A Phase II Randomized Clinical Trial Comparing Two Cycles Versus Four Cycles of Combination Therapy with Cetuximab, Avelumab, Cisplatin, and Docetaxel in Patients with Recurrent Metastatic Head and Neck Cancer - AVETUX-HN

Prior treatment

• Participation in another clinical trial with an investigational product within 4 weeks prior to randomization or until End of trial of the individual participant.
• Organ transplantation: Prior organ transplantation including allogenic stem-cell transplantation.
• Cardiovascular disease: 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.
• Vaccination: Vaccination within 4 weeks of the first dose of study medication and while on trials is prohibited except for administration of inactivated vaccine

Other illness

• Severe uncontrolled systemic disease (e.g., severe chronic obstructive pulmonary disease, severe cardiac disease).
• Participant has any history of idiopathic pulmonary fibrosis, organizing pneumonia, drug induced pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis
• Prior malignancy active within the previous 3 years except for locally curable cancers that have been apparently cured.
• History of severe hypersensitivity reactions to monoclonal antibodies or any components of the study drugs.
• Known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial
• Active autoimmune disease requiring systemic immunosuppressive treatment. Patients with controlled autoimmune disease not requiring systemic immunosuppressive treatment including diabetes type I, vitiligo, psoriasis, or hypo- or hyperthyroid diseases not requiring immunosuppressive treatment are eligible. Current use of immunosuppressive medication, EXCEPT for the following: a. intranasal, inhaled, topical steroids, or local steroid injection (e.g., intra-articular injection); b. Systemic corticosteroids at physiologic doses ≤ 10 mg/day of prednisone or equivalent; c. Steroids as premedication for hypersensitivity reactions (e.g., CT scan premedication).”

Lab values

• Infectious diseases as below: a. Active infection requiring systemic treatment, b. Known HIV infection, unless the participant can meet all the following criteria: i) Documented evidence of plasma HIV-1 RNA persistently <50 copies)/mL confirmed ≤3 months prior to AND at Screening; unless undetectable viral load is defined differently by local guidelines and agreed with the spnsor. In the >3 to 12 months prior to Screening, plasma HIV-1 RNA consistently <50 copies/mL is required; if single/isolated increases ≥50 copies/mL occurred and are thought not to be persistent andnot associated with antiretroviral resistance as per investigator assessment, the participant would be eligible AND ii) CD4 cell count ≥350 cells/mm3 over past 12 months and at Screening (and no measurement <350 cells/mm3 during that period) AND iii) Must be on an uninterrupted combination antiretroviral therapy regimen for at least 3 months prior to Screening, with combination antiretroviral therapy regimen consistent with locally recommended guidelines c. Participants who test positive for HCV antibodies and have positive HCV RNA. d. Untreated chronic hepatitis B or chronic HBV inactive carriers with HBV DNA >500 IU/mL (or >2500 copies/mL) at screening. Patients with chronic hepatitis B (HBsAg-positive) are eligible if they are on adequate antiviral prophylaxis (e.g., entecavir or tenofovir) per local standards and agree to continued monitoring.
• Laboratory abnormalities that may increase the risk associated with study participation or study treatment administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the patient inappropriate for entry into this study.

Other

• Active or untreated central nervous system (CNS) metastases and/or carcinomatous meningitis.
• Pregnant or breastfeeding women.
• Patients who are institutionalized by order of court or public authority
• Patients who might be dependent on the sponsor/ investigator or the trial site
• Patients not willing to assess QoL at the defined timepoints

• Patients (male, female, divers) must be ≥18 years of age
• Measurable disease based on RECIST 1.1 criteria.
• Eastern Cooperative Oncology Group (ECOG) performance status of ≤1.
• No prior systemic therapy administered in the recurrent or metastatic setting prior chemoradiation for locally advanced disease is allowed if completed at least 6 months before randomization. Systemic therapy, including anti-PD-(L)1 therapy, given as part of multimodal treatment for locally advanced disease is allowed and must be completed >6 months prior to signing consent. Any toxicity resulting from previous systemic treatment must be resolved or shall not exceed grade 1 based on CTCAE v.5 grading.
• Availability of archived tumor tissue (Block or at least 20 slides)
• Documentation of disease progression following curative intended treatment
• Written informed consent obtained from the patient prior to any study-specific procedures.
• Patient is willing to assess Quality of Life throughout the study
• Adequate hematologic function: Absolute neutrophil count (ANC) ≥1,500/μL, platelets ≥100,000/μL, hemoglobin ≥9.0 g/dL.
• Adequate hepatic function: Total bilirubin ≤1.5 × the upper limit of normal (ULN), AST and ALT ≤2.5 × ULN.
• Adequate renal function: Serum creatinine ≤1.5 × ULN or creatinine clearance ≥60 mL/min as calculated by the Cockcroft-Gault formula.
• Women of childbearing potential (WOCBP) must have a negative pregnancy test and agree to use highly effective contraception throughout the study and for at least 30 days after last treatment administration. Men must agree to use adequate contraception. a) For female participants: i) Confirmed post-menopausal state (defined as amenorrhea for at least 12 months), or ii) For women of childbearing potential (WOCBP): (1) Negative serum pregnancy test (β‐hCG) before inclusion/randomization, and (2) Practicing a highly effective birth control method (failure rate of less than 1%): I. combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation (oral/intravaginal/ transdermal), or II. progestogen-only hormonal contraception associated with inhibition of ovulation (oral/injectable/implantable), or III. intrauterine device (IUD), or IV. intrauterine hormone-releasing system (IUS), or V. bilateral tubal occlusion, or VI. vasectomised partner, or VII. heterosexual abstinence.
• Histologically or cytologically confirmed recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) that is not amenable to curative treatment. Primary tumors in the nasopharynx or cancer of unknown origin are excluded.
• Local PD-L1 CPS results for stratification with an expression score ≥1.
• Local p16 IHC indicating HPV association for oropharyngeal primary tumor