Table 2 Exclusion criteria

- Previous cancer within 5 years prior to study inclusion except for curatively treated cervical cancer in-situ, non-melanoma skin cancer and superficial bladder tumors (Ta, Tis and T1)

- Diagnostic of metastases within 6 months after the termination of adjuvant chemotherapy.

- Previous treatment for metastatic disease.

- Active cardiac disease including any of the following: congestive heart failure (class 2 NYHA), new-onset angina (begun within the last 3 months), previous myocardial infarction (within the last 6 months), cardiac arrhythmias requiring anti-arrhythmic therapy (beta-blockers or digoxin are permitted).

- ECG with a QT/QTc interval higher than 450 ms for men and higher than 470 ms for women.

- Uncontrolled hypertension, i.e.,: systolic blood pressure > 140 mmHg or diastolic pressure > 90 mmHg despite optimal medical management

- Arterial or venous thrombotic or embolic events such as cerebrovascular accident, deep vein thrombosis or pulmonary embolism within 6 months before the start of treatment.

- Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to first dose of treatment. Non-healing wound, ulcer, or bone fracture. History of gastrointestinal fistula or perforation.

- Persistent NCI-CTCAE v5 gr.3 proteinuria, i.e.: urinary protein ≥3.5 g/24 h)

- Peripheral neuropathy > gr.1

- Ongoing infection > gr.2. Live attenuated vaccines are prohibited 10 days before the treatment, during the treatment and 3 months after the treatment

- Known history of human immunodeficiency virus (HIV) infection and/or chronic hepatitis B or C infection.

- Seizure disorder requiring medication.

- Symptomatic metastatic brain or meningeal tumors.

- Evidence or history of any bleeding diathesis, irrespective of severity. Any hemorrhage or bleeding event ≥ gr.3 within 4 weeks prior to the start of study medication.

- History of organ allograft.

- Dehydration ≥ gr.1.

- Substance abuse, medical, psychological, or social conditions that may interfere with the patient’s participation in the study or evaluation of the study results.

- Known hypersensitivity to any of the study drugs, study drug classes, or any constituent of the products.

- Interstitial lung disease with ongoing signs and symptoms.

- Concomitant intakes of St. John’s Wort.

- Inability to swallow oral medication or any malabsorption condition.

- Pregnant or breast-feeding subjects.

- Participation in another clinical study with an investigational product during the last 30 days before inclusion. Any condition that, in the opinion of the investigator, would interfere with the evaluation of study treatment or interpretation of patient safety or study results

- Patients who might be interconnected with or dependent on the sponsor site or the investigator.

- Legal incapacity or limited legal capacity.