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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests the safety and effectiveness of a new drug combination for treating advanced kidney cancer, specifically clear cell renal cell carcinoma (ccRCC). The treatment combines Seleno-L Methionine (SLM) with two existing cancer drugs, Axitinib (Inlyta) and Pembrolizumab (KEYTRUDA), to determine if it can better control cancer growth. The trial may suit those with locally advanced or metastatic ccRCC who have not received prior treatment for their metastatic cancer. Participants should maintain a fully active lifestyle or be only slightly restricted in strenuous activities.

As a Phase 1, Phase 2 trial, this research aims to understand how the treatment works in people and measure its effectiveness in an initial, smaller group, offering participants a chance to contribute to groundbreaking advancements in cancer treatment.

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.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that combining Seleno-L Methionine (SLM) with Axitinib is generally safe. In earlier studies, high doses of SLM (4000 µg) with Axitinib produced promising results without major safety issues. This suggests that adding SLM to Axitinib and Pembrolizumab could be safe for clinical trial participants. While Pembrolizumab and Axitinib already treat certain cancers, researchers are closely monitoring for any new side effects from adding SLM. As studies continue, researchers will carefully observe how patients respond to this combination treatment. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Researchers are excited about the combination of Seleno-L Methionine (SLM), Axitinib, and Pembrolizumab for renal cell carcinoma because it offers a novel approach by integrating SLM, which may enhance the effectiveness of the other drugs. Unlike standard treatments that primarily involve Tyrosine Kinase Inhibitors (like Sunitinib) or immune checkpoint inhibitors alone, this combination uses SLM to potentially boost the immune system's response to cancer cells. Additionally, the unique delivery method, where SLM is taken orally alongside Axitinib, while Pembrolizumab is administered intravenously, could optimize both convenience and efficacy. This multi-pronged strategy might lead to better outcomes by targeting the cancer more comprehensively.

What evidence suggests that this trial's treatments could be effective for renal cell carcinoma?

Research shows that adding Seleno-L Methionine (SLM) to the drugs Axitinib and Pembrolizumab may enhance treatment effectiveness for kidney cancer. In this trial, participants will receive a combination of SLM, Axitinib, and Pembrolizumab. Early results in patients with advanced kidney cancer have been encouraging when SLM was combined with Axitinib. Among 15 patients who had tried other treatments, many experienced positive results with this combination. These findings suggest that including SLM could improve the effects of the usual Axitinib and Pembrolizumab treatment. This approach aims to help patients without increasing side effects. ^{1 2 4 6 7}

Who Is on the Research Team?

Bilal Rahim, MD

Principal Investigator

University of Iowa

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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 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 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]

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 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]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT05363631

Seleno-L Methionine (SLM)-Axitinib-Pembrolizumab The hypothesis is that adding SLM to the Pembrolizumab and Axitinib combination will improve efficacy without added toxicity. This is a two-part study:.

2. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/39879383/

Phase I Clinical Trial of High Doses of Seleno-L-methionine in ... The data provided the rationale for the development of this phase I clinical trial of SLM and axitinib in advanced or metastatic relapsed ccRCC.

3. aacrjournals.org aacrjournals.org/clincancerres/article-abstract/doi/10.1158/1078-0432.CCR-24-3234/751353/Phase-I-Clinical-Trial-of-High-Doses-of-Seleno-L

Phase I Clinical Trial of High Doses of Seleno-L-methionine in ... The data provided the rationale for the development of this phase I clinical trial of SLM and axitinib in advanced or metastatic relapsed ccRCC.

4. ascopubs.org ascopubs.org/doi/10.1200/JCO.2019.37.7_suppl.660

Preliminary results of phase I clinical trial of high doses ... Preliminary results of phase I clinical trial of high doses of seleno-L-methionine (SLM) in sequential combination with axitinib in previously ...

5. targetedonc.com targetedonc.com/view/promising-efficacy-and-safety-with-seleno-l-methionine-plus-axitinib-in-ccrcc

Promising Efficacy and Safety With Seleno-L-Methionine ... Out of 15 evaluable patients with ccRCC who progressed on one or more prior lines of treatment, responses were seen across all cohorts of ...

6. aacrjournals.org aacrjournals.org/clincancerres/article/31/7/1204/754267/Phase-I-Clinical-Trial-of-High-Doses-of-Seleno-L

Phase I Clinical Trial of High Doses of Seleno-L-methionine in ... The data provided the rationale for the development of this phase I clinical trial of SLM and axitinib in advanced or metastatic relapsed ccRCC.

7. urotoday.com urotoday.com/recent-abstracts/urologic-oncology/renal-cancer/157908-phase-i-clinical-trial-of-high-doses-of-seleno-l-methionine-in-combination-with-axitinib-in-patients-with-previously-treated-metastatic-clear-cell-renal-cell-carcinoma.html?page=1

Phase I Clinical Trial of High Doses of Seleno-L-methionine in ... SLM (4000 μg) in sequential combination with axitinib is well tolerated with encouraging efficacy. Clinical cancer research : an official journal of the ...