Radioactive Drug vs Everolimus for Neuroendocrine Cancer
Recruiting in Palo Alto (17 mi)
+28 other locations
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 2
Recruiting
Sponsor: National Cancer Institute (NCI)
Must be taking: Somatostatin analogues
Disqualifiers: Major surgery, Brain metastases, Heart failure, others
No Placebo Group
Prior Safety Data
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.
12345Is 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.
12678How 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.
1891011Eligibility 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
+16 more
Exclusion Criteria
Pregnant or breastfeeding women
My heart condition is not well-managed and is severe.
Patients with potential adverse events in nursing infants
+4 more
Trial 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
Participant Groups
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.
2Treatment groups
Experimental Treatment
Active Control
Group I: Arm I (177Lu-DOTATATE)Experimental Treatment5 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 Control5 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, United States 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
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Northwestern Medicine Cancer Center KishwaukeeDeKalb, IL
Northwestern Medicine Cancer Center DelnorGeneva, IL
Northwestern Medicine Cancer Center WarrenvilleWarrenville, IL
UM Sylvester Comprehensive Cancer Center at AventuraAventura, FL
More Trial Locations
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Who Is Running the Clinical Trial?
National Cancer Institute (NCI)Lead Sponsor
References
Toxicity of a combined therapy using the mTOR-inhibitor everolimus and PRRT with [177Lu]Lu-DOTA-TATE in Lewis rats. [2023]Label="PURPOSE" NlmCategory="OBJECTIVE">Peptide receptor radionuclide therapy (PRRT) with [177Lu]Lu-DOTA0,TYR3-octreotate ([177Lu]Lu-DOTA-TATE) and the mechanistic target of rapamycin (mTOR) inhibitor everolimus are both approved for the treatment of neuroendocrine tumours (NET). However, tumour progression is still frequent, and treatment strategies need further improvement. One possible approach could be to combine different therapy options. In this study, we investigated the toxicity of a combined treatment with everolimus and [177Lu]Lu-DOTA-TATE in female Lewis rats.
177Lu-DOTATATE peptide receptor radionuclide therapy versus Everolimus in advanced pancreatic neuroendocrine tumors: a systematic review and meta-analysis. [2023]Advanced pancreatic neuroendocrine tumors (pNETs) present a therapeutic challenge with targeted therapies like Everolimus and Lu-DOTATATE peptide receptor radionuclide therapy (PRRT) showing beneficial effects in various cohort studies and randomized trials. Currently there is a paucity of trials with head-to-head comparison between PRRT and Everolimus in advanced pNETs. This systematic review was conducted to compare the therapeutic efficacy and safety profile of Lu-DOTATATE and Everolimus in advanced pNETs.
Efficacy of RAD001 (everolimus) and octreotide LAR in advanced low- to intermediate-grade neuroendocrine tumors: results of a phase II study. [2023]Evaluate the activity of everolimus (RAD001) in combination with octreotide long-acting repeatable (LAR) in patients with advanced low- to intermediate-grade neuroendocrine tumors.
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]Everolimus is recognized as one of the standard drugs for the treatment of unresectable or recurrent gastroenteropancreatic neuroendocrine tumors (NET). However, recent evidence has suggested that addition of somatostatin analogs to everolimus may yield better survival outcomes as compared to everolimus alone. In April 2020, we have initiated a randomized phase III trial in Japan, to confirm the superiority of combined everolimus plus lanreotide therapy over everolimus monotherapy in patients with unresectable or recurrent gastroenteropancreatic NETs with poor prognostic factors (Ki-67 labeling index: LI 5%-20% or Ki-67 LI
NeuroEndocrine Tumor Therapy with Lutetium-177-octreotate and Everolimus (NETTLE): A Phase I Study. [2022]To establish the optimal safe dose of everolimus in combination with (177)Lu-octreotate peptide receptor radionuclide therapy (PRRT) of advanced progressive gastro-entero pancreatic neuroendocrine tumors (GEP-NETs) and to define dose-limiting toxicity.
Safety and efficacy of everolimus in gastrointestinal and pancreatic neuroendocrine tumors after (177)Lu-octreotate. [2015]Although (177)Lu-octreotate is an effective treatment for patients with gastroenteropancreatic neuroendocrine tumors (GEP-NETs), some patients will fail or develop disease progression necessitating further treatment. We examined whether the safety and efficacy of everolimus after prior treatment with (177)Lu-octreotate is different from the published safety profile of everolimus in GEP-NETs. In this multicenter study, 24 GEP-NET patients were included. Adverse events were assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 3.0. Tumor response was measured according to the Response Evaluation Criteria in Solid Tumors (RECIST), version 1.0. Major clinical adverse events (grade 3 or 4) during treatment with everolimus were hyperglycemia (20.8%), fatigue (8.3%), thrombocytopenia (8.3%), and elevated alanine transaminase levels (8.3%). By radiological review, there were four partial responses (16.7%), five patients (62.5%) with stable disease, and three patients (12.5%) with progressive disease. For two patients (8.3%), no data on tumor response were available. Median progression-free survival (PFS) was 13.1 months (95% CI, 11.5-21.2). Median PFS of the current study was longer when compared with the RADIANT-3 trial (13.1 vs 11.4 months) and shorter when compared with the RADIANT-1 trial (13.1 vs 16.7 months). In conclusion, the safety profile of everolimus is not influenced by previous treatment with peptide receptor radiotherapy.
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]Advanced neuroendocrine tumors (NETs) are a rare malignancy with considerable need for effective therapies. Everolimus is a mammalian target of rapamycin (mTOR) inhibitor approved by the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) in 2016 for treatment of adults with progressive, well-differentiated, non-functional NETs of gastrointestinal (GI) or lung origin that are unresectable, locally advanced, or metastatic.
Efficacy of Everolimus Combined with 177Lu-Dotatate in the Treatment of Neuroendocrine Tumors. [2022]Background: Both everolimus and peptide receptor radionuclide therapy (PRRT) are approved as monotherapies for advanced neuroendocrine tumors (NETs). Research in animal models showed synergism between the two treatment modalities. This study aimed to evaluate the safety and efficacy of combining everolimus and PRRT in the treatment of unresectable NETs. Methods: Adult patients (≥18 years) with progressing and unresectable histologically confirmed grade 1-2 NETs of all origins were enrolled. Everolimus was started at a 5 mg daily dose and was increased after the initial three patients to 10 mg daily. Patients were treated concurrently with 177Lu-DOTATATE at an 8-week interval, with planned four cycles. Safety was the primary endpoint, with response rate and progression-free survival (PFS) being secondary. Results: Eleven patients were enrolled. The trial was terminated early for poor accrual. The median age was 51 years (18-64), and 4 were males. The median number of cycles of 177Lu-DOTATATE was 3, and the median cumulative dose was 300 mCi. The most frequent grade 1-2 toxicities were stomatitis (90.9%) and nausea (72.7%). Less frequent were fatigue (63.6%), anorexia, diarrhea, and skin changes (each at a 36.4% rate). Grade 3 toxicities occurred in 36% (fatigue, infection, pneumonitis, neutropenia, and stroke). No patient developed grade 4 toxicity. Treatment was stopped because of progression in three patients, and toxicity in another three patients, in addition, in four patients due to therapy interruption and in one patient who developed stroke. One patient achieved partial response, and nine had stable disease. One patient developed disease progression. At a median follow-up of 18.9 months, three died and one was lost to follow-up. The median PFS was 23.3 months. Conclusions: The combination of everolimus at a dose of 10 mg daily and 177Lu-DOTATATE appears not to be feasible. A larger trial at a lower dose of everolimus is warranted.
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]Label="BACKGROUND" NlmCategory="BACKGROUND">Although neuroendocrine tumors (NET) are classed as rare, they have a high prevalence and their incidence is increasing. Effective treatment with lutetium 17-[177Lu]Lu-oxodotreotide (Lutathera®) is possible in patients with well-differentiated NET, improving progression-free survival (PFS), overall survival (OS), and quality of life (QoL). However, progression does occur. Retreatment with additional Lutathera® cycles is an option to extend PFS and OS. Two retreatment cycles are usually proposed. We aim to compare four versus two Lutathera® retreatment cycles in patients with new progression of a well-differentiated intestinal NET.
Peptide Receptor Radionuclide Therapy With 177Lu-Octreotate in Patients With Somatostatin Receptor Expressing Neuroendocrine Tumors: Six Years' Assessment. [2020]Peptide receptor radionuclide therapy (PRRT) with radiolabeled somatostatin analogues is a promising treatment for patients with inoperable, well to moderately differentiated metastatic neuroendocrine tumors (NETs). In continuation of our novel study with the radionuclide lutetium Lu, we now present further results of Lu DOTATATE therapy in managing NETs and other somatostatin receptor-expressing tumors in a larger and more diverse patient group.
Neuroendocrine Tumor Therapy with Lutetium-177: A Literature Review. [2020]The worldwide incidence of neuroendocrine tumors (NETs) has been increasing. They are a very diverse group of tumors which are commonly found in the gastrointestinal and bronchopulmonary tracts. These tumors usually express somatostatin receptors. Therefore, somatostatin analogs are used for symptom relief as well as treatment. Of the many therapeutic options available, peptide receptor radionuclide therapy (PRRT) has been shown to be very promising. In January 2018, the Food Drug and Authority (FDA) approved 177Lu-Dotatate for use in gastroenteropancreatic neuroendocrine tumors (GEP-NETs). Lutetium is a lower energy beta-emitting radionuclide. The therapeutic use of lutetium-177 (177Lu) has shown better results in advanced gastroenteropancreatic and bronchial neuroendocrine tumors when compared with other therapies available. Adverse effects associated with this therapy include myelotoxicity and nephrotoxicity as the radiopeptides are reabsorbed and accumulate in the renal interstitium. Everolimus is a good and safe option in patients pretreated with 177Lu-Dotatate. Lutetium, in combination with somatostatin analogs, has proven efficacy to treat gastroenteropancreatic neuroendocrine tumors in candidates with somatostatin receptor-positive advanced tumors and normal renal function. This therapy has great potential as it decreases tumor size, improves symptoms, and improves quality of life.