Combination Therapy vs Standard Treatment for Kidney Cancer

(CLEAR Trial)

Recruiting at 229 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

1069 Participants Needed

Trial Summary

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.

What data supports the effectiveness of the drug combination therapy for kidney cancer?

The combination of lenvatinib and everolimus is approved for treating advanced kidney cancer after previous treatments, showing it can be effective. Additionally, lenvatinib with pembrolizumab has shown promising results in early trials for kidney cancer. ^{1 2 3 4 5}

Is the combination therapy of lenvatinib and pembrolizumab or everolimus safe for treating kidney cancer?

The combination of lenvatinib with pembrolizumab or everolimus has been studied for safety in treating advanced kidney cancer. Common adverse reactions (side effects) have been identified, and strategies for managing these side effects are available, indicating that while there are risks, they are known and can be managed. ^{2 3 4 6 7}

What makes this drug combination unique for kidney cancer?

This drug combination is unique because it combines lenvatinib and everolimus, which are the first successful pairing of tyrosine kinase and mTOR inhibitors for kidney cancer after other treatments have failed. It offers a new option for patients who have developed resistance to standard therapies that target blood vessel growth in tumors. ^{1 2 3 4 8}

What is the purpose of this trial?

The primary purpose of the study is to demonstrate that lenvatinib in combination with everolimus (Arm A) or pembrolizumab (Arm B) is superior compared to sunitinib alone (Arm C) in improving progression-free survival (PFS) (by independent imaging review \[IIR\] using Response Evaluation Criteria in Solid Tumors \[RECIST 1.1\]) as first-line treatment in participants with advanced renal cell carcinoma (RCC).

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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

Findings from Research

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]

References

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

Lenvatinib plus Pembrolizumab or Everolimus for Advanced Renal Cell Carcinoma. [2022]

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

FDA Approves Drug Combo for Kidney Cancer. [2022]

3. England pubmed.ncbi.nlm.nih.gov

Lenvatinib plus everolimus or pembrolizumab versus sunitinib in advanced renal cell carcinoma: study design and rationale. [2022]

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

The implementation of lenvatinib/everolimus or lenvatinib/pembrolizumab combinations in the treatment of metastatic renal cell carcinoma. [2021]

5. Switzerland pubmed.ncbi.nlm.nih.gov

Assessing the Safety and Efficacy of Two Starting Doses of Lenvatinib Plus Everolimus in Patients with Renal Cell Carcinoma: A Randomized Phase 2 Trial. [2022]

6. 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]

7. England pubmed.ncbi.nlm.nih.gov

Targeting of tumor growth and angiogenesis underlies the enhanced antitumor activity of lenvatinib in combination with everolimus. [2021]

8. Belgium pubmed.ncbi.nlm.nih.gov

[Everolimus (RAD001/Afinitor) in the treatment of metastatic cell carcinoma]. [2021]