CBM588 + Nivolumab + Cabozantinib for Kidney Cancer

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: City of Hope Medical Center

Must be taking: Nivolumab, Cabozantinib

Must not be taking: Probiotics, Anticoagulants

Disqualifiers: Interstitial lung disease, 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: 2

Duration: 12 weeks

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new method to treat advanced kidney cancer that has spread to other parts of the body. It examines how a bacteria-based treatment, CBM588, might work with standard cancer drugs—nivolumab (an immunotherapy drug) and cabozantinib (a targeted therapy drug)—to alter the gut's microbiome and enhance cancer treatment. Participants will receive either the standard drugs alone or the standard drugs plus CBM588 to determine if the bacteria can boost the treatment's effectiveness. This trial may suit those with kidney cancer that cannot be cured with surgery or radiation and who have not received prior systemic treatments. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this new treatment.

Will I have to stop taking my current medications?

The trial does not specify if you must stop taking your current medications. However, you cannot use probiotics, yogurt, or bacterial fortified foods during the treatment period, and certain anticoagulants and recent cancer treatments are not allowed. 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 using CBM588, a type of bacteria, alongside the cancer drugs nivolumab and cabozantinib, may improve outcomes for people with kidney cancer. This combination might enhance the effectiveness of the drugs.

Regarding safety, nivolumab and cabozantinib are standard treatments and are generally well-tolerated by patients. While they have side effects, doctors are familiar with managing them. Other studies have tested the addition of CBM588 to these drugs, and no major safety issues have been reported. This suggests the combination is likely safe, but further research is needed to confirm this.

As this is a phase 1 trial, the primary goal is to ensure the treatment's safety and determine the correct dose. The results so far appear promising, but additional research is necessary for confirmation. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments for kidney cancer because they combine innovative approaches to boost effectiveness. Unlike standard treatments like sunitinib or pazopanib, which primarily focus on targeting tumor growth factors, the combination of nivolumab, a PD-1 inhibitor, and cabozantinib, a tyrosine kinase inhibitor, offers a dual attack on cancer. What makes this trial even more compelling is the addition of CBM588, a probiotic thought to enhance the immune response when paired with nivolumab. This unique trio could potentially enhance immune system engagement and improve outcomes for patients.

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

This trial will compare two treatment approaches for advanced kidney cancer. In one arm, participants will receive nivolumab and cabozantinib. In the other arm, participants will receive a combination of CBM588, nivolumab, and cabozantinib. Research has shown that combining CBM588, nivolumab, and cabozantinib may be promising for treating advanced kidney cancer. Studies have found that CBM588, a type of bacteria, can improve gut health, potentially enhancing the effectiveness of cancer treatments. Specifically, CBM588 has been linked to better outcomes for patients taking nivolumab and cabozantinib, two common cancer treatments. Nivolumab helps the immune system attack cancer cells, while cabozantinib inhibits enzymes that tumors need to grow. Early results suggest that adding CBM588 may improve patient response to treatment for advanced kidney cancer. ^{1 2 4 6 7}

Who Is on the Research Team?

Sumanta K. Pal

Principal Investigator

City of Hope Medical Center

Are You a Good Fit for This Trial?

Adults with advanced or metastatic kidney cancer who haven't had systemic therapy for it, except possibly one prior treatment if the cancer came back after at least 6 months. They should have a certain level of blood cells and organ function, not be pregnant, agree to use contraception, and can't have severe illnesses that would make the trial unsafe for them.

Inclusion Criteria

I have had only one prior treatment for kidney cancer, and if it came back, it was 6 months after treatment ended.

My white blood cell count is healthy without needing medication.

Capable of understanding and complying with the protocol requirements and must have signed the informed consent document

Exclusion Criteria

My heart's electrical activity (QTcF) is over 500 ms, or I have risk factors for a specific heart rhythm problem.

My brain metastases are stable and treated, with no changes for 4 weeks.

You are currently taking or planning to take probiotics, yogurt, or foods that have added bacteria during the treatment period.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive nivolumab IV and cabozantinib S-malate PO, with or without CBM588, in 28-day cycles

12 weeks

1 visit (in-person) every 28 days

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

1 visit (in-person)

Long-term follow-up

Participants are monitored for progression-free survival and other outcomes

Up to 2 years

What Are the Treatments Tested in This Trial?

Interventions

• Cabozantinib S-malate
• Clostridium butyricum CBM 588 Probiotic Strain
• Nivolumab

Trial Overview The trial is testing CBM588 (a probiotic strain) combined with nivolumab (an immune system booster) and cabozantinib (a cell growth blocker), to see if they work better together against kidney cancer that has spread. It's in phase I to check how this combo affects patients' gut bacteria and their response to treatment.

How Is the Trial Designed?

Group I: Arm 2 (CBM588, nivolumab, cabozantinib S-malate) Experimental Treatment 3 Interventions

Patients receive CBM588 PO BID, nivolumab IV over 30 minutes on day 1, and cabozantinib S-malate PO QD. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Group II: Arm I (nivolumab, cabozantinib S-malate) Active Control 2 Interventions

Patients receive nivolumab IV over 30 minutes on day 1 and cabozantinib S-malate PO QD. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

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?

City of Hope Medical Center

Lead Sponsor

Trials

614

Recruited

1,924,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

In a phase II trial involving 47 patients with advanced non-clear-cell renal cell carcinoma, the combination of cabozantinib and nivolumab showed a promising objective response rate of 47.5% in patients with papillary, unclassified, or translocation-associated RCC, along with a median progression-free survival of 12.5 months.

The treatment was less effective in chromophobe RCC, with no objective responses observed, highlighting the need for further research into genomic predictors of response, particularly mutations like NF2 and FH that were associated with better outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II Trial of Cabozantinib Plus Nivolumab in Patients With Non-Clear-Cell Renal Cell Carcinoma and Genomic Correlates. Lee, CH., Voss, MH., Carlo, MI., et al.[2023]

In a phase 3 trial involving 855 patients with untreated advanced renal-cell carcinoma, the combination of cabozantinib with nivolumab and ipilimumab significantly improved progression-free survival compared to nivolumab and ipilimumab alone, with a 12-month progression-free survival rate of 57% versus 49%.

However, the experimental group experienced a higher incidence of severe adverse events (grade 3 or 4) at 79%, compared to 56% in the control group, indicating a trade-off between efficacy and safety.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cabozantinib plus Nivolumab and Ipilimumab in Renal-Cell Carcinoma. Choueiri, TK., Powles, T., Albiges, L., et al.[2023]

Nivolumab plus cabozantinib significantly improved progression-free survival and overall survival compared to sunitinib in advanced renal cell carcinoma, as shown in the CheckMate 9ER study.

However, the combination treatment was found to be not cost-effective, with an incremental cost-effectiveness ratio of $863,720 per quality-adjusted life-year (QALY) gained, far exceeding the commonly accepted threshold of $150,000.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cost-Effectiveness Analysis of First-Line Nivolumab Plus Cabozantinib for Advanced Renal Cell Carcinoma in the United States. Liao, W., Lei, W., Feng, M., et al.[2021]

The European Association of Urology now recommends nivolumab and cabozantinib as preferred treatments for patients with renal cancer who have not responded to previous vascular endothelial growth factor-targeted therapies.

Recent data indicate that cabozantinib offers a survival benefit, reinforcing its efficacy as a treatment option in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

European Association of Urology Guidelines for Clear Cell Renal Cancers That Are Resistant to Vascular Endothelial Growth Factor Receptor-Targeted Therapy. Powles, T., Staehler, M., Ljungberg, B., et al.[2018]

In a phase 3 trial involving 651 patients with untreated advanced renal-cell carcinoma, the combination of nivolumab and cabozantinib significantly improved progression-free survival (16.6 months) compared to sunitinib (8.3 months), with a hazard ratio of 0.51, indicating a 49% reduction in the risk of disease progression or death.

Patients receiving nivolumab plus cabozantinib also had a higher overall survival rate at 12 months (85.7%) compared to those on sunitinib (75.6%), and a greater objective response rate (55.7% vs. 27.1%), although adverse events were common in both groups.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nivolumab plus Cabozantinib versus Sunitinib for Advanced Renal-Cell Carcinoma. Choueiri, TK., Powles, T., Burotto, M., et al.[2022]

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]

A 77-year-old male with metastatic papillary renal cell carcinoma and inferior vena cava tumor thrombus was successfully treated with nivolumab plus cabozantinib, leading to significant regression of all lesions.

Following treatment, the patient underwent radical nephrectomy and other surgeries, with no viable cancer cells found and no recurrence of the disease for 9 months, indicating the potential efficacy of this combination therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Complete response of metastatic papillary renal cell carcinoma with inferior vena cava tumor thrombus to nivolumab plus cabozantinib. Hayashida, M., Miura, Y., Yamaguchi, T., et al.[2023]

The combination of cabozantinib (a tyrosine kinase inhibitor) and nivolumab (an immune checkpoint inhibitor) significantly improved progression-free survival, overall survival, and objective response rates in patients with untreated advanced renal cell carcinoma compared to sunitinib, supporting its approval as a first-line therapy.

While the safety profile of the combination treatment is generally manageable, it requires careful monitoring and management of overlapping adverse events, such as diarrhea and hepatotoxicity, to maintain patient tolerability and treatment effectiveness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Management of adverse events associated with cabozantinib plus nivolumab in renal cell carcinoma: A review. McGregor, B., Mortazavi, A., Cordes, L., et al.[2023]

In a real-world analysis of adverse events from two combination therapies for advanced renal cell carcinoma, cabozantinib (CAB) plus nivolumab (NIVO) showed higher incidence rates of seven types of toxicities compared to ipilimumab (IPI) plus NIVO.

Conversely, IPI + NIVO was associated with higher rates of three types of toxicities and had a greater incidence of serious adverse events, suggesting that both therapies have distinct safety profiles that can guide treatment decisions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adverse Events of Cabozantinib Plus Nivolumab Versus Ipilimumab Plus Nivolumab. Blas, L., Shiota, M., Tsukahara, S., et al.[2023]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT05122546

Study Details | NCT05122546 | CBM588 in Combination ... This phase I trial evaluates the effects of CBM588 in combination with standard therapies, nivolumab and cabozantinib, in treating patients with kidney cancer.

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11405272/

Cabozantinib and nivolumab with or without live bacterial ... Supplementation with CBM588, a bifidogenic live bacterial product, has been associated with improved clinical outcomes in persons with ...

3. ascopubs.org ascopubs.org/doi/10.1200/JCO.2020.38.6_suppl.TPS764

A phase I trial to assess the biologic effect of CBM588 ... A phase I trial to evaluate the biologic effect of CBM588 (Clostridium butyricum) in combination with cabozantinib plus nivolumab for patients ...

4. ascopubs.org ascopubs.org/doi/10.1200/JCO.2024.42.16_suppl.4550

Impact of CBM588 on gut microbiome composition and ... Supplementation with CBM588 leads to a marked correction of gut dysbiosis and prevents the depletion of species previously associated with ICI response.

5. nature.com nature.com/articles/s41591-022-01694-6

Nivolumab plus ipilimumab with or without live bacterial ... The data suggest that CBM588 appears to enhance the clinical outcome in patients with metastatic renal cell carcinoma treated with nivolumab–ipilimumab.

6. withpower.com withpower.com/trial/cbm588-nivolumab-cabozantinib-for-kidney-cancer-cd1cd

CBM588 + Nivolumab + Cabozantinib for Kidney Cancer This trial is testing a special bacteria (CBM588) with two cancer drugs in patients with advanced kidney cancer. The bacteria might help the drugs work ...

7. centerwatch.com centerwatch.com/clinical-trials/listings/NCT05122546/cbm588-in-combination-with-nivolumab-and-cabozantinib-for-the-treatment-of-advanced-or-metastatic-kidney-cancer

CBM588 in Combination With Nivolumab and ... The primary aim of this study is to determine how CBM588 changes the microbiome of patients with metastatic renal cell carcinoma. Immunotherapy ...