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

36 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial studies how well lenvatinib and everolimus work in treating patients with advanced carcinoid tumors that cannot be removed by surgery. These medications are taken by mouth and aim to stop cancer cells from growing by blocking essential enzymes. The trial will evaluate how effective and safe these drugs are for these patients. Both lenvatinib and everolimus have shown effectiveness in treating various cancers.

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 the combination of Lenvatinib and Everolimus safe for humans?

The combination of Lenvatinib and Everolimus has been studied for safety in patients with renal cell carcinoma and thyroid cancer. Common side effects include high blood pressure, diarrhea, weight loss, protein in urine, fatigue, and hand-foot syndrome (redness and pain on the palms and soles), which sometimes require dose adjustments or stopping the medication. ^{1 2 3 4 5}

How is the drug combination of Lenvatinib and Everolimus unique for treating neuroendocrine tumors?

The combination of Lenvatinib and Everolimus is unique because it targets two different pathways involved in tumor growth: Lenvatinib inhibits the VEGF pathway, which is crucial for blood vessel formation in tumors, while Everolimus inhibits the mTOR pathway, which is involved in cell growth and proliferation. This dual approach may offer a more comprehensive treatment strategy for neuroendocrine tumors compared to using either drug alone. ^{1 2 6 7 8}

What data supports the effectiveness of the drug Everolimus for treating neuroendocrine tumors?

Everolimus has been shown to help control the growth of neuroendocrine tumors, especially in the pancreas, by improving progression-free survival (the time during which the disease does not get worse). It is approved for use in advanced cases and has been associated with disease stabilization in clinical trials. ^{1 6 7 8 9}

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]

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]

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]

Citations

1. United States 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. [2023]

2. England pubmed.ncbi.nlm.nih.gov

Anti-tumour activity of everolimus and sunitinib in neuroendocrine neoplasms. [2020]

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

Safety and efficacy of everolimus in adult patients with neuroendocrine tumors. [2021]

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

Does the dose matter? Antiproliferative efficacy and toxicity of everolimus in patients with neuroendocrine tumors - Experiences from a tertiary referral center. [2023]

5. England 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. [2022]

6. Germany pubmed.ncbi.nlm.nih.gov

Phase I study of sorafenib in combination with everolimus (RAD001) in patients with advanced neuroendocrine tumors. [2021]

7. Germany pubmed.ncbi.nlm.nih.gov

A phase 1b clinical trial of the multi-targeted tyrosine kinase inhibitor lenvatinib (E7080) in combination with everolimus for treatment of metastatic renal cell carcinoma (RCC). [2021]

8. Netherlands 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. [2022]

9. Switzerland 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. [2019]