Triple Drug Therapy for Kidney Cancer

Recruiting at 2 trial locations

Overseen By Eric Jonasch, MD

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: M.D. Anderson Cancer Center

Must not be taking: Corticosteroids, Immunosuppressives

Disqualifiers: Active infection, CNS metastasis, others

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

Compensation: Varies

Number of Visits: 4

Duration: 12 weeks

24 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial protocol does not specify if you need to stop taking your current medications. However, if you are on systemic corticosteroids or other immunosuppressive medications, you may need to stop them 14 days before starting the trial treatment.

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

The combination of nivolumab (Opdivo) and ipilimumab (Yervoy) has been shown to improve overall survival in patients with advanced renal cell carcinoma, as demonstrated in a large clinical trial. This combination is already approved for use in certain kidney cancer patients, indicating its effectiveness. ^{1 2 3 4 5}

Is the triple drug therapy for kidney cancer safe?

The combination of nivolumab and ipilimumab, part of the triple drug therapy, can cause significant side effects, including severe immune-related reactions. These side effects are more frequent and severe when the drugs are used together, but they are often manageable with medications like glucocorticoids. Close monitoring by experienced healthcare providers is essential to manage these reactions effectively. ^{3 6 7 8 9}

What makes the triple drug therapy for kidney cancer unique?

The triple drug therapy for kidney cancer is unique because it combines Ciforadenant with the already established combination of nivolumab (Opdivo) and ipilimumab (Yervoy), which are known to improve survival in patients with advanced renal cell carcinoma. This combination leverages the immune-boosting effects of nivolumab and ipilimumab, which are immune checkpoint inhibitors, potentially offering a novel approach by adding Ciforadenant, which may further enhance the immune response against cancer cells. ^{4 10 11 12 13}

What is the purpose of this trial?

To learn if the combination of ciforadenant, ipilimumab, and nivolumab can help to control advanced renal cell carcinoma

Research Team

Eric Jonasch, MD

Principal Investigator

M.D. Anderson Cancer Center

Eligibility Criteria

Adults with Stage IV metastatic renal cell carcinoma who have not had prior systemic therapy for advanced RCC. Participants must have adequate organ function, be willing to use contraception, and able to provide consent. Excluded are those with recent major surgery, active autoimmune diseases, or conditions requiring immunosuppressants.

Inclusion Criteria

Women who can have babies must have a negative pregnancy test within 24 hours before starting the treatment.

I have been diagnosed with clear cell renal cell carcinoma.

I have not received any systemic therapy for advanced kidney cancer.

Exclusion Criteria

I haven't had any cancer treatment, including immune or targeted therapies, in the last 6 months.

I cannot take pills by mouth or have a severe gut problem affecting drug absorption.

I haven't had major surgery in the last 28 days.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive ipilimumab, nivolumab, and ciforadenant to control advanced renal cell carcinoma

12 weeks

4 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

12 weeks

Treatment Details

Interventions

• Ciforadenant
• Ipilimumab
• Nivolumab

Trial Overview The trial is testing a combination of three drugs: Ciforadenant (an adenosine A2a receptor antagonist), Ipilimumab, and Nivolumab in patients with advanced renal cell carcinoma to see if this mix can control the disease better than current treatments.

Participant Groups

Group I: Ipilimumab, Nivolumab, and Ciforadenant Experimental Treatment 3 Interventions

To help control advanced renal cell carcinoma.

Who Is Running the Clinical Trial?

M.D. Anderson Cancer Center

Lead Sponsor

Trials

3,107

Recruited

1,813,000+

Findings from Research

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 52 patients with metastatic renal cell carcinoma treated with nivolumab plus ipilimumab, the 1-year progression-free survival rate was 55% and the overall survival rate was 75%, indicating promising efficacy of this treatment combination.

The treatment was associated with a 39% objective response rate, and while 69% of patients experienced immune-related adverse events, the incidence of severe events was lower compared to previous studies, suggesting a favorable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of first-line nivolumab plus ipilimumab in patients with metastatic renal cell carcinoma: A multicenter retrospective study. Tanaka, T., Hatakeyama, S., Numakura, K., et al.[2021]

The combination therapy of nivolumab and ipilimumab is effective for treating advanced renal cell carcinoma, as demonstrated in two case studies of patients receiving this treatment.

Both patients experienced severe immune-related adverse events, including fever, skin rash, and hypotension, which were ultimately diagnosed as anaphylaxis due to the contrast agent used in imaging, highlighting the need for careful monitoring during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Two cases of anaphylaxis due to contrast media during administration of nivolumab and ipilimumab in metastatic renal cell carcinoma. Nezu, K., Katayama, H., Kyan, A.[2020]

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]

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]

The PRISM study is investigating whether administering ipilimumab every 12 weeks instead of every 3 weeks, when combined with nivolumab, can reduce severe side effects in patients with metastatic renal cell carcinoma (mRCC) without affecting treatment effectiveness.

This phase II trial aims to recruit 189 participants and will primarily measure the rate of grade 3 or 4 adverse reactions over 12 months, while also assessing progression-free survival and other important health outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

PRISM protocol: a randomised phase II trial of nivolumab in combination with alternatively scheduled ipilimumab in first-line treatment of patients with advanced or metastatic renal cell carcinoma. Buckley, HL., Collinson, FJ., Ainsworth, G., et al.[2022]

Combined immune checkpoint blockade (ICB) using nivolumab and ipilimumab shows significant efficacy in treating advanced melanoma, but it also leads to a higher frequency and severity of adverse drug reactions (ADRs) compared to single-agent therapies, based on pooled safety data from 1551 patients.

Most immune-related ADRs are reversible with glucocorticoids, but due to the increased risk and rapid onset of these toxicities, clinicians must be well-trained to monitor and manage these side effects effectively.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combined immune checkpoint blockade (anti-PD-1/anti-CTLA-4): Evaluation and management of adverse drug reactions. Hassel, JC., Heinzerling, L., Aberle, J., et al.[2022]

In a long-term follow-up of 94 patients with advanced melanoma treated with nivolumab and ipilimumab, the 3-year overall survival rate was 63%, indicating a promising long-term efficacy of this combination therapy.

The treatment was associated with a 42% objective response rate, but also a significant incidence of grade 3 and 4 adverse events (59%), highlighting the need for careful monitoring of side effects during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nivolumab Plus Ipilimumab in Patients With Advanced Melanoma: Updated Survival, Response, and Safety Data in a Phase I Dose-Escalation Study. Callahan, MK., Kluger, H., Postow, MA., et al.[2021]

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]

In a phase II study involving 34 patients with metastatic renal cell carcinoma, a triple drug bio-chemotherapy regimen combining interleukin-2, interferon-alpha, and 5-fluorouracil achieved an overall objective response rate of 38%, with 9% of patients experiencing complete remission and 29% partial remission.

The treatment was well-tolerated, with only minor side effects reported and no treatment-related deaths, indicating that this regimen may provide significant clinical benefits with a favorable safety profile compared to traditional aggressive therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Immunochemotherapy for metastatic renal cell carcinoma using a regimen of interleukin-2, interferon-alpha and 5-fluorouracil. Hofmockel, G., Langer, W., Theiss, M., et al.[2013]

The 2018 NCCN Guidelines now endorse adjuvant sunitinib as the first therapy for patients with stage II and III clear cell renal cell carcinoma, indicating its potential effectiveness in this setting.

Ipilimumab plus nivolumab has been introduced as a promising frontline treatment for patients with intermediate and poor-risk advanced renal cell carcinoma, along with cabozantinib as a new first-line option for similar risk groups.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Updates to the Management of Kidney Cancer. Jonasch, E.[2019]

The treatment landscape for locally advanced or metastatic kidney tumors has rapidly evolved since 2005, with the introduction of targeted therapies and immune checkpoint inhibitors enhancing treatment options.

Selecting the most effective medication for patients in different treatment lines remains a significant challenge for clinicians, highlighting the need for comprehensive data and clinical trial results to guide therapy choices.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Second and further lines treatment options for locally advanced or metastatic renal cell carcinoma]. Nagyiványi, K., Géczi, L.[2023]

In a pilot study involving 27 patients with metastatic renal cell carcinoma, the combination of interferon-alpha, capecitabine, and thalidomide showed notable antitumor activity, with a 20% partial response rate and 24% of patients achieving stable disease for over 6 months.

The treatment was generally well tolerated, although some patients experienced significant side effects like hand-foot syndrome and neuropathy, indicating that while the combination therapy is promising, further research is needed to optimize its use in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Interferon-alpha plus capecitabine and thalidomide in patients with metastatic renal cell carcinoma: a pilot study. Amato, RJ., Rawat, A.[2022]

References

1. 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]

2. Australia pubmed.ncbi.nlm.nih.gov

Efficacy and safety of first-line nivolumab plus ipilimumab in patients with metastatic renal cell carcinoma: A multicenter retrospective study. [2021]

3. Singapore pubmed.ncbi.nlm.nih.gov

Two cases of anaphylaxis due to contrast media during administration of nivolumab and ipilimumab in metastatic renal cell carcinoma. [2020]

4. 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]

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

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

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

PRISM protocol: a randomised phase II trial of nivolumab in combination with alternatively scheduled ipilimumab in first-line treatment of patients with advanced or metastatic renal cell carcinoma. [2022]

7. Netherlands pubmed.ncbi.nlm.nih.gov

Combined immune checkpoint blockade (anti-PD-1/anti-CTLA-4): Evaluation and management of adverse drug reactions. [2022]

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

Nivolumab Plus Ipilimumab in Patients With Advanced Melanoma: Updated Survival, Response, and Safety Data in a Phase I Dose-Escalation Study. [2021]

9. Switzerland pubmed.ncbi.nlm.nih.gov

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

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

Immunochemotherapy for metastatic renal cell carcinoma using a regimen of interleukin-2, interferon-alpha and 5-fluorouracil. [2013]

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

Updates to the Management of Kidney Cancer. [2019]

12. Hungary pubmed.ncbi.nlm.nih.gov

[Second and further lines treatment options for locally advanced or metastatic renal cell carcinoma]. [2023]

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

Interferon-alpha plus capecitabine and thalidomide in patients with metastatic renal cell carcinoma: a pilot study. [2022]