PT2385 for Kidney Cancer

Not currently recruiting at 24 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Peloton Therapeutics, Inc., a subsidiary of Merck & Co., Inc. (Rahway, New Jersey USA)

Must not be taking: Warfarin, Immunotherapy

Disqualifiers: Brain metastasis, Hypertension, HIV, others

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

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Compensation: Varies

Number of Visits: 2

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine the optimal dose of MK-3795 (also known as PT2385) for individuals with advanced clear cell renal cell carcinoma, a type of kidney cancer. It will evaluate MK-3795 both alone and in combination with other treatments like nivolumab and cabozantinib. Individuals with advanced kidney cancer who have tried at least one other treatment may be suitable candidates. Participants should be able to swallow pills and have kidney cancer that has not responded to previous therapies. As a Phase 1 trial, this research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this new treatment.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you cannot participate if you are on warfarin or have certain medical conditions. 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 PT2385, now called MK-3795, is generally safe. In studies, patients with advanced clear cell renal cell carcinoma (ccRCC) tolerated it well. This is promising because the treatment aims to block a protein that helps tumors grow.

When combined with nivolumab, another cancer treatment, MK-3795 was also well-tolerated. Patients did not experience major side effects, and the combination showed positive results against tumors.

Belzutifan, a newer drug in the trial, has FDA approval for other uses, indicating it is generally safe. It is important to note that the current study is in its early stages, so researchers are still determining the best dose. This phase helps ensure any potential risks are understood before proceeding. ^{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 explore new ways to tackle the disease. Unlike traditional treatments like surgery or standard immunotherapy, MK-3795 is a novel agent aimed at targeting the HIF-2α pathway, which is crucial in kidney cancer cell survival. The combination of MK-3795 with other drugs like nivolumab, an immune checkpoint inhibitor, and cabozantinib, a tyrosine kinase inhibitor, offers a potentially more effective strategy by attacking the cancer from multiple angles. This multi-pronged approach may enhance the body's ability to fight the cancer and improve patient outcomes.

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

Research shows that PT2385, also known as MK-3795, may help treat advanced clear cell renal cell carcinoma (ccRCC), a type of kidney cancer. Previous studies found that it is generally safe and effective for patients who have already received treatment for ccRCC. It reduces the activity of certain genes that promote cancer growth. In this trial, one group of participants will receive MK-3795 alone. Another group will test the combination of MK-3795 with nivolumab, a drug that helps the immune system fight cancer and has shown promising results in shrinking tumors. Additionally, belzutifan, another drug in the trial, is already approved for treating kidney cancer related to von Hippel-Lindau disease, suggesting it might also work for similar kidney cancers. In a separate group, cabozantinib will be used with MK-3795, as both drugs target the mechanisms that allow cancer cells to survive and spread. ^{1 2 4 5 6}

Who Is on the Research Team?

Medical Director

Principal Investigator

Merck Sharp & Dohme LLC

Are You a Good Fit for This Trial?

This trial is for adults over 18 with advanced clear cell renal cell carcinoma who've had at least one prior treatment but no more than three, including a specific type of drug targeting blood vessel growth. They must expect to live at least 3 months, be able to take pills, and use approved birth control if necessary. Exclusions include recent major surgery, other clinical trials participation, untreated brain metastases, uncontrolled hypertension, certain heart conditions within the past 6 months.

Inclusion Criteria

My kidney cancer has spread and worsened despite treatment.

I've had 3 or fewer treatments for my advanced cancer.

I have had 1 or 2 treatments targeting blood vessel growth in my cancer.

Exclusion Criteria

I have untreated brain metastasis or a history of leptomeningeal disease or spinal cord compression.

I still have side effects from previous cancer treatments.

I am currently being treated for an infection.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment Part 1

Participants receive MK-3795 at escalating doses to determine the maximum tolerated dose (MTD) and/or recommended Phase 2 dose (RP2D).

Up to 1 year

Frequent visits for safety monitoring and dose escalation

Treatment Part 2

Participants receive MK-3795 in combination with nivolumab, transitioning to belzutifan with or without nivolumab as per protocol amendment.

Up to 1 year

Every 2 weeks for nivolumab infusion

Treatment Part 3

Participants receive MK-3795 in combination with cabozantinib to determine the MTD and RP2D.

Up to 1 year

Regular visits for safety monitoring and dose adjustments

Follow-up

Participants are monitored for safety and effectiveness after treatment completion.

Up to 9 years

What Are the Treatments Tested in This Trial?

Interventions

• Cabozantinib
• Nivolumab
• PT2385/MK-3795

Trial Overview The study tests different doses of MK-3795 alone and in combination with Nivolumab or Cabozantinib to find the highest dose patients can tolerate without severe side effects (MTD) and recommend for future studies (RP2D). It's divided into three parts: testing MK-3795 alone; then with Nivolumab; and finally with Cabozantinib.

How Is the Trial Designed?

Group I: Part 3: MK-3795 + Cabozantinib Experimental Treatment 2 Interventions

Participants with advanced ccRCC in the expansion phase receive the RP2D of MK-3795 in combination with cabozantinib 20mg up to 60mg orally QD for up to approximately 1 year (12 cycles; each cycle length = 28 days) or until unequivocal progression or treatment discontinuation, whichever occurs later.

Group II: Part 2: MK-3795 + Nivolumab + Belzutifan Experimental Treatment 3 Interventions

Participants with advanced ccRCC in the expansion phase receive the RP2D of MK-3795 orally in combination with nivolumab 240mg by IV infusion over \~60 minutes every 2 weeks for up to \~1 year (12 cycles; each cycle length = 28 days) or until unequivocal progression or treatment discontinuation, whichever occurs later. As per Amendment 09 (29 March 2024), participants will not receive MK-3795. Participants receive nivolumab 240mg by IV infusion over \~60 minutes every 2 weeks in combination with belzutifan 120 mg once daily (QD) for up to \~1 year (12 cycles; each cycle length = 28 days) or until unequivocal progression or treatment discontinuation, whichever occurs later. If participants experience an adverse event, then nivolumab will be discontinued and participants will continue to receive belzutifan 120 mg QD alone for up to \~1 year (12 cycles; each cycle length = 28 days) or until unequivocal progression or treatment discontinuation, whichever occurs later.

Group III: Part 1: MK-3795 Experimental Treatment 1 Intervention

Participants with advanced ccRCC receive MK-3795 at an initial dose level of 100mg orally, twice daily (BID) up to approximately 3 weeks. Dose levels will be escalated to identify the maximum tolerated dose (MTD) and/or Recommended Phase 2 Dose (RP2D) for MK-3795. Each escalated dose will be continued for up to approximately 3 weeks before escalating a dose again until a dose limiting toxicity (DLT) is experienced. Thereafter, participants receive RP2D dose of MK-3795 for up to 2 cycles (each cycle length = 28 days) for up to approximately 1 year. Participants may continue to receive MK-3795 beyond 1 year at the discretion of the Sponsor.

Cabozantinib is already approved in European Union, United States, Canada, Japan for the following indications:

Approved in European Union as Cabometyx for:

• Renal cell carcinoma
• Hepatocellular carcinoma

Approved in United States as Cabometyx for:

• Renal cell carcinoma
• Hepatocellular carcinoma

Approved in Canada as Cabometyx for:

• Renal cell carcinoma
• Hepatocellular carcinoma

Approved in Japan as Cabometyx for:

• Renal cell carcinoma

Who Is Running the Clinical Trial?

Peloton Therapeutics, Inc., a subsidiary of Merck & Co., Inc. (Rahway, New Jersey USA)

Lead Sponsor

Trials

8

Recruited

460+

Peloton Therapeutics, Inc.

Lead Sponsor

Trials

8

Recruited

460+

Published Research Related to This Trial

Cabozantinib has shown significant efficacy in treating advanced kidney cancer, with a 28% objective response rate and a median progression-free survival of 14.7 months based on a phase II trial involving patients with renal cancer.

The drug also demonstrated notable effectiveness in managing bone metastases, which is crucial for improving quality of life in patients, and further studies are planned to compare its effectiveness against standard VEGF inhibitors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cabozantinib as a novel therapy for renal cell carcinoma. Vaishampayan, U.[2022]

The CaboPoint trial is a phase II study designed to assess the efficacy and safety of cabozantinib, a multi-tyrosine kinase inhibitor, in patients with advanced renal cell carcinoma who have not responded to previous checkpoint inhibitor therapies.

Patients will receive cabozantinib for up to 18 months, with the primary goal of measuring the objective response rate, while also evaluating overall survival and progression-free survival as secondary outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CaboPoint: a phase II study of cabozantinib as second-line treatment in patients with metastatic renal cell carcinoma. Albiges, L., Schmidinger, M., Taguieva-Pioger, N., et al.[2022]

Cabozantinib (Cabometyx®) is now approved as a first-line treatment for advanced renal cell carcinoma (RCC) in treatment-naïve adults, expanding its use beyond patients who have already received VEGF-targeted therapy.

In a phase 2 trial, cabozantinib significantly improved median progression-free survival and objective response rates compared to the standard treatment sunitinib, while its side effects are manageable, similar to other tyrosine kinase inhibitors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cabozantinib as first-line treatment in advanced renal cell carcinoma: a profile of its use. Lyseng-Williamson, KA.[2020]

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 phase II trial involving 47 patients with advanced non-clear-cell renal cell carcinoma, the combination of cabozantinib and nivolumab showed a promising objective response rate of 47.5% in patients with papillary, unclassified, or translocation-associated RCC, along with a median progression-free survival of 12.5 months.

The treatment was less effective in chromophobe RCC, with no objective responses observed, highlighting the need for further research into genomic predictors of response, particularly mutations like NF2 and FH that were associated with better outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II Trial of Cabozantinib Plus Nivolumab in Patients With Non-Clear-Cell Renal Cell Carcinoma and Genomic Correlates. Lee, CH., Voss, MH., Carlo, MI., et al.[2023]

A 77-year-old male with metastatic papillary renal cell carcinoma and inferior vena cava tumor thrombus was successfully treated with nivolumab plus cabozantinib, leading to significant regression of all lesions.

Following treatment, the patient underwent radical nephrectomy and other surgeries, with no viable cancer cells found and no recurrence of the disease for 9 months, indicating the potential efficacy of this combination therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Complete response of metastatic papillary renal cell carcinoma with inferior vena cava tumor thrombus to nivolumab plus cabozantinib. Hayashida, M., Miura, Y., Yamaguchi, T., et al.[2023]

In a phase 3 trial involving 855 patients with untreated advanced renal-cell carcinoma, the combination of cabozantinib with nivolumab and ipilimumab significantly improved progression-free survival compared to nivolumab and ipilimumab alone, with a 12-month progression-free survival rate of 57% versus 49%.

However, the experimental group experienced a higher incidence of severe adverse events (grade 3 or 4) at 79%, compared to 56% in the control group, indicating a trade-off between efficacy and safety.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cabozantinib plus Nivolumab and Ipilimumab in Renal-Cell Carcinoma. Choueiri, TK., Powles, T., Albiges, L., et al.[2023]

The European Association of Urology now recommends nivolumab and cabozantinib as preferred treatments for patients with renal cancer who have not responded to previous vascular endothelial growth factor-targeted therapies.

Recent data indicate that cabozantinib offers a survival benefit, reinforcing its efficacy as a treatment option in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

European Association of Urology Guidelines for Clear Cell Renal Cancers That Are Resistant to Vascular Endothelial Growth Factor Receptor-Targeted Therapy. Powles, T., Staehler, M., Ljungberg, B., et al.[2018]

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 phase 3 trial involving 651 patients with untreated advanced renal-cell carcinoma, the combination of nivolumab and cabozantinib significantly improved progression-free survival (16.6 months) compared to sunitinib (8.3 months), with a hazard ratio of 0.51, indicating a 49% reduction in the risk of disease progression or death.

Patients receiving nivolumab plus cabozantinib also had a higher overall survival rate at 12 months (85.7%) compared to those on sunitinib (75.6%), and a greater objective response rate (55.7% vs. 27.1%), although adverse events were common in both groups.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nivolumab plus Cabozantinib versus Sunitinib for Advanced Renal-Cell Carcinoma. Choueiri, TK., Powles, T., Burotto, M., et al.[2022]

The combination of cabozantinib (a TKI) and nivolumab (an anti-PD-1 antibody) is an effective first-line treatment for previously-untreated advanced renal cell carcinoma (RCC), showing significantly longer progression-free and overall survival compared to sunitinib monotherapy in the CheckMate 9ER trial.

Patients receiving cabozantinib plus nivolumab reported better health-related quality of life, although the combination therapy had a higher incidence of serious adverse events compared to sunitinib, indicating a need for careful monitoring.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cabozantinib plus Nivolumab: A Review in Advanced Renal Cell Carcinoma. Markham, A.[2022]

Citations

1. ascopubs.org ascopubs.org/doi/10.1200/JCO.2019.37.7_suppl.558

Results from a phase I expansion cohort of the first-in-class ... The combination of PT2385 + nivolumab was well tolerated and demonstrated promising anti-tumor activity in advanced ccRCC patients.

2. clinicaltrials.gov clinicaltrials.gov/study/NCT02293980

A Phase 1, Dose-Escalation Trial of PT2385 Tablets In ... This is a Phase 1, multiple-dose, dose-escalation trial of MK-3795, where patients with advanced ccRCC will be assigned to sequential dose cohorts.

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC5946714/

Phase I Dose-Escalation Trial of PT2385, a First-in-Class ... In a mouse xenograft model of ccRCC, PT2385 treatment resulted in decreased expression of HIF-2α target genes, decreased circulating human VEGF-A protein, and ...

4. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/29257710/

Phase I Dose-Escalation Trial of PT2385, a First-in ... - PubMed PT2385 has a favorable safety profile and is active in patients with heavily pretreated ccRCC, validating direct HIF-2α antagonism for the treatment of ...

5. clinicaltrials.gov clinicaltrials.gov/study/NCT03108066

MK-3795 (PT2385) for the Treatment of Von Hippel-Lindau ... The primary objective of this study is to assess the overall response rate (ORR) of von Hippel-Lindau (VHL) disease-associated clear cell renal cell carcinoma ( ...

6. dana-farber.org dana-farber.org/clinical-trials/14-536

A Phase 1, Multiple-Dose, Dose-Escalation Trial of PT2385 ... The primary objective of this study is to identify the maximum tolerated dose (MTD) of MK-3795, formerly called PT2385 and/or the recommended Phase 2 dose (RP2 ...