This is a biomarker-driven trial that will enroll patients with recurrent or metastatic squamous cell carcinoma of the head and neck progressing after first-line platinum-based chemotherapy. Based on potential biomarkers and molecular alterations identified in the biopsy from the central platform, patients will be allocated in different cohorts. There will be biomarker-positive patient cohorts and immunotherapy cohorts.

General Inclusion Criteria:

• Histologically confirmed recurrent and/or metastatic SCCHN of the oral cavity, oropharynx, hypopharynx or larynx not amenable to curative treatment.
• At least one measurable lesion by MRI or CT-scan according to RECIST 1.1, evaluated within 2 weeks prior to registration. Such lesion must not have been previously irradiated; if the measurable lesion(s) have been irradiated, clear progression must be documented.
• Progressive disease after first line platinum-based chemotherapy with or without cetuximab given as palliative treatment or progressive disease within 1 year if platinum-based chemotherapy was given as a part of the multimodal curative treatment. Patients pre-treated with anti-PD1/anti-PDL1 are allowed.
• ECOG performance status 0 -1 with a life expectancy of at least 12 weeks.
• Tumor core biopsy from any accessible tumor at the recurrent or metastatic site available for central testing.
• Patients must have adequate organ function, evaluated within 14 days prior to cohort allocation:
• Hemoglobin ≥ 9 g/100 ml,
• Neutrophils ≥ 1,500/mm3,
• Platelets ≥ 100,000/mm3,
• Total bilirubin <1.5 times the upper limit of normal (ULN) (< 3 times the upper limit of normal for Gilbert's disease),
• Serum ALT and AST ≤ 2.5 x ULN,
• Adequate renal function measured by:
• Estimated creatinine clearance ≥45ml using Cockcroft and Gault formula or Creatinine ≤ 1.5 ULN
• International Normalized Ratio (INR) or Prothrombin Time (PT) must be within the normal ranges as per institution's standard. A window of 5% is allowed.
• Patients receiving anticoagulant therapy are allowed to participate as long as the PT/INR values are within the expected target range of their current dose.
• Clinically normal cardiac function based on -left ventricular ejection fraction (≥ 50%) as assessed either by multi-gated acquisition scan or cardiac ultrasound and 12 lead ECG without clinically relevant abnormalities.
• Patients ≥ 18 years old and must be able to give written informed consent.
• Patients ≥ 70 years old must undergo the G8 screening.
• Women of child-bearing potential must have a negative pregnancy test (serum or urine within the 72 hours prior to cohort allocation).
• Patients of childbearing / reproductive potential must agree to use highly effective methods of contraception based on the Clinical Trial Facilitation Group (CTFG) guidance as of registration and up to 6 months after the last treatment dose. Highly effective methods can achieve failure rate of less than 1% per year when used consistently and correctly. Such methods include: For Women: combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation (oral, intravaginal and transdermal), progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable, implantable), intrauterine device, intrauterine hormone-releasing system, bilateral tubal occlusion, vasectomized partner and sexual abstinence. For Men: condoms, sexual abstinence (the reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient) and no sperm donations during treatment and up to 6 months after last dose of treatment.
• Female subjects who are breast feeding should agree to discontinue nursing prior to the first dose of study treatment and up to 6 months after the last study treatment.
• Before patient registration/randomization, written informed consent must be given according to ICH/GCP, and national/local regulations.

General Exclusion Criteria:

• Unresolved and significant toxicity CTCAE version 4.03 grade ≥ 2 from previous anticancer therapy other than alopecia.
• History of any of the following cardiovascular conditions within 6 months prior to registration:
• myocardial infarction,
• severe/unstable angina,
• ongoing cardiac dysrhythmias of CTCAE version 4.03 Grade 2 or more,
• atrial fibrillation of any grade,
• coronary/peripheral artery bypass graft,
• symptomatic congestive heart failure according to New York Heart Association (NYHA) Class III or Class IV,
• significant active cardiac disease including uncontrolled high blood pressure defined as systolic ≥150 and diastolic ≥100.
• cerebrovascular accident including transient ischemic attack
• thromboembolic events like symptomatic pulmonary embolism.
• Nasopharynx and sino-nasal tumor.
• Surgery or investigational drugs or chemotherapy or other anticancer therapy within 3 weeks before cohort allocationor or for investigational drugs, within a time interval less than at least 5 half-lives of the investigational agent, whichever is shorter. Participant must have recovered from any surgical procedure. Curative radiation therapy (60-70 Gy) within 6 weeks of cohort allocation. Palliative radiation therapy (e.g. 8 Gy on a painful lesion) will be allowed.
• Known untreated and uncontrolled brain metastases or leptomeningeal carcinomatosis.
• Known diagnosis of immune deficiency or a positive serology of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).
• Active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA [qualitative] is detected) or pre-existing liver cirrhosis.
• Known pre-existing interstitial lung disease (ILD). Bronchoemphysema is not considered as ILD.
• Other uncontrolled active illnesses or nonmalignant systemic disease (examples include, but are not limited to active infections requiring antibiotics, bleeding disorders, uncontrolled diabetes, uncontrolled ventricular arrhythmia, uncontrolled major seizure disorder, unstable spinal cord compression, superior vena cava syndrome …).
• Any psychiatric, psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule.
• Any malignancy (other than SCCHN, non-melanoma skin cancer or localized cervical cancer or localized and presumed cured prostatic cancer or basal cell carcinoma of the skin and carcinoma in situ of the cervix or bladder) within the last 3 years prior to treatment allocation.