Loren Michel1, Jessica Ley2, Tanya M Wildes1, András Schaffer3, Anthony Robinson4, Se-Eun Chun5, Wooin Lee5, James Lewis6, Kathryn Trinkaus7, Douglas Adkins8. 1. Division of Medical Oncology, Washington University School of Medicine, St. Louis, MO, United States; Alvin J. Siteman Cancer Center, Washington University School of Medicine, United States. 2. Division of Medical Oncology, Washington University School of Medicine, St. Louis, MO, United States. 3. Department of Pathology and Immunology, Washington University School of Medicine, United States. 4. Department of Medicine, Washington University School of Medicine, United States. 5. Department of Pharmaceutical Sciences, Seoul National University College of Pharmacy, Seoul, Republic of Korea. 6. Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, United States. 7. Alvin J. Siteman Cancer Center, Washington University School of Medicine, United States; Division of Biostatistics, Washington University School of Medicine, United States. 8. Division of Medical Oncology, Washington University School of Medicine, St. Louis, MO, United States; Alvin J. Siteman Cancer Center, Washington University School of Medicine, United States. Electronic address: dadkins@dom.wustl.edu.
Abstract
OBJECTIVES: To test the safety of the CDK4/6 inhibitor palbociclib with cetuximab in patients with recurrent/metastatic head and neck squamous cell carcinoma (HNSCC). MATERIALS AND METHODS: A phase I trial using 3+3 design was performed to determine the dose limiting toxicity (DLT) and maximum tolerated dose (MTD) of palbociclib with standard dose weekly cetuximab. Palbociclib was administered orally days 1-21 every 28days: dose level 1 (100mg/d) and 2 (125mg/d; approved monotherapy dose). Pharmacokinetic assessments were performed on cycle 2, day 15. Cyclin D1, p16(INK4a), and Rb protein expression were measured on pre-treatment tumor. Tumor response was assessed using RECIST1.1. RESULTS: Nine patients (five p16(INK4a) negative; four positive) were enrolled across dose levels 1 (n=3) and 2 (n=6) and none experienced a DLT. A MTD of palbociclib was not reached. Myelosuppression was the most common adverse event. Six of nine patients had cetuximab-resistant and 4/9 had platin-resistant disease. Disease control (DC) occurred in 89%, including partial response (PR) in two (22%) and stable disease in six (67%) patients. PRs occurred in p16(INK4a) negative HNSCC. Five patients (56%) had measurable decreases in tumor target lesions. In cetuximab-resistant HNSCC, best tumor response was PR in 1 and DC in 5 and median TTP was 112days (range: 28-168). In platin-resistant HNSCC, best tumor response: PR in 1, DC in 3 and median TTP was 112days (range: 28-112). The Cmax and AUC0-24h appeared comparable in patients receiving 125 vs 100mg dose of palbociclib. CONCLUSION: This trial, the first to evaluate a CDK4/6 inhibitor in HNSCC, determined that palbociclib 125mg/day on days 1-21 every 28days with cetuximab was safe. Tumor responses were observed, even in cetuximab- or platin-resistant disease.
OBJECTIVES: To test the safety of the CDK4/6 inhibitor palbociclib with cetuximab in patients with recurrent/metastatic head and neck squamous cell carcinoma (HNSCC). MATERIALS AND METHODS: A phase I trial using 3+3 design was performed to determine the dose limiting toxicity (DLT) and maximum tolerated dose (MTD) of palbociclib with standard dose weekly cetuximab. Palbociclib was administered orally days 1-21 every 28days: dose level 1 (100mg/d) and 2 (125mg/d; approved monotherapy dose). Pharmacokinetic assessments were performed on cycle 2, day 15. Cyclin D1, p16(INK4a), and Rb protein expression were measured on pre-treatment tumor. Tumor response was assessed using RECIST1.1. RESULTS: Nine patients (five p16(INK4a) negative; four positive) were enrolled across dose levels 1 (n=3) and 2 (n=6) and none experienced a DLT. A MTD of palbociclib was not reached. Myelosuppression was the most common adverse event. Six of nine patients had cetuximab-resistant and 4/9 had platin-resistant disease. Disease control (DC) occurred in 89%, including partial response (PR) in two (22%) and stable disease in six (67%) patients. PRs occurred in p16(INK4a) negative HNSCC. Five patients (56%) had measurable decreases in tumor target lesions. In cetuximab-resistant HNSCC, best tumor response was PR in 1 and DC in 5 and median TTP was 112days (range: 28-168). In platin-resistant HNSCC, best tumor response: PR in 1, DC in 3 and median TTP was 112days (range: 28-112). The Cmax and AUC0-24h appeared comparable in patients receiving 125 vs 100mg dose of palbociclib. CONCLUSION: This trial, the first to evaluate a CDK4/6 inhibitor in HNSCC, determined that palbociclib 125mg/day on days 1-21 every 28days with cetuximab was safe. Tumor responses were observed, even in cetuximab- or platin-resistant disease.
Authors: John P Leonard; Ann S LaCasce; Mitchell R Smith; Ariela Noy; Lucian R Chirieac; Scott J Rodig; Jian Q Yu; Shankar Vallabhajosula; Heiko Schoder; Patricia English; Donna S Neuberg; Peter Martin; Michael M Millenson; Scott A Ely; Rachel Courtney; Naveed Shaik; Keith D Wilner; Sophia Randolph; Annick D Van den Abbeele; Selina Y Chen-Kiang; Jeffrey T Yap; Geoffrey I Shapiro Journal: Blood Date: 2012-03-01 Impact factor: 22.113
Authors: Christine H Chung; Joel S Parker; Kim Ely; Jesse Carter; Yajun Yi; Barbara A Murphy; K Kian Ang; Adel K El-Naggar; Adam M Zanation; Anthony J Cmelak; Shawn Levy; Robbert J Slebos; Wendell G Yarbrough Journal: Cancer Res Date: 2006-08-15 Impact factor: 12.701
Authors: Keith T Flaherty; Patricia M Lorusso; Angela Demichele; Vandana G Abramson; Rachel Courtney; Sophia S Randolph; M Naveed Shaik; Keith D Wilner; Peter J O'Dwyer; Gary K Schwartz Journal: Clin Cancer Res Date: 2011-11-16 Impact factor: 12.531
Authors: Larry H Kalish; Rhonda A Kwong; Ian E Cole; Richard M Gallagher; Robert L Sutherland; Elizabeth A Musgrove Journal: Clin Cancer Res Date: 2004-11-15 Impact factor: 12.531
Authors: Michaela K Keck; Zhixiang Zuo; Arun Khattri; Thomas P Stricker; Christopher D Brown; Matin Imanguli; Damian Rieke; Katharina Endhardt; Petra Fang; Johannes Brägelmann; Rebecca DeBoer; Mohamed El-Dinali; Serdal Aktolga; Zhengdeng Lei; Patrick Tan; Steve G Rozen; Ravi Salgia; Ralph R Weichselbaum; Mark W Lingen; Michael D Story; K Kian Ang; Ezra E W Cohen; Kevin P White; Everett E Vokes; Tanguy Y Seiwert Journal: Clin Cancer Res Date: 2014-12-09 Impact factor: 12.531
Authors: Juliette B Scantlebury; Jingqin Luo; Wade L Thorstad; Samir K El-Mofty; James S Lewis Journal: Hum Pathol Date: 2013-04-06 Impact factor: 3.466
Authors: Jorge S Reis-Filho; Kay Savage; Maryou B K Lambros; Michelle James; Dawn Steele; Robin L Jones; Mitch Dowsett Journal: Mod Pathol Date: 2006-04-28 Impact factor: 7.842
Authors: Nicholas J Gadsden; Cory D Fulcher; Daniel Li; Nitisha Shrivastava; Carlos Thomas; Jeffrey E Segall; Michael B Prystowsky; Nicolas F Schlecht; Evripidis Gavathiotis; Thomas J Ow Journal: Mol Cancer Res Date: 2021-01-25 Impact factor: 5.852