Lenvatinib + Pembrolizumab for Sarcoma

Recruiting at 6 trial locations

Overseen By Sujana Movva, MD

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Memorial Sloan Kettering Cancer Center

Must not be taking: Lenvatinib, Pazopanib, PD-1/PD-L1

Disqualifiers: Brain metastases, Hypertension, Autoimmune, others

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

Prior Safety Data This treatment has passed at least one previous human trial

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

Compensation: Varies

Number of Visits: Unknown

Duration: 2 years

52 Participants Needed

Trial Summary

What is the purpose of this trial?

The purpose of this study is to find out whether combining the study drugs, lenvatinib and pembrolizumab, is a safe and effective treatment for metastatic soft tissue sarcomas that cannot be removed with surgery.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, you cannot have any other anti-cancer therapy during the trial, and certain medications like therapeutic anticoagulation with unstable Vitamin-K antagonists are not allowed. It's best to discuss your specific medications with the trial team.

What data supports the effectiveness of the drug combination Lenvatinib and Pembrolizumab for treating sarcoma?

Research shows that the combination of Lenvatinib and Pembrolizumab has demonstrated strong antitumor activity and durable responses in various solid tumors, including advanced renal cell carcinoma and endometrial cancer, suggesting potential effectiveness for other cancers like sarcoma. ^{1 2 3 4 5}

Is the combination of Lenvatinib and Pembrolizumab generally safe for humans?

The combination of Lenvatinib and Pembrolizumab has been studied in various cancers, showing a manageable safety profile. Common side effects include high blood pressure, low thyroid function, diarrhea, nausea, vomiting, loss of appetite, fatigue, and weight loss. ^{1 3 4 6 7}

How is the drug combination of lenvatinib and pembrolizumab unique for treating sarcoma?

The combination of lenvatinib and pembrolizumab is unique because it targets both tumor growth and immune evasion by blocking VEGF (a protein that helps tumors grow blood vessels) and PD-1 (a protein that prevents the immune system from attacking cancer cells), potentially offering a new option for solid tumors like sarcoma that have limited treatments. ^{3 4 5 8 9}

Research Team

Sujana Movva, MD

Principal Investigator

Memorial Sloan Kettering Cancer Center

Eligibility Criteria

Adults with advanced soft tissue sarcoma that can't be surgically removed, who've had 1-3 prior systemic therapies (but not specific drugs like lenvatinib or PD-1/PD-L1 inhibitors), and are able to swallow pills. They must have good organ function, no untreated brain metastases, no recent serious bleeding or infections, and agree to effective contraception.

Inclusion Criteria

Presence of measurable disease per RECIST v1.1

I have had 1 to 3 treatments for my condition.

Availability of archival tissue for correlative studies; either a paraffin block or at least 20 unstained slides are acceptable

Exclusion Criteria

I have an immune system disorder or am on medication that weakens my immune system.

I am currently on dialysis for kidney failure.

I have had or currently have pneumonitis.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Run-in

Participants receive lenvatinib 20 mg orally daily for 2 weeks

2 weeks

Treatment

Participants receive pembrolizumab 200 mg intravenously every 3 weeks, with tumor assessments every 9 weeks for the first 27 weeks, then every 12 weeks

2 years

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Reinitiation (optional)

Participants who progress after completing 2 years of treatment or achieving CR may reinitiate therapy for an additional 1 year

1 year

Treatment Details

Interventions

• Lenvatinib
• Pembrolizumab

Trial Overview The trial is testing the combination of two drugs: Lenvatinib and Pembrolizumab for treating metastatic soft tissue sarcomas. The goal is to see if this drug duo is safe and works better together than when used separately.

Participant Groups

Group I: Vascular sarcomas (including angiosarcoma and epithelioid hemangioendothelioma) Experimental Treatment 2 Interventions

Patients enrolled in the study will be treated initially with a 2 week run-in of lenvatinib 20 mg orally daily. Subsequently, they will start pembrolizumab 200 mg intravenously every 3 weeks (21-day cycles). Treatment will continue until progression or other indications for study withdrawal. Otherwise, treatment will be discontinued after a maximum of 35 cycles of pembrolizumab (approximately 2 years) or after achieving CR. RECIST v1.1 tumor assessments will be made at baseline (CT or MRI) and approximately every 3 cycles (or every 9 weeks +/- 1 week) for the first 9 cycles (27 weeks), then every 4 cycles (or every 12 weeks +/- 1week). Patients who progress after having discontinued therapy after completing 2 years of treatment or after achieving confirmed CR may be eligible to reinitiate therapy for an additional 1 year (approximately 17 cycles).

Group II: Other soft tissue sarcomas (including synovial sarcoma and malignant peripheral nerve sheath tumor Experimental Treatment 2 Interventions

Patients enrolled in the study will be treated initially with a 2 week run-in of lenvatinib 20 mg orally daily. Subsequently, they will start pembrolizumab 200 mg intravenously every 3 weeks (21-day cycles). Treatment will continue until progression or other indications for study withdrawal. Otherwise, treatment will be discontinued after a maximum of 35 cycles of pembrolizumab (approximately 2 years) or after achieving CR. RECIST v1.1 tumor assessments will be made at baseline (CT or MRI) and approximately every 3 cycles (or every 9 weeks +/- 1 week) for the first 9 cycles (27 weeks), then every 4 cycles (or every 12 weeks +/- 1week). Patients who progress after having discontinued therapy after completing 2 years of treatment or after achieving confirmed CR may be eligible to reinitiate therapy for an additional 1 year (approximately 17 cycles).

Group III: Leiomyosarcoma Experimental Treatment 2 Interventions

Patients enrolled in the study will be treated initially with a 2 week run-in of lenvatinib 20 mg orally daily. Subsequently, they will start pembrolizumab 200 mg intravenously every 3 weeks (21-day cycles). Treatment will continue until progression or other indications for study withdrawal Otherwise, treatment will be discontinued after a maximum of 35 cycles of pembrolizumab (approximately 2 years) or after achieving CR. RECIST v1.1 tumor assessments will be made at baseline (CT or MRI) and approximately every 3 cycles (or every 9 weeks +/- 1 week) for the first 9 cycles (27 weeks), then every 4 cycles (or every 12 weeks +/- 1week). Patients who progress after having discontinued therapy after completing 2 years of treatment or after achieving confirmed CR may be eligible to reinitiate therapy for an additional 1 year (approximately 17 cycles).

Group IV: High grade undifferentiated pleomorphic sarcoma Experimental Treatment 2 Interventions

Patients enrolled in the study will be treated initially with a 2 week run-in of lenvatinib 20 mg orally daily. Subsequently, they will start pembrolizumab 200 mg intravenously every 3 weeks (21-day cycles). Treatment will continue until progression or other indications for study withdrawal . Otherwise, treatment will be discontinued after a maximum of 35 cycles of pembrolizumab (approximately 2 years) or after achieving CR. RECIST v1.1 tumor assessments will be made at baseline (CT or MRI) and approximately every 3 cycles (or every 9 weeks +/- 1 week) for the first 9 cycles (27 weeks), then every 4 cycles (or every 12 weeks +/- 1week). Patients who progress after having discontinued therapy after completing 2 years of treatment or after achieving confirmed CR may be eligible to reinitiate therapy for an additional 1 year (approximately 17 cycles).

Group V: Bone sarcomas (including osteosarcoma and chondrosarcoma) Experimental Treatment 2 Interventions

Patients enrolled in the study will be treated initially with a 2 week run-in of lenvatinib 20 mg orally daily. Subsequently, they will start pembrolizumab 200 mg intravenously every 3 weeks (21-day cycles). Treatment will continue until progression or other indications for study withdrawal. Otherwise, treatment will be discontinued after a maximum of 35 cycles of pembrolizumab (approximately 2 years) or after achieving CR. RECIST v1.1 tumor assessments will be made at baseline (CT or MRI) and approximately every 3 cycles (or every 9 weeks +/- 1 week) for the first 9 cycles (27 weeks), then every 4 cycles (or every 12 weeks +/- 1week). Patients who progress after having discontinued therapy after completing 2 years of treatment or after achieving confirmed CR may be eligible to reinitiate therapy for an additional 1 year (approximately 17 cycles).

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?

Memorial Sloan Kettering Cancer Center

Lead Sponsor

Trials

1,998

Recruited

602,000+

Merck Sharp & Dohme LLC

Industry Sponsor

Trials

4,096

Recruited

5,232,000+

Chirfi Guindo

Merck Sharp & Dohme LLC

Chief Marketing Officer since 2022

Degree in Engineering from Ecole Centrale de Paris, MBA from New York University Stern School of Business

Robert M. Davis

Merck Sharp & Dohme LLC

Chief Executive Officer since 2021

JD from Northwestern University Pritzker School of Law, MBA from Northwestern University Kellogg Graduate School of Management, Bachelor's in Finance from Miami University

Parker Institute for Cancer Immunotherapy

Collaborator

Trials

12

Recruited

460+

Findings from Research

In the CLEAR study involving 352 patients, the combination of lenvatinib and pembrolizumab showed a manageable safety profile, with common adverse reactions including fatigue (63.1%), diarrhea (61.9%), and hypertension (56.3%).

Most adverse reactions occurred within approximately 5 months of starting treatment, and effective management strategies such as monitoring and dose modifications were identified to ensure patient safety and support ongoing treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Characterization and Management of Adverse Reactions From the CLEAR Study in Advanced Renal Cell Carcinoma Treated With Lenvatinib Plus Pembrolizumab. Motzer, R., George, S., Merchan, JR., et al.[2023]

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 7 women with advanced or recurrent uterine carcinosarcoma (UCS) treated with pembrolizumab and lenvatinib, the combination therapy showed limited efficacy, with no observed partial or complete responses.

The median progression-free survival (PFS) was only 2.6 months and overall survival (OS) was 2.8 months, suggesting that this treatment may not be more effective than traditional chemotherapy options for UCS.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Lenvatinib plus pembrolizumab in patients with advanced or recurrent uterine carcinosarcoma. Hunt, JT., Chambers, LM., Yao, M., et al.[2022]

The combination of lenvatinib, a multikinase inhibitor, and pembrolizumab, a PD-1 inhibitor, shows promising antitumor activity and durable responses in various solid tumors, as indicated by preliminary results from the LEAP clinical trial program.

This combination therapy has a manageable safety profile, suggesting it could be a valuable new treatment option for solid cancers that currently have limited therapeutic alternatives.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The LEAP program: lenvatinib plus pembrolizumab for the treatment of advanced solid tumors. Taylor, MH., Schmidt, EV., Dutcus, C., et al.[2021]

The combination of pembrolizumab and lenvatinib demonstrated significantly higher objective response rates (ORRs) and progression-free survival (mPFS) compared to their individual therapies in solid cancers, with ORRs reaching up to 70% in renal cell carcinoma.

Despite a high incidence of adverse events (68.0% for the combination therapy), the toxicities were manageable and no unexpected safety issues were reported, indicating that the combination therapy is both effective and relatively safe.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and efficacy of pembrolizumab plus lenvatinib versus pembrolizumab and lenvatinib monotherapies in cancers: A systematic review. Mo, DC., Luo, PH., Huang, SX., et al.[2021]

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 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 2 study involving 38 patients with pleural mesothelioma, the combination of pembrolizumab and lenvatinib resulted in a promising objective response rate of 58%, indicating significant anti-tumor activity after prior chemotherapy.

However, the treatment was associated with considerable toxicity, with 26% of patients experiencing serious treatment-related adverse events, including one death, highlighting the need for careful monitoring and supportive care during therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab plus lenvatinib in second-line and third-line patients with pleural mesothelioma (PEMMELA): a single-arm phase 2 study. Douma, LH., Lalezari, F., van der Noort, V., et al.[2023]

In a phase 2 trial involving 29 patients with advanced gastric cancer, the combination of lenvatinib and pembrolizumab resulted in a promising objective response rate of 69%, indicating significant anti-tumor activity.

The treatment was generally well-tolerated, with the most common grade 3 adverse events being manageable, such as hypertension and proteinuria, and no serious treatment-related complications or deaths reported.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Lenvatinib plus pembrolizumab in patients with advanced gastric cancer in the first-line or second-line setting (EPOC1706): an open-label, single-arm, phase 2 trial. Kawazoe, A., Fukuoka, S., Nakamura, Y., et al.[2020]

References

1. England pubmed.ncbi.nlm.nih.gov

Characterization and Management of Adverse Reactions From the CLEAR Study in Advanced Renal Cell Carcinoma Treated With Lenvatinib Plus Pembrolizumab. [2023]

2. England 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. [2022]

3. Netherlands pubmed.ncbi.nlm.nih.gov

Lenvatinib plus pembrolizumab in patients with advanced or recurrent uterine carcinosarcoma. [2022]

4. England pubmed.ncbi.nlm.nih.gov

The LEAP program: lenvatinib plus pembrolizumab for the treatment of advanced solid tumors. [2021]

5. Netherlands pubmed.ncbi.nlm.nih.gov

Safety and efficacy of pembrolizumab plus lenvatinib versus pembrolizumab and lenvatinib monotherapies in cancers: A systematic review. [2021]

6. Switzerland pubmed.ncbi.nlm.nih.gov

Optimizing the use of lenvatinib in combination with pembrolizumab in patients with advanced endometrial carcinoma. [2023]

7. United States pubmed.ncbi.nlm.nih.gov

Adverse events and oncologic outcomes with combination lenvatinib and pembrolizumab for the treatment of recurrent endometrial cancer. [2023]

8. England pubmed.ncbi.nlm.nih.gov

Pembrolizumab plus lenvatinib in second-line and third-line patients with pleural mesothelioma (PEMMELA): a single-arm phase 2 study. [2023]

9. England pubmed.ncbi.nlm.nih.gov

Lenvatinib plus pembrolizumab in patients with advanced gastric cancer in the first-line or second-line setting (EPOC1706): an open-label, single-arm, phase 2 trial. [2020]