Combination Therapy vs Standard Treatment for Kidney Cancer

(CLEAR Trial)

Not currently recruiting at 270 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: Eisai Inc.

Must not be taking: Corticosteroids, Immunosuppressants

Disqualifiers: CNS metastases, Active malignancy, Cardiovascular impairment, others

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

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

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

Compensation: Varies

Number of Visits: 3

Duration: Up to approximately 46 months

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests new treatments for advanced kidney cancer to determine if they outperform the current standard treatment. It compares a combination of medications—lenvatinib (a targeted therapy), everolimus (an mTOR inhibitor), and pembrolizumab (an immunotherapy)—against sunitinib (a targeted therapy) alone. The goal is to delay the progression of the cancer. Individuals with advanced kidney cancer who have not yet begun treatment may be suitable candidates for this study. As a Phase 3 trial, this study represents the final step before potential FDA approval, offering participants an opportunity to contribute to the development of new, effective treatments.

Will I have to stop taking my current medications?

The trial protocol does not specify if you need to stop taking your current medications. However, it mentions that participants should not have received any systemic anticancer therapy for RCC or investigational drugs recently. It's best to discuss your current medications with the trial team to ensure they don't conflict with the study requirements.

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

Research shows that the combination of lenvatinib and pembrolizumab is generally well-tolerated, though common side effects include tiredness, diarrhea, and muscle pain in more than half of patients with advanced kidney cancer. Some patients needed to adjust their treatment due to these side effects.

For the lenvatinib and everolimus combination, studies indicate effectiveness even in patients who have undergone multiple treatments. However, it can cause high blood pressure, affecting about 42% of patients, with around 13% experiencing more severe cases.

These treatments have been studied in other contexts, demonstrating effectiveness and manageable safety profiles. Prospective participants should discuss possible side effects with a healthcare professional before joining a trial. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments because they bring new combinations and mechanisms to the fight against kidney cancer. Unlike the standard treatment with Sunitinib, which is a single drug, the combination of Lenvatinib with Pembrolizumab or Everolimus offers a multifaceted attack. Pembrolizumab boosts the immune system to better target cancer cells, while Lenvatinib and Everolimus work by blocking pathways that tumors use to grow. This dual or triple approach could potentially enhance treatment effectiveness and offer new hope for patients with kidney cancer.

What evidence suggests that this trial's treatments could be effective for advanced renal cell carcinoma?

Research has shown that using lenvatinib and pembrolizumab together, one of the treatment options in this trial, holds promise for treating advanced kidney cancer, known as renal cell carcinoma (RCC). Studies have found that about 66% of patients respond well to this treatment, with some even experiencing complete cancer remission. This combination also extends the time patients live without their cancer worsening compared to sunitinib, the standard treatment arm in this trial.

Another treatment option in this trial is the combination of lenvatinib and everolimus, which has also proven effective. Patients receiving this combination live an average of 15.7 months without cancer progression, longer than with sunitinib. While complete cancer remission is rare with this combination, many patients maintain a stable condition for an extended period. Both treatment options in this trial offer hope for better management of this type of kidney cancer. ^{4 6 7 8 9}

Are You a Good Fit for This Trial?

This trial is for adults with advanced renal cell carcinoma who have not had systemic cancer treatment for RCC. They must have at least one measurable lesion, be in good physical condition (KPS >=70), and have stable blood pressure and organ functions. Pregnant or breastfeeding women, those unwilling to use contraception, or individuals with certain medical conditions like CNS metastases, severe bleeding risks, recent live vaccines, uncontrolled diabetes, significant heart issues within the past year are excluded.

Inclusion Criteria

My kidney cancer is in an advanced stage.

Written informed consent

You have at least one specific type of tumor that can be measured and meets certain criteria.

Exclusion Criteria

I have had pneumonitis treated with steroids or have it now.

You have HIV.

I am a male who hasn't had a vasectomy and agree to use a condom and spermicide.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either lenvatinib in combination with everolimus or pembrolizumab, or sunitinib alone as first-line treatment for advanced renal cell carcinoma

Up to approximately 46 months

Every 3 weeks for pembrolizumab, 4 weeks on/2 weeks off for sunitinib

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to approximately 69 months

What Are the Treatments Tested in This Trial?

Interventions

• Everolimus
• Lenvatinib
• Pembrolizumab
• Sunitinib

Trial Overview

The study tests if lenvatinib combined with everolimus (Arm A) or pembrolizumab (Arm B) is more effective than sunitinib alone (Arm C) in delaying disease progression in first-line treatment of advanced RCC. Participants will be randomly assigned to one of these treatments and monitored for progression-free survival using standard criteria.

How Is the Trial Designed?

Group I: Lenvatinib 20 mg plus Pembrolizumab 200 mg Experimental Treatment 2 Interventions

Lenvatinib 20 mg administered orally, once daily, in each 21-day cycle plus pembrolizumab 200 mg administered intravenously (IV), every 3 weeks on Day 1 of each 21-day cycle.

Group II: Lenvatinib 18 mg plus Everolimus 5 mg Experimental Treatment 2 Interventions

Lenvatinib 18 milligrams (mg) administered orally, once daily, plus everolimus 5 mg administered orally, once daily in each 21-day cycle.

Group III: Sunitinib 50 mg Active Control 1 Intervention

Sunitinib 50 mg administered orally, once daily, on a schedule of 4 weeks on treatment followed by 2 weeks off treatment in each 21-day cycle.

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

Approved in United States as Afinitor for:

• Advanced renal cell carcinoma
• Subependymal giant cell astrocytoma
• Progressive neuroendocrine tumors of pancreatic origin
• Advanced hormone receptor-positive, HER2-negative breast cancer
• Tuberous sclerosis complex-associated partial-onset seizures

Approved in European Union as Votubia for:

• Subependymal giant cell astrocytoma
• Renal angiomyolipoma
• Tuberous sclerosis complex-associated partial-onset seizures

Approved in United States as Zortress for:

• Prevention of organ rejection in kidney transplant patients

Who Is Running the Clinical Trial?

Eisai Inc.

Lead Sponsor

Trials

524

Recruited

161,000+

Founded

Eisai Inc. was established in 1995 as the U.S. subsidiary of Eisai Co., Ltd.

Headquarters

Woodcliff Lake, NJ, USA

Known For

Neurology and Oncology

Top Products

Aricept (donepezil), Lenvima (lenvatinib), Leqembi (lecanemab), Halaven (eribulin)

Lynn Kramer

Eisai Inc.

Chief Medical Officer since 2019

MD

Tatsuyuki Yasuno

Eisai Inc.

Chief Executive Officer since 2023

MBA from Kellogg School of Management, Northwestern University; Bachelor of Political Science from Waseda University

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 a phase 3 trial with 1069 patients, the combination of lenvatinib and pembrolizumab significantly improved progression-free survival compared to sunitinib, with a median of 23.9 months versus 9.2 months, indicating a strong efficacy of this regimen.

Lenvatinib plus pembrolizumab also resulted in longer overall survival compared to sunitinib, while the combination of lenvatinib and everolimus did not show a survival advantage over sunitinib. However, both lenvatinib combinations had a high incidence of grade 3 or higher adverse events, similar to sunitinib.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Lenvatinib plus Pembrolizumab or Everolimus for Advanced Renal Cell Carcinoma. Motzer, R., Alekseev, B., Rha, SY., et al.[2022]

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]

Citations

1.

nejm.org

nejm.org/doi/full/10.1056/NEJMoa2035716

Lenvatinib plus Pembrolizumab or Everolimus for ...

Lenvatinib plus pembrolizumab was associated with significantly longer progression-free survival and overall survival than sunitinib.

2.

urologytimes.com

urologytimes.com/view/contemporary-rcc-trial-adds-fresh-lenvatinib-everolimus-pfs-perspective

Contemporary RCC trial adds fresh lenvatinib/everolimus ...

The median progression-free survival was 15.7 months with the combination of lenvatinib plus everolimus compared with 10.2 months with ...

3.

pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC7415534/

The efficacy of lenvatinib plus everolimus in patients with ...

Median overall survival was promising and ranged from 4–17 months. Clinical Practice Points: Patients with clear cell metastatic renal cell carcinoma (RCC) that ...

4.

lenvimahcp.com

lenvimahcp.com/2nd-line-advanced-renal-cell-carcinoma/efficacy-results

NCCN recommendation - LENVIMA ® (lenvatinib)

In RCC (renal cell carcinoma), hypertension occurred in 42% of patients on LENVIMA + everolimus (13% grade 3). Systolic blood pressure ≥160 mmHg occurred in 29% ...

5.

actionkidneycancer.org

actionkidneycancer.org/lenvatinib-plus-everolimus-for-patients-with-metastatic-kidney-cancer/

Lenvatinib plus everolimus for patients with metastatic ...

There were no complete responses and nearly 2 in 10 patients had stable disease. The average overall survival time was was just over 11 months ...

6.

pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC11025417/

Assessing the effectiveness and safety of lenvatinib and ...

In Italy, 12,600 new diagnoses of renal cell carcinoma (RCC) during 2022 were made, with a 5-year overall survival (OS) of 71% for both sexes ...

7.

keytrudalenvimahcp.com

keytrudalenvimahcp.com/advanced-renal-cell-carcinoma/

Advanced Renal Cell Carcinoma: Efficacy and Safety Results

Health care professionals can review efficacy data and safety results for a first-line treatment of adult patients with advanced renal cell carcinoma (RCC).

8.

ascopubs.org

ascopubs.org/doi/10.1200/JCO.2025.43.5_suppl.489

Efficacy and safety of lenvatinib plus everolimus in ...

LEN plus EVE shows promising efficacy and disease control in heavily pretreated mRCC patients after failure of ICIs and VEGFR TKIs, even beyond the fourth line.

9.

lenvimahcp.com

lenvimahcp.com/2nd-line-advanced-renal-cell-carcinoma/safety

Adverse reactions observed in Study 205

In RCC (renal cell carcinoma), hypertension occurred in 42% of patients on LENVIMA + everolimus (13% grade 3). Systolic blood pressure ≥160 mmHg occurred in 29% ...