Combination Immunotherapy for Kidney Cancer

(ARCITECT Trial)

Recruiting at12 trial locations

Overseen by Michael Atkins, MD

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 2

Recruiting

Sponsor: Michael B. Atkins, MD

Must not be taking: Steroids, Immunosuppressants

Disqualifiers: CNS metastases, Autoimmune disease, Cardiovascular, others

No Placebo Group

Prior Safety Data

Breakthrough Therapy

Trial Summary

What is the purpose of this trial?

This trial is testing two new drugs, botensilimab and balstilimab, in patients with advanced kidney cancer who haven't been treated before. The new drugs aim to help the immune system better recognize and attack cancer cells. The study will compare these treatments over several months.

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.

What data supports the effectiveness of the drug combination for kidney cancer?

Research shows that the combination of nivolumab (Opdivo) and ipilimumab (Yervoy) has been effective in improving overall survival in patients with advanced kidney cancer, particularly those with intermediate or poor-risk profiles. This was demonstrated in a large study comparing this combination to another drug, sunitinib, where patients receiving nivolumab and ipilimumab lived longer. ^{1 2 3 4 5}

Is combination immunotherapy with nivolumab and ipilimumab generally safe for humans?

Combination immunotherapy with nivolumab (Opdivo) and ipilimumab (Yervoy) has been studied for advanced kidney cancer, and while it can cause immune-related side effects like diarrhea, skin reactions, and fatigue, these are generally manageable with proper care and adjustments. The safety profile is considered manageable with strategies like dose modification and supportive care. ^{2 6 7 8 9}

What makes the combination immunotherapy for kidney cancer unique?

This treatment is unique because it combines multiple immune checkpoint inhibitors (drugs that help the immune system attack cancer cells) like Balstilimab, Botensilimab, Ipilimumab, and Nivolumab, which have shown promising results in improving response rates and progression-free survival in kidney cancer compared to traditional treatments like sunitinib. ^{1 10 11 12 13}

Research Team

Michael Atkins, MD

Principal Investigator

Georgetown University

Eligibility Criteria

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.

Trial Timeline

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

Treatment Details

Interventions

• Balstilimab (Monoclonal Antibodies)
• Botensilimab (Monoclonal Antibodies)
• Ipilimumab (Monoclonal Antibodies)
• Nivolumab (Monoclonal Antibodies)

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.

Participant Groups

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+

Dr. Ivica Labuda

Georgetown University

Chief Executive Officer since 2022

PhD in Biochemistry and Molecular & Cellular Biology from Slovak Academy of Sciences, University of Graz, and Rutgers University

Dr. Richard Ascione

Georgetown University

Chief Medical Officer since 2023

MD from Georgetown University Medical School

Findings from Research

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]

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 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]

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]

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 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]

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]

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]

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]

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]

References

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

Perioperative therapy in renal cancer in the era of immune checkpoint inhibitor therapy. [2021]

2. 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]

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

Immunomodulatory Activity of Nivolumab in Metastatic Renal Cell Carcinoma. [2022]

4. Egypt pubmed.ncbi.nlm.nih.gov

Efficacy and Safety of Nivolumab for Advanced Renal Cell Carcinoma: A Systematic Review and Meta-Analysis. [2022]

5. England pubmed.ncbi.nlm.nih.gov

Targeted therapies in metastatic renal cell carcinoma: the light at the end of the tunnel. [2021]

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

Adverse Events of Cabozantinib Plus Nivolumab Versus Ipilimumab Plus Nivolumab. [2023]

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

Management of adverse events associated with cabozantinib plus nivolumab in renal cell carcinoma: A review. [2023]

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

Prognostic impact of immune-related adverse events in metastatic renal cell carcinoma treated with nivolumab plus ipilimumab. [2022]

9. United States 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. [2023]

10. Hungary pubmed.ncbi.nlm.nih.gov

[Immunotherapy of renal cell cancer]. [2019]

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

In silico modeling of combination systemic therapy for advanced renal cell carcinoma. [2023]

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

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

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

Checkpoint Inhibitor Combo Effective for RCC. [2019]