Lutathera + Olaparib for Neuroendocrine Cancer

Overseen By Frank I Lin, M.D.

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: National Cancer Institute (NCI)

Must be taking: Somatostatin analogues

Must not be taking: CYP3A inhibitors, CYP3A inducers

Disqualifiers: Other malignancies, Brain metastases, HIV, others

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

Compensation: Varies

Number of Visits: 8

Duration: 32 weeks

56 Participants Needed

Trial Summary

What is the purpose of this trial?

Background: A neuroendocrine tumor is a rare type of tumor. It comes from body cells called neuroendocrine cells. Sometimes, these tumors develop in the gastrointestinal tract and pancreas. Researchers want to find out if a combination of drugs can shrink these tumors. Objective: To learn if people with certain neuroendocrine tumors can take a combination of 2 drugs, Lutathera and Olaparib, without having severe side effects, and if this treatment makes the tumors shrink. Eligibility: Adults 18 and older who have a neuroendocrine tumor in the pancreas or intestine that cannot be cured by surgery and has somatostatin receptors on the cells. Design: Eligible participants will get Lutathera through an intravenous (IV) infusion every 8 weeks for 4 cycles. One cycle is 8 weeks. Each cycle includes a follow-up visit at week 4. For the IV, a small plastic tube is put into an arm vein. Participants will also take Olaparib by mouth twice a day for 4 weeks of each cycle. They will use a medicine diary to track the doses. During the study, participants will have physical exams. They will have blood and urine tests. They will fill out questionnaires about their general well-being and function. Their heart function will be tested. They will have scans of their chest, abdomen, and pelvis. One type of scan will use an IV infusion of a radioactive tracer. Participants will have a follow-up visit about 4 weeks after treatment ends. Then they will have follow-up visits every 12 weeks for 3 years. Then they will have yearly phone calls.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop all current medications, but it does mention that you cannot use certain medications like strong CYP3A inhibitors or inducers close to the start of the trial. If you are on somatostatin analogue therapy, you must have been on a consistent dose for at least 3 months before joining the study.

What data supports the effectiveness of the treatment Lutathera + Olaparib for neuroendocrine cancer?

Research shows that Lutathera (a form of Lutetium-177-DOTATATE) is effective in treating neuroendocrine tumors, with significant tumor regression and improved quality of life. Patients treated with Lutathera have a median progression-free survival of over 40 months and a longer overall survival compared to other treatments. ^{1 2 3 4 5}

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

Lutathera (Lu-177-DOTATATE) is generally considered safe for humans, with side effects that are usually mild and reversible. Severe long-term side effects are rare, and most patients experience an improved quality of life. ^{1 5 6 7 8}

What makes the Lutathera + Olaparib treatment unique for neuroendocrine cancer?

Lutathera (Lu-177-DOTATATE) is a novel treatment for neuroendocrine tumors that targets somatostatin receptors, which are often present on these tumors, using a radioactive substance to deliver targeted radiation. This approach is unique because it combines targeted therapy with radiation, offering a new option for patients with limited treatment choices. ^{1 5 7 9 10}

Research Team

Frank I Lin, M.D.

Principal Investigator

National Cancer Institute (NCI)

Eligibility Criteria

Adults over 18 with inoperable neuroendocrine tumors in the pancreas or intestine, which have somatostatin receptors and haven't been cured by surgery. Participants must not be pregnant, agree to use contraception, and should not have had certain previous cancer treatments or uncontrolled illnesses.

Inclusion Criteria

Ability to understand and willingness to sign informed consent

I am fully active and can carry on all my pre-disease activities without restriction.

My cancer has grown or spread in the last 3 years, and there's at least one tumor that can be measured.

Exclusion Criteria

Known hypersensitivity to olaparib or Lutathera or any excipients of these products

I haven't had chemotherapy or radiotherapy in the last 4 weeks.

Involvement in the planning and/or conduct of the study

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive Lutathera through IV infusion every 8 weeks for 4 cycles and take Olaparib orally twice a day for 4 weeks of each cycle

32 weeks

4 visits (in-person) every 8 weeks, additional visits every 4 weeks for follow-up within each cycle

End of Treatment (EOT)

Safety end of treatment visit approximately 30 days after the last dose of study drug

4 weeks

1 visit (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment with follow-up visits every 12 weeks for 3 years, then yearly phone calls

3 years

Quarterly visits (in-person) for 3 years, then yearly phone calls

Treatment Details

Interventions

• Lu-177-DOTATATE
• Olaparib

Trial Overview The trial is testing if Lutathera (given via IV every 8 weeks for four cycles) combined with Olaparib (taken orally twice daily for four weeks each cycle) can safely shrink gastroenteropancreatic neuroendocrine tumors without causing severe side effects.

Participant Groups

Group I: 2/Lu-177-DOTATATE + Olaparib fixed dose Experimental Treatment 5 Interventions

Lu-177-DOTATATE and olaparib at the MTD

Group II: 1/Lu-177-DOTATATE + Olaparib escalation Experimental Treatment 5 Interventions

Lu-177-DOTATATE and escalating doses of olaparib to determine the maximum-tolerated dose (MTD)

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, the combination of (177)Lu-octreotate and capecitabine showed a manageable short-term toxicity profile, with no severe side effects like grade 3 or 4 leukopenia or neutropenia, and no significant renal impairment.

The treatment was deemed feasible and safe, prompting the initiation of a randomized controlled trial to further evaluate its anti-tumor efficacy compared to (177)Lu-octreotate alone.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Report on short-term side effects of treatments with 177Lu-octreotate in combination with capecitabine in seven patients with gastroenteropancreatic neuroendocrine tumours. van Essen, M., Krenning, EP., Kam, BL., et al.[2022]

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]

Treatment with (177)Lu-DOTATATE, a radiolabelled somatostatin analogue, shows promising results in managing inoperable or metastasized neuroendocrine tumors, with significant tumor regression and a median progression-free survival of over 40 months.

The therapy is associated with few and mild side effects, especially when kidney-protective agents are used, and it significantly improves patients' quality of life, suggesting it could become a first-choice treatment option for these patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Lutetium-labelled peptides for therapy of neuroendocrine tumours. Kam, BL., Teunissen, JJ., Krenning, EP., et al.[2022]

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]

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]

(177)Lu-DOTA-Tyr(3)-octreotate demonstrated the highest tumor uptake in small cell lung cancer (SCLC) models, indicating its potential as an effective therapeutic option compared to other radiopharmaceuticals.

(111)In-DTPA-octreotide showed better tumor localization than (99m)Tc-depreotide, suggesting that (111)In-DTPA-octreotide may be more effective for detecting SCLC due to its higher tumor-to-normal tissue activity concentration ratios.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Differences in biodistribution between 99mTc-depreotide, 111In-DTPA-octreotide, and 177Lu-DOTA-Tyr3-octreotate in a small cell lung cancer animal model. Schmitt, A., Bernhardt, P., Nilsson, O., et al.[2019]

Peptide receptor radionuclide therapy with (177)Lu-DOTATATE is effective for patients with metastasized or inoperable neuroendocrine tumors that show increased uptake on octreotide scintigraphy, leading to improved quality of life and partial tumor reduction or stabilization.

Side effects from this treatment are generally mild and reversible, with severe long-term side effects being rare; however, about 20% of patients may not experience any treatment effect.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Radionuclide therapy for neuroendocrine tumours]. Mortensen, J., Oturai, P., Højgaard, L., et al.[2019]

In a study of 219 Lutathera injections over 70 months, using a peristaltic pump (method 2) resulted in a 34.9% reduction in residual radioactivity compared to a volumetric infusion pump (method 1), indicating improved efficiency in drug delivery.

Despite method 2 having a higher cost per injection, it was reported to be safer and more suitable by operators, with no major incidents occurring during its use, suggesting it may be a better option for future radioligand therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

177Lu-Dotatate administration using an infusion pump or a peristaltic pump: comparison of two methods. Donzé, C., Rubira, L., Santoro, 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]

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

Report on short-term side effects of treatments with 177Lu-octreotate in combination with capecitabine in seven patients with gastroenteropancreatic neuroendocrine tumours. [2022]

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. Germany pubmed.ncbi.nlm.nih.gov

Lutetium-labelled peptides for therapy of neuroendocrine tumours. [2022]

5. 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]

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

Differences in biodistribution between 99mTc-depreotide, 111In-DTPA-octreotide, and 177Lu-DOTA-Tyr3-octreotate in a small cell lung cancer animal model. [2019]

8. Denmark pubmed.ncbi.nlm.nih.gov

[Radionuclide therapy for neuroendocrine tumours]. [2019]

9. England pubmed.ncbi.nlm.nih.gov

177Lu-Dotatate administration using an infusion pump or a peristaltic pump: comparison of two methods. [2022]

10. Japan pubmed.ncbi.nlm.nih.gov

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