Combination Immunotherapy for Kidney Cancer

(ARCITECT Trial)

Recruiting at 13 trial locations

Overseen By Rebecca Mottier

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Michael B. Atkins, MD

Must not be taking: Steroids, Immunosuppressants

Disqualifiers: CNS metastases, Autoimmune disease, Cardiovascular, 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

Compensation: Varies

Number of Visits: 9

120 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests new treatments for people with advanced kidney cancer that has spread (metastatic). It compares two drug combinations to determine which more effectively stops the cancer: botensilimab with balstilimab (both immunotherapy drugs) versus ipilimumab with nivolumab. People who haven't received prior treatment for their kidney cancer and have tumors that can't be surgically removed might be suitable for this study. Participants will continue receiving the treatment until it causes significant side effects, their cancer worsens, or they complete about two years of treatment. As a Phase 2 trial, this study measures the treatment's effectiveness in an initial, smaller group, allowing participants to contribute to important research.

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, you cannot participate if you require certain treatments like corticosteroids or other immunosuppressive medications within 14 days of starting the trial. 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 the combination of botensilimab and balstilimab is generally safe for patients. Previous patients experienced these treatments without major problems. Common side effects include fatigue and mild skin reactions.

For the ipilimumab and nivolumab combination, studies also indicate general safety, though side effects may include tiredness, skin rash, and diarrhea. Serious side effects are less common but can involve inflammation in various parts of the body.

Both treatment combinations have undergone previous study, providing extensive safety information. Overall, they are considered safe enough for continued testing in clinical trials. ^{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 different immunotherapy drugs to potentially enhance the body's ability to fight cancer. Unlike the standard approaches that often involve single-agent treatments, Arm A uses a combination of balstilimab and botensilimab, which are designed to work together to stimulate a stronger immune response. Arm B combines ipilimumab and nivolumab, two well-known immune checkpoint inhibitors, but in a novel dosing schedule that might improve effectiveness and reduce side effects. These combinations aim to offer better outcomes by leveraging the synergistic effects of multiple immunotherapy agents, providing hope for more effective treatment options.

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

This trial will compare two treatment options for metastatic kidney cancer. Participants in Arm A will receive a combination of botensilimab and balstilimab. Studies suggest that this combination might be promising for treating advanced kidney cancer, with an expected effectiveness of about 55%, compared to a 17% response rate in earlier trials. Meanwhile, participants in Arm B will receive ipilimumab and nivolumab, which are already approved for treating certain cancers, including kidney cancer, and have proven effective. This trial aims to determine the best approach for patients with metastatic kidney cancer by comparing both treatment options. ^{1 2 3 6 7}

Who Is on the Research Team?

Michael Atkins, MD

Principal Investigator

Georgetown University

Are You a Good Fit for This Trial?

Adults with advanced or metastatic renal cell carcinoma (kidney cancer) who haven't had certain treatments can join. They need measurable disease, proper organ function, and no recent major surgery. Women must test negative for pregnancy and agree to contraception; men too if with women of childbearing potential. HIV-positive patients can join under specific conditions.

Inclusion Criteria

You must have been categorized as having a low, medium, or high risk of the cancer getting worse based on certain clinical factors.

My cancer can be measured on scans and hasn't just been treated with radiation unless it's growing.

Women who can have babies need to have a negative pregnancy test within a week before starting the study.

Exclusion Criteria

I don't expect to need any other cancer treatment while in this trial.

I have been treated with specific immune or targeted therapies before.

I have not received a live vaccine within the last 30 days.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Induction Treatment

Participants receive induction treatment with either botensilimab and balstilimab or ipilimumab and nivolumab for 12 weeks

12 weeks

2 cycles, each lasting 6 weeks

Maintenance Treatment

Participants receive maintenance treatment with either botensilimab and balstilimab or nivolumab alone for up to 84 weeks

84 weeks

7 cycles, each lasting 12 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

5 years

What Are the Treatments Tested in This Trial?

Interventions

• Balstilimab
• Botensilimab
• Ipilimumab
• Nivolumab

Trial Overview The trial is testing botensilimab with balstilimab against ipilimumab with nivolumab in a randomized open-label study. Patients are assigned to one of two groups in a 2:1 ratio and treated until toxicity, progression, or up to 96 weeks.

How Is the Trial Designed?

Group I: Arm A (botensilimab and balstilimab) Experimental Treatment 2 Interventions

Arm A subjects will receive 2 cycles of induction treatment with each cycle lasting 6 weeks. Cycle 1 will consist of botensilimab 75mg IV in combination with balstilimab 450mg IV on Day 1 and Day 22. Cycle 2 will consist of balstilimab 450mg IV ONLY on Day 1 and Day 22. Botensilimab will NOT be given in Cycle 2. Subjects will receive 7 cycles of maintenance treatment with each cycle lasting 12 weeks. Cycles 3 and 4 will consist of botensilimab 75mg IV on Day 1 in combination with balstilimab 450mg IV on Day 1, 22, 43 and 64. Cycles 5-9 will consist of balstilimab alone 450 mg IV on Day 1, 22, 43 and 64.

Group II: Arm B (ipilimumab and nivolumab) Active Control 2 Interventions

Arm B subjects will receive 2 cycles of induction treatment with each cycle lasting 6 weeks. Cycle 1 and 2 will consist of ipilimumab 1 mg/kg IV and nivolumab 3 mg/kg on Day 1 and 22. Subjects will receive 7 cycles of maintenance treatment with each cycle lasting 12 weeks. Nivolumab 480mg IV will be given on Day 1, 29 and 57 of each cycle (every 4 weeks).

Who Is Running the Clinical Trial?

Michael B. Atkins, MD

Lead Sponsor

Trials

2

Recruited

280+

Agenus Inc.

Industry Sponsor

Trials

58

Recruited

4,900+

Georgetown University

Collaborator

Trials

355

Recruited

142,000+

Published Research Related to This Trial

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]

In a study of 91 patients with metastatic renal cell carcinoma (mRCC), nivolumab showed significant improvements in overall survival, with a median survival of 25.2 months for the highest dose (10 mg/kg) and not reached for treatment-naïve patients.

Nivolumab treatment led to substantial increases in tumor-associated lymphocytes and changes in chemokine levels, indicating its immunomodulatory effects, while no new safety concerns were identified.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Immunomodulatory Activity of Nivolumab in Metastatic Renal Cell Carcinoma. Choueiri, TK., Fishman, MN., Escudier, B., et al.[2022]

Nivolumab, when combined with ipilimumab, significantly improves overall survival (OS) and progression-free survival (PFS) in patients with advanced renal cell carcinoma (RCC), based on a meta-analysis of three high-quality randomized controlled trials involving 2550 patients.

The treatment with nivolumab did not lead to an increase in adverse events, indicating a manageable safety profile for patients undergoing this therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and Safety of Nivolumab for Advanced Renal Cell Carcinoma: A Systematic Review and Meta-Analysis. Zhang, S., Xu, X., Chen, J., et al.[2022]

Targeted therapies, particularly sunitinib and sorafenib, have shown significant improvements in progression-free survival for patients with metastatic renal cell carcinoma compared to traditional immunotherapies like interferon-alpha.

Temsirolimus has been found to provide better overall survival than interferon in patients with poor-risk characteristics, highlighting the importance of targeted treatments in managing this disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Targeted therapies in metastatic renal cell carcinoma: the light at the end of the tunnel. Pouessel, D., Culine, S.[2021]

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]

Combining VEGFR tyrosine kinase inhibitors with immune checkpoint blockers, like cabozantinib with nivolumab or axitinib with pembrolizumab, is now a standard treatment for advanced renal cell carcinoma, showing promising efficacy in clinical trials.

In silico drug modeling suggests that while these combinations are effective, the necessity of using both mechanisms may vary among patients, highlighting the potential for personalized treatment strategies based on tumor profiling.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

In silico modeling of combination systemic therapy for advanced renal cell carcinoma. Kotecha, RR., Hsu, DJ., Lee, CH., et al.[2023]

Targeted therapies and immunotherapies, including checkpoint inhibitors like anti-CTLA-4 and anti-PD-1, are showing promise in treating kidney cancer, particularly in metastatic clear cell renal carcinoma.

Recent clinical trials, such as CheckMate-025 and AGS-003, are exploring the effectiveness of these therapies, indicating a shift towards combination treatments that may enhance patient outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Immunotherapy of renal cell cancer]. Géczi, L., Nagyiványi, K., Maráz, A.[2019]

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]

Ongoing phase 3 trials are exploring the use of immune checkpoint inhibitors (ICIs) in nonmetastatic renal cell carcinoma (RCC) as adjuvant and neoadjuvant therapies, with several combinations being tested, including atezolizumab and pembrolizumab.

Early phase 1b/2 trials show promising safety and efficacy of ICIs, indicating they can induce dynamic changes in immune cell infiltration, which may help predict patient responses to therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Perioperative therapy in renal cancer in the era of immune checkpoint inhibitor therapy. Kuusk, T., Abu-Ghanem, Y., Mumtaz, F., et al.[2021]

In a phase III trial, the combination of nivolumab and ipilimumab resulted in a higher response rate (over 41%) compared to sunitinib (26.5%) in patients with intermediate or high-risk renal cell carcinoma.

Patients treated with the immunotherapy combination not only had longer progression-free survival but also experienced fewer side effects, indicating a potentially safer and more effective treatment option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Checkpoint Inhibitor Combo Effective for RCC. [2019]

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 study of 46 patients with metastatic renal cell carcinoma treated with nivolumab plus ipilimumab, 72% experienced immune-related adverse events (irAEs), which were linked to significantly longer progression-free survival (PFS) compared to those without irAEs.

While irAE development was an independent predictor of longer PFS, it did not affect overall survival (OS), suggesting that irAEs could serve as a useful prognostic marker for treatment outcomes in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Prognostic impact of immune-related adverse events in metastatic renal cell carcinoma treated with nivolumab plus ipilimumab. Ikeda, T., Ishihara, H., Nemoto, Y., et al.[2022]

In a study of 69 patients with metastatic renal cell carcinoma treated with nivolumab plus ipilimumab, those who experienced immune-related adverse events (irAEs) had significantly better overall survival (OS) and progression-free survival compared to those without irAEs, suggesting that irAEs may be a positive indicator of treatment response.

The study identified three key factors influencing OS: the presence of irAEs, C-reactive protein levels, and performance status, indicating that monitoring these factors could help predict patient outcomes in mRCC treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Prognostic Impact of Immune-Related Adverse Events as First-Line Therapy for Metastatic Renal Cell Carcinoma Treated With Nivolumab Plus Ipilimumab: A Multicenter Retrospective Study. Nukaya, T., Takahara, K., Yoshizawa, A., et al.[2023]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT05928806

Study Details | NCT05928806 | Advanced Renal Cell ... This study is a randomized, open label, multicenter Phase II trial to evaluate the efficacy and safety of botensilimab (a novel Fc enhanced Tree depleting ...

2. onclive.com onclive.com/view/dr-serzan-on-the-potential-of-botensilimab-balstilimab-to-address-unmet-needs-in-rcc

Dr Serzan on the Potential of Botensilimab/Balstilimab to ... Michael Serzan, MD, discusses the use of botensilimab/balstilimab in the treatment of patients with advanced renal cell carcinoma.

3. ascopubs.org ascopubs.org/doi/10.1200/JCO.2024.42.4_suppl.TPS492

Advanced renal cell cancer combination immunotherapy ... The primary endpoint is overall response rate (ORR) per RECIST 1.1. We hypothesize that Bot/Bal will lead to a superior ORR (55%) relative to ...

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11405281/

Botensilimab plus balstilimab in relapsed/refractory ... Most notably, the combination of BOT and BAL resulted in promising efficacy, with an ORR of 17% (17/101 patients; ORR 18% with an additional ...

5. cancer.gov cancer.gov/research/participate/clinical-trials-search/v?id=NCI-2023-08597

Botensilimab and Balstilimab versus Nivolumab and ... Giving botensilimab and balstilimab may be more safe and effective than standard treatment for patients with advanced clear cell renal cell carcinoma.

6. clinicaltrials.gov clinicaltrials.gov/study/NCT05529316

NCT05529316 | A Study of Botensilimab (AGEN1181) for ... This study is an open-label, 2-part, Phase 2, multicenter study to evaluate the efficacy, safety, tolerability, and pharmacokinetic profiles of botensilimab

7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11954509/

Emerging innovative treatment strategies for advanced clear ... This article reviews key findings that have transformed the way we understand and treat metastatic renal cell carcinoma and highlights novel treatment ...