Lutathera + Olaparib for Neuroendocrine Cancer

Overseen By Joy H Zou, R.N.

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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores whether combining two drugs, Lutathera (a radiopharmaceutical therapy) and Olaparib, can safely shrink neuroendocrine tumors in the pancreas or intestine. Neuroendocrine tumors are rare and challenging to treat, especially when surgery is not an option. Participants will receive Lutathera through an IV and take Olaparib pills to assess the treatment's effectiveness and tolerability. Individuals with neuroendocrine tumors that have certain receptors (somatostatin receptors) and cannot undergo surgery might be suitable for this study. As a Phase 1, Phase 2 trial, this research aims to understand how the treatment works and measure its effectiveness in an initial group, offering participants a chance to contribute to groundbreaking cancer treatment advancements.

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.

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

Studies have shown that both Lutathera and Olaparib have been used safely in various cancer treatments. Lutathera treats certain types of tumors and maintains a good safety record. Olaparib is commonly studied in cancer trials and is generally well-tolerated.

Research indicates that combining Lutathera and Olaparib is feasible. Patients with specific tumors that have certain cell markers have taken this combination with manageable side effects. Most side effects were mild or moderate, with some patients experiencing tiredness or nausea, but these were not severe enough to discontinue treatment.

This is an early-phase study, primarily aimed at ensuring the treatment's safety before assessing its efficacy. Current evidence suggests that this combination is well-tolerated by patients. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments because they combine Lu-177-DOTATATE, a targeted radiotherapy, with Olaparib, a PARP inhibitor, to tackle neuroendocrine cancer in a novel way. Lu-177-DOTATATE delivers radiation directly to cancer cells, sparing more healthy tissue compared to traditional chemotherapy, while Olaparib interferes with cancer cells' DNA repair mechanisms, potentially making them more vulnerable to treatment. This dual approach differs from standard treatments like somatostatin analogs and chemotherapy, offering a targeted attack on cancer cells with the potential for increased efficacy and fewer side effects.

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

This trial will evaluate the combination of Lu-177-DOTATATE and Olaparib for treating certain neuroendocrine tumors. Research has shown that this combination may be effective, with studies finding that most patients tolerate the treatment well, experiencing manageable side effects like low platelet counts. Early results suggest that this treatment might help shrink tumors, although more data is needed. The combination works by using radiation to target tumor cells and preventing them from repairing DNA damage, which could inhibit tumor growth. While further research is necessary, these initial findings offer hope for people with neuroendocrine tumors. ^{1 3 4 6 7}

Who Is on the Research Team?

Frank I Lin, M.D.

Principal Investigator

National Cancer Institute (NCI)

Are You a Good Fit for This Trial?

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

Involvement in the planning and/or conduct of the study

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

Timeline for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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 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]

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]

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 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]

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]

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]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT04086485

Study Details | NCT04086485 | Lu-177-DOTATATE ... Objective: To learn if people with certain neuroendocrine tumors can take a combination of 2 drugs, Lutathera and Olaparib, without having severe side effects, ...

2. jnm.snmjournals.org jnm.snmjournals.org/content/64/supplement_1/P1299

Phase 2 study of Lu-177-DOTATATE in combination with ... The combination of Lu-177-DOTATATE and olaparib is well-tolerated and shows early evidence of efficacy in this limited data set.

3. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/40015919/

177 Lu-DOTATATE in Combination with PARP Inhibitor ... This study demonstrates that combining olaparib with 177 Lu-DOTATATE is feasible, with toxicity primarily related to thrombocytopenia.

4. endocrine-abstracts.org endocrine-abstracts.org/ea/0098/ea0098c23

Phase 1/2 study of Lu-177-DOTATATE in combination with ... We report the first results of a phase 1/2 study evaluating the safety and efficacy of Lu-177-DOTATATE in combination with olaparib.

5. cancer.gov cancer.gov/research/participate/clinical-trials/intervention/lutetium-lu-177-dotatate?pn=1

Clinical Trials Using Lutetium Lu 177 Dotatate - NCI NCI supports clinical trials that test new and more effective ways to treat cancer. Find clinical trials studying lutetium lu 177 dotatate.

6. jnm.snmjournals.org jnm.snmjournals.org/content/66/5/707/tab-figures-data

177 Lu-DOTATATE in Combination with PARP Inhibitor ... Lu-DOTATATE in Combination with PARP Inhibitor Olaparib Is Feasible in Patients with Somatostatin-Positive Tumors: Results from the LuPARP Phase ...

7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9659917/

The evolution of PRRT for the treatment of neuroendocrine ... Lu-177 has been developed for the treatment of patients with peptide receptor radionuclide therapy (PRRT). A second generation pure ...