Valemetostat + Ipilimumab for Metastatic Prostate, Urothelial, and Renal Cell Cancers

Overseen By Ana Aparicio

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: M.D. Anderson Cancer Center

Must not be taking: EZH2 inhibitors, Monoclonal antibodies

Disqualifiers: Pregnancy, Carcinomatous meningitis, Autoimmune disease, Cardiovascular disease, others

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

Compensation: Varies

Number of Visits: 1

Duration: 21 days per cycle

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a combination of two treatments, valemetostat (also known as DS-3201 or Ezharmia) and ipilimumab, to determine the best dose and identify side effects in patients with certain advanced cancers. These treatments aim to stop cancer cells from growing and help the immune system fight the cancer. The trial targets individuals with prostate, bladder (urothelial), or kidney (renal) cancers that have spread, particularly if past treatments have failed. Good candidates for this trial include those experiencing ongoing cancer growth despite previous therapies. As a Phase 1 trial, the 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 protocol does not specify if you need to stop taking your current medications. However, it does mention that you should not have received certain treatments like chemotherapy or monoclonal antibodies within 2-4 weeks before 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 shows that combining valemetostat and ipilimumab might have manageable side effects. Studies of blood-related cancers have found that valemetostat helps stop cancer cells from growing. Although still under investigation for cancers like prostate, bladder, and kidney, this suggests potential safety.

Ipilimumab, approved by the FDA for other cancers, aids the immune system in fighting cancer. While it can cause side effects, these are usually known and carefully monitored.

As this trial is in an early stage, the main goal is to determine the safety of valemetostat and the optimal dose to use with ipilimumab. Safety information is still being collected. However, current knowledge about each drug provides some initial reassurance regarding their safety. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about valemetostat combined with ipilimumab for metastatic prostate, urothelial, and renal cell cancers because it introduces a unique dual approach. Unlike standard treatments that often focus solely on blocking hormonal pathways or inhibiting specific proteins, valemetostat is a novel EZH1/2 inhibitor, which targets enzymes involved in gene expression, potentially halting cancer growth. Paired with ipilimumab, an immune checkpoint inhibitor that helps the immune system recognize and attack cancer cells, this combination could enhance the body's natural defenses against tumors. This innovative partnership of targeting gene expression and boosting immune response offers a fresh avenue in cancer treatment, holding promise for improved outcomes.

What evidence suggests that this trial's treatments could be effective for metastatic prostate, urothelial, and renal cell cancers?

Research shows that valemetostat might stop cancer growth by blocking certain enzymes essential to cancer cells. Studies have demonstrated that valemetostat can slow the growth of various cancer cell types. Ipilimumab, a treatment that aids the immune system in attacking cancer cells, has successfully treated some cancers by enhancing the body's natural defenses. In this trial, participants will receive a combination of valemetostat and ipilimumab, potentially enhancing their effectiveness together and providing a stronger defense against metastatic prostate, bladder, and kidney cancers. Early results suggest that this combination might help control these advanced cancers by both halting their growth and aiding the immune system in fighting them. ^{2 3 4 5 6}

Who Is on the Research Team?

Ana Aparicio

Principal Investigator

M.D. Anderson Cancer Center

Are You a Good Fit for This Trial?

This trial is for adults with metastatic prostate, urothelial, or renal cell cancers who have an ECOG performance status of 0-1. They must have confirmed cancer spread and be recovered from previous treatments. Eligible participants need proper organ function and no active infections like hepatitis or HIV. Pregnant women, those with certain heart conditions or autoimmune diseases, and individuals on recent cancer therapies are excluded.

Inclusion Criteria

Your liver enzyme levels must be within a certain range, depending on whether you have liver cancer that has spread or not.

My scans show cancer has spread and cannot be treated with surgery or radiation.

Your hemoglobin level is at least 9 grams per deciliter.

Exclusion Criteria

I have not had a heart attack or stroke in the last 6 months.

I have a serious heart condition.

You have a known history of HIV infection.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive valemetostat orally once daily on days 1-21 and ipilimumab intravenously on day 1 of cycles 1 and 3. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.

21 days per cycle

1 visit per cycle (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment completion, with follow-up visits 30 and 60 days after the last valemetostat dose and/or 100 days after the last ipilimumab dose, and then every 6 months thereafter.

Up to 2 years

Multiple visits (in-person)

What Are the Treatments Tested in This Trial?

Interventions

• DS3201
• Ipilimumab

Trial Overview The trial tests the combination of DS3201 (Valemetostat) and Ipilimumab to determine safe dosages and side effects in treating advanced cancers. Valemetostat targets enzymes for tumor growth while Ipilimumab boosts the immune system's ability to fight cancer cells.

How Is the Trial Designed?

Group I: Treatment (valemetostat, ipilimumab) Experimental Treatment 2 Interventions

Patients receive valemetostat PO QD on days 1-21 and ipilimumab IV over 90 minutes on day 1 of cycles 1 and 3. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.

DS3201 is already approved in Japan for the following indications:

Approved in Japan as Valemetostat for:

• Aggressive adult T-cell leukemia/lymphoma

Who Is Running the Clinical Trial?

M.D. Anderson Cancer Center

Lead Sponsor

Trials

3,107

Recruited

1,813,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

Ipilimumab showed a best overall response rate (BORR) of 5.8% and a disease control rate (DCR) of 27% in patients with advanced melanoma, indicating some level of efficacy in this challenging population.

The treatment resulted in promising long-term survival rates, with 1- and 2-year survival rates of 47.2% and 32.8%, respectively, and a median overall survival of 10.2 months, while adverse events were primarily immune-related but manageable.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of ipilimumab monotherapy in patients with pretreated advanced melanoma: a multicenter single-arm phase II study. O'Day, SJ., Maio, M., Chiarion-Sileni, V., et al.[2022]

Monotherapy with anti-CTLA-4 (ipilimumab) or anti-PD-1 (nivolumab) has not shown significant clinical benefits for prostate cancer patients, indicating a need for alternative treatment strategies.

In a presurgical clinical trial, it was found that levels of the inhibitory molecule VISTA increased in macrophages of tumors treated with ipilimumab, suggesting that VISTA may serve as a compensatory mechanism that limits the effectiveness of current therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

VISTA is an inhibitory immune checkpoint that is increased after ipilimumab therapy in patients with prostate cancer. Gao, J., Ward, JF., Pettaway, CA., et al.[2022]

Ipilimumab, a monoclonal antibody targeting CTLA-4, has shown potential activity in prostate cancer, particularly in patients with lower disease burden, despite not improving overall survival in a Phase III study.

While immune-related adverse events are common with ipilimumab treatment, they can generally be managed effectively using standard immunosuppressive treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ipilimumab in the treatment of prostate cancer. Reese, Z., Straubhar, A., Pal, SK., et al.[2018]

Ipilimumab has shown a positive impact on overall survival in patients with stage IV melanoma, with long-term follow-up indicating its effectiveness compared to conventional treatments.

While 84.8% of patients experience drug-related adverse events, most are mild to moderate; however, severe reactions can occur, necessitating careful monitoring and management, especially when combined with other therapies like vemurafenib.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CTLA-4 blockade with ipilimumab: biology, safety, efficacy, and future considerations. Camacho, LH.[2022]

In a phase Ib trial involving 26 patients with advanced PD-L1-positive ovarian cancer, pembrolizumab demonstrated a confirmed objective response rate of 11.5%, indicating some level of antitumor activity, with 1 complete response and 2 partial responses observed.

The treatment was generally well-tolerated, with 73.1% of patients experiencing treatment-related adverse events, but no deaths or treatment discontinuations due to these events, suggesting that pembrolizumab has a manageable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab in patients with programmed death ligand 1-positive advanced ovarian cancer: Analysis of KEYNOTE-028. Varga, A., Piha-Paul, S., Ott, PA., et al.[2019]

In a phase 3 trial involving 799 men with metastatic castration-resistant prostate cancer, ipilimumab showed a median overall survival of 11.2 months compared to 10.0 months for placebo, suggesting potential benefits despite not reaching statistical significance (P = 0.053).

Ipilimumab was associated with a higher incidence of severe immune-related adverse events, with 26% of patients experiencing grade 3-4 side effects, including significant cases of diarrhea and colitis, indicating a need for careful monitoring during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Commentary on: "Ipilimumab versus placebo after radiotherapy in patients with metastatic castration-resistant prostate cancer that had progressed after docetaxel chemotherapy (CA184-043): A multicentre, randomised, double-blind, phase 3 trial." Kwon ED, Drake CG, Scher HI, Fizazi K, Bossi A, van den Eertwegh AJ, Krainer M, Houede N, Santos R, Mahammedi H, Ng S, Maio M, Franke FA, Sundar S, Agarwal N, Bergman AM, Ciuleanu TE, Korbenfeld E, Sengeløv L, Hansen S, Logothetis C, Beer TM, McHenry MB, Gagnier P, Liu D, Gerritsen WR, CA184-043 Investigators. Departments of Urology and Immunology and Mayo Clinic Comprehensive Cancer Center, Mayo Clinic, Rochester, MN, USA, Electronic address: [e-mail]; Johns Hopkins Sidney Kimmel Comprehensive Cancer Center and Brady Urological Institute, Baltimore, MD, USA; Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York, NY, USA; Institut Gustave Roussy, University of Paris-Sud, Villejuif, France; Institut Gustave Roussy, Villejuif, France; VU University Medical Centre, Amsterdam, Netherlands; Vienna General Hospital, Medical University Vienna, Vienna, Austria; Institut Bergonié, Bordeaux, France; CHU Caremeau, Nimes, France; Centro Médico Austral, Buenos Aires, Argentina; Centre Jean Perrin, Clermont-Ferrand, France; St John of God Hospital, Subiaco, WA, Australia; University Hospital of Siena, Istituto Toscano Tumori, Siena, Italy; Hospital de Caridade de Ijuí, Ijuí, Brazil; Nottingham University Hospital, Nottingham, UK; Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA; Netherlands Cancer Institute and Antoni van Leeuwenhoek Hospital, Amsterdam, Netherlands; Institute of Oncology Ion Chiricuta and University of Medicine and Pharmacy Iuliu Hatieganu, Cluj-Napoca, Romania; Hospital Británico de Buenos Aires, Buenos Aires, Argentina; Herlev Hospital, Herlev, Denmark; Odense University Hospital, Odense, Denmark; University of Texas MD Anderson Cancer Center, Houston, Trump, D.[2018]

In a study of 1346 prostate cancer patients, only 3.1% were found to have microsatellite instability-high (MSI-H) or mismatch repair-deficient (dMMR) tumors, indicating that this molecular phenotype is rare but significant for treatment options.

Among 11 patients with MSI-H/dMMR castration-resistant prostate cancer who received anti-PD-1/PD-L1 therapy, 54.5% experienced a significant decline in prostate-specific antigen levels, suggesting that this therapy can be effective for some patients with this specific tumor type.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Analysis of the Prevalence of Microsatellite Instability in Prostate Cancer and Response to Immune Checkpoint Blockade. Abida, W., Cheng, ML., Armenia, J., et al.[2022]

In a phase-2 trial involving 15 metastatic prostate cancer patients with AR-V7-expressing tumors, the combination of nivolumab and ipilimumab showed promising efficacy, particularly in patients with DNA-repair deficiency (DRD) mutations, where PSA response rates were higher (33% vs. 0% in DRD-negative tumors).

The study found that patients with DRD-positive tumors had significantly better progression-free survival (PFS) and overall survival (OS) compared to those without DRD mutations, indicating that targeting this specific tumor profile may enhance treatment outcomes without introducing new safety concerns.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ipilimumab plus nivolumab and DNA-repair defects in AR-V7-expressing metastatic prostate cancer. Boudadi, K., Suzman, DL., Anagnostou, V., et al.[2023]

In a study of 326 prostate adenocarcinoma patients from Spain and Norway, high expression of the immune checkpoint protein B7-H3 was linked to worse outcomes, including biochemical and clinical recurrence, indicating its potential as a target for immunotherapy.

Unlike B7-H3, PD-L1 expression did not show a correlation with clinical outcomes, suggesting that B7-H3 may be a more relevant biomarker for treatment strategies in prostate cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Immune checkpoint B7-H3 protein expression is associated with poor outcome and androgen receptor status in prostate cancer. Nunes-Xavier, CE., Kildal, W., Kleppe, A., et al.[2022]

Combining nivolumab and ipilimumab shows improved effectiveness in treating metastatic melanoma compared to using either drug alone, based on a retrospective analysis of approximately 7700 patients.

The combination therapy presents a safety profile that includes immune-related adverse events from both drugs, indicating that while the combination is effective, it also carries a heightened risk of toxicity that needs further investigation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Retrospective Side Effect Profiling of the Metastatic Melanoma Combination Therapy Ipilimumab-Nivolumab Using Adverse Event Data. Soldatos, TG., Dimitrakopoulou-Strauss, A., Larribere, L., et al.[2022]

A 67-year-old patient with castration-resistant metastatic prostate cancer developed immune-mediated large vessel vasculitis after receiving treatment with ipilimumab and nivolumab, which are immune checkpoint inhibitors.

This case highlights a potential safety concern associated with the use of these immunotherapies, indicating that while they can be effective in treating cancer, they may also lead to significant immune-related adverse effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Immune checkpoint inhibitor induced large vessel vasculitis. Henderson, D., Eslamian, G., Poon, D., et al.[2022]

In a phase 3 trial involving 799 men with metastatic castration-resistant prostate cancer, ipilimumab showed a median overall survival of 11.2 months compared to 10.0 months for placebo, suggesting potential benefits despite not reaching statistical significance (p=0.053).

Ipilimumab was associated with a higher incidence of severe immune-related adverse events, with 26% of patients experiencing grade 3-4 side effects, including significant cases of diarrhea and colitis, indicating a need for careful monitoring during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ipilimumab versus placebo after radiotherapy in patients with metastatic castration-resistant prostate cancer that had progressed after docetaxel chemotherapy (CA184-043): a multicentre, randomised, double-blind, phase 3 trial. Kwon, ED., Drake, CG., Scher, HI., et al.[2022]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT04388852

Study Details | NCT04388852 | DS3201 and Ipilimumab for ... This phase Ib trial studies the side effects and best dose of DS3201 when given together with and ipilimumab for the treatment of patients with prostate, ...

2. mdanderson.org mdanderson.org/patients-family/diagnosis-treatment/clinical-trials/clinical-trials-index/clinical-trials-detail.ID2019-0967.html

DS3201 With Ipilimumab In Patients With Metastatic ... This phase Ib trial studies the side effects and best dose of DS3201 when given together with and ipilimumab for the treatment of patients with prostate, ...

3. withpower.com withpower.com/trial/phase-1-prostatic-neoplasms-7-2020-06e09

Valemetostat + Ipilimumab for Metastatic Prostate, Urothelial, ... This trial tests DS3201 and ipilimumab together for patients with advanced prostate, urothelial, or renal cell cancer. DS3201 blocks enzymes to stop cancer ...

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9705507/

Valemetostat Tosilate: First Approval - PMC - PubMed Central Valemetostat displayed antiproliferative effects in various haematological cancer ... Metastatic prostate, urothelial, and renal cell cancers, 1 ...

5. researchgate.net researchgate.net/publication/361120540_Trial_in_progress_A_phase_I_trial_of_dual_EZH_12_inhibitor_valemetostat_tosylate_DS-3201b_in_pediatric_adolescent_and_young_adult_patients_with_malignant_solid_tumors

A phase I trial of dual EZH 1/2 inhibitor valemetostat ... Methods: This open-label multi-center phase I trial evaluates the safety and efficacy of valemetostat in pediatric, adolescent, and young adult ...

6. clinicaltrials.gov clinicaltrials.gov/study/NCT04388852

Study Details | NCT04388852 | DS3201 and Ipilimumab for ... This phase Ib trial studies the side effects and best dose of DS3201 when given together with and ipilimumab for the treatment of patients with prostate, ...