Radioactive Drug vs Everolimus for Neuroendocrine Cancer

Recruiting at 30 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: National Cancer Institute (NCI)

Must be taking: Somatostatin analogues

Disqualifiers: Major surgery, Brain metastases, Heart failure, 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: 2

Duration: 16 weeks

100 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial examines the effectiveness of the radioactive drug 177Lu-DOTATATE compared to standard treatments like everolimus (a targeted therapy), sunitinib, or cabozantinib for gastroenteropancreatic neuroendocrine tumors (GEPNET) that have spread and cannot be surgically removed. The study aims to determine if retreatment with the radioactive drug can more effectively slow or halt cancer progression. Suitable candidates for this trial include individuals with GEPNET who previously received 177Lu-DOTATATE and experienced cancer progression afterward. As a Phase 2 trial, this research focuses on assessing 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, if you are taking somatostatin analogues, you may continue them if you have carcinoid syndrome and are in the PRRT group, but not if you are in the everolimus group unless you have functional carcinoid syndrome.

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

Research has shown that retreatment with 177Lu-DOTATATE is generally well tolerated by patients. Common side effects include tiredness, nausea, vomiting, and diarrhea, occurring in over 15% of patients, though they are usually not severe. One study found that after retreatment, patients did not experience unexpected safety issues, suggesting it is safe for repeated use.

The safety of everolimus is well-known, as it is FDA-approved for other conditions. Everolimus can cause side effects like mouth sores, tiredness, and infections, but these are usually manageable.

Both treatments have safety data supporting their use, though they come with some side effects. Patients should consult their doctor to determine the best option based on their health and treatment goals. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments for neuroendocrine cancer because they offer innovative approaches compared to current options like somatostatin analogs and everolimus. Lutetium Lu 177 Dotatate is a unique radioactive drug that directly targets cancer cells with radiation, potentially increasing effectiveness while minimizing harm to surrounding healthy tissue. Everolimus, on the other hand, is an oral inhibitor that targets a specific pathway involved in cancer growth, offering a non-invasive treatment option that can be taken daily. These treatments provide fresh strategies for tackling neuroendocrine cancer, possibly leading to more effective and tailored therapies.

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

This trial will compare the effectiveness of 177Lu-DOTATATE and Everolimus for treating neuroendocrine tumors. Research shows that 177Lu-DOTATATE, one of the treatments in this trial, holds promise for treating neuroendocrine tumors. Studies like NETTER-1 found that it can significantly extend the time patients live without their disease worsening. Patients receiving 177Lu-DOTATATE reported a better quality of life. Additionally, those who received a second round of 177Lu-DOTATATE treatment showed improved outcomes, living longer without disease progression. This suggests that 177Lu-DOTATATE could be effective for patients whose tumors do not respond to other treatments.

Everolimus, another treatment option in this trial, stops tumor cells from growing and cuts off their blood supply. It has been used successfully in treating various cancers by slowing disease progression. While both treatments offer benefits, 177Lu-DOTATATE is notable for its potential to significantly delay tumor growth and improve quality of life for neuroendocrine cancer patients. ^{6 7 8 9 10}

Who Is on the Research Team?

Simron Singh

Principal Investigator

Canadian Cancer Trials Group

Are You a Good Fit for This Trial?

Adults with metastatic, well-differentiated midgut neuroendocrine tumors previously treated with PRRT and showing progression can join. They must have good organ function, no severe ongoing side effects from prior treatments, and an ECOG performance status of <=2. Women of childbearing potential must agree to use effective contraception.

Inclusion Criteria

Patients must agree to return to their primary care facility for any adverse events

Hemoglobin >= 80 g/L

Platelets >= 80 x 10^9/L

Exclusion Criteria

Pregnant or breastfeeding women

My heart condition is not well-managed and is severe.

Patients with potential adverse events in nursing infants

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive 177Lu-DOTATATE intravenously every 8 weeks for two cycles or everolimus orally on a daily basis

16 weeks

2 visits (in-person) for 177Lu-DOTATATE, ongoing monitoring for everolimus

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 3 years

Crossover

Participants whose cancer worsens on everolimus may cross over to receive 177Lu-DOTATATE

As needed

What Are the Treatments Tested in This Trial?

Interventions

• Everolimus
• Lutetium Lu 177 Dotatate

Trial Overview The trial compares retreatment using a radioactive peptide (177Lu-DOTATATE PRRT) against the usual treatment with everolimus in patients whose midgut NET has spread and cannot be surgically removed. The goal is to see which method better controls tumor growth.

How Is the Trial Designed?

Group I: Arm I (177Lu-DOTATATE) Experimental Treatment 6 Interventions

Patients receive 177Lu-DOTATATE IV over 30 minutes Q8W. Treatment repeats for two cycles in the absence of disease progression or unacceptable toxicities. Patients also undergo CT scan or MRI and collection of blood samples while on study.

Group II: Arm II (everolimus) Active Control 8 Interventions

Patients receive everolimus PO QD, sunitinib PO QD or cabozantinib PO QD. Treatment continues in the absence of disease progression or unacceptable toxicities. Patients whose cancer worsens may cross over to ARM I. Patients also undergo CT scan or MRI and collection of blood samples while on study.

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?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

This study aims to evaluate the efficacy of four additional cycles of Lutathera® compared to two cycles in patients with progressive well-differentiated intestinal neuroendocrine tumors (NET), with a total of 146 patients participating.

The primary goal is to determine if the additional cycles can improve disease control rates over 6 months without increasing safety concerns, potentially leading to new treatment recommendations for extending patient survival and quality of life.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A prospective, randomized, phase II study to assess the schemas of retreatment with Lutathera® in patients with new progression of an intestinal, well-differentiated neuroendocrine tumor (ReLUTH). Deshayes, E., Assenat, E., Meignant, L., et al.[2022]

The combination of everolimus and PRRT (177Lu-DOTATATE) for treating advanced neuroendocrine tumors showed significant safety concerns, with 36% of patients experiencing grade 3 toxicities, including fatigue and infection, although no grade 4 toxicities were reported.

Despite some patients achieving stable disease and a median progression-free survival of 23.3 months, the trial was terminated early due to poor patient enrollment and treatment-related toxicities, suggesting that a lower dose of everolimus may be necessary for future studies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy of Everolimus Combined with 177Lu-Dotatate in the Treatment of Neuroendocrine Tumors. Aljubran, A., Badran, A., Alrowaily, M., et al.[2022]

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]

Peptide receptor radionuclide therapy (PRRT) using 177Lu-Dotatate has been FDA-approved for treating gastroenteropancreatic neuroendocrine tumors (GEP-NETs) and has shown better results compared to other therapies, particularly in advanced cases.

While 177Lu-Dotatate is effective in reducing tumor size and improving quality of life, it can cause adverse effects like myelotoxicity and nephrotoxicity, making Everolimus a safe option for patients who have already received this treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neuroendocrine Tumor Therapy with Lutetium-177: A Literature Review. Maqsood, MH., Tameez Ud Din, A., Khan, AH.[2020]

In a study of 144 patients with metastatic neuroendocrine tumors, Lu DOTATATE therapy demonstrated a cumulative disease control rate of 59.09%, indicating it can effectively manage tumor progression in this patient population.

The therapy was found to be safe, with no grade 3 or 4 renal toxicities reported, although some patients experienced grade 3 and 4 hematological and hepatotoxic adverse events, which were generally manageable.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Peptide Receptor Radionuclide Therapy With 177Lu-Octreotate in Patients With Somatostatin Receptor Expressing Neuroendocrine Tumors: Six Years' Assessment. Hamiditabar, M., Ali, M., Roys, J., et al.[2020]

In a study involving female Lewis rats, the combination of everolimus and [177Lu]Lu-DOTA-TATE did not increase renal or blood toxicity compared to [177Lu]Lu-DOTA-TATE alone, suggesting a safe combination therapy for neuroendocrine tumors.

Everolimus treatment resulted in lower creatinine levels, indicating better renal function, while it also significantly reduced white blood cell counts, highlighting its effects on blood health without exacerbating the side effects of PRRT.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Toxicity of a combined therapy using the mTOR-inhibitor everolimus and PRRT with [177Lu]Lu-DOTA-TATE in Lewis rats. Zellmer, J., Yen, HY., Kaiser, L., et al.[2023]

Lu-DOTATATE demonstrated significantly better therapeutic efficacy in treating advanced pancreatic neuroendocrine tumors (pNETs) compared to Everolimus, with an objective response rate of 47% versus 12% and longer progression-free survival of 25.7 months compared to 14.7 months.

Lu-DOTATATE also had a superior safety profile, with fewer patients experiencing severe hematological toxicity (5% vs. 11%) and no treatment-related discontinuations, while Everolimus led to discontinuation in 59 out of 371 patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

177Lu-DOTATATE peptide receptor radionuclide therapy versus Everolimus in advanced pancreatic neuroendocrine tumors: a systematic review and meta-analysis. Satapathy, S., Mittal, BR.[2023]

In a study of 24 patients with gastroenteropancreatic neuroendocrine tumors (GEP-NETs) treated with everolimus after (177)Lu-octreotate, the safety profile remained consistent with previous findings, with major adverse events including hyperglycemia (20.8%) and fatigue (8.3%).

The efficacy of everolimus showed a median progression-free survival (PFS) of 13.1 months, which is longer than the RADIANT-3 trial but shorter than the RADIANT-1 trial, indicating that prior treatment with (177)Lu-octreotate does not negatively impact the effectiveness of everolimus.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and efficacy of everolimus in gastrointestinal and pancreatic neuroendocrine tumors after (177)Lu-octreotate. Kamp, K., Gumz, B., Feelders, RA., et al.[2015]

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]

A randomized phase III trial has been initiated in Japan to evaluate the effectiveness of combining everolimus with lanreotide for treating unresectable or recurrent gastroenteropancreatic neuroendocrine tumors (NETs), aiming to enroll 250 patients over 5 years.

The primary goal of the trial is to assess progression-free survival, while secondary endpoints include overall survival and the rate of adverse events, indicating a comprehensive approach to evaluating both efficacy and safety of the combined treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Study protocol for a multi-institutional randomized phase III study comparing combined everolimus plus lanreotide therapy and everolimus monotherapy in patients with unresectable or recurrent gastroenteropancreatic neuroendocrine tumors; Japan Clinical Oncology Group Study JCOG1901 (STARTER-NET study). Shimoyama, R., Hijioka, S., Mizuno, N., et al.[2021]

The maximum tolerated dose of everolimus when combined with (177)Lu-octreotate therapy for advanced gastro-entero pancreatic neuroendocrine tumors is 7.5 mg daily, as higher doses led to significant side effects like neutropenia and thrombocytopenia.

The treatment combination showed a promising overall response rate of 44% among 16 patients, with no disease progression observed during the 6-month treatment period, indicating potential efficacy in managing these tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

NeuroEndocrine Tumor Therapy with Lutetium-177-octreotate and Everolimus (NETTLE): A Phase I Study. Claringbold, PG., Turner, JH.[2022]

Citations

1. ncbi.nlm.nih.gov ncbi.nlm.nih.gov/books/NBK587368/

Neuroendocrine Tumor 177Lutetium-Dotatate Therapy - NCBI Clinical trials, including the landmark NETTER-1 study, have demonstrated significant improvements in progression-free survival, quality of life ...

2. jnm.snmjournals.org jnm.snmjournals.org/content/early/2025/06/05/jnumed.124.269416

Cost-Effectiveness of [177Lu]Lu-DOTATATE for the Treatment ... The NETTER-2 trial found superior median progression-free survival (22.8 mo vs. 8.5 mo) and similar adverse events and quality-of-life measures ...

3. lutathera-hcp.com lutathera-hcp.com/2l-netter-1-efficacy

2L: NETTER-1 | LUTATHERA® (lutetium Lu 177 dotatate) | HCP Median overall survival was 48 months with LUTATHERA plus 30 mg octreotide LAR versus 36.3 months. In the final OS analysis, there was no statistically ...

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11137281/

Long-term clinical outcomes of [177Lu]Lu-DOTATATE in ... The most frequently reported (>15%) nonhematologic treatment-related adverse events were fatigue, nausea, vomiting, and diarrhea. Clinically ...

5. asco.org asco.org/abstracts-presentations/ABSTRACT365496

Effectiveness and safety of retreatment with lutetium Lu 177 ... A regimen of 4 doses of lutetium Lu 177 (177Lu)-DOTATATE has been shown to improve both progression-free survival (PFS) and overall survival (OS) in patients ...

6. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/40310018/

Post-marketing Safety Evaluation of Lutathera ( 177 Lu- ... Results: After data processing, a total of 4284 AE reports associated with Lutathera were analyzed. The median time to AE onset was 113.5 days.

7. jnm.snmjournals.org jnm.snmjournals.org/content/65/5/746

Effectiveness and Safety of Retreatment with 177Lu ... Overall, our findings demonstrate that additional retreatment cycles of 177Lu-DOTATATE are well tolerated and can offer disease-control benefits ...

8. frontiersin.org frontiersin.org/journals/oncology/articles/10.3389/fonc.2024.1393317/full

Long-term clinical outcomes of [ 177 Lu]Lu-DOTATATE in ... The most frequently reported (>15%) nonhematologic treatment-related adverse events were fatigue, nausea, vomiting, and diarrhea. Clinically ...

9. ascopubs.org ascopubs.org/doi/10.1200/JCO.2024.42.16_suppl.4131

Safety and time to response of [ 177 Lu]Lu-DOTATATE in ... With a median TTR of 5.7 months, most responses to 177 Lu-DOTATATE occurred during scheduled treatment. Overall, the study confirmed the safety profile of 177 ...

10. onclive.com onclive.com/view/lutetium-lu-177-dotatate-yields-partial-responses-in-metastatic-bronchopulmonary-neuroendocrine-tumors

Lutetium Lu 177 Dotatate Yields Partial Responses in ... Real-world data showed that lutetium Lu 177 dotatate led to partial responses in patients with metastatic bronchopulmonary neuroendocrine tumors ...