Cabozantinib + Lu-177 for Neuroendocrine Cancer

Overseen By Mary McCormick, RN

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Providence Health & Services

Must be taking: Somatostatin analogues

Must not be taking: Anticoagulants, kinase inhibitors

Disqualifiers: Brain metastases, Uncontrolled hypertension, others

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

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Compensation: Varies

Number of Visits: 20

Duration: 32 weeks

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a combination of two treatments, cabozantinib (Cabometyx) and Lu-177, to determine the optimal dose for individuals with neuroendocrine cancer. These cancers affect hormone-producing cells, often in the digestive system. Participants should have a type of neuroendocrine tumor that is progressing and cannot be surgically removed, and they should have tried other treatments previously. The study aims to understand how these drugs work together to manage the disease. As a Phase 1 trial, the research focuses on understanding the treatment's effects in people, offering participants the opportunity to be among the first to receive this new combination therapy.

Do I need to stop my current medications for the trial?

The trial protocol does not specify if you need to stop taking your current medications. However, you cannot have taken certain cancer treatments or radiation therapy within a few weeks before starting the trial. It's best to discuss your specific medications with the trial team.

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

Research has shown that cabozantinib presents some safety concerns. In studies involving patients with advanced neuroendocrine tumors, 62–65% experienced severe side effects, compared to only 23–27% of those who took a placebo. While common side effects were significant, specific details were not provided in the sources.

Lu-177, a radioactive treatment, is often used in similar cases. Its safety profile is generally known, but combining it with cabozantinib in this study is new. This trial is in an early phase, so researchers are still determining the safest dose. The goal is to find the highest dose patients can tolerate without excessive side effects.

Both cabozantinib and Lu-177 have been used before, but not together as in this trial. Participants should be aware of possible severe side effects, and the trial aims to manage and minimize these. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of Cabozantinib and Lu-177 for neuroendocrine cancer because it offers a novel approach to treatment. Most existing therapies target tumor growth through traditional pathways, but Cabozantinib, a tyrosine kinase inhibitor, works by blocking several key proteins that fuel cancer cell growth. This, combined with Lu-177, a radiolabeled therapy that delivers targeted radiation to tumor cells, provides a dual-action strategy that may enhance effectiveness. This combination approach could potentially improve outcomes by both inhibiting cancer cell proliferation and delivering targeted radiation directly to tumors, which sets it apart from the usual treatments that typically focus on only one of these mechanisms.

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

This trial will evaluate the combination of cabozantinib and Lu-177 for neuroendocrine cancer. Studies have shown that cabozantinib can effectively treat neuroendocrine tumors, with research indicating a median progression-free survival of 8.4 months, compared to 3.9 months with a placebo. Additionally, cabozantinib reduced the risk of disease worsening or causing death by 60% in some patients. While information on using Lu-177 with cabozantinib is still developing, Lu-177 delivers targeted radiation to cancer cells, potentially enhancing treatment effectiveness. This trial will explore various dosing regimens of cabozantinib combined with Lu-177, aiming to slow tumor growth and improve patient outcomes. ^{2 3 4 6 7}

Who Is on the Research Team?

Hagen Kennecke, MD

Principal Investigator

Providence Health & Services

Are You a Good Fit for This Trial?

Adults with well-differentiated neuroendocrine tumors who have had prior systemic therapy, including somatostatin analogue therapy. They should be in good physical condition (ECOG 0-2), have adequate organ and marrow function, and not be pregnant or breastfeeding. Participants must agree to use contraception during the study and for 4 months after.

Inclusion Criteria

My tumor is a type of neuroendocrine tumor that cannot be surgically removed and is growing.

I have recovered from previous cancer treatment side effects, or they are minor and stable.

I can take care of myself and am up and about more than half of the day.

Exclusion Criteria

I do not have any major health issues like heart problems, serious wounds, or severe liver issues.

I haven't taken any kinase inhibitor medication in the last 2 weeks.

I am currently taking blood thinners.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive cabozantinib in combination with Lu-177 DOTATATE in four 8-week cycles with dose escalation

32 weeks

4 visits (in-person) for Lu-177 DOTATATE administration

Maintenance

Participants receive single-agent maintenance cabozantinib in 4-week cycles until disease progression

Until disease progression

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 2 years

Imaging every 16 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Cabozantinib
• Lu-177

Trial Overview

The trial is testing different doses of Cabozantinib (20 mg, 40 mg, and 60 mg) combined with a standard dose of Lu-177 dotatate given in four cycles over eight weeks each. The goal is to find the highest dose that patients can tolerate without severe side effects.

How Is the Trial Designed?

Group I: Cohort 5 Experimental Treatment 2 Interventions

Cabozantinib 60 mg qd with Lu-177 DOTATE administration IV. For cycles 5+, single-agent maintenance of cabozantinib is given at 60 mg qd until disease progression.

Group II: Cohort 4 Experimental Treatment 2 Interventions

Cabozantinib 60 mg qod alternating with 40 mg qod with Lu-177 DOTATE administration IV. For cycles 5+, single-agent maintenance of cabozantinib is given at 60 mg qd.

Group III: Cohort 3 Experimental Treatment 2 Interventions

Cabozantinib 40 mg qd with Lu-177 DOTATE administration IV. For cycles 5+, single-agent maintenance of cabozantinib is given at 40 mg qd.

Group IV: Cohort 2 Experimental Treatment 2 Interventions

Cabozantinib 40 mg qod alternating with 20 mg qod with Lu-177 DOTATE administration IV. For cycles 5+, single-agent maintenance of cabozantinib is given at 40 mg qd.

Group V: Cohort 1 Experimental Treatment 2 Interventions

Cabozantinib 20 mg daily with Lu-177 DOTATE administration IV. For cycles 5+, single-agent maintenance of cabozantinib is given at 20 mg qd.

Cabozantinib is already approved in European Union, United States, Canada, Japan for the following indications:

Approved in European Union as Cabometyx for:

• Renal cell carcinoma
• Hepatocellular carcinoma

Approved in United States as Cabometyx for:

• Renal cell carcinoma
• Hepatocellular carcinoma

Approved in Canada as Cabometyx for:

• Renal cell carcinoma
• Hepatocellular carcinoma

Approved in Japan as Cabometyx for:

• Renal cell carcinoma

Who Is Running the Clinical Trial?

Providence Health & Services

Lead Sponsor

Trials

131

Recruited

827,000+

Advanced Accelerator Applications

Industry Sponsor

Trials

37

Recruited

3,000+

Exelixis

Industry Sponsor

Trials

126

Recruited

20,500+

Michael M. Morrissey

Exelixis

Chief Executive Officer since 2010

PhD in Chemistry from Harvard University, BSc in Chemistry from the University of Wisconsin

Vicki L. Goodman

Exelixis

Chief Medical Officer since 2022

MD

Advanced Accelerator Applications SA

Collaborator

Trials

1

Recruited

6+

Published Research Related to This Trial

In a study of 22 patients with carcinoid syndrome, treatment with 177Lu-DOTATATE significantly reduced bowel movement frequency from an average of 6.1 to 4.6 per day and flushing episodes from 4.3 to 2.4 per day, indicating effective symptom relief.

The therapy also led to a notable decrease in urinary 5-hydroxyindolacetic acid excretion in 56% of patients, suggesting that 177Lu-DOTATATE can be a valuable option for managing symptoms in patients not adequately controlled by somatostatin analogs.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Peptide Receptor Radionuclide Therapy With 177Lu-DOTATATE for Symptomatic Control of Refractory Carcinoid Syndrome. Zandee, WT., Brabander, T., Blažević, A., et al.[2021]

The review highlights the importance of somatostatin analogs and peptide receptor-targeted therapies in the treatment of neuroendocrine tumors, showcasing their efficacy in managing the disease.

It emphasizes the need for improved clinical trial designs and the development of biomarkers to better assess treatment outcomes and guide future therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Accomplishments in 2008 in the management of gastrointestinal neuroendocrine tumors. Kulke, MH., Scherübl, H.[2021]

Peptide receptor radionuclide therapy (PRRT) using 177 Lu-DOTATATE has demonstrated significant efficacy in reducing the size of metastatic neuroendocrine tumors, achieving about a 20% reduction in lesions smaller than 3 cm.

In a specific case involving a 66-year-old man with a rapidly growing 10 cm metastatic nodal conglomerate, PRRT resulted in an impressive size reduction of over 75% after just 2 treatment cycles, indicating its potential effectiveness for aggressive neuroendocrine cancers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Striking Size Reduction of Rapidly Growing Pancreatic Neuroendocrine Carcinoma Metastatic Nodal Conglomerate After Only 2 Cycles of 177 Lu-DOTATATE. Somoza, EA., Duan, H., Shaheen, S., et al.[2022]

Surufatinib, a tyrosine kinase inhibitor, is well-absorbed in both rats and humans, with a median time to peak concentration of 4 hours after oral dosing, and a significantly longer half-life in humans (23.3 hours) compared to rats (3.12-6.48 hours).

The primary route of elimination for surufatinib in both species is fecal excretion, accounting for about 87% of the dose, indicating that the drug is largely eliminated unchanged, with no single metabolite making up more than 10% of the total radioactivity in circulation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Absorption, Metabolism and Excretion of Surufatinib in Rats and Humans. Li, K., Ma, S., Miao, L., et al.[2021]

Cabozantinib (Cabometyx) has received approval for the treatment of locally advanced or metastatic differentiated thyroid cancer that has not responded to previous therapies targeting vascular endothelial growth factor receptors.

This approval highlights Cabozantinib's efficacy in addressing a specific type of thyroid cancer that has progressed after other treatments, providing a new option for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

New Indication for Cabozantinib. Aschenbrenner, DS.[2023]

Cabozantinib (Cabometyx) has been approved by the FDA for treating locally advanced or metastatic differentiated thyroid cancer (DTC) in patients aged 12 and older who are RAI-refractory and have progressed after prior VEGFR-targeted therapy, marking a significant advancement in treatment options for this patient group.

In a clinical trial with 258 participants, cabozantinib demonstrated a median progression-free survival of 11.0 months compared to just 1.9 months for the placebo group, indicating its efficacy in prolonging survival without disease progression, although the overall response rate did not meet the study's endpoint.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FDA Approval Summary: Cabozantinib for Differentiated Thyroid Cancer. Duke, ES., Barone, AK., Chatterjee, S., et al.[2023]

In a study of 76 patients with advanced gastroenteropancreatic neuroendocrine tumors (GEP-NETs), the combination of 177Lu-DOTATATE and capecitabine showed a significantly higher objective response rate (38%) and longer progression-free survival (54 months) compared to octreotide LAR, which had a 15% response rate and 16 months of progression-free survival.

Both treatment regimens had similar rates of severe side effects (grade 3 or 4 toxicities), indicating that while 177Lu-DOTATATE plus capecitabine is more effective, it does not appear to increase the risk of serious adverse events compared to octreotide LAR.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

177Lu-DOTATATE Plus Radiosensitizing Capecitabine Versus Octreotide Long-Acting Release as First-Line Systemic Therapy in Advanced Grade 1 or 2 Gastroenteropancreatic Neuroendocrine Tumors: A Single-Institution Experience. Satapathy, S., Mittal, BR., Sood, A., et al.[2021]

Citations

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nejm.org/doi/full/10.1056/NEJMoa2403991

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pmc.ncbi.nlm.nih.gov/articles/PMC11821447/

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Previously treated epNET efficacy data

CABOMETYX doubled median PFS in epNET 1, 60% reduction in risk of progression or death, PFS results in epNET patients across select disease characteristics.

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The phase I objective of this study is to establish the maximal tolerated dose (MTD) of cabozantinib in 20 mg, 40 mg and 60 mg dose escalation cohorts.

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Previously treated pNET efficacy data

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NET Treatment Option | CABOMETYX® (cabozantinib)

WARNINGS AND PRECAUTIONS ... Hemorrhage: CABOMETYX can cause severe and fatal hemorrhages. The incidence of Grade 3-5 hemorrhagic events was 5% in CABOMETYX ...