exhibited tumor cell necrosis without neutrophilic or lymphocytic inflammatory response. Non-treated tumor nodules in 2 of 4 evaluable pts also showed necrosis. Repeated intratumoral injections of α-gal glycolipids are well tolerated, and tumor necrosis was seen in some tumor nodule biopsies after tumor injection with α-gal glycolipids.

Published
2016
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3. Pilot trial of the hu14.18-IL2 immunocytokine in patients with completely resectable recurrent stage III or stage IV melanoma

Author

Mary Beth Henry, Mark R. Albertini, Richard K. Yang, Stephen D. Gillies, David M. Mahvi, Greg Hartig, Erik A. Ranheim, Jacquelyn A. Hank, Lakeesha Carmichael, Heather B. Neuman, Jacek Gan, Renae M Quale, KyungMann Kim, Thomas McFarland, Sharon M. Weber, Tracey L. Weigel, Hans Loibner, Cindy L. Zuleger, and Paul M. Sondel

Subjects
0301 basic medicine, Adult, Male, Cancer Research, medicine.medical_specialty, Lymphocyte, medicine.medical_treatment, Immunology, Pilot Projects, Gastroenterology, Group A, Group B, Article, 03 medical and health sciences, Young Adult, 0302 clinical medicine, Lymphocytes, Tumor-Infiltrating, Internal medicine, medicine, Immunology and Allergy, Humans, Stage (cooking), Melanoma, Aged, Neoplasm Staging, business.industry, Antibodies, Monoclonal, Middle Aged, medicine.disease, Confidence interval, Tumor Burden, Survival Rate, 030104 developmental biology, medicine.anatomical_structure, Oncology, 030220 oncology & carcinogenesis, Monoclonal, Interleukin-2, Female, Neoplasm Recurrence, Local, business, Adjuvant, Follow-Up Studies
Abstract

Phase I testing of the hu14.18-IL2 immunocytokine (IC) in melanoma patients showed immune activation, reversible toxicities, and a maximal tolerated dose of 7.5 mg/m(2)/day. Preclinical data in IC-treated tumor bearing mice with low tumor burden documented striking antitumor effects. Patients with completely resectable recurrent stage III or stage IV melanoma were scheduled to receive 3 courses of IC at 6 mg/m(2)/d i.v. on days 1, 2 and 3 of each 28-day course. Patients were randomized to complete surgical resection either following neoadjuvant (Group A) or prior to adjuvant (Group B) IC course 1. Primary objectives were to: 1) evaluate histological evidence of anti-tumor activity and 2) evaluate recurrence-free survival (RFS) and OS. Twenty melanoma patients were randomized to Group A (11 patients) or B (9 patients). Two Group B patients did not receive IC due to persistent disease following surgery. Six of 18 IC-treated patients remained free of recurrence, with a median RFS of 5.7 months (95% confidence interval (CI): 1.8-not reached). The 24-month RFS rate was 38.9% (95% CI: 17.5–60.0%). The median followup of surviving patients was 50.0 months (range: 31.8–70.4). The 24-month OS rate was 65.0% (95% CI: 40.3–81.5%). Toxicities were similar to those previously reported. Exploratory tumorinfiltrating lymphocyte (TIL) analyses suggest prognostic value of TILs from Group A patients. Prolonged tumor-free survival was seen in some melanoma patients at high risk for recurrence who were treated with IC.

Published
2018

4. VcR-CVAD Induction Chemotherapy Followed by Maintenance Rituximab Produces Durable Remissions in Mantle Cell Lymphoma: A Wisconsin Oncology Network Study

Author

Lakeesha Carmichael, Walter L. Longo, Michael S. Huie, Natalie S. Callander, Julie E. Chang, Jules H. Blank, Christopher Peterson, Jae Werndli, David T. Yang, Anne M. Traynor, Brad S. Kahl, KyungMann Kim, Thomas McFarland, and Michael Volk

Subjects
0301 basic medicine, Oncology, Male, Cancer Research, medicine.medical_specialty, Hyper-CVAD, Lymphoma, Mantle-Cell, Article, 03 medical and health sciences, 0302 clinical medicine, Antineoplastic Agents, Immunological, Wisconsin, hemic and lymphatic diseases, Internal medicine, Overall survival, Medicine, Humans, Prospective Studies, Complete response, business.industry, Bortezomib, Remission Induction, Induction chemotherapy, Hematology, Induction Chemotherapy, Middle Aged, medicine.disease, Regimen, 030104 developmental biology, 030220 oncology & carcinogenesis, Rituximab, Mantle cell lymphoma, Female, business, medicine.drug
Abstract

Introduction VcR-CVAD was developed as an intermediate-intensity induction regimen with maintenance rituximab (MR) to improve remission durations after first-line therapy for mantle cell lymphoma (MCL) in older and younger patients with MCL. Patients and Methods Patients with previously untreated MCL received VcR-CVAD induction chemotherapy for 6 cycles (21-day cycles). Patients achieving at least a partial response received rituximab consolidation (375 mg/m2 × 4 weekly doses) and MR (375 mg/m2 every 12 weeks × 20 doses). The primary endpoints were overall and complete response (CR), and the secondary endpoints were progression-free survival (PFS) and overall survival (OS). Thirty patients were enrolled, with a median age of 61 years. There was an even distribution of patients Conclusions Long-term outcomes with VcR-CVAD are comparable with more intensive inductions and consolidation approaches. MCL is biologically heterogeneous, and durable remission can be achieved with intermediate intensity therapy. MR appears to contribute to these excellent outcomes.

Published
2017

5. 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
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6. VcR-CVAD induction chemotherapy followed by maintenance rituximab in mantle cell lymphoma: a Wisconsin Oncology Network study

Author

Jules H. Blank, Sangbum Choi, Michael S. Huie, Thomas McFarland, Leslie A. Gilbert, Jae Werndli, Brad S. Kahl, Walter L. Longo, Julie E. Chang, Michael Volk, KyungMann Kim, Natalie S. Callander, Eric S. Rogers, Christopher Peterson, Jens C. Eickhoff, and David T. Yang

Subjects
Oncology, Vincristine, medicine.medical_specialty, Chemotherapy, Cyclophosphamide, business.industry, medicine.medical_treatment, Induction chemotherapy, Hematology, medicine.disease, Regimen, International Prognostic Index, hemic and lymphatic diseases, Internal medicine, medicine, Mantle cell lymphoma, Rituximab, business, medicine.drug
Abstract

Summary Intensive chemotherapy regimens are not feasible in many adults with mantle cell lymphoma (MCL). We sought to build upon our previous experience with a non-intensive regimen, modified R-hyperCVAD chemotherapy (rituximab, cyclophosphamide, vincristine, doxorubicin, dexamethasone) with maintenance rituximab (MR), by the incorporation of bortezomib (VcR-CVAD) and the extension of MR beyond 2 years. Patients with previously untreated MCL received VcR-CVAD chemotherapy every 21 d for six cycles. Patients achieving at least a partial response to induction chemotherapy received rituximab consolidation (375 mg/m2 × 4 weekly doses) and MR (375 mg/m2 every 12 weeks × 20 doses). The primary end points were overall and complete response (CR), and secondary endpoints were progression-free (PFS) and overall survival (OS). Thirty patients were enrolled, with a median age of 61 years. All patients had advanced stage disease, and 60% had medium/high MCL International Prognostic Index risk factors. A CR or unconfirmed CR was achieved in 77% of patients. After a median follow-up of 42 months, the 3-year PFS and OS were 63% and 86%, respectively. The observed 3-year PFS and OS with VcR-CVAD in MCL were comparable to reported outcomes with more intensive regimens. A cooperative group trial (E1405) is attempting to replicate these promising results.

Published
2011
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7. Maintenance rituximab following induction chemo-immunotherapy for mantle cell lymphoma: long-term follow-up of a pilot study from the Wisconsin Oncology Network

Author

Brad S. Kahl, Wayne A. Bottner, Vaishalee P. Kenkre, Jens C. Eickhoff, Jules H. Blank, Walter L Long, Jae Werndli, Hamied Rezazedeh, Thomas McFarland, and Howard H. Bailey

Subjects
Adult, Male, Oncology, Vincristine, medicine.medical_specialty, Cancer Research, Cyclophosphamide, Antineoplastic Agents, Pilot Projects, Kaplan-Meier Estimate, Lymphoma, Mantle-Cell, Maintenance Chemotherapy, Antibodies, Monoclonal, Murine-Derived, Internal medicine, medicine, Humans, Aged, Neoplasm Staging, Aged, 80 and over, business.industry, Remission Induction, Induction chemotherapy, Induction Chemotherapy, Hematology, Middle Aged, medicine.disease, Lymphoma, Non-Hodgkin's lymphoma, Regimen, Treatment Outcome, Female, Rituximab, Mantle cell lymphoma, business, Follow-Up Studies, medicine.drug
Abstract

Mantle cell lymphoma (MCL) is challenging to manage, with a median survival of 3-5 years. While intensive strategies are often appropriate for younger patients, these approaches are often not appropriate for older patients. In 2006, we reported our initial results using modified R-hyperCVAD (rituximab with hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone) with maintenance rituximab. The complete response rate was 64%, and median progression-free survival (PFS) 37 months. Herein, we update our results, now with a median follow-up of 62 months. The median PFS is unchanged and the median overall survival (OS) is 70 months. The proportion of patients surviving at 5 years is 62%, comparable to studies using intensive strategies in similar patient populations. No late toxicities were noted in our cohort. These long-term results suggest that the modified R-hyperCVAD regimen with maintenance rituximab is an excellent option for older patients with newly diagnosed mantle cell lymphoma.

Published
2011
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8. Clinical activity of pazopanib in metastatic extraosseous Ewing sarcoma

Author

Steven Attia, Scott H. Okuno, Steven I. Robinson, Nicholas P. Webber, Daniel J. Indelicato, Robin L. Jones, Sanjay P. Bagaria, Courtney Sherman, Kevin R. Kozak, Cherise M. Cortese, Thomas McFarland, Jonathan C. Trent, and Robert G. Maki

Subjects
Pathology, medicine.medical_specialty, Histology, sarcoma, Phases of clinical research, Case Report, Liposarcoma, lcsh:RC254-282, Pazopanib, chemistry.chemical_compound, Metastatic Extraosseous Ewing Sarcoma, Regorafenib, Ewing, pazopanib, Medicine, In patient, business.industry, medicine.disease, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Oncology, chemistry, Cancer research, Osteosarcoma, Sarcoma, business, medicine.drug
Abstract

We report a response to pazopanib in a 69-year-old man with heavily pre-treated metastatic extraosseous Ewing sarcoma in addition to molecular profiling of his tumor. To our knowledge, this case is the earliest to demonstrate activity of an oral multi-targeted kinase inhibitor in Ewing sarcoma. This case provides rationale for adding a Ewing sarcoma arm to SARC024, a phase II study of regorafenib, another multi-targeted kinase inhibitor, in patients with liposarcoma, osteosarcoma and Ewing and Ewing-like sarcomas (NCT02048371). This national multi-institutional study is ongoing.

Published
2015

9. Durable Remissions with the VcR-CVAD Regimen for Mantle Cell Lymphoma (MCL), Regardless of Age: Long-Term Follow-up of a Wisconsin Oncology Network (WON) Study

Author

Jae Werndli, Michael S. Huie, Michael Volk, Walter L. Longo, David T. Yang, Anne M. Traynor, KyungMann Kim, Thomas McFarland, Brad S. Kahl, Natalie S. Callander, Christopher Peterson, Jules H. Blank, Julie E. Chang, and Lakeesha Carmichael

Subjects
Oncology, medicine.medical_specialty, business.industry, Immunology, Induction chemotherapy, Cell Biology, Hematology, CHOP, medicine.disease, Biochemistry, Chemotherapy regimen, Transplantation, Regimen, Chemoimmunotherapy, Internal medicine, Multicenter trial, medicine, Mantle cell lymphoma, business
Abstract

Introduction: There remains no clear standard first-line therapy for MCL. VcR-CVAD is a novel, intermediate-intensity chemoimmunotherapy regimen which incorporates bortezomib into modified hyper-CVAD chemotherapy. We hypothesized that the addition of bortezomib would improve the complete response (CR) rate, and maintenance rituximab (MR) would improve the remission duration. The results of this study were previously reported (Chang JE, et al. Br J Haematol 2011), with an observed overall response rate (ORR) of 90% (CR/unconfirmed CR in 77%), and 3-year progression-free survival (PFS) and overall survival (OS) of 63% and 86%, respectively. Long-term follow-up (LTFU) is reported from this multicenter trial. Methods: The study enrolled patients ≥18 years of age with histologically confirmed MCL. Patients were previously untreated, with the exception of 1 cycle of CHOP/CHOP-like chemotherapy. Patients received VcR-CVAD induction chemotherapy every 21 days for 6 cycles: rituximab (R) 375 mg/m2 intravenously (IV) on day 1; bortezomib/Velcade® (Vc) 1.3 mg/m2 IV, days 1 & 4; cyclophosphamide 300 mg/m2 IV every 12 hours, days 1-3 (total of 6 doses); doxorubicin 50 mg/m2 IV continuous infusion days 1-2 (total dose over 48 hours equal to 50 mg/m2); vincristine 1 mg IV day 3; and dexamethasone 40 mg orally days 1-4. Patients received G-CSF support beginning day 5-6 of each induction cycle, and all appropriate supportive care measures were permitted throughout treatment including tumor lysis prophylaxis, transfusion support and antibiotics. Patients achieving at least a partial response to induction therapy received R consolidation (R 375 mg/m2 IV X 4 weekly doses) and MR (R 375 mg/m2 IV every 12 weeks for a total of 5 years; total of 20 doses). Restaging CT scans were performed after cycles 2, 4, and 6 of induction, 12 weeks after consolidation, every 6 months during maintenance, and yearly during LTFU. The primary endpoint was ORR and CR to induction chemotherapy; secondary endpoints were PFS and OS. Results: Thirty patients were enrolled from 7/2005-5/2008. Median age was 61 years (range 48-74), 80% male, all patients had advanced stage disease, and 60% had MIPI score of medium- or high-risk disease. Six patients had blastic morphology. Long-term results are reported after a median follow-up of 7.8 years in surviving patients. Twenty patients are alive, and 15 (50%) are alive in ongoing remission (Figure 1). Estimates of 6-year PFS and OS are 53.1% and 69.8%, respectively (Table 1). The observed PFS and OS differences between patients Conclusions: VcR-CVAD is a moderate intensity chemotherapy regimen that is tolerable for many older and less fit adult patients as first-line therapy of MCL. LTFU of patients receiving VcR-CVAD induction followed by 5 years of MR demonstrates high rates of durable remission that are comparable with more intensive chemotherapy and consolidative autologous stem cell transplant (ASCT). The highly promising activity of the VcR-CVAD regimen was recapitulated in ECOG-ACRIN protocol E1405 (Chang et al, Blood 2014). A randomized phase 3 trial has recently confirmed the beneficial effects of bortezomib incorporation into standard immunochemotherapy (Robak et al, NEJM 2015). VcR-CVAD remains an effective therapy choice for initial treatment of MCL, both in younger and older MCL populations. Disclosures Kahl: Celgene: Consultancy; Seattle Genetics: Consultancy; Infinity: Consultancy; Gilead: Consultancy; Juno: Consultancy; Pharmacyclics: Consultancy.

Published
2016
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10. A phase 1/1b study of satraplatin (JM-216) in combination with docetaxel in patients with advanced solid tumors and metastatic castrate-resistant prostate cancer☆

Author

Jens C. Eickhoff, Thomas McFarland, Noelle K. LoConte, Jeremy Cetnar, Glenn Liu, Douglas G. McNeel, and George Wilding

Subjects
Oncology, Male, medicine.medical_specialty, Maximum Tolerated Dose, Organoplatinum Compounds, Urology, Satraplatin, Docetaxel, Neutropenia, Adenocarcinoma, Article, chemistry.chemical_compound, Prostate cancer, Prednisone, Prostate, Internal medicine, Neoplasms, Antineoplastic Combined Chemotherapy Protocols, medicine, Humans, Castration, Neoplasm Metastasis, Aged, Aged, 80 and over, business.industry, Cancer, Prostatic Neoplasms, Middle Aged, medicine.disease, Prognosis, Granulocyte colony-stimulating factor, medicine.anatomical_structure, chemistry, Female, Taxoids, business, medicine.drug
Abstract

Background Satraplatin is an oral platinum with potential advantages over other platinum agents. This study investigated the combination of satraplatin and docetaxel in a phase 1 study of patients with advanced solid tumor malignancies followed by a phase 1b study in men with chemotherapy naive metastatic castrate-resistant prostate cancer (CRPC). Methods In this single institution phase 1/1b study, patients received docetaxel on day 1 and satraplatin on days 1–5 of a 21-day cycle ± granulocyte colony stimulating factor (GCSF). For phase 1b, prednisone 10 mg daily was added. Results Twenty-nine patients received treatment. Based on 3 dose limiting toxicities (DLT) (grade 4 neutropenia) in 13 patients at dose levels 1 and −1 (docetaxel 60 mg/m 2 plus satraplatin 40 mg/m 2 and docetaxel 60 mg/m 2 plus satraplatin 50 mg/m 2 ) GCSF was administered with subsequent cohorts. A dose level of docetaxel 60 mg/m 2 plus satraplatin 50 mg/m 2 with GCSF was the starting dose level for phase 1b. At the highest dose in the phase 1b (docetaxel 75 mg/m 2 plus satraplatin 50 mg/m 2 ) there were no DLTs. Conclusion The combination of satraplatin and docetaxel is feasible in solid tumor malignancies. In advanced malignancies, the recommended phase 2 dose is docetaxel 60 mg/m 2 IV day 1 with satraplatin 40 mg/m 2 /d PO days 1–5, without G-CSF, and Docetaxel 70 mg/m 2 IV day 1 with Satraplatin 50 mg/m 2 /day PO days 1–5, with G-CSF support, repeated in 3-week cycles. For patients with CRPC the recommended phase 2 dose is docetaxel 75 mg/m 2 IV day 1 with satraplatin 50 mg/m 2 /d PO days 1–-5, with G-CSF and prednisone 10 mg daily, repeated in 3-week cycles.

Published
2011

11. Dose-escalation study of fixed-dose rate gemcitabine combined with capecitabine in advanced solid malignancies

Author

George Wilding, Steven Attia, Michael S. Huie, Sherry Morgan-Meadows, Dona Alberti, Toby C. Campbell, Amye J. Tevaarwerk, James F. Cleary, Anne M. Traynor, Kyle D. Holen, Howard H. Bailey, Jens C. Eickhoff, Daniel Mulkerin, Glenn Liu, Thomas McFarland, and William R. Schelman

Subjects
Oncology, Adult, Male, Cancer Research, medicine.medical_specialty, Neutropenia, Maximum Tolerated Dose, medicine.drug_class, Pharmacology, Toxicology, Antimetabolite, Deoxycytidine, Article, Capecitabine, Cohort Studies, chemistry.chemical_compound, Internal medicine, Neoplasms, Antineoplastic Combined Chemotherapy Protocols, medicine, Dose escalation, Humans, Pharmacology (medical), neoplasms, Aged, Aged, 80 and over, Dose-Response Relationship, Drug, business.industry, Fixed dose rate, Middle Aged, medicine.disease, Gemcitabine, Treatment Outcome, chemistry, Fluorouracil, Female, business, medicine.drug
Abstract

To define dose limiting toxicities (DLTs) and the maximum tolerated dose (MTD) of capecitabine with fixed-dose rate (FDR) gemcitabine.Eligible adults (advanced solid tumor; performance statusor=2) received capecitabine 500 mg/m(2) PO BID days 1-14 and FDR gemcitabine (400-1,000 mg/m(2) escalated by 200 mg/m(2) increments) at 10 mg/m(2)/min days 1 and 8 on a 21-day cycle. A traditional 3 + 3 cohort design was used to determine the MTD.Thirty patients (median age 59 years) were enrolled. The predominant gradeor=3 toxicity was myelosuppression, particularly neutropenia. At dose level 4 (1,000 mg/m(2) gemcitabine), two out of five evaluable patients had a DLT (grade 4 neutropeniaor=7 days). At dose level 3 (800 mg/m(2) gemcitabine), one patient had a DLT (grade 3 neutropeniaor=7 days) among six evaluable patients. Therefore, the MTD and recommended phase II dose was designated as capecitabine 500 mg/m(2) PO BID days 1-14 with 800 mg/m(2) FDR gemcitabine days 1 and 8 infused at 10 mg/m(2) per min on a 21-day cycle. Partial responses occurred in pretreated patients with esophageal, renal cell and bladder carcinomas.This regimen was well tolerated and may deserve evaluation in advanced gastrointestinal and genitourinary carcinomas.

Published
2008

13. Maintenance rituximab following induction chemoimmunotherapy may prolong progression-free survival in mantle cell lymphoma: a pilot study from the Wisconsin Oncology Network

Author

Jae Werndli, Carol D. Jones, James L. Zehnder, Jules H. Blank, H. Rezazedeh, Walter L. Longo, Howard H. Bailey, Jens C. Eickhoff, Wayne A. Bottner, Brad S. Kahl, and Thomas McFarland

Subjects
Oncology, Adult, Male, medicine.medical_specialty, Vincristine, medicine.medical_treatment, Pilot Projects, Lymphoma, Mantle-Cell, Dexamethasone, Disease-Free Survival, Drug Administration Schedule, Antibodies, Monoclonal, Murine-Derived, Maintenance therapy, Chemoimmunotherapy, Internal medicine, Multicenter trial, Antineoplastic Combined Chemotherapy Protocols, Medicine, Humans, Progression-free survival, Cyclophosphamide, Aged, Aged, 80 and over, Chemotherapy, business.industry, Remission Induction, Antibodies, Monoclonal, Hematology, Middle Aged, medicine.disease, Survival Analysis, Treatment Outcome, Doxorubicin, Mantle cell lymphoma, Rituximab, Female, business, Immunosuppressive Agents, medicine.drug
Abstract

Background: There is no standard first line treatment for mantle cell lymphoma. Patients and methods: This was a multicenter phase II pilot study of rituximab and modified hyper-fractionated cyclophosphamide, vincristine doxorubicin, dexamethasone (modified R-hyperCVAD) administered every 28 days for four to six cycles followed by rituximab maintenance therapy consisting of four weekly doses every 6 months for 2 years. Unlike traditional hyperCVAD regimens, no methotrexate or cytarabine was administered. Results: Of 22 patients, the overall response rate was 77% and the complete response rate was 64%. With a median follow-up time of 37 months in surviving patients, the median PFS was 37 months and the median OS was not reached. The achievement of a molecular remission did not correlate with improved outcome. The major toxicity was expected myelosuppression. Two patients died during induction treatment. There were no major adverse effects during maintenance therapy. Conclusion: In a multicenter trial, modified R-hyperCVAD was tolerable and effective induction therapy for untreated MCL. Maintenance rituximab appeared to prolong PFS without increasing toxicity.

Published
2006

14. A phase II trial of gemcitabine, 5-fluorouracil and leucovorin in advanced esophageal carcinoma

Author

Thomas J. Saphner, Jordan Berlin, KyungMann Kim, James P. Thomas, Thomas McFarland, Alcee Jumonville, Sherry Morgan-Meadows, Howard H. Bailey, Daniel Mulkerin, Harish Ahuja, and Richard M. Hansen

Subjects
Oncology, Adult, Male, Cancer Research, medicine.medical_specialty, Esophageal Neoplasm, Esophageal Neoplasms, medicine.drug_class, Leucovorin, Adenocarcinoma, Antimetabolite, Thymidylate synthase, Deoxycytidine, Drug Administration Schedule, Internal medicine, Antineoplastic Combined Chemotherapy Protocols, medicine, Carcinoma, Humans, Neoplasm Metastasis, Infusions, Intravenous, Survival analysis, Aged, Aged, 80 and over, biology, business.industry, Esophageal disease, General Medicine, Middle Aged, medicine.disease, Survival Analysis, Gemcitabine, Surgery, Treatment Outcome, Fluorouracil, Injections, Intravenous, biology.protein, Carcinoma, Squamous Cell, Female, business, medicine.drug
Abstract

Background: The aim of this study was to evaluate the overall response rate, toxicity and overall survival in patients with locally advanced or metastatic esophageal cancer treated with gemcitabine, 5-fluorouracil (5-FU) and leucovorin. Patients and Methods: Patients with either adenocarcinoma or squamous cell carcinoma of the esophagus could enroll; however, patients could not have received prior chemotherapy for metastatic disease. Treatment cycles consisted of infusions of all three agents at days 1, 8 and 15, repeated every 28 days. Patients received gemcitabine 1,000, leucovorin 25 and 5-FU 600 mg/m2. Tumor assessment was performed every 2 cycles. Responses were assessed using the Eastern Cooperative Oncology Group solid tumor response criteria. Results: Thirty-five patients with metastatic or locally advanced esophageal cancer enrolled. One complete response and ten partial responses were observed for an overall response rate of 31.4%. An additional 11 patients had stable disease as their best response. The median survival was 9.8 months with a 1-year survival rate of 37.1%. Toxicity was predominately hematologic, with 58% of patients experiencing grade 3 or 4 neutropenia. Conclusion: The combination of gemcitabine, 5-FU and leucovorin had activity in advanced esophageal cancer. Patients tolerated the regimen well, with myelosuppression occurring most commonly. The combination merits further investigation as a treatment for esophageal cancer.

Published
2004

15. Abstract 2538: Immune responses to common melanoma-associated antigens following intratumoral injection of alpha-gal glycolipids in patients with advanced melanoma

Author

Thomas McFarland, Jacquelyn A. Hank, Giles F. Whalen, Uri Galili, Mark R. Albertini, Jennifer Collins, Erin Clements, Erik A. Ranheim, Paul M. Sondel, and Cindy L. Zuleger

Subjects
Cancer Research, Pathology, medicine.medical_specialty, biology, business.industry, T cell, Melanoma, medicine.disease, Epitope, Tumor antigen, medicine.anatomical_structure, Immune system, Oncology, Antigen, medicine, Cancer research, biology.protein, Antibody, Antigen-presenting cell, business
Abstract

Background: One mechanism of immune escape in the tumor microenvironment is the inhibition of processes involved in tumor antigen uptake by antigen presenting cells (APC). Effective uptake of tumor cells by APC is achieved pre-clinically by labeling them with α-gal glycolipids (α-gal) and exploiting the natural anti-Gal antibody response that constitutes approximately 1% of immunoglobulins in humans. The current study involves intratumoral injection of glycolipids expressing α-gal epitopes in patients (pts) with advanced melanoma and evaluates, in HLA-A2+ treated pts, the development of immune responses to common melanoma-associated antigens (MAA). Methods: Eligibility criteria included unresectable metastatic melanoma (recurrent stage III or stage IV); at least one readily resectable cutaneous, subcutaneous, or readily palpable lymph node metastasis; and a serum anti-Gal titer above 1:50. Pts received 2 injections of alpha-gal glycolipids four weeks apart at 0.1 mg/injection (n=3; dose level 1), 1.0 mg/injection (n=3; dose level 2), or 10 mg/injection (n=3; dose level 3). Ex vivo pre-treatment and Day 57 post-treatment peripheral blood mononuclear cells (PBMC) from pts who were HLA-A2+ (8 of 9 treated pts) were stained with pooled MAA pentamers (gp100209-217, gp100154-162, Melan-A/MART-126-35, NY-ESO-1157-165, and Tyrosinase368-376) and evaluated by flow cytometry. Cells stained with cytomegalovirus (CMV) pp65495-504 or HTLV-1 Tax11-19 served as positive or negative controls, respectively. Results: MAA pentamer+ T cells were detected in 7 of 8 HLA-A2+ pts, both pre- and post-treatment. The frequency of MAA pentamer+ T cells post- versus pre-treatment increased approximately 2-fold for 2 pts [one from dose level 2 and one from dose level 3 (0.16% vs. 0.082%, and 0.033% vs. 0.017%, respectively (background subtracted))]. Similar increases were not observed for the other 5 pts with detectable MAA pentamer+ cells. Furthermore, the median fluorescence intensity (MFI) of MAA pentamer+ T cells, an indirect measure of T cell activation potential, was markedly higher post-treatment, as compared to pre-treatment, for 2 of 3 pts in dose level 1 (11227 vs. 3027, and 4045 vs. 1581). Substantial changes in MFI were not observed for the other pts.. Conclusions: Intratumoral injection of α-gal glycolipids can increase the ex vivo frequency of circulating MAA reactive T cells in some pts with advanced melanoma. Based on this finding, we are pursuing functional characterization of these pre- and post-treatment PBMC. Citation Format: Cindy L. Zuleger, Paul M. Sondel, Jacquelyn A. Hank, Erik A. Ranheim, Thomas A. McFarland, Jennifer Collins, Erin Clements, Giles Whalen, Uri Galili, Mark R. Albertini. Immune responses to common melanoma-associated antigens following intratumoral injection of alpha-gal glycolipids in patients with advanced melanoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2538. doi:10.1158/1538-7445.AM2014-2538

Published
2014
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16. Phase I study to evaluate toxicity and feasibility of intratumoral injection of alpha-gal glycolipids in patients with advanced melanoma

Author

Thomas McFarland, MaryBeth Henry, Heather B. Neuman, Sharon M. Weber, Jacquelyn A. Hank, Jennifer Collins, Erin Clements, Paul M. Sondel, Michael A. Newton, Giles F. Whalen, Uri Galili, Cindy L. Zuleger, Alan J. Bridges, Erik A. Ranheim, and Mark R. Albertini

Subjects
Cancer Research, Pathology, medicine.medical_specialty, biology, business.industry, Alpha (ethology), Tumor cells, Phase i study, Glycolipid, Oncology, Toxicity, Cancer research, biology.protein, Medicine, In patient, Antibody, business, Advanced melanoma
Abstract

3088 Background: Effective uptake of tumor cells by antigen-presenting cells is achieved pre-clinically by labeling them with α-gal glycolipids (α-gal) that bind the natural anti-Gal antibody. We a...

Published
2014
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17. A pilot trial of hu14.18-IL2 in patients with completely resectable recurrent stage III or stage IV melanoma

Author

MaryBeth Henry, Erik A. Ranheim, Paul M. Sondel, Heather B. Neuman, David A. Mahvi, KyungMann Kim, Stephen D. Gillies, Sharon M. Weber, Erin Clements, Thomas McFarland, Mark R. Albertini, Richard K. Yang, Jacek Gan, Tracey L. Weigel, Cindy L. Zuleger, Gregory K. Hartig, Jacquelyn A. Hank, and Jennifer Collins

Subjects
musculoskeletal diseases, Oncology, Cancer Research, medicine.medical_specialty, medicine.drug_class, business.industry, Melanoma, Pilot trial, hemic and immune systems, chemical and pharmacologic phenomena, Hu14.18-IL2, Monoclonal antibody, medicine.disease, Surgery, stomatognathic diseases, immune system diseases, Internal medicine, medicine, Stage iv melanoma, In patient, Stage (cooking), business, Immune activation
Abstract

9044 Background: Phase I testing of the hu14.18-IL2 immunocytokine (IC), a mAb reactive with GD2 disialoganglioside, linked to IL2, in patients (pts) with melanoma showed immune activation, reversi...

Published
2014
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18. A phase II study of tivozanib in patients with metastatic and nonresectable soft-tissue sarcomas

Author

Mark Agulnik, Brian A. Van Tine, Keith M. Skubitz, Rasima Cehic, Catherine Humphreys, Susan Abbinanti, Alfred Rademaker, Steven I. Robinson, Lauren Nye, Ariel Polish, Scott H. Okuno, Mohammed M. Milhem, Thomas McFarland, and Claudia Roxana Vintilescu

Subjects
Cancer Research, medicine.medical_specialty, Tivozanib, business.industry, Phases of clinical research, Treatment options, Soft tissue, macromolecular substances, Disease, Surgery, carbohydrates (lipids), stomatognathic diseases, Oncology, otorhinolaryngologic diseases, medicine, bacteria, In patient, Radiology, Stage (cooking), business, medicine.drug
Abstract

10515 Background: Despite a multi-modality approach, many patients (pts) with early stage soft tissue sarcomas (STS) will develop recurrent or metastatic disease. Treatment options for these pts ar...

Published
2014
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19. VcR-CVAD Produces a High Complete Response Rate in Untreated Mantle Cell Lymphoma: A Phase II Study from the Wisconsin Oncology Network

Author

Michael Volk, Jules H. Blank, Natalie S. Callander, Michael S. Huie, Eric S. Rogers, Christopher Peterson, Jens C. Eickhoff, Julie Chang, Walter L. Longo, Thomas McFarland, Jae Werndli, Leslie A. Gilbert, and Brad S. Kahl

Subjects
Oncology, medicine.medical_specialty, Vincristine, Cyclophosphamide, business.industry, Standard treatment, Immunology, Phases of clinical research, Cell Biology, Hematology, medicine.disease, Biochemistry, Regimen, Median follow-up, Internal medicine, medicine, Rituximab, Mantle cell lymphoma, business, medicine.drug
Abstract

Introduction: There is no standard treatment for Mantle cell lymphoma (MCL). Intensive treatment strategies such as conventional R-hyperCVAD with alternating R-cytarabine/methotrexate or autologous stem cell transplant appear to improve PFS but the effect on OS is unclear. In addition, approximately 50% of newly diagnosed patients are not candidates for intensive therapies. Novel treatment strategies are needed. We have published the results of a study using a modified R-hyperCVAD induction followed by maintenance rituximab (Kahl et al, Ann Oncol 2006). This induction strategy yielded a complete response (CR) rate of 64% and the entire treatment program yielded a median PFS of 37 months. Bortezomib (Velcade) has demonstrated promising activity in relapsed MCL (Fisher et al, J Clin Onc, 2006). We hypothesized that the incorporation of Velcade (Vc) into the induction regimen would improve the CR rate. The new regimen, VcRCVAD, was tested for safety and efficacy in a phase II study at the University of Wisconsin and within the Wisconsin Oncology Network. Methods: Eligible patients had histologically confirmed mantle cell lymphoma, PS 0–2, and adequate end organ function. The final treatment plan included: Velcade 1.3 mg/m2 days 1 and 4, rituximab 375 mg/m2 IV day 1, cyclophosphamide 300 mg/m2 IV over 3 hrs q 12 hrs X 6 doses days 1–3, doxorubicin 50 mg/m2 continuous infusion over 48 hrs days 1–2, vincristine 1 mg IV day 3, dexamethasone 40 mg po days 1–4. Due to excessive painful peripheral neuropathy (PN), 2 dose modifications were required during the course of the study. Patients 1–7 received 1.5 mg/m2 Velcade and 2 mg vincristine. Patients 8–14 received 1.3 mg/m2 Velcade and 2 mg vincristine. Patients 15–30 received 1.3 mg/m2 Velcade and 1 mg vincristine. Cycles were repeated every 21 days for 6 cycles and all patients received G-CSF cytokine support. Patients achieving at least a PR receive maintenance rituximab therapy for 5 years. Results: Enrollment is complete and all 30 patients are evaluable for response to VcRCVAD induction. Baseline characteristics include median age 60.5 (48–74), 24M:6F, 26/30 (87%) stage IV, and 12 (40%) low-risk, 8 (27%) int-risk, and 10 (33%) high-risk by MIPI. 3 patients (10%) experienced PD during induction therapy and 27 (90%) responded with 23 CR/CRu (77%) and 4 PR (13%). With a median follow up of approximately 18 months, the 18-month PFS and OS are 73% and 97%, respectively. The major toxicity of this treatment regimen is painful PN and expected hematologic toxicity. 5/7 patients in cohort 1 and 3/7 patients in cohort 2 developed grade 3 painful PN and 1 patient in cohort 2 developed grade 4 painful PN. Only 1/16 patients in the final cohort experienced grade 3 painful PN. All neuropathy eventually improved to ≤ grade 2, but 10 patients require chronic medication for symptom relief. 13/167 (8%) of the treatment cycles were complicated by neutropenic fever/infection. There were no treatment related deaths. Conclusion: The VcR-CVAD induction has produced high overall response (90%) and CR rate (77%) in a very representative MCL patient population. Comparing these data to our previous frontline MCL study, the CR rate appears to be enhanced (77% vs 64%) by the addition of Velcade. Longer follow up is needed before determining if the higher CR rate will translate into an improved PFS and OS. Because of the risk for painful PN, caution must be exercised when using vincristine and Velcade in combination. The MTD for this combination was 1 mg vincristine and 1.3 mg/m2 Velcade. The encouraging complete response rate provided the rationale for ECOG study E1405, which is testing the safety and efficacy of this induction regimen in a cooperative group setting.

Published
2008
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20. A feasibility study of VcR-CVAD with maintenance rituximab for untreated mantle cell lymphoma

Author

T. Myers, Jules H. Blank, Michael S. Huie, Jens C. Eickhoff, Natalie S. Callander, Christopher Peterson, Thomas McFarland, Jae Werndli, and Brad S. Kahl

Subjects
Oncology, Cancer Research, medicine.medical_specialty, business.industry, Internal medicine, medicine, Treatment strategy, Rituximab, Mantle cell lymphoma, business, medicine.disease, medicine.drug
Abstract

8062 Introduction: Novel treatment strategies are needed for Mantle Cell Lymphoma (MCL). We have published the results of a study using a modified R-hyperCVAD induction followed by maintenance rituximab (Kahl et al, Ann Oncol 2006). This induction strategy yielded a complete response (CR) rate of 64%. Given the promising activity of bortezomib (VELCADER) in relapsed MCL, we hypothesized that the incorporation of VELCADE (Vc) into the induction regimen would improve the CR rate. Methods: Eligible patients have histologically confirmed MCL, PS 0–2, and adequate end organ function. VcR-CVAD regimen: Velcade 1.3 mg/m2 days 1 and 4, rituximab 375 mg/m2 IV day 1, cyclophosphamide 300 mg/m2 IV over 3 hrs q 12 hrs X 6 doses days 1–3, doxorubicin 50 mg/m2 CI over days 1–2, vincristine 2 mg IV day 3, dexamethasone 40 mg po days 1–4. The first 7 patients received a Vc dose of 1.5mg/m2 on days 1 and 4 but this was modified to 1.3 mg/m2 due to excessive peripheral neuropathy (PN). Cycles are repeated every 21 days for 6 cycles and all patients receive G-CSF cytokine support. Patients achieving at least a PR receive maintenance rituximab therapy. Results: Currently 15 patients are enrolled with 13 having completed the VcR-CVAD induction and two in active treatment. Patient characteristics: 11M, 4F, median age 64 (49–73), and 13/15 stage IV. Of the 13 assessable patients, one experienced PD during induction therapy and expired. The remaining 12 patients have all achieved a complete response (CR rate 92%) and are currently receiving maintenance rituximab. The major toxicities of this treatment regimen are painful PN and expected hematological toxicity. Five/seven patients at 1.5 mg/m2 and 3/6 patients at 1.3 mg/m2 experienced grade 3–4 PN. All PN eventually resolved to grade 1- 2 and resolved faster in the patients receiving 1.3 mg/m2. Conclusion: The VcR-CVAD induction has produced high overall and complete response rates (92%) in a very representative MCL patient population. A Vc dose of 1.3 mg/m2 is better tolerated than a dose of 1.5 mg/m2. However, PN remains an issue and the final cohort in this feasibility study will receive a vincristine dose of 1 mg. The encouraging response rates noted in this pilot study provide the basis for ECOG protocol 1405, which will test this regimen in a cooperative group setting. No significant financial relationships to disclose.

Published
2007
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