Radioactive Drug vs Everolimus for Neuroendocrine Cancer

Recruiting at 28 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

Trial Summary

What is the purpose of this trial?

This phase II trial compares the effect of retreatment with 177Lu-DOTATATE peptide receptor radionuclide therapy (PRRT) to the usual approach of treatment with everolimus in patients who have previously received 177Lu-DOTATATE for midgut neuroendocrine tumor (NET) that has spread from where it first started (primary site) to other places in the body (metastatic) and that cannot be removed by surgery (unresectable). PRRT is a type of radiation therapy for which a radioactive chemical is linked to a peptide (small protein) that targets cancer cells. When this radioactive peptide is injected into the body, it binds to a specific receptor found on some cancer cells. The radioactive peptide builds up in these cells and helps kill the cancer cells without harming normal cells. In this trial 177Lu-DOTATATE is used for PRRT. 177Lu-DOTATATE PRRT may increase the length of time until worsening of the midgut NET compared to the usual approach. Everolimus is in a class of medications called kinase inhibitors. It is also a type of angiogenesis inhibitor. Everolimus works by stopping cancer cells from reproducing and by decreasing blood supply to the cancer cells. Retreating with 177Lu-DOTATATE may work better than everolimus in shrinking or stabilizing tumor in patients with metastatic and unresectable NET who were previously treated with 177Lu-DOTATATE.

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.

What data supports the effectiveness of the drug Everolimus for neuroendocrine cancer?

Research shows that Everolimus, when used alone or in combination with other treatments like lanreotide or Lutetium-177-octreotate, can be effective for treating neuroendocrine tumors. Studies suggest that combining Everolimus with other therapies may improve survival outcomes compared to using Everolimus alone. ^{1 2 3 4 5}

Is the combination of Everolimus and Lutetium Lu 177 Dotatate safe for treating neuroendocrine tumors?

The combination of Everolimus and Lutetium Lu 177 Dotatate has shown some safety concerns, with common mild side effects like mouth sores and nausea, and more serious side effects like fatigue, infections, and lung inflammation occurring in some patients. The combination was not considered feasible at higher doses of Everolimus, suggesting that further research at lower doses is needed. ^{1 2 6 7 8}

How does the treatment with Lutetium Lu 177 Dotatate and Everolimus differ from other treatments for neuroendocrine cancer?

This treatment is unique because it combines Lutetium Lu 177 Dotatate, a radioactive drug that targets somatostatin receptors on tumors, with Everolimus, a drug that inhibits a protein involved in cell growth. This combination aims to enhance treatment effectiveness by using two different mechanisms to slow tumor progression and improve patient outcomes. ^{1 8 9 10 11}

Research Team

Simron Singh

Principal Investigator

Canadian Cancer Trials Group

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

Group I: Arm I (177Lu-DOTATATE) Experimental Treatment 5 Interventions

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

Group II: Arm II (everolimus) Active Control 5 Interventions

Patients receive everolimus 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 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+

Findings from Research

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]

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]

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]

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]

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]

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]

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]

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]

References

1. Germany 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. [2023]

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

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

3. 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]

4. Switzerland 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). [2021]

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

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

6. England pubmed.ncbi.nlm.nih.gov

Safety and efficacy of everolimus in gastrointestinal and pancreatic neuroendocrine tumors after (177)Lu-octreotate. [2015]

7. 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]

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

Efficacy of Everolimus Combined with 177Lu-Dotatate in the Treatment of Neuroendocrine Tumors. [2022]

9. England 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). [2022]

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

Peptide Receptor Radionuclide Therapy With 177Lu-Octreotate in Patients With Somatostatin Receptor Expressing Neuroendocrine Tumors: Six Years' Assessment. [2020]

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

Neuroendocrine Tumor Therapy with Lutetium-177: A Literature Review. [2020]