Lutathera for Pheochromocytoma/Paraganglioma

Overseen By Frank I Lin, M.D.

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: National Cancer Institute (NCI)

Must be taking: Somatostatin analogues

Must not be taking: Antidepressants

Disqualifiers: Liver dysfunction, 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 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 17

Duration: 32 weeks

130 Participants Needed

Trial Summary

What is the purpose of this trial?

Background: Pheochromocytoma and paraganglioma are rare tumors. They usually form inside and near the adrenal gland or in the neck region. Not all these tumors can be removed with surgery, and there are no good treatments if the disease has spread. Researchers think a new drug may be able to help. Objective: To learn the safety and tolerability of Lu-177-DOTATATE. Also, to see if it improves the length of time it takes for the cancer to return. Eligibility: Adults who have an inoperable tumor of the study cancer that can be detected with Ga-68-DOTATATE PET/CT imaging Design: Participants will be screened with a medical history, physical exam, and blood tests. Eligible participants will be admitted to the NIH Clinical Center. Participants will get the study drug in an intravenous infusion. They will get 4 doses, given about 8 weeks apart. Between 4 and 24 hours after each study drug dose, participants will have scans taken. They will lie on their back on a scanner table. Participants will have vital signs taken. They will give blood and urine samples. During the study, participants will have other scans taken. Some scans will use a radioactive tracer. Participants will complete quality of life questionnaires. Participants will be contacted by phone 1-3 days after they leave the Clinical Center. They will then be followed every 3 to 6 months for 3 years or until their disease gets worse.

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 on somatostatin analogue therapy, it should not be started or changed within 3 months of joining the study. If you are on short-term octreotide, you may need to pause it for 24 hours before receiving the study drug.

What data supports the effectiveness of the treatment Lutathera for Pheochromocytoma/Paraganglioma?

Research shows that Lutathera, a treatment using a radiolabeled somatostatin analog, has been effective in treating various neuroendocrine tumors, including paragangliomas, by targeting specific receptors on tumor cells. This suggests potential effectiveness for Pheochromocytoma/Paraganglioma as well. ^{1 2 3 4 5}

Is Lutathera (Lu-177-DOTATATE) generally safe for human use?

Lutathera (Lu-177-DOTATATE) has been used in treating neuroendocrine tumors and is generally considered safe, but it can have side effects. Some reported adverse effects include potential toxicity to the kidneys, liver, and blood cells, as well as a risk of developing a second cancer. It is important for patients to discuss these risks with their healthcare provider. ^{1 2 4 6 7}

What makes the drug Lutathera unique for treating pheochromocytoma/paraganglioma?

Lutathera is unique because it is a radioligand therapy that specifically targets somatostatin receptors, which are often present in pheochromocytoma and paraganglioma tumors. This allows it to deliver targeted radiation directly to the tumor cells, potentially reducing side effects compared to traditional chemotherapy. ^{1 2 4 8 9}

Research Team

Frank I Lin, M.D.

Principal Investigator

National Cancer Institute (NCI)

Eligibility Criteria

Adults with inoperable pheochromocytoma or paraganglioma that shows up on a Ga-68-DOTATATE PET/CT scan. They should have progressive disease, no severe liver or kidney issues, and not be pregnant. Participants must agree to use non-hormonal contraception for 6 months post-treatment if of childbearing potential.

Inclusion Criteria

Negative serum pregnancy test for women of childbearing potential

Agreement to use effective, non-hormonal contraception

Must have outside endocrinologist/medical oncologist who can follow the participant after receiving PRRT (NIH only requirement)

Exclusion Criteria

Pregnancy or lactation

Patient weight > 400 lbs

Participation in any therapeutic clinical study with an investigational agent within the last 30 days

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment

Participants receive Lu-177-DOTATATE via intravenous infusion every 8 weeks for a total of 4 doses

32 weeks

4 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment, with follow-up every 12 weeks until 3 years after the first administration

3 years

Remote or telemedicine visits every 12 weeks

Long-term follow-up

Participants are contacted yearly to assess survival and disease status after the initial 3-year follow-up period

Until death

Treatment Details

Interventions

• Lu-177-DOTATATE

Trial Overview The trial is testing Lu-177-DOTATATE's safety and effectiveness against rare tumors near the adrenal gland or neck region. Patients receive four intravenous doses about eight weeks apart, followed by scans and regular check-ups including quality of life assessments over three years.

Participant Groups

Group I: 1/Lu-177-DOTATATE Experimental Treatment 4 Interventions

Lu-177-DOTATATE is administered IV every 8 (+/- 2) weeks, for a total of 4 administrations. A Ga-68-DOTATATE PET and F-18-FDG-PET, as well as CT/ MRI for RECIST monitoring, will be obtained post 2 administrations and post 4 administrations. Concomitant administration of an IV infusion of an amino acid (AA) solution will also be done for renal protection. Concomitant administration of an IV infusion of an amino acid (AA) solution will also be done for renal protection.

Lu-177-DOTATATE is already approved in European Union, United States 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 and children aged 12 years and older

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 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]

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]

177Lu-DOTA-Peptide 2, a new radioantagonist, showed high stability and selective binding to somatostatin receptors in HT-29 colorectal cancer cells, indicating its potential for targeted therapy.

The study demonstrated that 177Lu-DOTA-Peptide 2 has a low internalization rate and a high tumor uptake, making it a promising candidate for radionuclide therapy in treating somatostatin receptor-positive tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Preclinical study of a new 177Lu-labeled somatostatin receptor antagonist in HT-29 human colorectal cancer cells. Behnammanesh, H., Erfani, M., Hajiramezanali, M., et al.[2023]

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]

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 development of a single vial kit for (177) Lu-DOTATATE allows for safe and efficient preparation of this radiopharmaceutical in hospital settings, making it more accessible for treating patients with inoperable neuroendocrine tumors.

Preclinical studies showed that (177) Lu-DOTATATE is rapidly cleared from the body through the kidneys, indicating a favorable biodistribution profile that supports its use in peptide receptor radionuclide therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Single vial kit formulation of DOTATATE for preparation of (177) Lu-labeled therapeutic radiopharmaceutical at hospital radiopharmacy. Mukherjee, A., Lohar, S., Dash, A., et al.[2019]

Lutetium Lu-177 dotatate is an effective treatment for gastroenteropancreatic neuroendocrine tumors, significantly improving progression-free survival, as shown in European studies.

In a study of 12 patients, tumor flare reactions were observed in 5 patients, but these reactions can be effectively managed with corticosteroids or other strategies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Lutetium Lu-177 Dotatate Flare Reaction. Salner, AL., Blankenship, B., Dunnack, H., et al.[2022]

[177Lu]Lu-DOTA-TATE shows promising antitumor activity in treating advanced somatostatin receptor-positive tumors, including pheochromocytoma/paraganglioma and bronchial neuroendocrine tumors, based on a systematic review of 16 studies.

The treatment is generally safe, with most side effects being mild to moderate and transient, similar to those observed in patients with gastroenteropancreatic neuroendocrine tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and Safety of [177Lu]Lu-DOTA-TATE in Adults with Inoperable or Metastatic Somatostatin Receptor-Positive Pheochromocytomas/Paragangliomas, Bronchial and Unknown Origin Neuroendocrine Tumors, and Medullary Thyroid Carcinoma: A Systematic Literature Review. Hertelendi, M., Belguenani, O., Cherfi, A., et al.[2023]

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. 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]

3. Iran pubmed.ncbi.nlm.nih.gov

Preclinical study of a new 177Lu-labeled somatostatin receptor antagonist in HT-29 human colorectal cancer cells. [2023]

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. 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]

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

Single vial kit formulation of DOTATATE for preparation of (177) Lu-labeled therapeutic radiopharmaceutical at hospital radiopharmacy. [2019]

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

Lutetium Lu-177 Dotatate Flare Reaction. [2022]

8. Switzerland pubmed.ncbi.nlm.nih.gov

Efficacy and Safety of [177Lu]Lu-DOTA-TATE in Adults with Inoperable or Metastatic Somatostatin Receptor-Positive Pheochromocytomas/Paragangliomas, Bronchial and Unknown Origin Neuroendocrine Tumors, and Medullary Thyroid Carcinoma: A Systematic Literature Review. [2023]

9. Japan pubmed.ncbi.nlm.nih.gov

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