The purpose of this research study is to see if it is feasible to combine a fixed dose of pembrolizumab and a daily dose of oral lenvatinib, along with daily treatments of an abbreviated course of pelvic external beam radiation therapy, to support cancer cells in multiplying and spreading to other body sites.
Biopsy-proven recurrent pMMR EC following surgery alone or de novo unresectable pMMR EC for whom EBRT has been determined as an appropriate therapeutic approach. Eligible tumor histologies include the following: endometrioid adenocarcinoma, adenocarcinoma with squamous differentiation, mucinous, mixed carcinoma, undifferentiated carcinoma, clear cell adenocarcinoma, serous adenocarcinoma, and uterine carcinosarcoma histologies as determined by tissue from an archival sample or newly obtained core or excisional biopsy of a tumor lesion. For patients with recurrent disease greater than 12 months (>12 months), a fresh biopsy must be obtained.
Measurable disease of at least 1.0 cm in size defined by RECIST 1.1 on imaging studies with at least one (1) site located in the pelvis and/or vagina without any foci of extra-pelvic disease (including the para-aortic region or inguinal-femoral lymph nodes).
Patients must have Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 (Karnofsky score ≥50).
Patients must have pMMR tumor subtype(s).
Patients who are currently in or have participated in a study of an investigational agent or used an investigational device within 4 weeks of the first dose of study treatment.
Patients with Mismatch repair deficient (dMMR) and endometrial carcinomas.
Patients with dMMR and uterine carcinosarcomas.
Patients with known active central nervous system (CNS) metastases and/or carcinomatous meningitis.
Single group
Lenvatinib
DrugLenvatinib will be self-administered orally (PO) by participants in a 3+3 escalation/de-escalation design. Participants will receive one of the following four dose levels: * Dose level 1: 4 mg * Dose level 2: 8 mg * Dose level 3: 12 mg (Starting dose) * Dose level 4: 16 mg
Pembrolizumab
DrugPembrolizumab 200 mg will be administered intravenously (IV) once on Days 1, 22 and 43.
Hypofractionated External Beam Radiation Therapy
RadiationWhole pelvic HypoFx EBRT consisting of 16 fractions of radiation given at a dose of 2.5 Gy per fraction for a total dose of 40.0 Gy. A pelvic boost HypoFx EBRT consisting of 7 fractions of radiation given at a dose of 2.5 Gy per fraction for a total dose of 17.5 Gy, delivered to site(s) of gross disease of at least 1.0 cm in size.
High-Dose Rate (HDR) Brachytherapy
RadiationVaginal high-dose rate (HDR) brachytherapy administered per standard of care (SoC) techniques.
Recommended Phase 2 Dose (RP2D) of Lenvatinib
The RP2D will be the highest dose of Lenvatinib that in combination with Pembrolizumab and Hypofractionated (HypoFx) pelvic External Beam Radiotherapy (EBRT) yields less than 2 Dose Limiting Toxicities (DLTs) in 6 patients.
Number of Participants Experiencing Treatment-Related Toxicity: Dose-Limiting Toxicities (DLTs)
The number of participants experiencing treatment-related DLTs will be reported. DLTs will be assessed by the treating physician using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0.
Number of Participants Experiencing Treatment-Related Toxicity: Adverse Events (AEs)
The number of participants experiencing treatment-related adverse events (AEs) will be reported. AEs will be assessed by the treating physician using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0.
Overall Response Rate (ORR)
ORR is defined as the number of participants achieving a Complete Response (CR) or Partial Response (PR) to study therapy according to Response Evaluation Criteria in Solid Tumors (RECIST v1.1).
Number of Participants Experiencing Non-Treatment-Related Adverse Events
The number of participants experiencing non-treatment-related adverse events (AEs) will reported. AEs will be assessed by the treating physician using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0.
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Aaron Wolfson
Lead sponsor
University of Miami
Sponsor institution
