Radium-223 + Cabozantinib for Kidney Cancer with Bone Metastasis

Recruiting at 42 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: National Cancer Institute (NCI)

Must be taking: Bisphosphonates, Denosumab

Must not be taking: CYP3A4 inducers, CYP3A4 inhibitors

Disqualifiers: Brain metastases, Cardiovascular disorders, Gastrointestinal 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: 6

Duration: 6 months

134 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial requires that you stop taking any small molecular kinase inhibitors at least 2 weeks before joining, and you cannot be on certain anticoagulants like warfarin. You also need to avoid strong CYP3A4 inducers or inhibitors shortly before starting the trial. It's best to discuss your current medications with the trial team to see if any adjustments are needed.

What data supports the effectiveness of the drug combination Radium-223 and Cabozantinib for kidney cancer with bone metastasis?

Cabozantinib has shown promising results in treating kidney cancer, especially in cases with bone metastases, by improving bone scans and reducing bone turnover markers. It has demonstrated significant benefits in patients with bone metastatic renal cell carcinoma, making it a valuable option for managing this condition. ^{1 2 3 4 5}

Is the combination of Radium-223 and Cabozantinib safe for humans?

Cabozantinib has been used safely in patients with advanced kidney cancer, with side effects like fatigue and diarrhea being manageable with medical intervention. However, specific safety data for the combination of Radium-223 and Cabozantinib is not provided in the available research. ^{1 3 6 7 8}

What makes the drug Radium-223 + Cabozantinib unique for kidney cancer with bone metastasis?

This drug combination is unique because it combines Radium-223, a radiopharmaceutical that targets bone metastases with high-energy alpha particles, with Cabozantinib, which inhibits pathways involved in tumor growth and spread. This dual approach targets both the bone metastases and the cancer cells, potentially offering a novel treatment option for kidney cancer with bone metastasis. ^{9 10 11 12 13}

What is the purpose of this trial?

This phase II trial studies whether adding radium-223 dichloride to the usual treatment, cabozantinib, improves outcomes in patients with renal cell cancer that has spread to the bone. Radioactive drugs such as radium-223 dichloride may directly target radiation to cancer cells and minimize harm to normal cells. Cabozantinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Giving radium-223 dichloride and cabozantinib may help lessen the pain and symptoms from renal cell cancer that has spread to the bone, compared to cabozantinib alone.

Research Team

Rana R McKay

Principal Investigator

Alliance for Clinical Trials in Oncology

Eligibility Criteria

This trial is for adults with advanced kidney cancer that has spread to the bones. Participants must be in stable condition, have a certain level of physical ability (Karnofsky score >= 60%), and not have had major surgery or certain cancer treatments recently. They should not be pregnant or nursing, and those with brain metastases must be stable post-treatment.

Inclusion Criteria

Imaging tests show that cancer has spread to the bones.

I am not taking certain blood thinners.

I do not have any other serious health conditions.

Exclusion Criteria

You are allergic to the drug formulation.

I haven't received any cancer treatment in the last 3 weeks.

I have had heart, stomach, or bleeding issues recently.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Patients receive radium Ra 223 dichloride and cabozantinib or cabozantinib alone in 28-day cycles

6 months

Monthly visits for treatment administration and monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 5 years

Every 6 months

Treatment Details

Interventions

• Cabozantinib
• Radium-223 Dichloride

Trial Overview The study is testing if adding radium-223 dichloride to cabozantinib improves outcomes for bone-spread kidney cancer. Radium-223 targets radiation at cancer cells while cabozantinib blocks enzymes needed for cell growth. The goal is to reduce pain and symptoms more effectively than with cabozantinib alone.

Participant Groups

Group I: Arm A (radium Ra 223 dichloride, cabozantinib s-malate) Experimental Treatment 9 Interventions

Patients receive radium Ra 223 dichloride IV over 1 minute on day 1 of cycles 1-6 and cabozantinib S-malate PO QD on days 1-28 of every cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo blood sample collection, bone scan, CT, or MRI, and may undergo FDG-PET or NaF-PET throughout the study.

Group II: Arm B (cabozantinib s-malate) Active Control 8 Interventions

Patients receive cabozantinib S-malate PO QD on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo blood sample collection, bone scan, CT, or MRI, and may undergo FDG-PET or NaF-PET throughout the study.

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?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

Findings from Research

Cabozantinib has shown significant efficacy in treating advanced kidney cancer, with a 28% objective response rate and a median progression-free survival of 14.7 months based on a phase II trial involving patients with renal cancer.

The drug also demonstrated notable effectiveness in managing bone metastases, which is crucial for improving quality of life in patients, and further studies are planned to compare its effectiveness against standard VEGF inhibitors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cabozantinib as a novel therapy for renal cell carcinoma. Vaishampayan, U.[2022]

Cabozantinib significantly reduces the proliferation of renal cell carcinoma (RCC) cells, particularly enhancing its effectiveness against Caki-1 cells when they are cocultured with osteoblasts, indicating a synergistic effect in the tumor microenvironment.

The treatment not only directly inhibits RCC cell growth but also modulates the molecular profile of osteoblasts, which may further contribute to its antitumor activity, although this effect was not observed in the 786-O cell line.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Antitumor Effect of Cabozantinib in Bone Metastatic Models of Renal Cell Carcinoma. Iuliani, M., Simonetti, S., Pantano, F., et al.[2021]

Cabozantinib (Cabometyx®) is now approved as a first-line treatment for advanced renal cell carcinoma (RCC) in treatment-naïve adults, expanding its use beyond patients who have already received VEGF-targeted therapy.

In a phase 2 trial, cabozantinib significantly improved median progression-free survival and objective response rates compared to the standard treatment sunitinib, while its side effects are manageable, similar to other tyrosine kinase inhibitors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cabozantinib as first-line treatment in advanced renal cell carcinoma: a profile of its use. Lyseng-Williamson, KA.[2020]

In a study of 39 patients with metastatic renal cell carcinoma treated with cabozantinib, significant reductions in bone turnover markers (CTx and PINP) were observed after 3 months, indicating effective inhibition of bone resorption.

Cabozantinib also caused a transient increase in parathyroid hormone (PTH) levels, but changes in bone turnover markers were not linked to patient outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of cabozantinib on bone turnover markers in real-world metastatic renal cell carcinoma. Ratta, R., Verzoni, E., Mennitto, A., et al.[2022]

Cabozantinib, a multitargeted tyrosine kinase inhibitor, shows promise in improving bone scans, bone turnover markers, and pain response in men with castration-resistant prostate cancer (CRPC), indicating its efficacy in managing bone metastases.

Despite its effectiveness, cabozantinib is associated with significant adverse events that can lead to dose reductions and treatment discontinuation; however, lower doses maintain high activity with reduced toxicity, suggesting a potential for safer administration.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Targeting MET and vascular endothelial growth factor receptor signaling in castration-resistant prostate cancer. Lee, RJ., Smith, MR.[2023]

Cabozantinib was designated as a breakthrough drug by the FDA and approved in 2016 for treating advanced clear cell renal cell carcinoma (ccRCC), which is the most common kidney cancer type, accounting for about 90% of cases.

The METEOR trial demonstrated significant efficacy for cabozantinib in advanced RCC, and ongoing studies like the CABOSUN trial will further clarify its effectiveness compared to other treatments like sunitinib.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical use of cabozantinib in the treatment of advanced kidney cancer: efficacy, safety, and patient selection. Yu, SS., Quinn, DI., Dorff, TB.[2022]

Cabozantinib significantly improves progression-free survival (PFS) and overall survival (OS) in patients with advanced renal cell carcinoma (RCC) who have previously undergone antiangiogenic therapy, as demonstrated in the METEOR trial.

The drug also shows a higher objective response rate compared to everolimus, while maintaining a manageable safety profile, making it a valuable treatment option for advanced RCC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cabozantinib: A Review in Advanced Renal Cell Carcinoma. Al-Salama, ZT., Keating, GM.[2018]

Cabozantinib shows promising anti-tumor activity in patients with metastatic clear cell renal cell carcinoma (RCC), with a partial response observed in 28% of the 25 heavily pretreated participants.

The treatment demonstrated a median progression-free survival of 12.9 months and a median overall survival of 15.0 months, with a safety profile consistent with other similar therapies, indicating its potential as a viable option for advanced RCC patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase I study of cabozantinib (XL184) in patients with renal cell cancer. Choueiri, TK., Pal, SK., McDermott, DF., et al.[2021]

In a study of 36 patients with bone-metastatic, castration-resistant prostate cancer, radium-223 treatment led to significant reductions in pain scores, particularly when used as second-line and third-line therapy.

While some patients experienced an increase in prostate-specific antigen levels, radium-223 showed early biochemical benefits and was associated with a decrease in alkaline phosphatase levels in chemotherapy-naive patients, with anemia being the most common adverse event at 16.7%.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Radium-223 for metastatic, castration-resistant prostate cancer: A retrospective chart review study of real-world use in a tertiary hospital in Taiwan. Weng, WC., Huang, LH., Tseng, NC., et al.[2022]

Radium-223 combined with VEGF-targeted therapies (pazopanib or sorafenib) showed significant biological activity in patients with advanced renal cell carcinoma and bone metastases, as evidenced by a decline in bone turnover markers after 8 and 16 weeks of treatment.

The treatment was found to be safe, with no dose-limiting toxicities reported, although 40% of patients experienced grade ≥3 adverse events, indicating that while the combination therapy is promising, further randomized-controlled trials are necessary to fully understand its efficacy and safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Radium-223 Dichloride in Combination with Vascular Endothelial Growth Factor-Targeting Therapy in Advanced Renal Cell Carcinoma with Bone Metastases. McKay, RR., Bossé, D., Gray, KP., et al.[2023]

In a study of 83 patients with metastatic castration-resistant prostate cancer, treatment with Radium-223 significantly improved pain scores and showed a mean overall survival of 10.1 months, with a median overall survival not yet reached.

Patients who completed all 6 cycles of Radium-223 therapy experienced the greatest benefits in overall survival and progression-free survival, highlighting the importance of completing the treatment regimen.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

223Ra-chloride therapy in men with hormone-refractory prostate cancer and skeletal metastases: Real-world experience. Boni, G., Mazzarri, S., Cianci, C., et al.[2019]

Radium-223 dichloride is an effective treatment for patients with castration-resistant prostate cancer (CRPC) and symptomatic bone metastases, as it prolongs overall survival and time to first symptomatic skeletal event compared to placebo, based on the ALSYMPCA trial.

The treatment is generally well tolerated, with low rates of myelosuppression and manageable gastrointestinal side effects, making it a promising option for patients, and it shows potential for use in other cancers with bone metastases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Alpha-emitter radium-223 in the management of solid tumors: current status and future directions. Nilsson, S.[2018]

In a phase I study involving 6 Japanese patients with castration-resistant prostate cancer, radium-223 was administered intravenously and showed rapid elimination from the blood, with 85% of the injected activity retained in the body after 24 hours.

Radium-223 demonstrated a strong preference for bone uptake, with maximum activity observed within 2 hours post-injection, and no detectable activity in other organs, indicating a targeted approach that minimizes radiation exposure to healthy tissues.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacokinetics of single dose radium-223 dichloride (BAY 88-8223) in Japanese patients with castration-resistant prostate cancer and bone metastases. Yoshida, K., Kaneta, T., Takano, S., et al.[2018]

References

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

Cabozantinib as a novel therapy for renal cell carcinoma. [2022]

2. Switzerland pubmed.ncbi.nlm.nih.gov

Antitumor Effect of Cabozantinib in Bone Metastatic Models of Renal Cell Carcinoma. [2021]

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

Cabozantinib as first-line treatment in advanced renal cell carcinoma: a profile of its use. [2020]

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

Effects of cabozantinib on bone turnover markers in real-world metastatic renal cell carcinoma. [2022]

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

Targeting MET and vascular endothelial growth factor receptor signaling in castration-resistant prostate cancer. [2023]

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

Clinical use of cabozantinib in the treatment of advanced kidney cancer: efficacy, safety, and patient selection. [2022]

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

Cabozantinib: A Review in Advanced Renal Cell Carcinoma. [2018]

8. England pubmed.ncbi.nlm.nih.gov

A phase I study of cabozantinib (XL184) in patients with renal cell cancer. [2021]

9. Singapore pubmed.ncbi.nlm.nih.gov

Radium-223 for metastatic, castration-resistant prostate cancer: A retrospective chart review study of real-world use in a tertiary hospital in Taiwan. [2022]

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

Radium-223 Dichloride in Combination with Vascular Endothelial Growth Factor-Targeting Therapy in Advanced Renal Cell Carcinoma with Bone Metastases. [2023]

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

223Ra-chloride therapy in men with hormone-refractory prostate cancer and skeletal metastases: Real-world experience. [2019]

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

Alpha-emitter radium-223 in the management of solid tumors: current status and future directions. [2018]

13. Japan pubmed.ncbi.nlm.nih.gov

Pharmacokinetics of single dose radium-223 dichloride (BAY 88-8223) in Japanese patients with castration-resistant prostate cancer and bone metastases. [2018]