A Single-arm Phase II Study of Cetuximab Plus Platinum and Taxane-based Chemotherapy Followed by AVElumab and Cetuximab as First-line Therapy for Recurrent/Metastatic (R/M) Head and Neck Squamous Cell Carcinoma (HNSCC) Patients With PD-L1 Combined Positive Score (CPS)≥1≤19: the Immunotherapy Sequenc
This phase II interventional clinical trial aims to evaluate whether combining cetuximab and avelumab, after three cycles of platinum and taxane-based chemotherapy, can improve treatment outcomes for patients with recurrent or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) with a PD-L1 combined positive score (CPS) between 1 and 19. Specifically, the study seeks to determine if this approach can increase the 6-month progression-free survival (PFS) rate from 40% to 55%. The trial will include adult patients with confirmed R/M HNSCC, who have not previously received systemic therapy for their advanced disease. By testing this sequential treatment strategy, researchers hope to improve outcomes for this specific patient population, which has shown poorer responses to existing immunotherapy options compared to those with higher PD-L1 expression levels. Participants will first undergo an induction phase, consisting of three cycles of chemotherapy with paclitaxel, platinum (cisplatin or carboplatin), and cetuximab. After this initial treatment, they will move to a maintenance phase, where they will receive avelumab and cetuximab every two weeks until disease progression or the occurrence of unacceptable side effects. The study aims to answer several key questions: Can this treatment approach improve progression-free survival at 6 months? What impact does it have on overall survival, response rates, and the duration of response? Is this combination therapy safe and well-tolerated? In addition to the treatment itself, participants will be asked to provide blood and tumor tissue samples for translational research, helping scientists better understand how biomarkers influence treatment response. Regular follow-up assessments will also be conducted to monitor disease progression and overall health. By testing this innovative treatment sequence, researchers hope to bridge the gap between different PD-L1 subgroups, potentially offering a more effective and personalized approach for patients with R/M HNSCC.
⁃ Subjects able to sign the informed consent and ≥18 y-old.
⁃ Histologically or cytologically confirmed diagnosis of HNSCC.
⁃ Confirmed R/M HNSCC (i.e. oral cavity, oropharynx, larynx, hypopharynx) not suitable for curative loco-regional therapy.
⁃ PD-L1 CPS≥1≤19 (assessment allowed either on primary and/or recurrent/metastatic site of disease).
⁃ Measurable disease according to RECIST Criteria 1.1.6. Subjects should not have had prior systemic therapy administered in the R/M HNSCC setting.
• Systemic therapy that was completed more than 6 months prior to signing consent, if given as a part of multimodal curative treatment for locally advanced disease, is allowed.
• ECOG Performance Status (PS) 0-1. 9.Adequate bone marrow function: neutrophils ≥ 1.5 x 109/L, platelets ≥ 100 x 109/L, hemoglobin ≥ 9 g/dL.
⁃ Adequate liver function: total bilirubin level \< 1.5 X Upper Limit of Normal (ULN) (except for known medical reason not interfering with liver function, such as Gilbert syndrome), AP, GGT \<3 x ULN and AST and ALT levels ≤ 2.5 × ULN.
⁃ Adequate renal function: calculated or analyzed creatinine clearance ≥ 30 mL/min.
⁃ Archival or fresh tissue of primary disease (i.e. T and/or N and/or M) OR recurrent/metastatic disease available at baseline (before starting TPE) (available as Formalin-Fixed Paraffin-Embedded - FFPE - or as unstained 10-20 slices).
⁃ Participants have to provide peripheral blood samples (at least 8-10 mL stored in EDTA) according the timing described in the translational part of the current protocol.
⁃ Palliative radiotherapy and/or surgery within 4 weeks before the study entry are allowed.
⁃ Symptomatic peripheral neuropathy NCI-CTC v5.0 grade ≥ 2 and / or ototoxicity grade ≥ 2, (except for cases in which ototoxicity is due to trauma or tumor-related mechanical impairment) or creatinine clearance \< 60 mL/min are acceptable and they must be approached with carboplatin (instead of cisplatin) since the trial start.