Ramucirumab and Carbo-Paclitaxel for Untreated Thymic Carcinoma / B3 Thymoma With Carcinoma (RELEVENT)

Inclusion Criteria:

1. provision of written informed consent before treatment initiation

2. pathologically confirmed thymic carcinoma and B3 thymomas, with areas of carcinomalocally advanced as per central histological revision, recurrent and/or metastatic,not amenable to potentially curative treatments.

3. age>= 18 years old

4. provision of archival or fresh tissue (block or at least 15 charged slides 4μM ofthickness).

5. Blood and plasma sampling at baseline and at first clinical revaluation

6. measurable disease (defined according to Response Evaluation Criteria in SolidTumours [RECIST] version 1.1);7. Eastern Cooperative Oncology Group (ECOG)performance status of 0 or 1;

7. adequate hematologic function, as evidenced by an absolute neutrophil count (ANC) ≥1500/μL, haemoglobin

≥9 g/dL (5.58 mmol/L), and platelets ≥100,000/μL; 9. adequate coagulation function as defined by International Normalized Ratio (INR) ≤ 1.5, and a partial thromboplastin time (PTT) ≤ 5 seconds above the ULN (unless receiving anticoagulation therapy). Patients receiving warfarin must be switched to low molecular weight heparin and have achieved stable coagulation profile prior to first dose of protocol therapy 10. adequate hepatic function as defined by a total bilirubin ≤1.5times the upper limit of normal (ULN), (Except for patients with Gilbert's syndrome who may only be included in the total bilirubin is < 3.0 x ULN or direct bilirubin < 1.5 x ULN) and aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 3.0 times the upper limit of normal (or 5.0 times the ULN in the setting of liver metastases) 11. adequate renal function as defined by a serum creatinine ≤1.5 times the ULN, or creatinine clearance (measured via 24-hour urine collection) ≥40 mL/minute (that is, if serum creatinine is >1.5 times the ULN, a 24-hour urine collection to calculate creatinine clearance must be performed). The patient's urinary protein is

≤1+ on dipstick or routine urinalysis (UA; if urine dipstick or routine analysis is ≥2+, a 24-hour urine collection for protein must demonstrate <1000 mg of protein in 24 hours to allow participation in this protocol).

12. sexually active patients, must be postmenopausal, surgically sterile, or usingeffective contraception (hormonal or barrier methods). Female patients ofchildbearing potential must have a negative serum pregnancy test within 7 days priorto first dose of protocol therapy. 13. Prior radiation therapy is allowed.

• In case of chest radiotherapy a 28 days interval is needed between the end of theradiation treatment and the start of treatment .

• In the case of focal or palliative radiation treatment a 7 days interval is neededfrom last radiation treatment to start of treatment (and provided that 25% or lessof total bone marrow had been irradiated).

• In the case of CNS radiation a minimum of 14 days interval is needed from the end ofradiation treatment to start of treatment.

Exclusion Criteria:

1. previous systemic treatment for locally advanced/metastatic thymic carcinoma/B3thymomas; patients treated in the neoadjuvant or adjuvant setting can be enrolledafter discussion with PI

2. untreated CNS metastases. Patients with treated brain metastases are eligible ifthey are clinically stable with regard to neurologic function, off steroids aftercranial irradiation (whole brain radiation therapy, focal radiation therapy, andstereotactic radiosurgery) ending at least 2 weeks prior to start of treatment, orafter surgical resection performed at least 28 days prior to start of treatment. Thepatient may have no evidence of Grade ≥1 CNS haemorrhage based on pre-treatmentMagnetic Resonance Imaging (MRI) or IV contrast CT scan (performed within 28 daysbefore start of treatment)

3. any Grade 3-4 GI bleeding within 3 months prior to first dose of protocol therapy

4. peripheral neuropathy ≥ G2History of deep vein thrombosis (DVT), pulmonary embolism (PE), or any other significant thromboembolism (venous port or catheter thrombosisor superficial venous thrombosis are not considered "significant") during the 3months prior to first dose of protocol therapy.

5. patient has experienced hemoptysis (defined as bright red blood or ≥ 1/2 teaspoon)within 2 months prior to first dose of protocol therapy

6. radiographic evidence of intra-tumour cavitation, radiologically documented evidenceof major blood vessel invasion or encasement by cancer

7. history of uncontrolled hereditary or acquired thrombotic disorder

8. The patient has:

• cirrhosis at a level of Child-Pugh B (or worse) or

• cirrhosis (any degree) and a history of hepatic encephalopathy or clinicallymeaningful ascites resulting from cirrhosis. Clinically meaningful ascites isdefined as ascites from cirrhosis requiring diuretics or paracentesis.

9. clinically relevant congestive heart failure (NYHA II-IV) or symptomatic or poorlycontrolled cardiac arrhythmia

10. The patient has experienced any arterial thromboembolic events, including but notlimited to myocardial infarction, transient ischemic attack, cerebrovascularaccident, or unstable angina, within 6 months prior to first dose of protocoltherapy.uncontrolled or poorly-controlled hypertension (>160 mmHg systolic or > 100mmHg diastolic for >4 weeks) despite standard medical management.

11. serious or no healing wound, ulcer, or bone fracture within 28 days prior to startof treatment

12. significant bleeding disorders, vasculitis, or experienced grade 3/4gastrointestinal (GI) bleeding within 3 months prior to start of treatment

13. history of GI perforation and / or fistulae within 6 months prior to start oftreatment

14. bowel obstruction, history or presence of inflammatory enteropathy or extensiveintestinal resection, Crohn's disease, ulcerative colitis, or chronic diarrhoea

15. peripheral neuropathy ≥grade 2 (NCI-CTCAE v 4.0)

16. serious illness or medical condition(s) including, but not limited to, thefollowing: -Known human immunodeficiency virus (HIV) infection or acquiredimmunodeficiency syndrome (AIDS)- related illness.

• Active or uncontrolled clinically serious infection.

• Previous or concurrent malignancy except for basal or squamous cell skin cancerand/or in situ carcinoma of the cervix, or other solid tumours treatedcuratively and without evidence of recurrence for at least 3 years prior tostart of treatment.

• Uncontrolled metabolic disorders or other non-malignant organ or systemicdiseases or secondary effects of cancer that induce a high medical risk and/ormake assessment of survival uncertain.

• Other severe acute or chronic medical or psychiatric condition or laboratoryabnormality that may increase the risk associated with study participation orstudy drug administration and in the judgment of the investigator would makethe patient ineligible for entry into this study.

• significant third-space fluid retention (for example, ascites or pleuraleffusion), and is not amenable for required repeated drainage

17. known allergy or hypersensitivity reaction to any of the treatment components

18. known history of active drug abuse

19. patient is pregnant or breastfeeding

20. major surgery within 28 days prior to first dose of protocol therapy, or minorsurgery/subcutaneous venous access device placement within 7 days prior to firstdose of protocol therapy

21. elective or planned major surgery to be performed during the course of the clinicaltrial

22. patient is receiving concurrent treatment with other anticancer therapy

23. patient is receiving chronic antiplatelet therapy, including aspirin, nonsteroidalanti-inflammatory drugs (NSAIDs, including ibuprofen, naproxen, and others),dipyridamole or clopidogrel, or similar agents.

Once-daily aspirin use (maximum dose 325 mg/day) is permitted.