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

NCT05603910 | Recruiting Phase 1 DMC FDA Drug FDA Device

• 1 other identifier: 20220813
• Study Type: interventional
• Target: 18
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Unresectable Endometrial Carcinoma; Recurrent Endometrial Carcinoma

Outcome Measures

Primary Outcomes (3)

• 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.

  Up to 12 weeks

• 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.

  Up to 12 weeks

• 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.

  Up to 12 weeks

Secondary Outcomes (2)

• Overall Response Rate (ORR)

  Up to 12 weeks

• Number of Participants Experiencing Non-Treatment-Related Adverse Events

  Up to 12 weeks

Study Arms (1)

Lenvatinib, Pembrolizumab and Hypofractionated (HypoFx) External Beam Radiation Therapy (EBRT) Group

EXPERIMENTAL

Participants in this group will receive a combination treatment of Lenvatinib, Pembrolizumab, and HypoFx Pelvic EBRT over a period of approximately 10 to 12 weeks: * Lenvatinib self-administered daily starting on Day 1 of the study treatment period and continuing until the last dose of whole pelvic HypoFx EBRT is received. * Pembrolizumab administered on Day 1, 22 and 43. * Whole pelvic HypoFx EBRT beginning on Day 22. After receiving whole pelvic Hypo EBRT, participants will receive a boost course of radiation therapy using one of the following techniques: * Pelvic boost HypoFx EBRT to be administered over a period of 1.5 to 2 weeks; OR * Vaginal HDR brachytherapy boost to be administered over a period of 2 to 3 weeks, depending on the lesion thickness; OR * Both pelvic boost HypoFx EBRT pelvic plus vaginal HDR brachytherapy boost. The overall radiation therapy treatment time for whole pelvic HypoFx RT and radiation boost treatments is approximately 7 weeks.

Drug: Lenvatinib; Drug: Pembrolizumab; Radiation: Hypofractionated External Beam Radiation Therapy; Radiation: High-Dose Rate (HDR) Brachytherapy

Interventions

Pembrolizumab DRUG

Pembrolizumab 200 mg will be administered intravenously (IV) once on Days 1, 22 and 43.

Also known as: Keytruda

Lenvatinib, Pembrolizumab and Hypofractionated (HypoFx) External Beam Radiation Therapy (EBRT) Group

Lenvatinib DRUG

Lenvatinib 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

Also known as: Lenvima

Lenvatinib, Pembrolizumab and Hypofractionated (HypoFx) External Beam Radiation Therapy (EBRT) Group

Hypofractionated External Beam Radiation Therapy RADIATION

Whole 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.

Lenvatinib, Pembrolizumab and Hypofractionated (HypoFx) External Beam Radiation Therapy (EBRT) Group

High-Dose Rate (HDR) Brachytherapy RADIATION

Vaginal high-dose rate (HDR) brachytherapy administered per standard of care (SoC) techniques.

Lenvatinib, Pembrolizumab and Hypofractionated (HypoFx) External Beam Radiation Therapy (EBRT) Group

Eligibility Criteria

• Age: 18 Years+
• Sex: female
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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 must have normal organ and marrow function as defined below:
• Absolute neutrophil count (ANC) ≥1,500 cells/mm³
• Platelets ≥100,000 cells/mm³
• Hemoglobin ≥9.0 g/dL
• Serum creatinine ≤ 1.5 x upper limit of normal (ULN) or creatine clearance (CrCl) ≥ 40 mL/min or Measured or calculated a creatinine clearance glomerular filtration rate (GFR) can also be used in place of creatinine
• Serum total bilirubin \<1.0 ULN
• Aspartate aminotransferase (AST) serum glutamic-oxaloacetic transaminase (SGOT) and alanine transaminase (ALT) serum glutamic-pyruvic transaminase (SGPT) Aminotransferase (AST and ALT) ≤ 2.5 x ULN or 5 X ULN for patients with liver metastases
• Albumin ≥2.5 mg/dL CrCl should be calculated per institutional standard.
• Female participants of childbearing potential (those who have not been surgically sterilized or have not been without menses for \>1 year) should be willing to use 2 methods of birth control at the same time or be surgically sterile or abstain from heterosexual activity for the course of the study and for at least 120 days after the last study dose.
• Ability to understand and the willingness to sign a written informed consent document.
• Prior treatment with lenvatinib, anti-programmed cell death protein 1 (anti-PD-1), anti-Programmed death-ligand 1 (anti-PD-L1) , or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways is allowed provided that the participant has not received any of these treatments within three weeks (+/- 3 days) of the first dose of study treatment.

You may not qualify if:

• 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.
• EXCEPTION: Patients with previously treated brain metastases, including receiving prior brain irradiation, may participate provided they are stable (without evidence of progression by imaging for at least 3 months prior to the first dose of study treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, are not using steroids for at least 28 days prior to study treatment, and have not received prior cranial irradiation for at least 3 months prior to study treatment.
• Patients with a known additional malignancy that is progressing or requires active treatment. EXCEPTIONS include basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or in situ cervical cancer that has undergone potentially curative therapy.
• No prior external beam radiation therapy to the vagina, pelvis, and/or abdomen will be allowed.
• Uncontrolled intercurrent illness including, but not limited to, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or other serious medical condition or social situations that in the judgement of the Investigator(s) would interfere or limit compliance with study requirements/treatments.
• Receiving systemic steroid therapy or any other form of immunosuppressive therapy within 21 days prior to the first dose of study treatment. Note: Patients with 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) and/or requiring replacement therapy (i.e., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.
• Evidence of interstitial lung disease or active, non-infectious pneumonitis.
• Evidence of uncontrolled hypertension as documented in the patient's medical record.
• Known psychiatric illness/condition or substance abuse disorders that in the judgement of the Investigator(s) would interfere with cooperation with requirements of the study.
• Is pregnant or breastfeeding or expecting to conceive within the projected duration of the study, starting with the pre-screening or screening visit through 120 days after the last dose of study treatment.
• Patients with uncontrolled human immunodeficiency virus (HIV) infection, which is defined as follows:
• Antiviral therapy treatment for \<4 weeks AND

Sponsors & Collaborators

• Aaron Wolfson: lead

Study Sites (1)

University of Miami

Miami, Florida, 33136, United States

RECRUITING

MeSH Terms

Conditions

Endometrial Neoplasms

Interventions

lenvatinib; pembrolizumab; Brachytherapy

Condition Hierarchy (Ancestors)

Uterine Neoplasms; Genital Neoplasms, Female; Urogenital Neoplasms; Neoplasms by Site; Neoplasms; Uterine Diseases; Genital Diseases, Female; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Genital Diseases

Intervention Hierarchy (Ancestors)

Radiotherapy; Therapeutics

Study Officials

• Aaron H Wolfson, MD, FACR

  University of Miami

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Aaron H Wolfson, MD, FACR

CONTACT

954-698-3680; awolfson@med.miami.edu

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Professor of Radiation Oncology

Study Record Dates

• First Submitted: October 28, 2022
• First Posted: November 3, 2022
• Study Start: April 15, 2023
• Primary Completion (Estimated): April 15, 2029
• Study Completion (Estimated): April 15, 2034
• Last Updated: August 3, 2026

Record last verified: 2026-07

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)