Antonio Jimeno1, Marshall R Posner2, Lori J Wirth3, Nabil F Saba4, Roger B Cohen5, Elizabeta C Popa6, Athanassios Argiris7, Kenneth F Grossmann8, Ammar Sukari9, Dawn Wilson10, Xiaosha Zhang10, Jade Sun10, Chad Glasser10, Kenneth M Attie10, Matthew L Sherman10, Susan S Pandya10, Jared Weiss11. 1. Departments of Medicine and Otolaryngology, University of Colorado Cancer Center and Gates Center for Regenerative Medicine, Aurora, Colorado. 2. Departments of Medicine and Otolaryngology, Icahn School of Medicine at Mount Sinai, New York, New York. 3. Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts. 4. Department of Hematology and Medical Oncology, Emory University Winship Cancer Institute, Atlanta, Georgia. 5. Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania. 6. Department of Medicine, Joan and Sanford I Weill Cornell Medical College of Cornell University, New York, New York. 7. Department of Medicine, Institute of Drug Development, University of Texas Health Science Center at San Antonio, San Antonio, Texas. 8. Department of Internal Medicine, Huntsman Cancer Institute, Salt Lake City, Utah. 9. Karmanos Cancer Center, Wayne State University, Detroit, Michigan. 10. Acceleron Pharma, Cambridge, Massachusetts. 11. Department of Hematology and Oncology, University of North Carolina, Chapel Hill, North Carolina.
Abstract
BACKGROUND: Patients with platinum-refractory, recurrent or metastatic squamous cell carcinoma of the head and neck (RM-SCCHN) have limited options. Activin receptor-like kinase 1 (ALK1) is a type I receptor of the transforming growth factor β superfamily expressed on activated endothelial cells. Dalantercept is an ALK1 receptor fusion protein that acts as a ligand trap to block signaling through ALK1 and inhibits stages of angiogenesis involved in blood vessel maturation and stabilization. In a phase 1 study, dalantercept demonstrated clinical activity in patients with RM-SCCHN. The objective of the current study was to evaluate the activity of dalantercept in RM-SCCHN. METHODS: Forty-six patients received dalantercept at doses of 80 mg (n = 2), 0.6 mg/kg (n = 13), or 1.2 mg/kg (n = 31) subcutaneously every 3 weeks. The primary endpoint was the overall response rate according to Response Evaluation Criteria in Solid Tumors (RECIST version 1.1). Secondary endpoints included progression-free survival and overall survival, safety and tolerability, and pharmacokinetic and pharmacodynamic assessments. RESULTS: Forty patients were evaluable for response (13 who received dalantercept 0.6 mg/kg and 27 who received dalantercept 1.2 mg/kg). The overall response rate was 5% (n = 2), and 35% of patients had stable disease; 44% of patients who received 1.2 mg/kg and 30.8% of those who received 0.6 mg/kg achieved disease control (partial response or stable disease). The median progression-fee survival was 1.4 months (95% confidence interval, 1.3-2.2 months), and the median overall survival was 7.1 months (95% confidence interval, 5.5-11.1 months). Drug-related adverse events (>15%) were anemia, fatigue, peripheral edema, headache, and hyponatremia. CONCLUSIONS: In an unselected, heavily pretreated population of patients with RM-SCCHN, dalantercept monotherapy resulted in a favorable safety profile but only modest dose-dependent activity, and it did not meet the primary efficacy objective of the study. Cancer 2016;122:3641-9.
BACKGROUND: Patients with platinum-refractory, recurrent or metastatic squamous cell carcinoma of the head and neck (RM-SCCHN) have limited options. Activin receptor-like kinase 1 (ALK1) is a type I receptor of the transforming growth factor β superfamily expressed on activated endothelial cells. Dalantercept is an ALK1 receptor fusion protein that acts as a ligand trap to block signaling through ALK1 and inhibits stages of angiogenesis involved in blood vessel maturation and stabilization. In a phase 1 study, dalantercept demonstrated clinical activity in patients with RM-SCCHN. The objective of the current study was to evaluate the activity of dalantercept in RM-SCCHN. METHODS: Forty-six patients received dalantercept at doses of 80 mg (n = 2), 0.6 mg/kg (n = 13), or 1.2 mg/kg (n = 31) subcutaneously every 3 weeks. The primary endpoint was the overall response rate according to Response Evaluation Criteria in Solid Tumors (RECIST version 1.1). Secondary endpoints included progression-free survival and overall survival, safety and tolerability, and pharmacokinetic and pharmacodynamic assessments. RESULTS: Forty patients were evaluable for response (13 who received dalantercept 0.6 mg/kg and 27 who received dalantercept 1.2 mg/kg). The overall response rate was 5% (n = 2), and 35% of patients had stable disease; 44% of patients who received 1.2 mg/kg and 30.8% of those who received 0.6 mg/kg achieved disease control (partial response or stable disease). The median progression-fee survival was 1.4 months (95% confidence interval, 1.3-2.2 months), and the median overall survival was 7.1 months (95% confidence interval, 5.5-11.1 months). Drug-related adverse events (>15%) were anemia, fatigue, peripheral edema, headache, and hyponatremia. CONCLUSIONS: In an unselected, heavily pretreated population of patients with RM-SCCHN, dalantercept monotherapy resulted in a favorable safety profile but only modest dose-dependent activity, and it did not meet the primary efficacy objective of the study. Cancer 2016;122:3641-9.
Keywords:
activin receptor-like kinase 1 (ALK1); angiogenesis; bone morphogenetic protein 9 (BMP9); dalantercept. squamous cell carcinoma of the head and neck (SCCHN)
Authors: Christine H Chung; Joel S Parker; Gamze Karaca; Junyuan Wu; William K Funkhouser; Dominic Moore; Dale Butterfoss; Dong Xiang; Adam Zanation; Xiaoying Yin; William W Shockley; Mark C Weissler; Lynn G Dressler; Carol G Shores; Wendell G Yarbrough; Charles M Perou Journal: Cancer Cell Date: 2004-05 Impact factor: 31.743
Authors: E A Eisenhauer; P Therasse; J Bogaerts; L H Schwartz; D Sargent; R Ford; J Dancey; S Arbuck; S Gwyther; M Mooney; L Rubinstein; L Shankar; L Dodd; R Kaplan; D Lacombe; J Verweij Journal: Eur J Cancer Date: 2009-01 Impact factor: 9.162
Authors: Christine Elser; Lillian L Siu; Eric Winquist; Mark Agulnik; Gregory R Pond; Soo F Chin; Peggy Francis; Robin Cheiken; James Elting; Angela McNabola; Dean Wilkie; Oana Petrenciuc; Eric X Chen Journal: J Clin Oncol Date: 2007-08-20 Impact factor: 44.544
Authors: Dianne Mitchell; Eileen G Pobre; Aaron W Mulivor; Asya V Grinberg; Roselyne Castonguay; Travis E Monnell; Nicolas Solban; Jeffrey A Ucran; R Scott Pearsall; Kathryn W Underwood; Jasbir Seehra; Ravindra Kumar Journal: Mol Cancer Ther Date: 2010-02-02 Impact factor: 6.261
Authors: Sara I Cunha; Evangelia Pardali; Midory Thorikay; Charlotte Anderberg; Lukas Hawinkels; Marie-José Goumans; Jasbir Seehra; Carl-Henrik Heldin; Peter ten Dijke; Kristian Pietras Journal: J Exp Med Date: 2010-01-11 Impact factor: 14.307
Authors: Martin H Voss; Rupal S Bhatt; Nicholas J Vogelzang; Mayer Fishman; Robert S Alter; Brian I Rini; J Thaddeus Beck; Monika Joshi; Ralph Hauke; Michael B Atkins; Earle Burgess; Theodore F Logan; David Shaffer; Rahul Parikh; Nauman Moazzam; Xiaosha Zhang; Chad Glasser; Matthew L Sherman; Elizabeth R Plimack Journal: Cancer Date: 2019-04-05 Impact factor: 6.860
Authors: Andreas Benn; Christian Hiepen; Marc Osterland; Christof Schütte; An Zwijsen; Petra Knaus Journal: FASEB J Date: 2017-07-21 Impact factor: 5.191
Authors: Maria Catalina Gomez-Puerto; Prasanna Vasudevan Iyengar; Amaya García de Vinuesa; Peter Ten Dijke; Gonzalo Sanchez-Duffhues Journal: J Pathol Date: 2018-11-27 Impact factor: 7.996
Authors: Ghassan K Abou-Alfa; Rebecca A Miksad; Mohamedtaki A Tejani; Stephen Williamson; Martin E Gutierrez; Olugbenga O Olowokure; Manish R Sharma; Imane El Dika; Matthew L Sherman; Shuchi S Pandya Journal: Oncologist Date: 2018-10-23
Authors: Richard M Salmon; Jingxu Guo; Jennifer H Wood; Zhen Tong; John S Beech; Aleksandra Lawera; Minmin Yu; David J Grainger; Jill Reckless; Nicholas W Morrell; Wei Li Journal: Nat Commun Date: 2020-04-01 Impact factor: 14.919
Authors: Wei Li; Lu Long; Xudong Yang; Zhen Tong; Mark Southwood; Ross King; Paola Caruso; Paul D Upton; Peiran Yang; Geoffrey A Bocobo; Ivana Nikolic; Angelica Higuera; Richard M Salmon; He Jiang; Katharine M Lodge; Kim Hoenderdos; Rebecca M Baron; Paul B Yu; Alison M Condliffe; Charlotte Summers; Sussan Nourshargh; Edwin R Chilvers; Nicholas W Morrell Journal: Am J Respir Crit Care Med Date: 2021-06-01 Impact factor: 30.528