Concurrent IMRT with cetuximab (C), an EGFR-specific monoclonal antibody (mAb), provides suboptimal disease control in intermediate or high risk HNSCC. C induces cell-mediated immunity, but also immunosuppressive regulatory T cells (Treg) expressing CTLA-4, which correlate negatively with clinical outcomes. Thus, we conducted a phase I trial adding ipilimumab (ipi), an anti-CTLA-4 mAb, to standard C-IMRT.
Key eligibility included: stage III-IVb PULA HNSCC (pharynx, larynx); high risk (HPV-) or intermediate risk (HPV+ and either: ≥ 10 pack-year tobacco and ≥ N2 disease; or T4 or N3 disease). A 3 + 3 dose-escalation design was used to determine recommended phase II dose (RP2D, see Table). Dose limiting toxicity (DLT) was defined as any grade 4 adverse event (AE) except in-field radiation dermatitis or any immune-related (ir) AE requiring ≥ 2 weeks of systemic steroids.
From July 2013-May 2016, 18 pts enrolled: 5 larynx, 3 hypopharynx, 3 HPV- oropharynx, 7 HPV+ oropharynx; 14 smokers; 2 stage III, 13 stage IVa, 3 stage IVb. Two of 6 pts in cohort 1 experienced grade 3 ir-dermatologic DLT's, perforating folliculitis and autoimmune dermatitis, distinct from typical cetuximab-induced acneiform rash. No DLTs were observed in 6 pts completing treatment in cohort -1, which was expanded to N = 12. Among 16 pts who have completed treatment (2 ongoing), irAE included: grade 1, 2, and 3 dermatitis (2, 1, and 3 cases), grade 4 colitis (1; expansion cohort), and TPO auto-Ab-mediated, grade 1 hyperthyroidism (1). No hepatitis or hypophysitis was observed.
The RP2D for ipi in combination with standard C-IMRT is 1mg/kg dosed weeks 5, 8, 11, and 14. Dermatologic irAEs were unique to this regimen and dose-limiting; the spectrum of irAEs was otherwise typical for ipi.
|Week of Treatment|
|IMRT 70-74 Gy, daily fractionation, 7 weeks||X||X||X||X||X||X||X|
|Cetuximab 400 mg/m2 load then 250 mg/m2/week||X||X||X||X||X||X||X||X|
|Cohort -1: 1 mg/kg Cohort 1 (start): 3 mg/kg Cohort 2: 10 mg/kg|
Clinical trial identification
Clinical trial information: NCT01935921.
Legal entity responsible for the study
Robert L. Ferris, MD, PhD, Julie E. Bauman, MD, MPH
National Cancer Institute grant P50 CA097190 (to Dr. Ferris)
J. Bauman: In the past 24 months, I have served on scientific advisory boards for the following pharmaceutical companies: Incyte, Merck-Serono, Merck, Kolltan. R.L. Ferris: Paid member Advisory Board (Ad-Hoc)- Merck, Celgene, Bristol Myers Squibb, AZ, Medimmune Grant/Research funding- VentiRx, Bristol Myers Squibb, AZ/Medimmune All other authors have declared no conflicts of interest.