SLM-Axitinib-Pembrolizumab for Renal Cell Carcinoma

Overseen By Bilal Rahim, MD

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Mohammed Milhem

Must not be taking: CYP3A4 drugs

Disqualifiers: Pregnancy, Breastfeeding, CNS metastases, others

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

Compensation: Varies

Number of Visits: 21

55 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial does not specify if you need to stop all current medications, but you cannot take drugs that affect the enzyme CYP3A4, like certain antibiotics and antifungals. It's best to discuss your current medications with the trial team.

What data supports the effectiveness of the drug combination Axitinib and Pembrolizumab for Renal Cell Carcinoma?

Research shows that the combination of Axitinib and Pembrolizumab has a 73% response rate in patients with advanced renal cell carcinoma, and it improves overall survival and progression-free survival compared to another drug, sunitinib, in patients with metastatic renal cell carcinoma. ^{1 2 3 4 5}

What safety data exists for the combination of Axitinib and Pembrolizumab in treating renal cell carcinoma?

The combination of Axitinib and Pembrolizumab has been studied for safety in patients with advanced renal cell carcinoma. Common side effects include diarrhea, high blood pressure, fatigue, decreased appetite, nausea, voice changes, hand-foot syndrome (redness and swelling of the hands and feet), and hypothyroidism (underactive thyroid). These side effects were generally manageable. ^{1 3 6 7 8}

How is the drug combination of Axitinib and Pembrolizumab unique for treating renal cell carcinoma?

The combination of Axitinib and Pembrolizumab is unique because it is a standard first-line treatment for advanced renal cell carcinoma, offering a high response rate of 73% in previously untreated patients. This combination works by targeting both the blood vessels that supply the tumor and the immune system to enhance the body's ability to fight cancer. ^{1 2 3 4 7}

What is the purpose of this trial?

The purpose of this research study is to test the safety and effectiveness of Seleno-L Methionine (SLM) when combined with the standard dose and schedule of Axitinib and Pembrolizumab in patients who have locally advanced or metastatic clear cell renal cell carcinoma (ccRCC).

Research Team

Bilal Rahim, MD

Principal Investigator

University of Iowa

Eligibility Criteria

This trial is for adults with advanced or metastatic clear cell renal cell carcinoma (ccRCC) who haven't been treated for it in the metastatic setting. They must be physically active or able to do light work, have normal organ function, controlled blood pressure, and agree to use effective contraception. Those with other cancers, untreated brain metastases, recent major surgery, HIV/AIDS complications, or needing certain drugs are excluded.

Inclusion Criteria

I agree to use effective birth control during and 6 months after the study.

Written and voluntary informed consent

My liver tests are within the required limits, even with liver metastases.

Exclusion Criteria

My eligibility is not affected by my sex, race, or ethnicity.

I haven't had a heart attack, severe chest pain, heart failure, or stroke in the last 6 months.

I am not using, nor will I need, strong medication that affects liver enzymes.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Escalation Part 1

Dose-escalation study to find the maximum tolerated dose (MTD) of Seleno-L Methionine (SLM)

Varies

Multiple visits (in-person)

Expansion Part 2

Participants receive SLM and Axitinib orally, and Pembrolizumab intravenously at the start of each 21-day cycle

21-day cycles

Every 21 days (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 3 years

Treatment Details

Interventions

• Axitinib
• Pembrolizumab
• Seleno-L Methionine (SLM)

Trial Overview The study tests the safety and effectiveness of Seleno-L Methionine (SLM) combined with standard doses of Axitinib and Pembrolizumab in treating ccRCC. It aims to see if adding SLM improves outcomes compared to just Axitinib and Pembrolizumab.

Participant Groups

Group I: Seleno-L Methionine (SLM) in Combination with Axitinib and Pembrolizumab Experimental Treatment 3 Interventions

SLM only will be taken by mouth during a two-week run in period. Then patients will receive SLM and Axitinib drugs by mouth, and Pembrolizumab intravenously (IV), at the start of each 21 day cycle.

Axitinib is already approved in European Union, United States, United Kingdom for the following indications:

Approved in European Union as Inlyta for:

• Renal cell carcinoma

Approved in United States as Inlyta for:

• Advanced renal cell carcinoma

Approved in United Kingdom as Inlyta for:

• Advanced renal cell carcinoma

Who Is Running the Clinical Trial?

Mohammed Milhem

Lead Sponsor

Trials

9

Recruited

240+

Bilal G. Rahim

Lead Sponsor

Trials

2

Recruited

100+

Yousef Zakharia

Lead Sponsor

Trials

5

Recruited

160+

University of Iowa

Collaborator

Trials

486

Recruited

934,000+

Findings from Research

In a study of 52 treatment-naïve patients with advanced renal cell carcinoma receiving axitinib and pembrolizumab, higher baseline levels of immune-related biomarkers like CD8 and CXCL10 were associated with longer progression-free survival and better response rates.

The presence of IL6 at baseline was linked to shorter progression-free survival, suggesting that certain biomarkers could help predict treatment outcomes and warrant further investigation in future studies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Angiogenic and Immune-Related Biomarkers and Outcomes Following Axitinib/Pembrolizumab Treatment in Patients with Advanced Renal Cell Carcinoma. Martini, JF., Plimack, ER., Choueiri, TK., et al.[2023]

In a real-world study of 355 patients with advanced clear cell renal cell carcinoma, the combination of axitinib and pembrolizumab showed a best overall response rate of 47.9% and a one-year overall survival rate of 73.5%.

Treatment-related toxicity was the primary reason for dose adjustments, but over 80% of patients who experienced treatment management events were able to continue their therapy, suggesting that dose holds can be an effective strategy to manage side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Real-World Therapy Management and Outcomes of First-Line Axitinib Plus Pembrolizumab in Patients With Advanced Renal Cell Carcinoma in the United States. Zakharia, Y., Thomaidou, D., Li, B., et al.[2022]

In the phase III JAVELIN Renal 101 trial, avelumab plus axitinib demonstrated significantly improved progression-free survival (PFS) of 13.9 months compared to 8.5 months for sunitinib, indicating better efficacy in treating advanced renal cell carcinoma.

The overall survival (OS) trend also favored avelumab plus axitinib, with a hazard ratio of 0.79 compared to sunitinib, although the data is still immature and requires further follow-up.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Extended follow-up from JAVELIN Renal 101: subgroup analysis of avelumab plus axitinib versus sunitinib by the International Metastatic Renal Cell Carcinoma Database Consortium risk group in patients with advanced renal cell carcinoma. Haanen, JBAG., Larkin, J., Choueiri, TK., et al.[2023]

The combination of axitinib and pembrolizumab shows a high response rate of 73% in patients with previously untreated advanced renal cell carcinoma, indicating strong efficacy for this treatment regimen.

This finding suggests that the dual approach of targeting both tumor growth and immune response may be effective in managing advanced kidney cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Axitinib plus Pembrolizumab Is Effective in Renal Cell Carcinoma. [2019]

In a subgroup analysis of 94 Japanese patients with metastatic renal cell carcinoma, the combination of pembrolizumab and axitinib showed improved overall survival and progression-free survival compared to sunitinib, consistent with results from the larger global study.

The safety profile was also favorable, with fewer grade ≥3 treatment-related adverse events in the pembrolizumab-axitinib group (70%) compared to sunitinib (78%), and no deaths from treatment-related adverse events were reported.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab plus axitinib versus sunitinib in metastatic renal cell carcinoma: outcomes of Japanese patients enrolled in the randomized, phase III, open-label KEYNOTE-426 study. Tamada, S., Kondoh, C., Matsubara, N., et al.[2022]

Axitinib is an effective second-line treatment for advanced renal cell carcinoma (RCC), showing significantly prolonged median progression-free survival compared to sorafenib in the phase III AXIS trial.

The tolerability profile of axitinib is manageable, with common side effects including diarrhea, hypertension, and fatigue, making it a viable option for patients who have already received other treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Axitinib: a review in advanced renal cell carcinoma. Keating, GM.[2018]

In a study of 38 patients with metastatic renal cell carcinoma (mRCC) receiving pembrolizumab/axitinib as second-line or later therapy, the treatment showed a median progression-free survival (PFS) of 9.7 months and an objective response rate (ORR) of 25%, indicating its effectiveness even after prior treatments.

The safety profile of pembrolizumab/axitinib was consistent with earlier studies, with 86.8% of patients experiencing adverse events, but no grade 5 adverse events were reported, suggesting it is a relatively safe option for patients who have already undergone other therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Outcomes With Combination Pembrolizumab and Axitinib in Second and Further Line Treatment of Metastatic Renal Cell Carcinoma. Dizman, N., Austin, M., Considine, B., et al.[2023]

In a long-term study of 52 patients with advanced renal-cell carcinoma, the combination of axitinib and pembrolizumab showed promising efficacy, with a median progression-free survival of 23.5 months and an overall response rate of 73.1%.

After nearly 4 years of follow-up, the treatment was associated with significant clinical benefits and no new safety concerns, although 73.1% of patients experienced grade III/IV adverse events, leading to treatment discontinuation in 38.5% of cases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Axitinib plus pembrolizumab in patients with advanced renal-cell carcinoma: Long-term efficacy and safety from a phase Ib trial. Atkins, MB., Plimack, ER., Puzanov, I., et al.[2021]

References

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

Angiogenic and Immune-Related Biomarkers and Outcomes Following Axitinib/Pembrolizumab Treatment in Patients with Advanced Renal Cell Carcinoma. [2023]

2. Switzerland pubmed.ncbi.nlm.nih.gov

Real-World Therapy Management and Outcomes of First-Line Axitinib Plus Pembrolizumab in Patients With Advanced Renal Cell Carcinoma in the United States. [2022]

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

Extended follow-up from JAVELIN Renal 101: subgroup analysis of avelumab plus axitinib versus sunitinib by the International Metastatic Renal Cell Carcinoma Database Consortium risk group in patients with advanced renal cell carcinoma. [2023]

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

Axitinib plus Pembrolizumab Is Effective in Renal Cell Carcinoma. [2019]

5. Japan pubmed.ncbi.nlm.nih.gov

Pembrolizumab plus axitinib versus sunitinib in metastatic renal cell carcinoma: outcomes of Japanese patients enrolled in the randomized, phase III, open-label KEYNOTE-426 study. [2022]

6. New Zealand pubmed.ncbi.nlm.nih.gov

Axitinib: a review in advanced renal cell carcinoma. [2018]

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

Outcomes With Combination Pembrolizumab and Axitinib in Second and Further Line Treatment of Metastatic Renal Cell Carcinoma. [2023]

8. England pubmed.ncbi.nlm.nih.gov

Axitinib plus pembrolizumab in patients with advanced renal-cell carcinoma: Long-term efficacy and safety from a phase Ib trial. [2021]