Lu-DOTA-TATE for Neuroendocrine Carcinoma

Overseen By NET Coordinator

Age: Any Age

Sex: Any

Trial Phase: Phase 2

Sponsor: AHS Cancer Control Alberta

Must be taking: Somatostatin analogues

Must not be taking: mTOR inhibitors, Tyrosine kinase inhibitors

Disqualifiers: Uncontrolled diabetes, Brain metastases, 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

Approved in 3 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 13

500 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial protocol does not specify if you need to stop taking your current medications. However, certain treatments like mTOR inhibitors, tyrosine kinase inhibitors, chemotherapy, and interferon must not have been used within specific time frames before joining the trial.

What data supports the effectiveness of the treatment Lutetium-177 Octreotate for neuroendocrine carcinoma?

Research shows that Lutetium-177 Octreotate is effective in treating patients with neuroendocrine tumors, including those that are metastasized (spread to other parts of the body) or inoperable. It has been used successfully in patients with bronchial and gastroenteropancreatic neuroendocrine tumors, showing positive results in terms of efficacy and safety. ^{1 2 3 4 5}

Is Lu-DOTA-TATE safe for human use?

Lu-DOTA-TATE has been used in patients with neuroendocrine tumors, and studies have looked at its safety. It is important to ensure that the radiochemical purity is within specific limits to avoid unwanted side effects, and measures like adding DTPA can help reduce radiation exposure to bones. Overall, it has been used safely in clinical settings with proper precautions. ^{1 2 4 6 7}

What makes the drug Lu-DOTA-TATE unique for treating neuroendocrine carcinoma?

Lu-DOTA-TATE is unique because it is a targeted therapy that uses a radioactive substance, Lutetium-177, to deliver radiation directly to cancer cells that have somatostatin receptors, which are common in neuroendocrine tumors. This approach allows for precise treatment of tumors while minimizing damage to surrounding healthy tissue. ^{1 2 4 8 9}

What is the purpose of this trial?

Neuroendocrine tumours (NETs) are rare, slow growing, and diagnosis is often delayed with advanced metastases at presentation. In select patient populations, radioisotope therapy with Lutetium-177 (Lu-DOTA-TATE) has been shown to be a safe and effective palliative therapy, and has been widely used by research groups in Europe. A brand of Lu-DOTA-TATE (Lutathera(R)) is approved for the treatment of gastroenteropancreatic NETs in Europe, the U.S., and more recently in Canada. While Lutathera(R) is approved in Canada, it is not publicly funded in Alberta. Lu-DOTA-TATE has been used at the Cross Cancer Institute to treat more than 300 patients with NETs since August, 2010. Our Lu-DOTA-TATE treatment was initially given under Health Canada's Special Access Programme (SAP), with each individual treatment requiring separate approval. In 2014, Health Canada requested we conduct a clinical trial with Lu-DOTA-TATE instead. The purpose of this study is to: 1) assess the efficacy of Lu-DOTA-TATE treatment in patients with somatostatin receptor positive tumours; 2) assess the safety of Lu-DOTA-TATE; 3) assess the effect of Lu-DOTA-TATE on Quality of Life and survival.

Research Team

Donald W Morrish, MD, PhD

Principal Investigator

Professor of Endocrinology and Oncology, University of Alberta, Cross Cancer Institute

Eligibility Criteria

This trial is for individuals with neuroendocrine tumors, aged 14-90, who have a life expectancy of more than 12 weeks and are physically able to perform daily activities (ECOG ≤2). They must have somatostatin receptor positive tumors confirmed by imaging and meet specific blood test criteria. Those previously treated with Lu-DOTA-TATE or having certain medical conditions are excluded.

Inclusion Criteria

I have previously received Lu-DOTA-TATE treatment.

My liver is functioning well, and my blood protein levels are normal.

I have a confirmed diagnosis of a neuroendocrine tumor.

Exclusion Criteria

Group A (Primary Therapy): Another significant medical, psychiatric or surgical condition uncontrolled by treatment

Group A (Primary Therapy): Breast feeding

Group A (Primary Therapy): Pregnancy

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Induction Treatment

Participants receive Lu-DOTA-TATE every 10-14 weeks for up to 4 treatments. An amino acid solution is infused prior to and during the Lu-DOTA-TATE infusion to protect the kidneys.

40-56 weeks

4 visits (in-person)

Maintenance Treatment

Participants with stable or improving disease status continue to receive Lu-DOTA-TATE every 22-40 weeks, up to a maximum of 8 treatments.

176-320 weeks

Up to 8 visits (in-person)

Follow-up

Participants are monitored for progression-free survival and overall survival at 6 months, 1 year, 2 years, 3 years, and 5 years after the last treatment.

5 years

Periodic visits (in-person and virtual)

Treatment Details

Interventions

• Lutetium-177 Octreotate

Trial Overview [177]Lu-DOTA-TATE therapy is being tested for its effectiveness in treating neuroendocrine tumors and its impact on patients' quality of life and survival. The study will also evaluate the safety of this treatment which has been used under special access but now requires clinical trial assessment.

Participant Groups

Group I: [177]Lu-DOTA-TATE Therapy Experimental Treatment 1 Intervention

Nominal, induction stage dose of 150 mCi (5.55 GBq) \[177\]Lu-DOTA-TATE every 10 - 14 weeks for 4 treatments. Nominal maintenance stage dose of 75 mCi (2.78 GBq) \[177\]Lu-DOTA-TATE every 22 - 40 weeks, up to a maximum of 8 treatments.

Lutetium-177 Octreotate is already approved in European Union, United States, Canada for the following indications:

Approved in European Union as Lutathera for:

• Unresectable or metastatic, progressive, well differentiated (G1 and G2), somatostatin receptor positive gastroenteropancreatic neuroendocrine tumours (GEP-NETs) in adults

Approved in United States as Lutathera for:

• Somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumors (GEP-NETs), including foregut, midgut, and hindgut neuroendocrine tumors in adults

Approved in Canada as Lutathera for:

• Gastroenteropancreatic NETs

Who Is Running the Clinical Trial?

AHS Cancer Control Alberta

Lead Sponsor

Trials

188

Recruited

26,900+

Findings from Research

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]

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]

177Lu-octreotate therapy showed potential effectiveness in treating paragangliomas and meningiomas, with some patients experiencing tumor regression or stable disease, although response rates were lower than in gastroenteropancreatic neuroendocrine tumors.

The treatment did not demonstrate any antitumor effects in patients with small cell lung carcinoma or melanoma, highlighting the need for further studies to confirm these findings due to the small patient sample size.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of therapy with [177Lu-DOTA0, Tyr3]octreotate in patients with paraganglioma, meningioma, small cell lung carcinoma, and melanoma. van Essen, M., Krenning, EP., Kooij, PP., et al.[2013]

The study developed and validated a high-performance liquid chromatography (HPLC) method for quality control of the radiopeptide [177Lu]Lu-DOTA-TATE, ensuring its radiochemical purity meets therapeutic standards (95-105% of label claim).

The HPLC method demonstrated accuracy, precision, and sensitivity, making it suitable for clinical samples, which is crucial for the safe and effective use of [177Lu]Lu-DOTA-TATE in treating neuroendocrine tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The development and validation of a high performance liquid chromatography method to determine the radiochemical purity of [177Lu]Lu-HA-DOTA-TATE in pharmaceutical preparations. van Andel, L., Aalbersberg, EA., Geluk-Jonker, MM., et al.[2021]

Salvage treatment with [177Lu-DOTA,Tyr3]octreotate is effective and safe for patients with progressive bronchial neuroendocrine tumors (NET) or gastroenteropancreatic NET (GEP-NET), showing a median overall survival of 80.8 months after initial treatment.

The treatment resulted in low rates of severe side effects, with only 6.6% and 7.7% of patients experiencing grade III/IV bone marrow toxicity after re-treatment and re-re-treatment, respectively, and no cases of severe kidney toxicity were reported.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Salvage peptide receptor radionuclide therapy with [177Lu-DOTA,Tyr3]octreotate in patients with bronchial and gastroenteropancreatic neuroendocrine tumours. van der Zwan, WA., Brabander, T., Kam, BLR., et al.[2020]

A study of 32 administrations of [177Lu]Lu-DOTA-TATE showed that using lead aprons significantly reduced radiation exposure for medical staff, with reductions of up to 71% for physicians and 68% for nurses.

The average radiation dose measured was consistent across different monitoring methods, indicating that with proper safety measures, administering [177Lu]Lu-DOTA-TATE can be done safely, although regular monitoring is essential to stay within annual dose limits.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Radiation exposure assessment of nuclear medicine staff administering [177Lu]Lu-DOTA-TATE with active and passive dosimetry. Riveira-Martin, M., Struelens, L., Muñoz Iglesias, J., et al.[2023]

Incorporating DTPA with (177)Lu-DOTA(0),Tyr(3)octreotate before administration significantly reduces the accumulation of free (177)Lu(3+) in bones, which can cause unwanted radiation exposure to bone marrow.

The study demonstrated that (177)Lu-DTPA has rapid renal clearance and lower total body retention compared to (177)LuCl(3), suggesting it is a safer option for managing free (177)Lu(3+) in peptide receptor-targeted radionuclide therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The addition of DTPA to [177Lu-DOTA0,Tyr3]octreotate prior to administration reduces rat skeleton uptake of radioactivity. Breeman, WA., van der Wansem, K., Bernard, BF., et al.[2019]

A 60-year-old woman with a metastatic neuroendocrine tumor showed a partial response after 4 cycles and a complete response after 2 additional maintenance cycles of (177)Lu DOTATATE therapy, indicating its efficacy in treating such tumors.

This case suggests that maintenance therapy with (177)Lu DOTATATE could enhance treatment outcomes for patients with neuroendocrine tumors, warranting further research in this area.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Complete Resolution of Neuroendocrine Tumor Soft Tissue Metastases After 177Lu DOTATATE PRRT Induction and Maintenance Therapy. Makis, W., McCann, K., Buteau, FA., et al.[2019]

A ready-to-use formulation of 177Lu-DOTA-TATE was developed for treating neuroendocrine tumors, achieving over 90% radiolabeling yields and maintaining safety for human use for more than a week with high radiochemical purity.

The optimized production process allows for bulk scale preparation, ensuring consistent availability of this effective radiopharmaceutical for patient treatment across various nuclear medicine centers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bulk Scale Formulation of Therapeutic Doses of Clinical Grade Ready-to-Use 177Lu-DOTA-TATE: The Intricate Radiochemistry Aspects. Mathur, A., Prashant, V., Sakhare, N., et al.[2018]

References

1. 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]

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

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

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

Effects of therapy with [177Lu-DOTA0, Tyr3]octreotate in patients with paraganglioma, meningioma, small cell lung carcinoma, and melanoma. [2013]

4. Netherlands pubmed.ncbi.nlm.nih.gov

The development and validation of a high performance liquid chromatography method to determine the radiochemical purity of [177Lu]Lu-HA-DOTA-TATE in pharmaceutical preparations. [2021]

5. Germany pubmed.ncbi.nlm.nih.gov

Salvage peptide receptor radionuclide therapy with [177Lu-DOTA,Tyr3]octreotate in patients with bronchial and gastroenteropancreatic neuroendocrine tumours. [2020]

6. Germany pubmed.ncbi.nlm.nih.gov

Radiation exposure assessment of nuclear medicine staff administering [177Lu]Lu-DOTA-TATE with active and passive dosimetry. [2023]

7. Germany pubmed.ncbi.nlm.nih.gov

The addition of DTPA to [177Lu-DOTA0,Tyr3]octreotate prior to administration reduces rat skeleton uptake of radioactivity. [2019]

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

Complete Resolution of Neuroendocrine Tumor Soft Tissue Metastases After 177Lu DOTATATE PRRT Induction and Maintenance Therapy. [2019]

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

Bulk Scale Formulation of Therapeutic Doses of Clinical Grade Ready-to-Use 177Lu-DOTA-TATE: The Intricate Radiochemistry Aspects. [2018]