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

6 Participants Needed

Trial Summary

What is the purpose of this trial?

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 in combination with Lu-177 dotatate at a standard dose of 7.4 GBq in four (4) 8-week cycles followed by continuation cabozantinib.

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.

What data supports the effectiveness of the treatment Cabozantinib + Lu-177 for neuroendocrine cancer?

Research shows that Lu-177, when used in a treatment called 177Lu-DOTATATE, can help control symptoms and improve quality of life in patients with neuroendocrine tumors. It has also been effective in reducing the size of tumors in some cases. ^{1 2 3 4 5}

Is the combination of Cabozantinib and Lu-177 safe for treating neuroendocrine cancer?

Cabozantinib, also known as Cabometyx, has been used safely in humans for treating thyroid cancer, with common side effects including diarrhea, fatigue, and high blood pressure. No new safety concerns were identified in recent studies, except for low calcium levels, which are now included in the safety warnings. ^{6 7 8 9 10}

How is the drug Cabozantinib + Lu-177 different from other treatments for neuroendocrine cancer?

Cabozantinib + Lu-177 is unique because it combines a tyrosine kinase inhibitor (Cabozantinib) with a radiolabeled therapy (Lu-177), potentially offering a dual approach by targeting cancer cell growth and delivering radiation directly to the tumor. This combination may provide a novel treatment option compared to existing therapies that typically use these components separately. ^{5 11 12 13 14}

Research Team

Hagen Kennecke, MD

Principal Investigator

Providence Health & Services

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

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+

Findings from Research

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]

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]

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]

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]

References

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

Peptide Receptor Radionuclide Therapy With 177Lu-DOTATATE for Symptomatic Control of Refractory Carcinoid Syndrome. [2021]

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

Accomplishments in 2008 in the management of gastrointestinal neuroendocrine tumors. [2021]

3. England pubmed.ncbi.nlm.nih.gov

Neuroendocrine tumors: insights into innovative therapeutic options and rational development of targeted therapies. [2014]

4. United States 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. [2022]

5. United States 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. [2021]

6. Switzerland pubmed.ncbi.nlm.nih.gov

Population Pharmacokinetic Model of Cabozantinib in Patients with Medullary Thyroid Carcinoma and Its Application to an Exposure-Response Analysis. [2018]

7. England pubmed.ncbi.nlm.nih.gov

Cabozantinib for the treatment of progressive metastatic medullary thyroid cancer. [2015]

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

New Indication for Cabozantinib. [2023]

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

FDA Approval Summary: Cabozantinib for Differentiated Thyroid Cancer. [2023]

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

Correlative analyses of RET and RAS mutations in a phase 3 trial of cabozantinib in patients with progressive, metastatic medullary thyroid cancer. [2022]

11. Netherlands pubmed.ncbi.nlm.nih.gov

Absorption, Metabolism and Excretion of Surufatinib in Rats and Humans. [2021]

12. Switzerland pubmed.ncbi.nlm.nih.gov

Emerging Treatment Options for Gastroenteropancreatic Neuroendocrine Tumors. [2020]

13. Germany pubmed.ncbi.nlm.nih.gov

Phase II study of radiopeptide 177Lu-octreotate and capecitabine therapy of progressive disseminated neuroendocrine tumours. [2022]

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

Capecitabine, Oxaliplatin, Irinotecan, and Bevacizumab Combination Followed by Pazopanib Plus Capecitabine Maintenance for High-Grade Gastrointestinal Neuroendocrine Carcinomas. [2021]