Lutathera for Neuroendocrine Tumors

(NETTER-2 Trial)

Not currently recruiting at 51 trial locations

Overseen By Novartis Pharmaceuticals

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: Advanced Accelerator Applications

Must be taking: Somatostatin analogs

Must not be taking: Interferons, Everolimus, Chemotherapy

Disqualifiers: Pregnancy, Brain metastases, Diabetes, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 4

Duration: 32 weeks

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores whether a combination of Lutathera (a targeted radiotherapy) and octreotide (a long-acting injection) can slow the progression of certain fast-growing neuroendocrine tumors in the stomach, intestines, or pancreas more effectively than octreotide alone. The trial targets individuals diagnosed with these tumors, whether recently or in the past, who continue to experience symptoms despite previous treatments. Participants must have a specific type of tumor growth and must not have undergone certain treatments before joining the study. As a Phase 3 trial, this study represents the final step before FDA approval, offering participants an opportunity to contribute to potentially groundbreaking treatment advancements.

Do I need to stop my current medications to join the trial?

If you are taking short-acting octreotide, you must stop it 24 hours before and after Lutathera. If you are on long-acting SSAs like octreotide, you need to stop them at least 6 weeks before starting Lutathera.

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

Research has shown that Lutathera, when combined with octreotide, is generally safe for treating neuroendocrine tumors. In a study involving 360 patients, the most common serious side effects included low white blood cell counts in about 44% of patients, increased liver enzyme levels in 20%, and vomiting in 7%. Although these side effects might seem concerning, medical care can manage them.

The FDA has already approved Lutathera for treating certain types of neuroendocrine tumors, confirming its safety and effectiveness for those uses. This approval provides additional confidence in its safety, though individual reactions can vary. Patients should always consult their healthcare provider about possible side effects to understand how this treatment might affect them. ^{1 2 3 4 5}

Why are researchers excited about this study treatment for neuroendocrine tumors?

Lutathera is unique because it targets neuroendocrine tumors with a different approach than standard treatments like surgery or chemotherapy. It uses a radioactive compound that binds to tumor cells, delivering targeted radiation to shrink or eliminate them while sparing healthy tissue. Researchers are excited about Lutathera because it combines precision targeting with a new mechanism of action, potentially offering more effective treatment with fewer side effects compared to traditional options.

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

In this trial, participants in the investigational arm will receive Lutathera combined with octreotide. Research shows this combination may effectively treat neuroendocrine tumors. One study found that Lutathera extends the period patients live without disease progression to 22.8 months, compared to 8.5 months with high-dose octreotide alone, the control arm in this trial. Additionally, treatment with Lutathera and octreotide results in a 43% rate of tumor shrinkage or disappearance, four times higher than with octreotide alone. Lutathera has also improved patients' quality of life, making it a promising option for those with these tumors. ^{6 7 8 9 10}

Who Is on the Research Team?

Novartis Pharmaceuticals

Principal Investigator

Novartis Pharmaceuticals

Are You a Good Fit for This Trial?

This trial is for adults and adolescents (15 years or older, over 40 kg) with advanced Grade 2 or Grade 3 gastroenteropancreatic neuroendocrine tumors (GEP-NET), diagnosed within the last 6 months. Participants must have a certain level of tumor cell proliferation (Ki67 index ≥10 and ≤55%), express somatostatin receptors on all target lesions, and have a Karnofsky Performance Score of at least 60. Pregnant women, those unable to use effective contraception, or patients who've had certain prior treatments are excluded.

Inclusion Criteria

The tumor uptake observed in the target lesions must be > normal liver uptake

My GEP-NET tumor is advanced, cannot be removed by surgery, and was diagnosed within the last 6 months.

My GEP-NET tumor is advanced, cannot be removed by surgery, and was diagnosed within the last 6 months.

Exclusion Criteria

Total bilirubin > 3 x ULN

Patients for whom in the opinion of the investigator other therapeutic options (eg chemo-, targeted therapy) are considered more appropriate than therapy offered in the study, based on patient and disease characteristics

My potassium levels are high and not corrected before joining the study.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive Lutathera plus octreotide LAR or high dose octreotide LAR

32 weeks

4 visits (in-person) every 8 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

42 months

Optional Cross-over

Participants in the control arm may cross over to receive Lutathera upon progression

Optional Re-treatment

Participants in the Lutathera arm may receive additional cycles upon progression

What Are the Treatments Tested in This Trial?

Interventions

• high dose long-acting octreotide
• long-acting octreotide
• Lutathera

Trial Overview

The NETTER-2 study tests whether Lutathera combined with long-acting octreotide can extend the time without disease progression in GEP-NET patients compared to high-dose long-acting octreotide alone. It's designed for first-line treatment; some participants may cross over to Lutathera after progression or receive re-treatment.

How Is the Trial Designed?

Group I: Optional post-progression re-treatment with Lutathera Experimental Treatment 1 Intervention

Participants who received Lutathera in experimental arm and who progressed and met re-treatment eligibility criteria received additional 2 - 4 cycles of Lutathera (7.4 GBq/200 mCi x 4 cycles)

Group II: Lutathera® plus Octreotide LAR 30 mg (Investigational arm) Experimental Treatment 3 Interventions

Lutathera treatment consisted of a cumulative administered radioactivity of 29.6 GBq (800mCi) (7.4 GBq/200 mCi x 4 administrations every 8 +/- 1 week). Participants in the Lutathera arm were concomitantly administered with octreotide LAR 30 mg (Sandostatin LAR Depot) the day after each administration of Lutathera and no earlier than 4 hours after completion of the Lutathera infusion. Once Lutathera treatment completed, participants continued the 4-week interval administrations of 30 mg octreotide LAR until the completion of the Treatment Phase. Concomitantly with Lutathera, sterile amino acid solution was administered to minimize renal radiation exposure during Lutathera treatment.

Group III: Octreotide LAR 60 mg (Control arm) Active Control 1 Intervention

Participants were administered with octreotide LAR 60 mg (Sandostatin LAR Depot) at 4-week intervals until the completion of the Treatment Phase.

Group IV: Optional post-progression cross-over to Lutathera Active Control 1 Intervention

Participants who received Octreotide LAR in Active comparator arm and who progressed and met cross-over eligibility criteria received maximum 4 cycles of Lutaathera (7.4 GBq/200 mCi x 4 cycles) plus octreotide long-acting (30 mg every 8 weeks).

Group V: Optional post-progression re-treatment with Lutathera after cross-over Active Control 2 Interventions

Participants who received Octreotide LAR in Active comparator arm subsequently entered cross-over, received Lutathera in cross-over, progressed for the second time and met re-treatment eligibility criteria could receive additional 2 - 4 cycles of Lutathera (7.4 GBq/200 mCi x 4 cycles).

Who Is Running the Clinical Trial?

Advanced Accelerator Applications

Lead Sponsor

Trials

37

Recruited

3,000+

Published Research Related to This Trial

In a study involving seven patients with neuroendocrine tumors, the peptide [(177)Lu-DOTA(0),Tyr(3)]octreotate ((177)Lu-DOTATATE) demonstrated a longer residence time in tumors compared to [(177)Lu-DOTA(0),Tyr(3)]octreotide ((177)Lu-DOTATOC), suggesting it may be more effective for peptide receptor radionuclide therapy (PRRT).

Although (177)Lu-DOTATATE resulted in longer residence times in the kidneys, the overall tumor dose was still higher, making (177)Lu-DOTATATE the preferred choice for PRRT despite potential kidney dose concerns.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparison of [(177)Lu-DOTA(0),Tyr(3)]octreotate and [(177)Lu-DOTA(0),Tyr(3)]octreotide: which peptide is preferable for PRRT? Esser, JP., Krenning, EP., Teunissen, JJ., et al.[2019]

Lutetium Lu 177 dotatate (Lutathera®) is an approved targeted therapy specifically for patients with advanced gastroenteropancreatic neuroendocrine tumors (GEP-NETs), offering a new treatment option for this heterogeneous group of tumors.

Patients who are already receiving octreotide long-acting release may be eligible for this second-line therapy, highlighting the importance of personalized treatment plans in managing advanced NETs.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Targeted Therapy: New Radiolabeled Somatostatin Analogs to Treat Gastroenteropancreatic Neuroendocrine Tumors. Boucher, JE., Sommers, R.[2019]

In a study of 79 patients with progressive neuroendocrine tumors treated with Lu-DOTATATE, 13% showed a partial response and 64% had stable disease, with a median time to progression of 28 months overall.

The treatment was found to be safe, with only a few patients experiencing mild toxicity, including grade 1 haematotoxicity and nephrotoxicity, supporting its use as an effective option for managing these tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Early efficacy of and toxicity from lutetium-177-DOTATATE treatment in patients with progressive metastatic NET. Pencharz, D., Walker, M., Yalchin, M., et al.[2019]

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]

Lutathera, approved in Japan in 2021, is the first peptide receptor radionuclide therapy specifically designed for treating somatostatin receptor-positive neuroendocrine tumors, providing a much-needed treatment option for these patients.

Current imaging methods in Japan for assessing somatostatin receptor expression in tumors primarily rely on In-111 pentetreotide scintigraphy, but advancements like 68Ga-DOTA-SSA PET/CT are being explored to improve evaluation techniques.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[68Ga-DOTATOC PET/CT for Diagnosing Neuroendocrine Tumors]. Koyasu, S., Shimizu, Y., Nakamoto, Y.[2022]

Citations

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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 ...

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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 ...

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clinicaltrials.gov

clinicaltrials.gov/study/NCT04665739

NCT04665739 | Testing Lutetium Lu 177 Dotatate in ...

Lutetium Lu 177 dotatate may be more effective than everolimus in shrinking or stabilizing advanced bronchial neuroendocrine tumors. Detailed Description.

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lutathera-hcp.com

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1L: NETTER-2 | LUTATHERA® (lutetium Lu 177 dotatate) | HCP

Overall Response Rate (Full Analysis Set) ... 43% overall response rate for LUTATHERA plus 30 mg octreotide, which is 4x greater ...

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pmc.ncbi.nlm.nih.gov

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

Long-term clinical outcomes of [177Lu]Lu-DOTATATE in ...

They established an estimated median PFS of 36.4 months (about 3 years) and the mean OS was 61.9, 52.2, and 38.4 months (about 3 years) in WHO ...

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accessdata.fda.gov

accessdata.fda.gov/drugsatfda_docs/label/2024/208700s031lbl.pdf

LUTATHERA® (lutetium Lu 177 dotatate) injection, for ...

The safety data of LUTATHERA with octreotide was evaluated in NETTER-1 [see ... neuroendocrine tumors (GEP-NETs) was assessed in 360 patients in the ...

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lutathera-hcp.com

lutathera-hcp.com/2l-netter-1-safety

2L: NETTER-1 Safety | HCP

The most common grade 3/4 adverse reactions with a higher incidence in the LUTATHERA arm were lymphopenia (44%), increased GGT (20%), vomiting (7%), ...

8.

pubmed.ncbi.nlm.nih.gov

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

Post-marketing Safety Evaluation of Lutathera ( 177 Lu- ...

This study aims to conduct a comprehensive analysis of the adverse events (AEs) associated with Lutathera using FDA Adverse Event Reporting System (FAERS) data.

9.

jnm.snmjournals.org

jnm.snmjournals.org/content/66/3/449

Dosimetry of [177Lu]Lu-DOTATATE in Patients with Advanced ...

This substudy of the phase III NETTER-1 trial evaluated [177Lu]Lu-DOTATATE (hereafter 177Lu-DOTATATE) for advanced midgut neuroendocrine tumors ...

10.

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 ...