Phase Ib/II Trial of Combining Pembrolizumab and Lenvatinib With SBRT for HCC Patients With Portal Vein Thrombosis.

Exclusion Criteria

• •1. A WOCBP who has a positive urine pregnancy test within 72 hours prior to \[allocation\]. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.
• •2. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti PD L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (eg, CTLA-4, OX 40, CD137).
• •3. Has received prior systemic anti-HCC therapy including investigational agents or other local therapy within 4 weeks prior to \[allocation\].
• •4. Has received prior radiotherapy to non-liver sites within 2 weeks of start of study intervention. Participants must have recovered from all radiation-related toxicities, not require corticosteroids, and not have had radiation pneumonitis. A 1-week washout is permitted for palliative radiation (≤2 weeks of radiotherapy) to non-CNS disease.
• •5. Has received a live vaccine within 30 days prior to the first dose of study drug. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette-Guérin (BCG), and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (eg, FluMist®) are live attenuated vaccines and are not allowed.
• •6. 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 of immunosuppressive or modulation therapy within 7 days prior to the first dose of study drug.
• •7. Has a known additional malignancy that is progressing or has required active treatment within the past 5 years. Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the skin or carcinoma in situ (eg, breast carcinoma, cervical cancer in situ) that have undergone potentially curative therapy are not excluded.
• •8. Has known active CNS metastases and/or carcinomatous meningitis. Participants with previously treated brain metastases may participate provided they are radiologically stable, 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), clinically stable and without requirement of steroid treatment for at least 14 days prior to first dose of study intervention.
• •9. Has severe hypersensitivity (≥Grade 3) to pembrolizumab/Lenvatinib and/or any of their excipients.
• •10. Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (eg., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment and is allowed.
• •11. Has a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis.
• •12. Has an active infection requiring systemic therapy.
• •13. Has a known history of Human Immunodeficiency Virus (HIV) infection.
• •14. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the participant's participation for the full duration of the study, or is not in the best interest of the participant to participate, in the opinion of the treating investigator.
• •15. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
• •16. Is pregnant or breastfeeding or expecting to conceive or father children within the projected duration of the study, starting with the screening visit through 120 days after the last dose of trial treatment.
• •17. Has had an allogenic tissue/solid organ transplant.
• •18. Child-Pugh class B or C cirrhosis of liver.
• •19. Patients with a history of selective internal radiation therapy (eg, microsphere radioembolization) or who have received radiotherapy to the abdominal area prior to the initiation of study treatment.
• •20. Patients who have an inadequate hepatic reserve, as judged by the investigator; ie, normal liver tissue volume \<700 mL.
• •21. Patients who fail to follow the radiation dose constraint of any critical organ.
• •22. Has a preexisting Grade ≥3 gastrointestinal or non-gastrointestinal fistula.
• •23. Has clinically significant hemoptysis from any source or tumor bleeding within 2 weeks prior to the first dose of study intervention.
• •24. Has significant cardiovascular impairment within 12 months prior to the first dose of study intervention such as history of congestive heart failure greater than NYHA Class II, unstable angina, myocardial infarction or cerebrovascular accident stroke, or cardiac arrhythmia associated with hemodynamic instability.
• •25. Has had major surgery to the liver within 4 weeks prior to the first dose of study intervention.
• •Note: f participant underwent major surgery, they must have adequately recovered from the toxicity and/or complications from the intervention prior to starting study intervention.
• •26. Has had a minor surgery (ie, simple excision) within 7 days prior to the first dose of study intervention (Cycle 1 Day 1).
• •27. Has serious nonhealing wound, ulcer, or bone fracture.
• •28. Participants with proteinuria \>1+ on urine dipstick testing will undergo 24-hour urine collection for quantitative assessment of proteinuria. Participants with urine protein ≥1 g/24 hours will be ineligible.
• •29. Has prolongation of corrected QT (QTc) interval to \>480 ms (corrected by Fridericia Formula) or is taking drugs known to prolong the QT interval, including Class Ia and III antiarrhythmics (Quinidine, Procainamide, Disopyramide, Amiodarone, Sotalol, Ibutilide, Dofetilide \& Dronedarone).
• •30. Has LVEF below the institutional normal range as determined by MUGA or echocardiogram (ECHO).
• •31. Has dual active HBV infection (HbsAg positive and /or detectable HBV DNA) and HCV infection (anti-HCV Ab positive and detectable HCV RNA) at study entry.
• •32. Uncontrolled blood pressure \> 140/90 mmHg in spite of an optimal regimen of antihypertensive medication.