This phase II interventional clinical trial aims to evaluate whether combining cetuximaband avelumab, after three cycles of platinum and taxane-based chemotherapy, can improvetreatment outcomes for patients with recurrent or metastatic (R/M) head and neck squamouscell 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-monthprogression-free survival (PFS) rate from 40% to 55%.The trial will include adult patients with confirmed R/M HNSCC, who have not previouslyreceived systemic therapy for their advanced disease. By testing this sequentialtreatment strategy, researchers hope to improve outcomes for this specific patientpopulation, which has shown poorer responses to existing immunotherapy options comparedto those with higher PD-L1 expression levels.Participants will first undergo an induction phase, consisting of three cycles ofchemotherapy with paclitaxel, platinum (cisplatin or carboplatin), and cetuximab. Afterthis initial treatment, they will move to a maintenance phase, where they will receiveavelumab and cetuximab every two weeks until disease progression or the occurrence ofunacceptable side effects.The study aims to answer several key questions:Can this treatment approach improve progression-free survival at 6 months? What impactdoes it have on overall survival, response rates, and the duration of response? Is thiscombination therapy safe and well-tolerated? In addition to the treatment itself,participants will be asked to provide blood and tumor tissue samples for translationalresearch, helping scientists better understand how biomarkers influence treatmentresponse. Regular follow-up assessments will also be conducted to monitor diseaseprogression and overall health.By testing this innovative treatment sequence, researchers hope to bridge the gap betweendifferent PD-L1 subgroups, potentially offering a more effective and personalizedapproach for patients with R/M HNSCC.
This clinical study, titled AVEC-119, is a phase II, single-arm trial designed to
evaluate the efficacy and safety of an innovative treatment approach for recurrent and
metastatic head and neck squamous cell carcinoma (R/M HNSCC). The study aims to explore
whether reversing the conventional immunotherapy sequence-initiating treatment with
anti-EGFR-based chemotherapy induction followed by checkpoint inhibition-can
significantly improve patient outcomes. The therapy consists of Cetuximab in combination
with platinum- and taxane-based chemotherapy during the induction phase, followed by
maintenance therapy with Avelumab (a PD-L1 inhibitor) and Cetuximab.
Objective:
The primary goal of this study is to determine whether this unique sequential treatment
strategy can enhance six-month progression-free survival (PFS) rates in patients with
PD-L1 CPS≥1≤19 R/M HNSCC. By leveraging the potential immune-stimulating effects of
anti-EGFR therapy and chemotherapy, followed by immunotherapy maintenance, the study aims
to improve overall survival and tumor response rates compared to standard treatment
regimens.
Rationale:
Over the past decade, immune checkpoint inhibitors (ICIs) have reshaped the first-line
treatment landscape for R/M HNSCC. Findings from the Keynote-048 trial demonstrated that
pembrolizumab, administered alone or in combination with chemotherapy, led to prolonged
overall survival (OS) compared to the EXTREME regimen (Cetuximab + platinum + 5-FU).
However, these improvements were primarily observed in patients with a PD-L1 CPS≥20. In
contrast, those with PD-L1 CPS between 1 and 19 did not achieve significant benefits in
progression-free survival (PFS) or overall response rate (ORR), highlighting an area of
unmet clinical need.
Previous studies have demonstrated that regimens incorporating Cetuximab with platinum-
and taxane-based chemotherapy offer comparable efficacy and superior safety profiles
compared to platinum + 5-FU regimens. Furthermore, taxanes and anti-EGFR therapies may
enhance anti-tumor immune responses, priming the tumor microenvironment for subsequent
immunotherapy.
AVEC-119 aims to harness this synergy by first reducing the tumor burden and modulating
the immune microenvironment through induction therapy with Cetuximab and chemotherapy,
followed by immune checkpoint inhibition with Avelumab in combination with Cetuximab.
This innovative treatment approach is designed to improve response rates and extend
survival in patients who typically derive limited benefit from standard checkpoint
inhibitors.
Study Design:
Study Type: Multicenter, single-arm, phase II trial Participating Sites: 8 specialized
oncology centers in Italy Target Population: Patients with R/M HNSCC and PD-L1 CPS
between 1 and 19 Planned Enrollment: A total of 67 patients
Treatment Plan:
Induction Phase (TPE - 9 weeks):
- Paclitaxel: 175 mg/m² IV infusion every 21 days (3 cycles)
- Cisplatin: 75 mg/m² IV infusion every 21 days (3 cycles) (Carboplatin AUC 5 may be
substituted for patients with renal impairment or neuropathy)
- Cetuximab: Initial dose of 400 mg/m² IV infusion, followed by 250 mg/m² weekly for 3
cycles
Maintenance Phase (AVEC - Until Disease Progression or Toxicity):
- Avelumab: 800 mg IV every 2 weeks
- Cetuximab: 500 mg/m² IV every 2 weeks Translational Research and Biomarker Analysis
AVEC-119 integrates a comprehensive translational research component aimed at
unraveling the molecular mechanisms underlying treatment response and resistance.
The study will:
- Conduct pre-treatment gene expression (GE) analysis in tumor samples to explore
correlations between hypoxia, immune activity, and response to therapy.
- Utilize single-cell sequencing to track immune cell population changes in blood
samples collected at four critical time points: pre-TPE, post-TPE, during
maintenance (6 months), and at disease progression.
- Investigate whether the hypoxic and immune landscape of tumors shifts following EGFR
inhibition, potentially enhancing response to subsequent PD-L1 blockade.
Ethical and Regulatory Aspects
- The study adheres to Good Clinical Practice (GCP) standards and has obtained
approval from the relevant ethics committees.
- All participants provide informed consent prior to enrollment.
- Patient safety is continuously monitored, with predefined stopping criteria in place
should unacceptable toxicity levels arise.
Conclusion AVEC-119 represents a paradigm shift in the treatment of R/M HNSCC,
particularly for patients with PD-L1 CPS between 1 and 19, a group that has historically
exhibited suboptimal responses to checkpoint inhibitors. By reversing the conventional
immunotherapy sequence-priming the immune system with a chemotherapy/EGFR-targeted
induction before introducing checkpoint blockade-this study aims to achieve higher
response rates, prolong progression-free survival, and shed new light on tumor-immune
dynamics. If successful, this approach may redefine first-line treatment strategies for a
challenging subset of head and neck cancer patients, offering new hope and improved
clinical outcomes.
Drug: Cetuximab/avelumab
Study Maintenance therapy: AVEC (each cycle every 2 weeks) Cetuximab will be administered
at 500 mg/m2 dose (as a 2-hour intravenous infusion) every 2 weeks until disease
progression or unacceptable side effects.
Cetuximab will be administered by IV infusion over 120 minutes. The initial dose should
be given slowly and speed of infusion must not exceed 5 mg/min.
Avelumab will be administered at 800 mg flat dose (as a 1-hour intravenous fusion) every
2 weeks until disease progression or unacceptable side effects.
Inclusion Criteria:
1. Subjects able to sign the informed consent and ≥18 y-old.
2. Histologically or cytologically confirmed diagnosis of HNSCC.
3. Confirmed R/M HNSCC (i.e. oral cavity, oropharynx, larynx, hypopharynx) not suitable
for curative loco-regional therapy.
4. PD-L1 CPS≥1≤19 (assessment allowed either on primary and/or recurrent/metastatic
site of disease).
5. Measurable disease according to RECIST Criteria 1.1.6. Subjects should not have had
prior systemic therapy administered in the R/M HNSCC setting.
7.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.
8.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.
10.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.
11.Adequate renal function: calculated or analyzed creatinine clearance ≥ 30 mL/min.
12.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).
13.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.
14.Palliative radiotherapy and/or surgery within 4 weeks before the study entry are
allowed.
15.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.
Exclusion criteria:
1. Nasopharyngeal, salivary gland, nasal sinus, and non-melanoma skin cancers are not
allowed.
2. Life expectancy lower than 3 months according to the judgement of trial investigator
is not allowed.
3. Previous chemotherapy, or biological therapy (i.e. Cetuximab), or immunotherapy
administered for R/M setting of HNSCC is not allowed.
4. Diagnosis of immunodeficiency or subjects receiving systemic steroid therapy (> 10
mg/day of prednisone or equivalent) or any other form of immunosuppressive therapy
within 30 days prior to start of study treatment which cannot be interrupted.
5. Known allergic/hypersensitivity reaction to investigational products or any
component in their formulations.
6. Active autoimmune disease that has required systemic treatment in past 2 years (i.e.
with use of disease modifying agents, corticosteroids or immunosuppressive drugs).
7. Active autoimmune disease that might deteriorate when receiving an
immuno-stimulatory agent. Patients with type I diabetes, vitiligo, psoriasis, or
hypo- or hyperthyroid diseases not requiring immunosuppressive treatment are
eligible.
8. Any diagnosed and/or treated additional malignancy within 5 years before the study
entry with the exception of: curatively treated basal cell carcinoma of the skin,
curatively treated squamous cell carcinoma of the skin, curatively treated prostate
cancer, curatively resected in situ cervical cancer, and curatively resected in situ
breast cancer.
9. Subjects with a history or current evidence of any condition, therapy, or laboratory
abnormality that might confound the results of the trial, interfere with the
subjects' participation for the full duration of the trial, or is not in the best
interest of the subject to participate, according to the opinion of the treating
investigator.
10. Significant neurologic or known psychiatric or substance abuse disorders that would
interfere with cooperation and the requirements of the trial.
11. Clinically significant (i.e., active) cardiovascular disease: cerebral vascular
accident/stroke (≤6 months prior to enrollment), myocardial infarction (≤6 months
prior to enrollment), unstable angina, congestive heart failure (≥ New York Heart
Association Classification Class II), or serious cardiac arrhythmia requiring
medication.
12. Prior organ transplantation including allogenic stem-cell transplantation.
13. Active uncontrolled infection requiring systemic therapy (i.e. I.V. antibiotics).
14. Known history of testing positive for HIV or known acquired immunodeficiency
syndrome.
15. Hepatitis B virus (HBV) or hepatitis C virus (HCV) infection at screening (positive
HBV surface antigen or HCV RNA if anti-HCV antibody screening tests positive).
16. Live vaccination within 30 days of planned start of study treatment (inactivated
vaccines are allowed).
17. Pregnancy (absence of pregnancy must be confirmed by negative serum or urine
pregnancy test - ß-HCG - for women of childbearing potential) and/or breast-feeding
are not allowed. Subjects of childbearing potential willing to use effective
contraceptive method [Pearl Index < 1; e.g. oral contraceptive (pill), hormone
spiral, hormone implant, transdermal patch, a combination of two barrier methods
(condom and diaphragm), sterilization, sexual abstinence] for the entire study
duration and 30 days post-dosing.
Irccs Humanitas Research Hospital
Rozzano, Milano, Italy
Ospedale Oncologico "A. Businco" ARNAS BROTSU
Cagliari, Italy
Azienda Ospedaliero-Universitaria Policlinico "G. Rodolico-S. Marco
Catania, Italy
Azienda Ospedaliero-Universitaria Careggi
Firenze, Italy
Fondazione IRCCS Istituto Nazionale dei Tumori (INT) di Milano
Milano, Italy
Irccs Fondazione G. Pascale
Napoli, Italy
AOU Luigi Vanvitelli
Napoli, Italy
Azienda Ospedaliero-Universitaria Sant'Andrea
Roma, Italy
Not Provided