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

•This is the first trial to evaluate a selective CDK4/6 inhibitor in HNSCC.•The novel combination of palbociclib and cetuximab was feasible and safe.•The palbociclib dose recommended is 125 mg/day 1–21 q 28 days with cetuximab.•Measureable decreases in target lesions occurred in 56% of patients.•The disease control rate was 89% and median TTP was 112 days (upper range 224).

SummaryObjectivesTo 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 MethodsA 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 28 days: dose level 1 (100 mg/d) and 2 (125 mg/d; approved monotherapy dose). Pharmacokinetic assessments were performed on cycle 2, day 15. Cyclin D1, p16INK4a, and Rb protein expression were measured on pre-treatment tumor. Tumor response was assessed using RECIST1.1.ResultsNine patients (five p16INK4a 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 p16INK4a 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 112 days (range: 28–168). In platin-resistant HNSCC, best tumor response: PR in 1, DC in 3 and median TTP was 112 days (range: 28–112). The Cmax and AUC0-24h appeared comparable in patients receiving 125 vs 100 mg dose of palbociclib.ConclusionThis trial, the first to evaluate a CDK4/6 inhibitor in HNSCC, determined that palbociclib 125 mg/day on days 1–21 every 28 days with cetuximab was safe. Tumor responses were observed, even in cetuximab- or platin-resistant disease.