Cabozantinib for Pancreatic Neuroendocrine Tumors

Recruiting at 494 trial locations

Overseen By Jonathan R. Strosberg

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: National Cancer Institute (NCI)

Must not be taking: Warfarin, Strong CYP3A4 inhibitors

Disqualifiers: Congestive heart failure, Cardiac arrhythmia, Hypertension, others

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

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 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 13

Duration: 36 months

298 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This phase III trial studies cabozantinib to see how well it works compared with placebo in treating patients with neuroendocrine or carcinoid tumors that may have spread from where it first started to nearby tissue, lymph nodes, or distant parts of the body (advanced). Cabozantinib is a chemotherapy drug known as a tyrosine kinase inhibitor, and it targets specific tyrosine kinase receptors, that when blocked, may slow tumor growth.

Will I have to stop taking my current medications?

The trial requires stopping certain medications before participating. You must stop taking strong CYP3A4 inhibitors and inducers at least 14 days before joining. Full-dose oral anticoagulants are not allowed, but low-dose aspirin and stable doses of low molecular weight heparin are permitted.

Is cabozantinib generally safe for humans?

Cabozantinib has been studied for various cancers, and common side effects include skin reactions on hands and feet, high blood pressure, fatigue, and diarrhea. Serious side effects like gastrointestinal perforation and bleeding have also been reported, but these are managed with dose adjustments and supportive care. ^{1 2 3 4 5}

How is the drug Cabozantinib unique for treating pancreatic neuroendocrine tumors?

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. This drug has shown promising results in reducing tumor growth and inhibiting angiogenesis (formation of new blood vessels) in both laboratory and animal models, making it a novel option compared to other treatments. ^{6 7 8 9 10}

What data supports the effectiveness of the drug Cabozantinib for treating pancreatic neuroendocrine tumors?

Cabozantinib is known to inhibit multiple tyrosine kinases, which play a key role in the development of neuroendocrine tumors. A phase II trial is assessing its safety and activity in combination with another drug for treating well-differentiated neuroendocrine tumors, including those in the pancreas. ^{6 7 11 12 13}

Who Is on the Research Team?

Jennifer A Chan

Principal Investigator

Alliance for Clinical Trials in Oncology

Are You a Good Fit for This Trial?

Adults with advanced neuroendocrine or carcinoid tumors that have spread and worsened after prior therapy can join. They must be able to swallow pills, not pregnant, no severe allergies to similar drugs as cabozantinib/placebo, and have a decent performance status (able to carry out daily activities). People with certain heart conditions, uncontrolled blood pressure, recent bleeding or clotting events, or other cancers within the last 5 years cannot participate.

Inclusion Criteria

Not pregnant and not nursing

You do not have any hollow spaces in your lungs.

I do not have a history of inherited long QT syndrome.

Exclusion Criteria

My cancer is not a high-grade neuroendocrine, adenocarcinoid, or goblet cell carcinoid tumor.

Patient is living outside the US

I have had a condition where my lymphocytes grow abnormally.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment

Participants receive cabozantinib S-malate or placebo orally once daily in 28-day cycles, with regular blood and urine sample collection, and imaging studies

36 months

Monthly visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment completion, with follow-up every 12 weeks until disease progression or new therapy, then every 6 months

Up to 8 years

Every 12 weeks, then every 6 months (in-person)

What Are the Treatments Tested in This Trial?

Interventions

• Cabozantinib S-malate

Trial Overview This phase III trial is testing if cabozantinib works better than a placebo for treating advanced neuroendocrine or carcinoid tumors. Cabozantinib is a chemotherapy drug that blocks specific receptors which may slow tumor growth. Patients will also undergo scans and quality-of-life assessments.

How Is the Trial Designed?

Group I: Arm I (cabozantinib S-malate) Experimental Treatment 6 Interventions

Patients receive cabozantinib S-malate PO QD on days 1-28 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo blood and urine sample collection, and CT, MRI, and/or x-ray imaging during screening and on study.

Group II: Arm II (placebo) Placebo Group 6 Interventions

Patients receive placebo PO QD on days 1-28 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo blood and urine sample collection, and CT, MRI, and/or x-ray imaging during screening and on study. Patients may crossover to receive cabozantinib S-malate at the time of disease progression.

Cabozantinib S-malate is already approved in United States, European Union for the following indications:

Approved in United States as Cabometyx for:

• Advanced renal cell carcinoma (RCC)
• Hepatocellular carcinoma (HCC)
• Locally advanced or metastatic differentiated thyroid cancer (DTC)

Approved in United States as Cometriq for:

• Medullary thyroid cancer

Approved in European Union as Cabometyx for:

• Advanced renal cell carcinoma (RCC)
• Hepatocellular carcinoma (HCC)
• Locally advanced or metastatic differentiated thyroid cancer (DTC)

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

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]

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]

In a study of 67 patients with pancreatic and small bowel neuroendocrine tumors, treatment with (90)Y-DOTATATE resulted in a median progression-free survival of 25 months for pancreatic NETs and 28 months for small bowel NETs, indicating its effectiveness in managing these tumors.

The median overall survival was 42 months for pancreatic NETs and 38.5 months for small bowel NETs, with no significant differences in survival outcomes based on tumor type, suggesting that (90)Y-DOTATATE may be equally effective for both types of NETs.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-term efficacy of (90)Y-DOTATATE in patients with nonresectable pancreatic and small bowel neuroendocrine neoplasms. Rogowski, W., Wachuła, E., Lewczuk, A., et al.[2017]

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]

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 is an effective treatment for advanced hepatocellular carcinoma (HCC) after failure of sorafenib, showing significant improvement in overall survival and progression-free survival compared to placebo in the phase 3 CELESTIAL trial.

Common side effects of cabozantinib include palmar-plantar erythrodysesthesia, hypertension, fatigue, and diarrhea, which are important to manage in patients undergoing treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cabozantinib for the Treatment of Advanced Hepatocellular Carcinoma: Current Data and Future Perspectives. Trojan, J.[2021]

Cabozantinib is an oral multitargeted tyrosine kinase inhibitor approved for advanced renal cell carcinoma and progressive metastatic medullary thyroid cancer, showing potential advantages over single-receptor TKIs.

The article reviews clinical trial data and management strategies for common adverse events associated with cabozantinib, highlighting its expanding use in treating various cancers such as prostate, hepatocellular, and lung cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cabozantinib: A Multitargeted Oral Tyrosine Kinase Inhibitor. Markowitz, JN., Fancher, KM.[2019]

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]

Citations

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

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

2. 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]

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

Long-term efficacy of (90)Y-DOTATATE in patients with nonresectable pancreatic and small bowel neuroendocrine neoplasms. [2017]

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

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

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. New Zealand pubmed.ncbi.nlm.nih.gov

Cabozantinib: a review of its use in patients with medullary thyroid cancer. [2022]

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

Incidence and risk of hand-foot skin reaction with cabozantinib, a novel multikinase inhibitor: a meta-analysis. [2018]

8. 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]

9. New Zealand pubmed.ncbi.nlm.nih.gov

Cabozantinib for the Treatment of Advanced Hepatocellular Carcinoma: Current Data and Future Perspectives. [2021]

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

Cabozantinib: A Multitargeted Oral Tyrosine Kinase Inhibitor. [2019]

11. England pubmed.ncbi.nlm.nih.gov

Sunitinib for advanced pancreatic neuroendocrine tumors. [2018]

12. Italy pubmed.ncbi.nlm.nih.gov

Pancreatic neuroendocrine neoplasms. [2018]

13. England pubmed.ncbi.nlm.nih.gov

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