Cabozantinib for Neuroendocrine Cancer

Overseen By Nikolaos Trikalinos

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Washington University School of Medicine

Must not be taking: Anticoagulants, Kinase inhibitors

Disqualifiers: Other malignancy, Brain metastases, GI disorders, 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

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

Approved in 4 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 4 months

32 Participants Needed

Trial Summary

What is the purpose of this trial?

High grade neuroendocrine neoplasm patients are treated with platinum doublets such as carboplatin and etoposide mimicking the current guidelines for small cell lung cancer (SCLC). Unfortunately, recurrences are common and most patients with metastatic disease succumb to it within a year. There is no extensive literature or consensus on second- or third-line options (which include FOLFOX, FOLFIRI, capecitabine and temozolomide, taxanes or immunotherapy) and there is urgent need for better regimens.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, you cannot take certain blood thinners like warfarin, and you must not have taken any small molecule kinase inhibitors or other systemic anticancer therapies within a few weeks before starting the trial.

What data supports the effectiveness of the drug Cabozantinib for neuroendocrine cancer?

Research shows that Cabozantinib can effectively reduce tumor growth and spread in neuroendocrine tumors by blocking certain proteins that help tumors grow and form new blood vessels. Studies in lab models and animals have shown promising results, suggesting it could be a useful treatment for these types of cancers. ^{1 2 3 4 5}

Is cabozantinib safe for humans?

Cabozantinib has been studied for safety in combination with lanreotide for neuroendocrine tumors, and it showed promising activity in both lab and animal models. However, specific safety data from these studies are not detailed in the available research. ^{1 2 4 6 7}

How is the drug Cabozantinib unique in treating neuroendocrine cancer?

Cabozantinib is unique because it targets multiple tyrosine kinases, including c-MET and VEGFR2, which play a key role in the development of neuroendocrine tumors. It also shows a novel effect by halting cell cycle progression, which hasn't been reported for other similar drugs. ^{1 2 4 6 8}

Research Team

Nikolaos Trikalinos

Principal Investigator

Washington University School of Medicine

Eligibility Criteria

Adults with high-grade neuroendocrine tumors that have worsened after first-line therapy can join this trial. They must not have small cell lung cancer, be in good physical condition, and agree to use contraception. Pregnant or breastfeeding women, those who've had cabozantinib before, recent major surgery or other cancer treatments are excluded.

Inclusion Criteria

My high-grade neuroendocrine tumor has worsened after treatment, but it's not small cell lung cancer.

I have recovered from side effects of previous treatments.

Ability to understand and willingness to sign an IRB approved written informed consent document

Exclusion Criteria

I have not had major surgery recently.

Currently receiving any other investigational agents

Pregnant and/or breastfeeding

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive Cabozantinib 60 mg by mouth daily on days 1-21

4 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

1 year

Treatment Details

Interventions

• Cabozantinib

Trial Overview The trial tests Cabozantinib's effectiveness on neuroendocrine tumors. Participants will also undergo tissue biopsies and blood tests for biomarkers. The goal is to find better treatment options since current second- and third-line therapies lack consensus.

Participant Groups

Group I: Cabozantinib Experimental Treatment 3 Interventions

-Cabozantinib 60 mg by mouth daily on days 1-21

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?

Washington University School of Medicine

Lead Sponsor

Trials

2,027

Recruited

2,353,000+

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

Findings from Research

The LOLA trial is the first prospective phase II study evaluating the safety and efficacy of cabozantinib combined with lanreotide in patients with advanced well-differentiated neuroendocrine tumors (NETs), aiming to enroll up to 69 participants over 42 months.

Cabozantinib targets key pathways in NET pathogenesis, and the trial will assess its optimal dosing and safety profile, with a focus on overall response rate and potential biomarkers, which could provide valuable insights for treating these rare tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Assessing the safety and activity of cabozantinib combined with lanreotide in gastroenteropancreatic and thoracic neuroendocrine tumors: rationale and protocol of the phase II LOLA trial. Corti, F., Brizzi, MP., Amoroso, V., et al.[2023]

Cabozantinib (CAB) demonstrated significant antitumor activity against neuroendocrine tumors (NETs) in both in vitro cell cultures and in vivo models, showing a dose-dependent effect on cell viability and proliferation.

CAB not only inhibited cell growth but also halted cell cycle progression and significantly reduced NET-induced angiogenesis and cell migration in a zebrafish model, suggesting its potential as an effective treatment for NETs.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cabozantinib in neuroendocrine tumors: tackling drug activity and resistance mechanisms. Cella, CA., Cazzoli, R., Fazio, N., et al.[2023]

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]

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]

Neuroendocrine tumors, which make up 1-2% of all cancers, can be slow-growing but may also be aggressive, with a high likelihood of metastasis to the liver, impacting survival rates significantly.

Current treatment options include somatostatin analogues, chemotherapy, and emerging targeted therapies like everolimus and sunitinib, with ongoing clinical trials exploring new strategies to improve outcomes for patients with advanced neuroendocrine tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Systemic treatment of neuroendocrine tumors with hepatic metastases. Demirkan, BH., Eriksson, B.[2019]

In a phase II study involving 109 patients with advanced neuroendocrine tumors, sunitinib demonstrated a 16.7% objective response rate in pancreatic endocrine tumor patients and 2.4% in carcinoid patients, with a significant proportion of patients experiencing stable disease.

The treatment resulted in a median time to tumor progression of 7.7 months for pancreatic neuroendocrine tumors and 10.2 months for carcinoid tumors, with one-year survival rates of approximately 81% for pancreatic and 83% for carcinoid patients, indicating potential efficacy and safety for further investigation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Activity of sunitinib in patients with advanced neuroendocrine tumors. Kulke, MH., Lenz, HJ., Meropol, NJ., et al.[2022]

In a study involving 242 patients with advanced neuroendocrine tumors treated with surufatinib, the presence of treatment-related adverse events (TRAEs) like hypertension, proteinuria, and hemorrhage in the first 4 weeks was linked to a longer progression-free survival (PFS) of 11.1 months compared to 9.2 months for those without these events.

The findings suggest that TRAEs could serve as potential biomarkers for predicting the efficacy of surufatinib treatment, indicating that patients experiencing these side effects may have better treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment-related adverse events as predictive biomarkers of efficacy in patients with advanced neuroendocrine tumors treated with surufatinib: results from two phase III studies. Li, J., Cheng, Y., Bai, C., et al.[2022]

Sunitinib has been shown to significantly improve progression-free survival in patients with unresectable, advanced, or metastatic gastroenteropancreatic neuroendocrine tumors (GEP-NETs), making it the first targeted therapy approved for this condition.

Ongoing trials are exploring other promising treatments, including multitargeted tyrosine kinase inhibitors and monoclonal antibodies, which may further enhance therapeutic options for GEP-NETs.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Therapy innovations: tyrosine kinase inhibitors for the treatment of pancreatic neuroendocrine tumors. Raymond, E., Hobday, T., Castellano, D., et al.[2022]

References

1. England pubmed.ncbi.nlm.nih.gov

Assessing the safety and activity of cabozantinib combined with lanreotide in gastroenteropancreatic and thoracic neuroendocrine tumors: rationale and protocol of the phase II LOLA trial. [2023]

2. England pubmed.ncbi.nlm.nih.gov

Cabozantinib in neuroendocrine tumors: tackling drug activity and resistance mechanisms. [2023]

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

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

4. Netherlands pubmed.ncbi.nlm.nih.gov

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

5. Turkey pubmed.ncbi.nlm.nih.gov

Systemic treatment of neuroendocrine tumors with hepatic metastases. [2019]

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

Activity of sunitinib in patients with advanced neuroendocrine tumors. [2022]

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

Treatment-related adverse events as predictive biomarkers of efficacy in patients with advanced neuroendocrine tumors treated with surufatinib: results from two phase III studies. [2022]

8. Netherlands pubmed.ncbi.nlm.nih.gov

Therapy innovations: tyrosine kinase inhibitors for the treatment of pancreatic neuroendocrine tumors. [2022]