First-line CBDCA/PTX/LEN/Pembrolizumab Combination for Previously Untreated Advanced or Recurrent Thymic Carcinomas (Artemis)

Inclusion Criteria:

1. Patients aged 18 years or older at the time of informed consent, who arepathologically (histologically or cytologically) diagnosed with thymic carcinoma forprimary or metastatic thymic lesions, are included. They are preferred to be positivefor CD5 or c-KIT by immunohistochemical staining. For those with non-squamousepithelial carcinoma negative for p40 or p63, non-primary cases should be excludedbased on their clinical and pathological findings. In addition, those with thymoma areexcluded.
2. Patients with unresectable advanced thymic carcinoma (equivalent to stage IVa or IVbof Masaoka-Koga classification), metastatic or recurrent, who have not been treatedwith systemic cancer chemotherapy. Or, in the case of stage III Masaoka-Koga classification, patients who are judged tobe incapable of radical resection (R0 resection is not possible due to the combinedresection of invasive lesions in surrounding organs (pericardial sac, lung, greatvessels, etc.) or who are not eligible for curative treatment with chemoradiotherapy.A history of adjuvant chemotherapy and radiation therapy is acceptable forperioperative adjuvant therapy prior to the finding of recurrence. Ifplatinum-containing cancer chemotherapy has been administered as adjuvant therapy, itis eligible if there is an interval of at least 24 weeks before registration.
3. No symptomatic brain metastases, carcinomatous meningitis, or spinal metastasesrequiring radiotherapy or surgery
4. No prior history of an antiangiogenetic agent targeting VEGFR for thymic carcinoma
5. Not receiving radiotherapy within 14 days before registration Male participants
6. A male participant must agree to use contraception as detailed in Appendix 3 of thisprotocol during the treatment period and for at least 135 days after the last dose ofstudy treatment and refrain from donating sperm during this period. Female participants:
7. A female participant is eligible to participate if she is not pregnant (see Appendix 3), not breastfeeding, and at least one of the following conditions applies:
8. Not a woman of childbearing potential (WOCBP) as defined in Appendix 3 OR
9. A WOCBP who agrees to follow the contraceptive guidance in Appendix 3 during thetreatment period and for at least 120 days after the last dose of studytreatment.
10. The participant provides written informed consent for the trial
11. Have measurable disease based on RECIST 1.1. Lesions situated in a previouslyirradiated area are considered measurable if progression has been demonstrated in suchlesions
12. Meet the following criteria for Hepatitis B and C Patients with no history of HBV orHCV infection or who meet the following criteria 10.1 Hepatitis B positive subjectsParticipants who are HBsAg positive are eligible if they have received HBV antiviraltherapy for at least 4 weeks and have an undetectable HBV viral load prior toregistration. Participants should remain on anti-viral therapy throughout the study intervention andfollow local guidelines for HBV anti-viral therapy post-completion of the studyintervention. 10.2 Participants with a history of HCV infection Participants are eligible if HCVviral load is undetectable at screening. Participants must have completed curativeanti-viral therapy at least 4 weeks prior to registration.
13. Have provided archival tumor tissue sample or newly obtained core or excisional biopsyof a tumor lesion not previously irradiated. Formalin-fixed, paraffin-embedded (FFPE)tissue blocks are preferred to slides. Newly obtained biopsies are preferred toarchived tissue.
14. Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1.Evaluation of ECOG is to be performed within 14 days before registration.
15. Have adequate organ function as defined in the following table (Table 8). Specimensmust be collected within 14 days prior to registration.
16. Have a predicted life expectancy of >12 weeks

Exclusion Criteria:

1. Has diagnosed as thymomas
2. Has related immune-related complications such as myasthenia gravis, pure red cellaplasia, or hypogammaglobulinemia
3. Patients with ECG QT correction interval prolongation or history of such prolongation (patients with QTcF > 480 ms)
4. Has a LVEF below the institutional normal range, as determined by multigatedacquisition (MUGA) or echocardiogram (ECHO)
5. A WOCBP who has a positive urine pregnancy test within 72 hours prior to registration (see Appendix 3). If the urine test is positive or cannot be confirmed as negative, aserum pregnancy test will be required
6. Has urine protein ≥1 g/24 hours Note: Participants with proteinuria ≥2+ (≥100 mg/dL)on urine dipstick testing (urinalysis) will undergo 24-hour urine collection forquantitative assessment of proteinuria
7. Has had major surgery within 3 weeks prior to the first dose of study interventions
8. Has clinically significant cardiovascular disease within 12 months from the first doseof study intervention, including New York Heart Association Class III or IV congestiveheart failure, unstable angina, myocardial infarction, cerebral vascular accident, orcardiac arrhythmia associated with hemodynamic instability
9. Has any of the following a) to i):
10. History of interstitial pneumonia or evidence of interstitial lung disease
11. Uncontrollable autoimmune disease receiving chronic systemic steroid therapy (indosing exceeding 10 mg daily of prednisone equivalent) or any other form ofimmunosuppressive therapy
12. History or complications of hypertensive crisis or hypertensive encephalopathy
13. Surgery under general anesthesia within 28 days before registration
14. History of total gastrectomy
15. Complication of congenital bleeding predisposition or abnormal coagulation
16. Complication of Grade 3 or higher gastrointestinal or non-gastrointestinalfistula with CTCAE v5.0
17. History of Grade 3 or higher bleeding (site not specified) with CTCAE v5.0 within 28 days prior to registration
18. Blood pressure is not well controlled (with 2 or fewer antihypertensive drugs* 2,systolic blood pressure is 150 mmHg or less and diastolic blood pressure is 90mmHg or less) *Antihypertensive drugs are counted by the number of compounds
19. Has radiographic evidence of encasement or invasion of a major blood vessel, or ofintratumoral cavitation.
20. Gastrointestinal malabsorption or any other condition that might affect the absorptionof lenvatinib
21. Active hemoptysis (bright red blood of at least 0.5 teaspoons) within 3 weeks prior tothe first dose of the study drug
22. Has received prior radiotherapy within 14 days before registration. Participants musthave recovered from all radiation-related toxicities, not require corticosteroids, andnot have had radiation pneumonitis. A 1-week washout is permitted for palliativeradiation (≤ 2 weeks of radiotherapy) to non-CNS disease
23. Has received a live vaccine or live-attenuated vaccine within 30 days prior to thefirst dose of study drug. Administration of killed vaccines is allowed. ApprovedCOVID-19 vaccines (excluding live vaccines and/or live-attenuated vaccines) areallowed
24. Is currently participating in or has participated in a study of an investigationalagent or has used an investigational device within 4 weeks prior to the first dose ofstudy intervention Note: Participants who have entered the follow-up phase of aninvestigational study may participate as long as it has been 4 weeks after the lastdose of the previous investigational agent
25. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form ofimmunosuppressive therapy within 7 days prior to the first dose of the study drug
26. Has a known additional malignancy that is progressing or has required active treatmentwithin the past 3 years. Participants with basal cell carcinoma of the skin, squamouscell carcinoma of the skin, or carcinoma in situ (eg, breast carcinoma, cervicalcancer in situ) that have undergone potentially curative therapy are not excluded
27. Has known active CNS metastases and/or carcinomatous meningitis. Participants withpreviously treated brain metastases may participate provided they are radiologicallystable, i.e. without evidence of progression for at least 4 weeks by repeat imaging (note that the repeat imaging should be performed during study screening),clinicallystable and without the requirement of steroid treatment for at least 14 days prior tothe first dose of the study intervention
28. Has severe hypersensitivity (≥ Grade 3) to pembrolizumab and/or any of its excipients
29. Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with the use of disease-modifying agents, corticosteroids or immunosuppressivedrugs). Replacement therapy (e.g. thyroxine, insulin, or physiologic corticosteroidreplacement therapy for adrenal or pituitary insufficiency, etc.) is not considered aform of systemic treatment and is allowed
30. Has a history of (non-infectious) pneumonitis/interstitial lung disease that requiredsteroids or has current pneumonitis/interstitial lung disease
31. Has an active infection requiring systemic therapy
32. Has a known history of Human Immunodeficiency Virus (HIV) infection
33. Concurrent active Hepatitis B ( defined as HBsAg positive and detectable HBV DNA) andHepatitis C virus (defined as anti-HCV Ab positive and detectable HCV RNA) infection
34. Has a history or current evidence of any condition, therapy, or laboratory abnormalitythat might confound the results of the study, interfere with the participant'sparticipation for the full duration of the study, or is not in the best interest ofthe participant to participate, in the opinion of the treating investigator
35. Has known psychiatric or substance abuse disorders that would interfere withcooperation with the requirements of the trial
36. Is pregnant or breastfeeding or expecting to conceive within the projected duration ofthe study, starting with the screening visit through 120 days after the last dose oftrial treatment. Is expecting to father children within 135 days after the last doseof trial treatment
37. Has had an allogeneic tissue/solid organ transplant