Pembrolizumab + Lenvatinib with/without FMT for Melanoma

Overseen By Danielle L Bednarz, RN

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Diwakar Davar

Must not be taking: Antibiotics, Steroids

Disqualifiers: Non-cutaneous melanoma, Active infections, 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: 3

Duration: 104 weeks

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests whether adding a gut microbiome transplant (using healthy donor stool) to the cancer drugs pembrolizumab (a PD-1 inhibitor) and lenvatinib (a targeted therapy) can treat melanoma that no longer responds to PD-1 inhibitor drugs. The researchers aim to determine if the microbiome transplant can enhance the body's response to cancer treatment by altering inflammation levels. This trial targets individuals with advanced melanoma who previously received PD-1 drugs but did not respond well. Participants must have measurable disease, and those with certain types of melanoma or prior treatment with lenvatinib are not eligible. As a Phase 2 trial, this research focuses on assessing the treatment's effectiveness in an initial, smaller group of people.

Will I have to stop taking my current medications?

The trial does not specify if you must stop taking your current medications, but it does mention a 2-week period without certain prior therapies before starting the study. It's best to discuss your specific medications with the study team.

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

Research has shown that combining pembrolizumab and lenvatinib is generally safe, as observed in earlier studies. In trials like LEAP-003 and LEAP-017, side effects matched previous findings, indicating the treatment is usually well-tolerated, though some side effects can occur.

Adding fecal microbiota transplant (FMT) to this treatment appears promising. FMT has been safely used in small groups of melanoma patients and has even helped some who didn’t respond to other treatments. In these cases, FMT was administered in capsule form and appeared safe.

Overall, past research has demonstrated the safety of all treatments in this study, but side effects can still occur. Participants should discuss any concerns with the study team. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments because they combine pembrolizumab and lenvatinib with the potential addition of fecal microbiota transplantation (FMT), offering a unique approach to treating melanoma. Unlike standard treatments that primarily rely on immune checkpoint inhibitors like pembrolizumab alone, this combination introduces lenvatinib, a tyrosine kinase inhibitor, which may enhance the immune response against cancer cells. The experimental arm includes FMT, which could modify the gut microbiome to further boost the body's immune system. This innovative combination and method may offer a more robust attack on melanoma, potentially improving outcomes beyond the current standard therapies.

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

Research shows that using pembrolizumab and lenvatinib together yields promising results for treating melanoma, a type of skin cancer. In some studies, this combination has helped patients live longer without disease progression and appears to shrink or control tumor growth. In this trial, one group of participants will receive only pembrolizumab and lenvatinib.

Another group will receive pembrolizumab and lenvatinib with fecal microbiota transplantation (FMT). Early research suggests that adding FMT can improve survival rates by altering gut bacteria, enhancing the body's response to treatments. This new approach could help overcome resistance to current therapies, offering hope to those with advanced melanoma. ^{1 2 3 6 7}

Who Is on the Research Team?

Diwakar Davar, MD

Principal Investigator

UPMC Hillman Cancer Center

Are You a Good Fit for This Trial?

This trial is for adults with advanced melanoma that has not responded to anti-PD-1 therapy. They must have stable, treated brain metastases if present, agree to use contraception, and be willing to undergo endoscopic FMT. Excluded are those with certain types of melanoma (uveal, mucosal), recent major surgery, severe allergies or gastrointestinal conditions affecting drug absorption, unmanaged side effects from previous treatments, active infections including COVID-19 or hepatitis B/C virus infection.

Inclusion Criteria

You have a disease that can be measured using specific guidelines.

I have skin melanoma or melanoma of unknown primary, not uveal, mucosal, or acral-lentiginous melanoma.

I agree to follow the study's rules for using contraception and not donate sperm for 120 days after the last treatment.

Exclusion Criteria

You have severe allergies to certain foods like shellfish, nuts, or seafood.

A WOCBP who has a positive urine pregnancy test at Screening (see Appendix 3). If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.

You have a severe allergic reaction (Grade 3 or higher) to anti-PD(L)1 inhibitor.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive pembrolizumab and lenvatinib, with or without hdFMT, over a 104-week period

104 weeks

Pembrolizumab every 3 weeks, lenvatinib daily, hdFMT at specific intervals

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 5 years

What Are the Treatments Tested in This Trial?

Interventions

• Lenvatinib
• Pembrolizumab
• Responder-Derived FMT

Trial Overview The study tests whether adding Responder-Derived Fecal Microbiota Transplantation (R-FMT) to the combination of Pembrolizumab and Lenvatinib improves outcomes in patients whose melanoma hasn't responded to PD-1 inhibitors. It's a randomized phase II trial over 104 weeks where participants' intestinal microbiome composition is considered as a mediator for their response.

How Is the Trial Designed?

Group I: hdFMT + pembrolizumab/lenvatinib (Arm A) Experimental Treatment 3 Interventions

* Pembrolizumab will be administered at 200 mg every 3 weeks (Q3W) as a 30-minute IV infusion (treatment intervals may be increased due to toxicity as described). * Lenvatinib will be administered at 20 mg daily. * hdFMT (induction) will be administered at C1D1 and C4D1 via colonoscopy or oral capsules * hdFMT (maintenance) will be repeated every 9 weeks starting with C4D1 via sigmodoscopy or oral capsules

Group II: pembrolizumab/lenvatinib (Arm B) Active Control 2 Interventions

* Pembrolizumab will be administered at 200 mg every 3 weeks (Q3W) as a 30-minute IV infusion (treatment intervals may be increased due to toxicity as described). * Lenvatinib will be administered at 20 mg daily.

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?

Diwakar Davar

Lead Sponsor

Trials

12

Recruited

420+

Gateway for Cancer Research

Collaborator

Trials

47

Recruited

2,500+

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

Published Research Related to This Trial

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]

In a phase 3 study involving 487 patients with advanced urothelial carcinoma, the combination of pembrolizumab and lenvatinib did not show improved progression-free survival (4.5 months) or overall survival (11.8 months) compared to pembrolizumab with placebo.

The combination treatment resulted in a higher rate of severe adverse events (51%) compared to the placebo group (27%), leading to the conclusion that the benefit-to-risk ratio was not favorable for using lenvatinib with pembrolizumab as first-line therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab with or Without Lenvatinib as First-line Therapy for Patients with Advanced Urothelial Carcinoma (LEAP-011): A Phase 3, Randomized, Double-Blind Trial. Matsubara, N., de Wit, R., Balar, AV., et al.[2023]

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 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]

Combination therapy with pembrolizumab and lenvatinib is effective as a first-line treatment for clear cell renal carcinoma and as a second-line option for recurrent or metastatic endometrial carcinoma, based on data from five completed clinical trials and two ongoing trials.

This non-chemotherapy regimen helps spare patients from prolonged myelosuppression and lowers the risk of infection, making it a safer alternative for cancer treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combined use of pembrolizumab and lenvatinib: A review. Eisinger, C., Muluneh, B.[2023]

In the phase II LEAP-004 study involving 103 patients with advanced melanoma who had disease progression on PD-1 inhibitors, the combination of lenvatinib and pembrolizumab achieved an objective response rate of 21.4%, indicating its potential effectiveness in this challenging population.

The treatment demonstrated a median progression-free survival of 4.2 months and an overall survival of 14.0 months, with a manageable safety profile, including a 45.6% incidence of grade 3-5 adverse events, primarily hypertension.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II LEAP-004 Study of Lenvatinib Plus Pembrolizumab for Melanoma With Confirmed Progression on a Programmed Cell Death Protein-1 or Programmed Death Ligand 1 Inhibitor Given as Monotherapy or in Combination. Arance, A., de la Cruz-Merino, L., Petrella, TM., 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 involving 137 patients with advanced solid tumors, the combination of lenvatinib and pembrolizumab showed a manageable safety profile, with common side effects including fatigue, diarrhea, and hypertension.

The treatment demonstrated promising antitumor activity, with objective response rates at week 24 ranging from 25% to 63% across different cancer types, indicating its potential effectiveness in various advanced cancers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase IB/II Trial of Lenvatinib Plus Pembrolizumab in Patients With Advanced Renal Cell Carcinoma, Endometrial Cancer, and Other Selected Advanced Solid Tumors. Taylor, MH., Lee, CH., Makker, V., et al.[2021]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10170280/

Lenvatinib/Pembrolizumab as second line treatment for ... Median progression-free survival (PFS) and overall survival (OS) remained unchanged at 4.2 and 14 months, respectively, while 17.8% of patients ...

2. merck.com merck.com/news/merck-and-eisai-provide-update-on-phase-3-trials-of-keytruda-pembrolizumab-plus-lenvima-lenvatinib-in-certain-patients-with-advanced-melanoma-leap-003-and-metastatic-colorectal-cance/

Merck and Eisai Provide Update on Phase 3 Trials of ... A trend toward improvement was also observed in key secondary endpoints of PFS, objective response rate (ORR) and duration of response (DOR) ...

3. targetedonc.com targetedonc.com/view/pembrolizumab-plus-lenvatinib-shows-encouraging-efficacy-in-uveal-melanoma

Pembrolizumab Plus Lenvatinib Shows Encouraging ... Key Takeaways. Pembrolizumab and lenvatinib showed promising PFS in uveal melanoma patients, with 31.8% and 60.7% rates in different cohorts.

4. merck.com merck.com/news/new-data-from-investigational-study-of-lenvima-lenvatinib-and-keytruda-pembrolizumab-combination-in-three-different-tumor-types-presented-at-the-society-for-immunotherapy-of-cancer/

New Data from Investigational Study of LENVIMA® ... The LENVIMA and KEYTRUDA combination demonstrated encouraging anti-tumor activity. These data support further evaluation of the combination.

5. eisai.com eisai.com/news/2018/news201897.html

NEW DATA FROM INVESTIGATIONAL STUDY OF ... The LENVIMA and KEYTRUDA combination demonstrated encouraging anti-tumor activity and was generally well tolerated.

6. targetedonc.com targetedonc.com/view/pembrolizumab-plus-lenvatinib-misses-it-mark-in-melanoma-and-crc-study-populations

Pembrolizumab Plus Lenvatinib Misses it Mark in ... Neither the LEAP-003 nor LEAP-017 studies study showed survival benefit with pembrolizumab plus lenvatinib for patients with melanoma or colorectal cancer.

7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10540481/

Combined use of pembrolizumab and lenvatinib: A review Data suggests that combination therapy with pembrolizumab and lenvatinib can be used first line for clear cell renal carcinoma in patients with favorable risk.