Lenvatinib + Pembrolizumab + Radiation for Endometrial Cancer

Overseen By Matthew Schlumbrecht, MD, MPH

Age: 18+

Sex: Female

Trial Phase: Phase 1

Sponsor: Aaron Wolfson

Must not be taking: Steroids, Immunosuppressants, Antivirals, Biologics

Disqualifiers: CNS metastases, Uncontrolled HIV, Hepatitis, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Compensation: Varies

Number of Visits: Unknown

Duration: 10-12 weeks

18 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine if a set dose of pembrolizumab (an immunotherapy drug), a daily dose of lenvatinib (a targeted therapy drug), and a course of radiation therapy can be safely combined to treat endometrial cancer. The focus is on stopping cancer cells from multiplying and spreading. Participants will receive a combination of these treatments over approximately 10 to 12 weeks. Women with endometrial cancer that has recurred after surgery or cannot be surgically removed, and who have been advised to try radiation therapy, might be suitable candidates for this trial. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants a chance to contribute to groundbreaking research.

Do I need to stop my current medications to join the trial?

The trial protocol does not specify if you need to stop taking your current medications. However, you cannot participate if you are on systemic steroid therapy or any other form of immunosuppressive therapy within 21 days prior to the first dose of study treatment. It's best to discuss your specific medications with the trial team.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Previous studies have examined the use of lenvatinib and pembrolizumab together for cancer treatment. This combination can be effective but may cause side effects. For instance, lenvatinib has been linked to high blood pressure in about 42% of patients when combined with everolimus, with 13% experiencing very high blood pressure. However, not everyone will experience this side effect.

Research on pembrolizumab, often used for various cancers, has not revealed any new safety concerns in recent studies. It has been used alone and with other treatments and generally maintains a good safety record.

The treatment under study also includes a shorter course of radiation therapy called hypofractionated external beam radiation therapy. Other studies have used this type of radiation, and it is usually well-tolerated. However, like any radiation treatment, side effects can occur and vary from person to person.

This trial is in an early stage (Phase 1), focusing on testing safety and dosage. Limited data exist on the safety of this specific combination. Participants may have different reactions, and the study aims to gather more information on this. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of Lenvatinib, Pembrolizumab, and hypofractionated radiation therapy for endometrial cancer because it offers a multi-pronged approach that could enhance treatment effectiveness. Lenvatinib targets specific proteins to inhibit tumor growth, while Pembrolizumab leverages the immune system to attack cancer cells. The addition of hypofractionated radiation therapy is significant because it delivers higher doses of radiation over fewer sessions, potentially increasing precision and reducing side effects. This combination aims to improve outcomes by attacking the cancer from multiple angles, offering a promising alternative to standard treatments like surgery, chemotherapy, and conventional radiation.

What evidence suggests that this trial's treatments could be effective for endometrial cancer?

Research has shown that using lenvatinib and pembrolizumab together holds promise for treating advanced endometrial cancer. Studies have found that this combination can lead to better outcomes than traditional chemotherapy. Over five years, data showed a 16.7% survival rate, marking a significant improvement. In this trial, participants will receive a combination of lenvatinib, pembrolizumab, and hypofractionated external beam radiation therapy (EBRT). When combined with radiation therapy, patients have experienced better cancer control and symptom relief. These findings suggest that this treatment could effectively manage endometrial cancer. ^{6 7 8 9 10}

Who Is on the Research Team?

Aaron Wolfson, MD

Principal Investigator

University of Miami

Are You a Good Fit for This Trial?

This trial is for women aged 18 or older with recurrent or unresectable endometrial carcinoma that's not mismatch repair deficient. They must have a specific performance status, normal organ and marrow function, no recent investigational drug use, and agree to contraception if of childbearing potential. Exclusions include certain prior treatments, uncontrolled conditions like hypertension or infections (HIV/HBV/HCV), active CNS metastases, other progressing cancers, major surgery recovery, and immunosuppressive therapy within 21 days before the study.

Inclusion Criteria

My blood tests for organ and bone marrow function are normal.

I am a woman aged 18 or older.

My cancer is one of the specified types, confirmed by a biopsy.

Exclusion Criteria

I have another cancer that is getting worse or needs treatment.

I am scheduled for internal radiation therapy as part of my pelvic treatment.

I am still recovering from a major surgery.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive a combination of Lenvatinib, Pembrolizumab, and Hypofractionated Pelvic EBRT over approximately 10 to 12 weeks

10-12 weeks

Multiple visits for drug administration and radiation therapy

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 1 year

What Are the Treatments Tested in This Trial?

Interventions

• Hypofractionated External Beam Radiation Therapy
• Lenvatinib
• Pembrolizumab

Trial Overview The trial tests combining pembrolizumab (an immune checkpoint inhibitor) with lenvatinib (a targeted therapy) alongside a shortened course of pelvic radiation therapy in patients with endometrial cancer. The goal is to determine if this combination can prevent cancer cells from multiplying and spreading.

How Is the Trial Designed?

Group I: Lenvatinib, Pembrolizumab and Hypofractionated (Hypofx) External Beam Radiation Therapy (EBRT) Group Experimental Treatment 3 Interventions

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. 1. Lenvatinib - administered in a 3 plus 3 escalation/de-escalation design. Participants will receive 1 of 4 of the following dose levels: Dose level 1- 4 mg Dose level 2- 8 mg Dose level 3 (Starting dose) - 12 mg Dose level 4- 16 mg 2. Pembrolizumab- 200 mg IV will be administered on Day 1, 22 and 43 3. HypoFx whole pelvic EBRT begins on Day 22 and continues for a total of 16 fractions of radiation given at a dose of 2.5 Gy per fraction for a total dose of 40.0 Gy delivered to the pelvis. A pelvic boost HypoFx EBRT consisting of 7 fractions of radiation given at a dose of 2.5 Gy per fraction that will be delivered to site(s) of gross disease of at least 1.0 cm in size. An additional boost total dose of 17.5 Gy administered will be administered over a period of 1.5 to 2.0 weeks.

Lenvatinib is already approved in United States, European Union for the following indications:

Approved in United States as Lenvima for:

• Differentiated Thyroid Cancer
• Renal Cell Carcinoma
• Hepatocellular Carcinoma
• Endometrial Cancer

Approved in European Union as Lenvima for:

• Thyroid Cancer
• Renal Cell Carcinoma
• Hepatocellular Carcinoma
• Endometrial Cancer

Approved in European Union as Kisplyx for:

• Renal Cell Carcinoma

Who Is Running the Clinical Trial?

Aaron Wolfson

Lead Sponsor

Trials

1

Recruited

20+

Matthew Schlumbrecht

Lead Sponsor

Trials

1

Recruited

20+

Published Research Related to This Trial

The combination of lenvatinib and pembrolizumab is effective for treating advanced endometrial carcinoma, particularly in patients who have not responded to prior therapies, with manageable safety profiles similar to each drug used alone.

Common adverse reactions include hypothyroidism (51% incidence), fatigue, hypertension, and nausea, which typically occur within the first 10 weeks of treatment and can be effectively managed with dose adjustments and supportive care.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Characterization and Management of Adverse Reactions in Patients with Advanced Endometrial Carcinoma Treated with Lenvatinib Plus Pembrolizumab. Makker, V., Taylor, MH., Oaknin, A., et al.[2022]

The combination of lenvatinib and pembrolizumab significantly improved treatment outcomes for patients with advanced endometrial cancer compared to chemotherapy, regardless of tumor characteristics, based on data from Study-309/KEYNOTE-775.

Common adverse reactions included hypothyroidism, hypertension, and fatigue, with effective management strategies involving patient education, monitoring, and appropriate dose adjustments to minimize treatment interruptions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Characterization and Management of Adverse Reactions in Patients With Advanced Endometrial Cancer Receiving Lenvatinib Plus Pembrolizumab. Colombo, N., Lorusso, D., Monk, BJ., et al.[2023]

In a study of 108 patients with advanced endometrial carcinoma, the combination of lenvatinib and pembrolizumab resulted in a 38% objective response rate at 24 weeks, with particularly high efficacy (63.6%) in patients with microsatellite instability (MSI)-high tumors.

The treatment demonstrated a median duration of response of 21.2 months and a median overall survival of 16.7 months, while the combination therapy had a manageable safety profile, with 66.9% of patients experiencing grade 3 or 4 treatment-related adverse events.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Lenvatinib Plus Pembrolizumab in Patients With Advanced Endometrial Cancer. Makker, V., Taylor, MH., Aghajanian, C., et al.[2021]

In a study of 43 patients with recurrent endometrial cancer treated with lenvatinib and pembrolizumab, 84% experienced significant adverse events (AEs), with hypertension and weight loss being the most common.

Patients starting on a reduced dose of lenvatinib (10 mg or 14 mg) had significantly longer progression-free survival compared to those on the standard dose (20 mg), suggesting that dose optimization may improve treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adverse events and oncologic outcomes with combination lenvatinib and pembrolizumab for the treatment of recurrent endometrial cancer. Zammarrelli, WA., Ma, W., Espino, K., et al.[2023]

In a phase 3 trial involving 104 Japanese patients with advanced endometrial cancer, the combination of lenvatinib and pembrolizumab showed promising efficacy, with improved overall survival (OS) and progression-free survival (PFS) compared to treatment of physician's choice (TPC).

The safety profile was manageable, although 36.5% of patients in the lenvatinib plus pembrolizumab group experienced adverse events leading to treatment discontinuation, compared to only 7.8% in the TPC group.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Lenvatinib plus pembrolizumab in Japanese patients with endometrial cancer: Results from Study 309/KEYNOTE-775. Yonemori, K., Yunokawa, M., Ushijima, K., et al.[2022]

In a phase 1b study involving 6 Japanese patients with metastatic solid tumors, the combination of lenvatinib and pembrolizumab was well-tolerated, with no dose-limiting toxicities reported.

The treatment showed promising antitumor activity, with an objective response rate of 33.3%, particularly in patients with urothelial cancer, indicating potential efficacy for this combination therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A feasibility study of lenvatinib plus pembrolizumab in Japanese patients with advanced solid tumors. Kitano, S., Fujiwara, Y., Shimizu, T., et al.[2022]

The combination of lenvatinib and pembrolizumab shows significant clinical benefits for patients with endometrial carcinoma, with a safety profile consistent with each drug's individual use, primarily involving manageable side effects like hypertension and hypothyroidism.

Effective management of lenvatinib's common adverse events is crucial to maximize its efficacy, as most side effects can be prevented or mitigated through proactive monitoring and intervention during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Optimizing the use of lenvatinib in combination with pembrolizumab in patients with advanced endometrial carcinoma. Lorusso, D., Danesi, R., Locati, LD., et al.[2023]

In a phase 2 study involving 54 patients with advanced endometrial cancer, the combination of lenvatinib and pembrolizumab resulted in a 39.6% objective response rate at week 24, indicating significant anti-tumor activity.

The treatment was generally well-tolerated, with serious adverse events occurring in 30% of patients, including one treatment-related death; however, the safety profile was consistent with previous studies of the individual drugs, except for a higher incidence of hypothyroidism.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Lenvatinib plus pembrolizumab in patients with advanced endometrial cancer: an interim analysis of a multicentre, open-label, single-arm, phase 2 trial. Makker, V., Rasco, D., Vogelzang, NJ., et al.[2020]

The combination of pembrolizumab and lenvatinib has shown promising efficacy in treating advanced endometrial cancer, with previous trials indicating improved objective response rates and survival outcomes compared to standard chemotherapy.

This ongoing phase 3 trial aims to determine if pembrolizumab plus lenvatinib is superior to the chemotherapy regimen of paclitaxel plus carboplatin in newly diagnosed patients, with a target enrollment of about 875 participants and results expected in 2022.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase 3, randomized, open-label study of pembrolizumab plus lenvatinib versus chemotherapy for first-line treatment of advanced or recurrent endometrial cancer: ENGOT-en9/LEAP-001. Marth, C., Tarnawski, R., Tyulyandina, A., et al.[2022]

In a study of 70 patients with recurrent endometrial cancer, a lower starting dose of lenvatinib (14 mg daily) combined with pembrolizumab was found to be safe and effective, showing similar response rates compared to the recommended dose (20 mg).

Patients with carcinosarcoma histology experienced notable clinical benefits, with a response rate of 25% and a clinical benefit rate of 58.3%, indicating that this treatment combination may be particularly effective for this subtype of cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Toxicity and efficacy of the combination of pembrolizumab with recommended or reduced starting doses of lenvatinib for treatment of recurrent endometrial cancer. How, JA., Patel, S., Fellman, B., et al.[2022]

Citations

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Phase 1 Clinical Trial of Lenvatinib, Pembrolizumab and ... 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, ...

2. eisai.com eisai.com/news/2025/news202573.html

LENVIMA® (lenvatinib) Plus KEYTRUDA® ... “These five-year data highlight the durable survival benefit of LENVIMA plus KEYTRUDA in patients with advanced endometrial carcinoma who have ...

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KEYTRUDA® (pembrolizumab) Plus LENVIMA® ... At five years, KEYTRUDA plus LENVIMA showed a 16.7% overall survival (OS) rate for these patients with mismatch repair proficient (pMMR) advanced ...

4. withpower.com withpower.com/trial/phase-1-carcinoma-11-2022-740c3

Lenvatinib + Pembrolizumab + Radiation for Endometrial ... The combination of lenvatinib and pembrolizumab significantly improved treatment outcomes for patients with advanced endometrial cancer compared to chemotherapy ...

5. ncbi.nlm.nih.gov ncbi.nlm.nih.gov/books/NBK603321/

Pembrolizumab (Keytruda) in Combination With Lenvatinib ... Key outcomes identified by the patient advocacy groups as important to patients with endometrial cancer included improved symptoms, cancer control, fewer ...

6. clinicaltrials.gov clinicaltrials.gov/ct2/show/NCT06538337

Study Details | NCT06538337 | Hypofractionated External ... After surgery to remove the main endometrial and/or cervical tumor, most women receive radiation therapy. This study uses hypo-fractionated radiation ...

7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11467485/

Evidence-based clinical recommendations for ... Furthermore, hypofractionated RT is potentially more beneficial for tumors with a low α/β ratio compared with conventional fractionation RT.

8. e-roj.org e-roj.org/include/download.php?filedata=1598%7Croj-2023-01046.pdf

exploring efficacy and safety-Part 3. Genitourinary a What are the Indications, Efficacy, and Toxicity of Hypofractionated. Postoperative Radiotherapy in. Gynecological Cancer Patients?

9. ascopubs.org ascopubs.org/doi/10.1200/JCO.2023.41.16_suppl.TPS5631

RT-PACE: Phase I/II study of adjuvant whole pelvic ... Background: Whole pelvic radiation therapy (WPRT) improves locoregional control in women with high-intermediate and high-risk endometrial ...

10. ejgo.org ejgo.org/Synapse/Data/PDFData/1114JGO/jgo-37-e4.pdf

Postoperative conventional versus A recent study on ultra- hypofractionation, which administered 30 Gy in 5 fractions to patients with endometrial cancer using stereotactic body ...