Phase 1 Clinical Trial of Lenvatinib, Pembrolizumab and Hypofractionated Pelvic Radiation Therapy for PMMR Recurrent/Unresectable Endometrial Carcinoma

Inclusion Criteria:

1. Biopsy-proven recurrent pMMR EC following surgery alone or de novo unresectable pMMREC for whom External beam radiation therapy (EBRT) has been determined as anappropriate therapeutic approach. Eligible tumor histologies include the following:endometrioid adenocarcinoma, adenocarcinoma with squamous differentiation, mucinous,mixed carcinoma, undifferentiated carcinoma, clear cell adenocarcinoma, and serousadenocarcinoma histologies as determined by tissue from an archival sample or newlyobtained core or excisional biopsy of a tumor lesion. For patients with recurrentdisease greater than six months (>6 months), a fresh biopsy must be obtained.

2. Measurable disease of at least 1.0 cm in size defined by RECIST 1.1 on imagingstudies with at least one (1) site located in the pelvis and/or vagina without anyfoci of extra-pelvic disease (including the para-aortic region or inguinal-femorallymph nodes).13

3. Patients must have Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 (Karnofsky score ≥50). See APPENDIX A.

4. Patients must have pMMR tumor subtype(s).

5. Patients must have normal organ and marrow function as defined below: System Laboratory Value Hematological Absolute neutrophil count (ANC)

• 1,500 cells/mm³ Platelets

• 100,000 cells/mm³ Hemoglobin

• 9.0 g/dL Renal Serum creatinine or Measured or calculated a creatinineclearance glomerular filtration rate (GFR) can also be used in place ofcreatinine or creatinine clearance (CrCl) ≤ 1.5 x upper limit of normal (ULN) or CrCl ≥ 40 mL/min Hepatic Serum totalbilirubin <1.0 ULN Aspartate aminotransferase (AST) serum glutamic-oxaloacetictransaminase (SGOT) and alanine transaminase (ALT) serum glutamic-pyruvictransaminase (SGPT) Aminotransferase (AST and ALT) ≤ 2.5 x ULN or 5 X ULN forpatients with liver metastases Albumin

• 2.5 mg/dL a CrCl should be calculated per institutional standard.

6. Female participants of childbearing potential (those who have not been surgicallysterilized or have not been without menses for >1 year) should be willing to use 2methods of birth control at the same time or be surgically sterile or abstain fromheterosexual activity for the course of the study and for at least 120 days afterthe last study dose. For more information, see Section 4.8.

7. Ability to understand and the willingness to sign a written informed consentdocument.

8. Women age ≥18 years old.

Exclusion Criteria:

1. Patients who are currently in or have participated in a study of an investigationalagent or used an investigational device within 4 weeks of the first dose of studytreatment.

2. Patients with Mismatch repair deficient (dMMR) and endometrial carcinomas.

3. Patients with dMMR and uterine carcinosarcomas.

4. Patients with known active central nervous system (CNS) metastases and/orcarcinomatous meningitis. EXCEPTION: Patients with previously treated brain metastases, including receivingprior brain irradiation, may participate provided they are stable (without evidenceof progression by imaging for at least 3 months prior to the first dose of studytreatment and any neurologic symptoms have returned to baseline), have no evidenceof new or enlarging brain metastases, are not using steroids for at least 28 daysprior to study treatment, and have not received prior cranial irradiation for atleast 3 months prior to study treatment.

5. Patients with a known additional malignancy that is progressing or requires activetreatment. EXCEPTIONS include basal cell carcinoma of the skin, squamous cell carcinoma of theskin, or in situ cervical cancer that has undergone potentially curative therapy.

6. Prior treatment with lenvatinib, anti-programmed cell death-1(PD)-1, anti-PD-L1, orany other antibody or drug specifically targeting T-cell co-stimulation orcheckpoint pathways.

7. Patients who are planned to receive vaginal brachytherapy as their pelvic boostcourse of radiation as determined by their treating physician(s).

8. No prior radiation therapy to the vagina, pelvis, or abdomen will be allowed.

9. Uncontrolled intercurrent illness including, but not limited to, symptomaticcongestive heart failure, unstable angina pectoris, cardiac arrhythmia, or otherserious medical condition or social situations that in the judgement of theInvestigator(s) would interfere or limit compliance with studyrequirements/treatments.

10. Receiving systemic steroid therapy or any other form of immunosuppressive therapywithin 21 days prior to the first dose of study treatment. Note: Patients with active autoimmune disease that has required systemic treatmentin the past 2 years (i.e., with use of disease-modifying agents, corticosteroids orimmunosuppressive drugs) and/or requiring replacement therapy (i.e., thyroxine,insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitaryinsufficiency, etc.) is not considered a form of systemic treatment.

11. Evidence of interstitial lung disease or active, non-infectious pneumonitis.

12. Evidence of uncontrolled hypertension as documented in the patient's medical record.

13. Known psychiatric illness/condition or substance abuse disorders that in thejudgement of the Investigator(s) would interfere with cooperation with requirementsof the study.

14. Is pregnant or breastfeeding or expecting to conceive within the projected durationof the study, starting with the pre-screening or screening visit through 120 daysafter the last dose of study treatment.

15. Patients with uncontrolled human immunodeficiency virus (HIV) infection, which isdefined as follows:

16. Antiviral therapy treatment for <4 weeks AND

17. Have an HIV viral load ≥400 copies/mL prior to enrollment.

18. Patients with uncontrolled hepatitis B virus (HBV) infection or who are chroniccarriers of hepatitis B infection, which is defined as:

19. Hepatitis B surface antigen reactive (HbsAg-positive), undetectable or low HBVDNA, and with normal ALT levels who are not on HBV therapy

20. Individuals who have serologic evidence of a resolved prior HBV infection (ie,HBSAg-negative and anti-core hepatitis B antibody positive (anti-Hepatitis Bcore -positive)

21. Patients with active, untreated hepatitis C virus (HCV) infection or who have notcompleted their HCV antiviral regimen. Patients with a history of HCV infection mayparticipate in this study if their HCV ribonucleic acid (RNA) level is below thelimit of quantification.

22. Received live vaccine within 30 days prior to the first dose of study treatment.

23. Patient has active Mycobacterium tuberculosis infection (tuberculosis or TB).

24. A QT interval corrected for heart rate using Bazett's formula (QTcB) ≥ 480msec.

25. Patient receiving concurrent additional biologic therapy.

26. Patients with impaired decision-making capacity.

27. Patients who have not recovered from major surgery.