Lutathera for Neuroendocrine Tumors

(NETTER-2 Trial)

Recruiting at 44 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

226 Participants Needed

Trial Summary

What is the purpose of this trial?

This trial is testing if a combination of targeted radiation therapy and a hormone-like drug can slow down disease progression in patients with fast-growing gastroenteropancreatic neuroendocrine tumors. The treatment aims to deliver radiation directly to cancer cells while using the hormone-like drug to manage symptoms and slow tumor growth. The study includes patients who have not previously used similar treatments or have used them without their disease getting worse.

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.

What data supports the effectiveness of the treatment Lutathera for neuroendocrine tumors?

Research shows that Lutathera, a targeted therapy, is effective in treating well-differentiated neuroendocrine tumors by improving progression-free survival (the time during which the disease does not get worse), overall survival, and quality of life. It is especially beneficial for patients with advanced gastroenteropancreatic neuroendocrine tumors. ^{1 2 3 4 5}

How is the drug Lutathera unique for treating neuroendocrine tumors?

Lutathera is unique because it is the first drug approved for peptide receptor radionuclide therapy (PRRT), specifically targeting somatostatin receptor-positive neuroendocrine tumors. It combines a radioactive component with a somatostatin analogue to deliver targeted radiation to tumor cells, causing DNA damage and cell death, which is different from traditional chemotherapy or surgery. ^{1 2 3 5 6}

Research Team

Novartis Pharmaceuticals

Principal Investigator

Novartis Pharmaceuticals

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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 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]

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]

References

1. England pubmed.ncbi.nlm.nih.gov

Early efficacy of and toxicity from lutetium-177-DOTATATE treatment in patients with progressive metastatic NET. [2019]

2. 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]

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

Targeted Therapy: New Radiolabeled Somatostatin Analogs to Treat Gastroenteropancreatic Neuroendocrine Tumors. [2019]

4. Germany 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? [2019]

5. Japan pubmed.ncbi.nlm.nih.gov

[68Ga-DOTATOC PET/CT for Diagnosing Neuroendocrine Tumors]. [2022]

6. Switzerland pubmed.ncbi.nlm.nih.gov

Lutathera®: The First FDA- and EMA-Approved Radiopharmaceutical for Peptide Receptor Radionuclide Therapy. [2020]