Lenvatinib + Everolimus for Neuroendocrine Tumors

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: M.D. Anderson Cancer Center

Must not be taking: Steroids, Anti-epileptics, Warfarin, others

Disqualifiers: Brain metastases, Concurrent malignancies, HIV, 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

Compensation: Varies

Number of Visits: 3

Duration: 28 days per cycle

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests the effectiveness of two drugs, lenvatinib and everolimus, in treating advanced carcinoid tumors, a type of neuroendocrine tumor. These tumors have spread and cannot be surgically removed. The drugs aim to halt tumor growth by blocking enzymes necessary for cell growth. Individuals with carcinoid tumors that have worsened over the past year and cannot be surgically removed might be suitable candidates for this study. As a Phase 2 trial, the research focuses on evaluating the treatment's effectiveness in an initial, smaller group of participants.

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 may continue somatostatin analogues if needed for symptom control. 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?

Research has shown that using lenvatinib and everolimus together is generally safe. One study found that this combination controlled the disease more effectively and had a higher response rate than everolimus alone. However, concerns about side effects remain. Approximately 67.5% of patients experienced serious side effects, known as grade 3 or 4 adverse events. These side effects occurred more frequently with lenvatinib and everolimus than with cabozantinib.

Thus, while this treatment shows promise in fighting the tumor, awareness of the potential for significant side effects is crucial. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of lenvatinib and everolimus for treating neuroendocrine tumors because this duo targets the disease in a novel way. Unlike traditional treatments like somatostatin analogs or surgery, lenvatinib is a tyrosine kinase inhibitor that disrupts the blood supply tumors need to grow, while everolimus inhibits mTOR, a protein that helps cancer cells survive. This combination could potentially offer a more comprehensive attack on tumor growth and survival, offering hope for improved outcomes in patients with this condition.

What evidence suggests that lenvatinib and everolimus might be effective for neuroendocrine tumors?

Research has shown that the combination of lenvatinib and everolimus can help treat certain tumors. In studies, this treatment reduced the risk of tumor growth or death by 63% in patients with advanced kidney cancer. In this trial, participants with neuroendocrine tumors will receive lenvatinib and everolimus, which have demonstrated good results in achieving key goals like progression-free survival (PFS), the time a patient lives without the disease worsening. This combination blocks enzymes that tumor cells need to grow. These findings suggest that lenvatinib and everolimus might help control tumor growth in patients with advanced carcinoid tumors that cannot be surgically removed. ^{6 7 8 9 10}

Who Is on the Research Team?

Nageshwara V. Dasari

Principal Investigator

M.D. Anderson Cancer Center

Are You a Good Fit for This Trial?

This trial is for patients with advanced, unresectable carcinoid tumors. Eligible participants must have well-differentiated tumors, may have MEN1 syndrome, and show disease progression over the last year. They should be in good physical condition (ECOG 0-1), not pregnant, able to swallow pills, without HIV or hepatitis B/C, and free from other cancers in the past 3 years.

Inclusion Criteria

Your platelet count is at least 100 billion per liter.

Written informed consent must be obtained prior to any screening procedures.

Your hemoglobin level is at least 9 grams per deciliter.

Exclusion Criteria

Patients with concurrent severe and/or uncontrolled concurrent medical conditions that could compromise participation in the study

I haven't had major surgery in the last 3 weeks or still have major side effects from it.

I am willing and able to follow the study's requirements.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive lenvatinib and everolimus orally daily on days 1-28, with treatments repeating every 28 days in the absence of disease progression or unacceptable toxicity

28 days per cycle

Visits every 2 weeks for the first 2 cycles, then every cycle

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

1 visit (in-person) at 30 days post-treatment

What Are the Treatments Tested in This Trial?

Interventions

• Everolimus
• Lenvatinib

Trial Overview The study tests lenvatinib and everolimus' effectiveness on advanced carcinoid tumors that can't be surgically removed. These drugs aim to inhibit tumor growth by blocking enzymes necessary for cell proliferation.

How Is the Trial Designed?

Group I: Treatment (lenvatinib, everolimus) Experimental Treatment 2 Interventions

Patients receive lenvatinib PO daily and everolimus PO daily on days 1-28. Treatments repeat every 28 days in the absence of disease progression or unacceptable toxicity.

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?

M.D. Anderson Cancer Center

Lead Sponsor

Trials

3,107

Recruited

1,813,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

The combination of everolimus (RAD001) and octreotide LAR showed promising antitumor activity in patients with advanced neuroendocrine tumors, achieving a 20% response rate and a median progression-free survival of 60 weeks across 60 enrolled patients.

The treatment was well tolerated, with the most common side effect being mild aphthous ulceration, and significant reductions in tumor proliferation markers were observed, indicating a potential mechanism of action for the therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy of RAD001 (everolimus) and octreotide LAR in advanced low- to intermediate-grade neuroendocrine tumors: results of a phase II study. Yao, JC., Phan, AT., Chang, DZ., et al.[2023]

Everolimus, an mTOR inhibitor approved for advanced neuroendocrine tumors (NETs), shows significant clinical benefits, including longer progression-free survival for patients with gastrointestinal and lung NETs.

The budget impact of everolimus on a typical US health plan is minimal, estimated at $0.0568-$0.1443 per member per month for GI NETs and $0.0181-$0.0355 for lung NETs, largely due to the low prevalence of these rare diseases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Budget impact of everolimus for the treatment of progressive, well-differentiated, non-functional neuroendocrine tumors of gastrointestinal or lung origin that are advanced or metastatic. Rose, DB., Nellesen, D., Neary, MP., et al.[2022]

Lenvatinib (LEN) is an effective multikinase inhibitor used for treating certain types of cancer, but it often causes significant adverse events (AEs) like hypertension and diarrhea, which can lead to dose modifications or discontinuation of treatment.

A multidisciplinary approach to managing these AEs is crucial for maintaining treatment efficacy and patient safety, as it helps address the side effects that frequently arise during LEN therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Lenvatinib Long-Term Responses in Refractory Thyroid Cancer: Our Mono-Institutional Real-Life Experience with the Multidisciplinary Approach and Review of Literature. Denaro, N., Latina, A., Cesario, F., et al.[2019]

Patients with advanced renal cell carcinoma treated with the combination of lenvatinib (LEN) and everolimus (EVE) experienced a significant improvement in quality-adjusted time without symptoms of disease progression or toxicity (Q-TWiST), gaining an average of 3.7 months compared to those receiving EVE alone.

The LEN+EVE combination resulted in a 24% relative gain in Q-TWiST, indicating a clinically important benefit in quality survival time for patients who had previously undergone antiangiogenic therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Quality-adjusted Time Without Symptoms or Toxicity (Q-TWiST) for Lenvatinib plus Everolimus Versus Everolimus Monotherapy in Patients with Advanced Renal Cell Carcinoma. Lee, CH., Wan, Y., Smith, A., et al.[2022]

Citations

1. onclive.com onclive.com/view/lenvatinib-plus-everolimus-safe-effective-following-immunotherapy-in-clear-cell-rcc

Lenvatinib Plus Everolimus Safe, Effective Following ... Lenvatinib (Lenvima) in combination with everolimus (Afinitor) has proven to be safe and effective when used in the treatment of patients ...

2. withpower.com withpower.com/trial/phase-3-neoplasms-6-2019-f4355

Lenvatinib + Everolimus for Neuroendocrine Tumors This trial studies how well lenvatinib and everolimus work in treating patients with advanced carcinoid tumors that cannot be removed by surgery.

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC6064188/

Everolimus in treatment of neuroendocrine tumors All three arms achieved the pre-planned statistical objective of a 9-month PFS rate >20%, with a median PFS of 11.8, 12.5 and 8.5 months in combination arm, ...

4. curetoday.com curetoday.com/view/lenvima-and-afinitor-approved-for-advanced-renal-cell-carcinoma

Lenvima and Afinitor Approved for Advanced Renal Cell ... In the trial, known as Study 205, the combination of Lenvima and Afinitor reduced the risk of progression or death by 63 percent compared with ...

5. cda-amc.ca cda-amc.ca/sites/default/files/pcodr/Reviews2019/10140LenvatinibRCC_fnCGR_REDACT_Post_04Jan2019_final.pdf

pan-Canadian Oncology Drug Review Final Clinical ... The majority of patients considered lenvatinib and everolimus to be a very effective therapy against their kidney cancer affording them a high ...

6. ascopubs.org ascopubs.org/doi/10.1200/JCO.2025.43.16_suppl.4145

A phase II study of lenvatinib plus everolimus in advanced ... Conclusions: L + E demonstrated markedly superior ORR and a trend toward prolonged PFS compared to E alone with a manageable safety profile.

7. clinicaltrials.gov clinicaltrials.gov/study/NCT02678780

Lenvatinib Efficacy in Metastatic Neuroendocrine Tumors This is a prospective, international, multi-center, open label, stratified, exploratory phase II study evaluating the efficacy and safety of lenvatinib in ...

8. erc.bioscientifica.com erc.bioscientifica.com/view/journals/erc/32/4/ERC-24-0292.pdf

Real-world outcomes of lenvatinib therapy for advanced ... This real-world cohort demonstrates encouraging evidence of lenvatinib activity in metastatic NENs, even when used at lower doses than ...

9. cancernetwork.com cancernetwork.com/view/lenvatinib-everolimus-beats-cabozantinib-in-phase-2-rcc-study

Lenvatinib/Everolimus Beats Cabozantinib in Phase 2 ... The combination of lenvatinib (Lenvima) and everolimus (Afinitor) reduced the risk of progression or death by 49% compared with cabozantinib ...

10. targetedonc.com targetedonc.com/view/dr-hahn-on-the-phase-2-lencabo-trial-in-rcc

Dr Hahn on the Phase 2 LenCabo Trial in RCC The incidence of grade 3 or 4 adverse events (AEs) was higher in the lenvatinib/everolimus arm at 67.5% compared with 50% for cabozantinib.