Phase I trial of palbociclib, a selective cyclin dependent kinase 4/6 inhibitor, in combination with cetuximab in patients with recurrent/metastatic head and neck squamous cell carcinoma.
To test the safety of the CDK4/6 inhibitor palbociclib with cetuximab in patients with recurrent/metastatic head and neck squamous cell carcinoma (HNSCC).



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.



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.



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.
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.
Loren
L
Michel
Division of Medical Oncology, Washington University School of Medicine, St. Louis, MO, United States.
Jessica
J
Ley
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.
Tanya M
TM
Wildes
Department of Pathology and Immunology, Washington University School of Medicine, United States.
András
A
Schaffer
Department of Medicine, Washington University School of Medicine, United States.
Anthony
A
Robinson
Department of Pharmaceutical Sciences, Seoul National University College of Pharmacy, Seoul, Republic of Korea.
Se-Eun
SE
Chun
Department of Pharmaceutical Sciences, Seoul National University College of Pharmacy, Seoul, Republic of Korea.
Wooin
W
Lee
Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, United States.
James
J
Lewis
Alvin J. Siteman Cancer Center, Washington University School of Medicine, United States; Division of Biostatistics, Washington University School of Medicine, United States.
Kathryn
K
Trinkaus
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.
Douglas
D
Adkins
D000328:Adult; D000368:Aged; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy*; D000068818:Cetuximab / Q000627:therapeutic use*; D051358:Cyclin-Dependent Kinase 4 / Q000037:antagonists & inhibitors; D051361:Cyclin-Dependent Kinase 6 / Q000037:antagonists & inhibitors; D005260:Female; D006258:Head and Neck Neoplasms / Q000188:drug therapy*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy*; D010879:Piperazines / Q000627:therapeutic use*; D011725:Pyridines / Q000627:therapeutic use*
D010879:Piperazines; D011725:Pyridines; D051358:Cyclin-Dependent Kinase 4; D051361:Cyclin-Dependent Kinase 6; C500026:palbociclib; D000068818:Cetuximab
Cetuximab; Head and neck cancer; Palbociclib; Phase I; Squamous cell carcinoma