CBM588 + Nivolumab/Ipilimumab for Kidney Cancer

Overseen By Sumanta K. Pal, M.D.

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Osel, Inc.

Must not be taking: Probiotics, Yogurt

Disqualifiers: Interstitial lung disease, Brain metastases, Autoimmune disease, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: 12

28 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This is a single arm open-label phase 1 study evaluating the safety and efficacy of escalating doses of CBM588 in combination with nivolumab and ipilimumab. A standard 3+3 dose escalation schema will be used initially to assess the maximum tolerated dose (MTD) followed by a dose expansion of 10 patients at the MTD to further evaluate safety and efficacy.

Will I have to stop taking my current medications?

The trial information does not specify if you need to stop taking your current medications. However, you cannot use probiotics, yogurt, or bacterial fortified foods during the treatment period. It's best to discuss your current medications with the study team.

Is the combination of CBM588, Nivolumab, and Ipilimumab safe for humans?

Nivolumab and Ipilimumab, when used together, have been approved for treating advanced kidney cancer, but they can cause side effects like kidney inflammation and immune-related issues. There are reports of safe use in specific cases, but potential side effects should be discussed with a doctor. Information on CBM588's safety in this combination is not provided. ^{1 2 3 4 5}

How is the CBM588 + Nivolumab/Ipilimumab treatment for kidney cancer different from other treatments?

The CBM588 + Nivolumab/Ipilimumab treatment is unique because it combines an immune checkpoint blockade (Nivolumab and Ipilimumab) with CBM588, a probiotic (a beneficial bacteria) that may enhance the immune response, potentially offering a novel approach compared to standard therapies that do not include probiotics. ^{6 7 8 9 10}

What data supports the effectiveness of the drug combination CBM588, Nivolumab, and Ipilimumab for kidney cancer?

Research shows that the combination of nivolumab and ipilimumab, which are part of the treatment, has been effective in treating advanced renal-cell carcinoma, achieving better responses than some other treatments. This suggests potential effectiveness when combined with CBM588 for kidney cancer. ^{6 8 11 12 13}

Who Is on the Research Team?

Alexander Chehrazi-Raffle, M.D.

Principal Investigator

City of Hope Medical Center

Are You a Good Fit for This Trial?

This trial is for adults with advanced kidney cancer, specifically Renal Cell Carcinoma. Participants must be able to take oral medication and have not been treated with Nivolumab or Ipilimumab before. People who've had certain other treatments or health conditions that could interfere with the study are excluded.

Inclusion Criteria

I have recovered from the side effects of my previous cancer treatment.

Measurable disease by RECIST 1.1

Documented informed consent of the participant and/or legally authorized representative

Exclusion Criteria

I have or had lung inflammation that needed treatment.

I have recently had cancer treatment with drugs or radiation.

Noncompliance with study procedures

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Dose Escalation

Participants receive escalating doses of CBM588 in combination with nivolumab and ipilimumab to determine the maximum tolerated dose (MTD)

28 days

Regular visits for dose escalation monitoring

Dose Expansion

10 additional patients are enrolled at the MTD to further evaluate safety and efficacy

90 days

Regular visits for safety and efficacy evaluation

Follow-up

Participants are monitored for safety and effectiveness after treatment

12 weeks

Re-evaluation every 12 weeks

What Are the Treatments Tested in This Trial?

Interventions

• CBM588
• Ipilimumab
• Nivolumab

Trial Overview The study tests different doses of CBM588 capsules combined with standard doses of Nivolumab and Ipilimumab to find the highest dose patients can tolerate without severe side effects (MTD). After finding MTD, they'll expand the group to further check safety and how well it works.

How Is the Trial Designed?

Group I: CBM588 Capsules Experimental Treatment 3 Interventions

This will be a dose escalation study of CBM588 oral capsules at two potencies in combination with nivolumab and ipilimumab dual immune checkpoint therapy: 1x Capsule containing 4.0E+8 CFU/capsule; and 10x Capsule containing 4.0E+9 CFU/capsule. The dose escalation will begin with one 1x Capsule administered twice a day followed by three 1x Capsules b.i.d., and then one 10x Capsule b.i.d. until disease progression or dose limiting toxicity occurs.

Who Is Running the Clinical Trial?

Osel, Inc.

Lead Sponsor

Trials

7

Recruited

250+

City of Hope Comprehensive Cancer Center

Collaborator

Trials

6

Recruited

230+

Miyarisan Pharmaceutical Co., Ltd.

Collaborator

Trials

1

Recruited

30+

Published Research Related to This Trial

In a phase 3 trial involving 1096 patients with untreated advanced renal-cell carcinoma, nivolumab plus ipilimumab significantly improved overall survival rates (75% at 18 months) compared to sunitinib (60% at 18 months), indicating a more effective treatment option for patients with intermediate or poor prognostic risk.

The objective response rate was also higher with nivolumab plus ipilimumab (42%) compared to sunitinib (27%), although both treatments had a high incidence of treatment-related adverse events, with nivolumab plus ipilimumab showing a slightly lower rate of severe (grade 3 or 4) events (46% vs. 63%).

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nivolumab plus Ipilimumab versus Sunitinib in Advanced Renal-Cell Carcinoma. Motzer, RJ., Tannir, NM., McDermott, DF., et al.[2022]

Combining nivolumab with ipilimumab results in higher response rates in cancer treatment compared to using nivolumab alone, indicating a potentially more effective therapeutic strategy.

This combination therapy may enhance the immune response against cancer, but specific details on the number of subjects or study duration are not provided in the abstract.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nivolumab plus Ipilimumab Achieves Responses in dMMR/MSI-H Tumors. [2019]

Nivolumab, an immune checkpoint inhibitor, shows improved survival in some patients with metastatic clear cell renal cell carcinoma (ccRCC), but traditional predictive factors like PD-L1 status are not effective in this context.

The study identified that T-cell infiltration is positively associated with treatment response, while certain molecular pathways, such as the RIG-I-MDA5 pathway, may contribute to resistance in highly T-cell infiltrated tumors, suggesting new avenues for patient selection and treatment strategies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Molecular correlates of response to nivolumab at baseline and on treatment in patients with RCC. Ross-Macdonald, P., Walsh, AM., Chasalow, SD., et al.[2021]

The approval of the dual immune checkpoint inhibitors nivolumab and ipilimumab marks a significant advancement in the treatment of advanced renal cell carcinoma (aRCC), moving away from traditional VEGF monotherapy.

Emerging data suggests that combining immune checkpoint inhibitors with VEGF inhibitors may further enhance treatment options for aRCC, indicating a shift towards more effective combination therapies in frontline treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Evolving Landscape of Immunotherapy-Based Combinations for Frontline Treatment of Advanced Renal Cell Carcinoma. Amin, A., Hammers, H.[2023]

In a study of 18 patients with non-clear cell renal cell carcinoma (nccRCC) treated with ipilimumab plus nivolumab, 33.3% achieved partial responses, indicating that this combination therapy can be effective for this type of cancer.

However, the treatment was associated with significant toxicity, with 61.1% of patients experiencing treatment-related adverse events, including serious conditions like colitis and hepatotoxicity, highlighting the need for careful monitoring.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical Activity of Ipilimumab Plus Nivolumab in Patients With Metastatic Non-Clear Cell Renal Cell Carcinoma. Gupta, R., Ornstein, MC., Li, H., et al.[2021]

Nivolumab combined with ipilimumab significantly improves overall survival in adult patients with intermediate/poor-risk advanced renal cell carcinoma compared to sunitinib, with a hazard ratio of 0.63, indicating a 37% reduction in the risk of death.

In the study involving 1096 patients, the median overall survival was not reached for the nivolumab + ipilimumab group, while it was 25.95 months for the sunitinib group, highlighting the potential of this combination therapy for better long-term outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

European Medicines Agency extension of indication to include the combination immunotherapy cancer drug treatment with nivolumab (Opdivo) and ipilimumab (Yervoy) for adults with intermediate/poor-risk advanced renal cell carcinoma. Ali, S., Camarero, J., Hennik, P., et al.[2021]

Nivolumab, an immune-checkpoint inhibitor used to treat lung adenocarcinoma, can lead to autoimmune side effects, as demonstrated by a case of acute tubulointerstitial nephritis in a 67-year-old patient after three infusions.

The kidney biopsy revealed specific histological changes, including proliferation of certain immune cells, indicating that nivolumab can trigger significant immune responses that may affect organ function.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tubulointerstitial nephritis as adverse effect of programmed cell death 1 inhibitor, nivolumab, showed distinct histological findings. Uchida, A., Watanabe, M., Nawata, A., et al.[2021]

Ipilimumab, an immune checkpoint inhibitor approved for metastatic melanoma, can cause immune-related toxicities such as colitis, hepatitis, and dermatitis, but also rare effects like acute renal failure.

In a reported case, acute renal failure due to ipilimumab was successfully treated with high-dose corticosteroids, emphasizing the need for careful monitoring of less common side effects as more patients are treated with this medication.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ipilimumab-induced immune-related renal failure--a case report. Forde, PM., Rock, K., Wilson, G., et al.[2017]

Ipilimumab is a pioneering immune checkpoint inhibitor that enhances the anti-tumor response of T cells by blocking CTLA-4, which is crucial for its mechanism of action against cancer.

Combining ipilimumab with anti-PD-1 antibodies has shown clinical benefits in treating advanced melanoma and renal cell cancer, indicating improved efficacy in these malignancies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Clinical Significance of Ipilimumab and the Combination Therapy as Immune Checkpoint Inhibitor]. Muto, Y., Kitano, S.[2019]

The combination of nivolumab and ipilimumab, which targets PD-1 and CTLA-4 pathways, is an approved frontline therapy for metastatic clear-cell renal cell carcinoma (mccRCC).

This case study demonstrates the safe and effective use of this combination therapy in a 53-year-old patient with mccRCC and end-stage renal disease (ESRD) on hemodialysis, highlighting its potential applicability in populations often excluded from clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safe and effective use of nivolumab plus ipilimumab in a patient with metastatic clear-cell renal cell carcinoma with sarcomatoid dedifferentiation and end stage renal disease on hemodialysis. Shaw, LK., Wiele, AJ., Sircar, K., et al.[2022]

In a study of 45 Japanese patients with untreated metastatic renal cell carcinoma, the combination therapy of nivolumab and ipilimumab showed a 41.5% objective response rate and a median progression-free survival of 17.8 months over a 2-year follow-up period.

The 2-year analysis indicated that nivolumab plus ipilimumab therapy's effectiveness aligns with previous studies, and second-line therapy following this combination also demonstrated a 20% objective response rate with a median progression-free survival of 9.8 months.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Real-world effectiveness of nivolumab plus ipilimumab and second-line therapy in Japanese untreated patients with metastatic renal cell carcinoma: 2-year analysis from a multicenter retrospective clinical study (J-cardinal study). Kojima, T., Kato, R., Sazuka, T., et al.[2022]

A patient on hemodialysis with advanced clear-cell renal cell carcinoma successfully received combined immune checkpoint blockade therapy with nivolumab and ipilimumab, showing no significant immune-related adverse events.

This case supports the safety and efficacy of using nivolumab and ipilimumab in patients on hemodialysis, suggesting that renal function does not significantly impact the treatment's pharmacokinetics or safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nivolumab and ipilimumab immunotherapy for hemodialysis patients with advanced renal cell carcinoma. Kobayashi, Y., Arai, H., Honda, M.[2023]

A 73-year-old hemodialysis patient with metastatic renal cell carcinoma was treated with the combination of ipilimumab and nivolumab, which was administered safely without any adverse events.

This case suggests that ipilimumab-nivolumab can be a viable treatment option for metastatic renal cell carcinoma in patients on hemodialysis, a group that typically has limited treatment options.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safe administration of ipilimumab plus nivolumab to a dialysis patient with renal cell carcinoma. Iwaki, T., Niimi, A., Kano, M., et al.[2022]

Citations

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

Nivolumab plus Ipilimumab versus Sunitinib in Advanced Renal-Cell Carcinoma. [2022]

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

Nivolumab plus Ipilimumab Achieves Responses in dMMR/MSI-H Tumors. [2019]

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

Molecular correlates of response to nivolumab at baseline and on treatment in patients with RCC. [2021]

4. Switzerland pubmed.ncbi.nlm.nih.gov

The Evolving Landscape of Immunotherapy-Based Combinations for Frontline Treatment of Advanced Renal Cell Carcinoma. [2023]

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

Clinical Activity of Ipilimumab Plus Nivolumab in Patients With Metastatic Non-Clear Cell Renal Cell Carcinoma. [2021]

6. England pubmed.ncbi.nlm.nih.gov

European Medicines Agency extension of indication to include the combination immunotherapy cancer drug treatment with nivolumab (Opdivo) and ipilimumab (Yervoy) for adults with intermediate/poor-risk advanced renal cell carcinoma. [2021]

7. Japan pubmed.ncbi.nlm.nih.gov

Tubulointerstitial nephritis as adverse effect of programmed cell death 1 inhibitor, nivolumab, showed distinct histological findings. [2021]

8. Greece pubmed.ncbi.nlm.nih.gov

Ipilimumab-induced immune-related renal failure--a case report. [2017]

9. Japan pubmed.ncbi.nlm.nih.gov

[Clinical Significance of Ipilimumab and the Combination Therapy as Immune Checkpoint Inhibitor]. [2019]

10. England pubmed.ncbi.nlm.nih.gov

Safe and effective use of nivolumab plus ipilimumab in a patient with metastatic clear-cell renal cell carcinoma with sarcomatoid dedifferentiation and end stage renal disease on hemodialysis. [2022]

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

Real-world effectiveness of nivolumab plus ipilimumab and second-line therapy in Japanese untreated patients with metastatic renal cell carcinoma: 2-year analysis from a multicenter retrospective clinical study (J-cardinal study). [2022]

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

Nivolumab and ipilimumab immunotherapy for hemodialysis patients with advanced renal cell carcinoma. [2023]

13. Australia pubmed.ncbi.nlm.nih.gov

Safe administration of ipilimumab plus nivolumab to a dialysis patient with renal cell carcinoma. [2022]