Triple Therapy for Bladder Cancer

Overseen By Omar Alhalabi, MD

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: M.D. Anderson Cancer Center

Must be taking: Immune checkpoint inhibitors

Must not be taking: BCRP substrates, P-gp substrates, CYP3A4 drugs

Disqualifiers: CNS metastases, Autoimmune disorders, HIV, others

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

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 4

Duration: 12 weeks

20 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a combination of three treatments—Etrumadenant (an experimental treatment), Pemetrexed, and Zimberelimab—targeting advanced urothelial cancer, a type of bladder cancer. The trial focuses on patients with MTAP-deficient cancer who have previously received a specific immune treatment. Individuals with measurable cancer growth who have already tried immune therapy might be suitable for this study. As a Phase 2 trial, the research measures the treatment's effectiveness in an initial, smaller group, offering participants a chance to contribute to significant advancements in cancer treatment.

Will I have to stop taking my current medications?

The trial requires that you stop taking certain medications that could interact with the study drugs. Specifically, you must not have taken certain drugs like BCRP substrates, P-gp substrates, strong CYP3A4 inducers, and inhibitors within 4 weeks or 5 half-lives of the drug before starting the trial. It's best to discuss your current medications with the study team to see if any need to be stopped.

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

Previous studies have tested the combination of pemetrexed, etrumadenant, and zimberelimab for safety. Research shows these treatments are generally well-tolerated. However, like most treatments, some side effects have been reported. Etrumadenant has been studied before and is generally safe for humans. Zimberelimab, used in some cancer treatments, also appears safe based on past research. The FDA has already approved pemetrexed for other cancers, so its safety is well known. Overall, data suggest this combination is tolerable, with side effects similar to those of many cancer treatments. Always consult a healthcare provider before joining a clinical trial. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the triple therapy combining Etrumadenant, Pemetrexed, and Zimberelimab for bladder cancer because it introduces a novel approach to treatment. Unlike standard chemotherapy, Etrumadenant acts as an A2a receptor antagonist, potentially enhancing the immune system's response against cancer cells. Zimberelimab, a PD-1 inhibitor, further boosts the immune system's ability to detect and destroy cancerous cells. This combination aims to not only attack the cancer directly but also empower the body's own defenses, offering a promising strategy that might improve outcomes for patients with bladder cancer.

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

Research has shown that combining etrumadenant, pemetrexed, and zimberelimab can help manage advanced urothelial cancer, which affects the bladder, urethra, and ureters. In this trial, all participants will receive this combination therapy. Pemetrexed, a chemotherapy drug, attacks cancer cells, while zimberelimab boosts the immune system's ability to fight cancer. Etrumadenant may enhance immune therapies by blocking a protein that allows cancer cells to evade the immune system. Early results suggest this combination may benefit patients who have already tried other treatments, especially after immunotherapy. This method aims to attack cancer in several ways, potentially leading to better outcomes for patients with this challenging cancer. ^{1 2 3 4 6}

Who Is on the Research Team?

Omar Alhalabi, MD

Principal Investigator

M.D. Anderson Cancer Center

Are You a Good Fit for This Trial?

Adults with MTAP-deficient advanced urothelial cancer who've had prior immunotherapy can join this Phase 2 trial. They must have measurable disease, adequate organ function, and an ECOG performance status ≤ 2. Pregnant women, those with certain heart conditions or severe allergies to antibodies, and individuals with uncontrolled illnesses are excluded.

Inclusion Criteria

I have a mild or well-controlled autoimmune condition that doesn't majorly affect my immune system.

I have previously received anti-PD-1/PD-L1 therapy.

My cancer is mainly in my bones but can be measured or seen as a mass.

Exclusion Criteria

Known allergy or hypersensitivity to study drug formulations.

QTc ≥480 msec using Fredericia's QT correction formula

I have not had any live vaccines in the last 4 weeks and will not while on the trial, except for the COVID-19 vaccine.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive the triplet combination therapy of pemetrexed, Etrumadenant (AB928), and Zimberelimab (AB122). Pemetrexed and Zimberelimab are administered intravenously every 3 weeks, and Etrumadenant is taken orally daily.

12 weeks

4 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Etrumadenant
• Pemetrexed
• Zimberelimab

Trial Overview The study tests a combination of Pemetrexed plus AB928 (Etrumadenant) & AB122 (Zimberelimab) in patients previously treated for advanced bladder cancer. It's open-label at MD Anderson Cancer Center and includes participants as second-line treatment or beyond.

How Is the Trial Designed?

Group I: Pemetrexed Plus AB928 (Etrumadenant) Plus AB122 (Zimberelimab) Experimental Treatment 3 Interventions

All patients will receive combination therapy of pemetrexed and ZIMBERELIMAB (AB122) intravenously every 3 weeks as well as ETRUMADENANT (AB928) orally daily.

Who Is Running the Clinical Trial?

M.D. Anderson Cancer Center

Lead Sponsor

Trials

3,107

Recruited

1,813,000+

Published Research Related to This Trial

In a study of 319 patients with locally advanced bladder cancer, those treated with dose dense MVAC chemotherapy showed a significantly higher rate of complete pathological response (ypT0N0) compared to those treated with gemcitabine and cisplatin (28.0% vs 14.6%).

Patients receiving dose dense MVAC also had better overall survival rates, with a mean survival of 7.0 years compared to 4.2 years for those on gemcitabine and cisplatin, indicating that dose dense MVAC may be a more effective neoadjuvant treatment option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neoadjuvant Dose Dense MVAC versus Gemcitabine and Cisplatin in Patients with cT3-4aN0M0 Bladder Cancer Treated with Radical Cystectomy. Zargar, H., Shah, JB., van Rhijn, BW., et al.[2022]

The standard treatment for locally advanced and metastatic transitional cell carcinoma includes the four-drug combination MVAC (methotrexate, vinblastine, doxorubicin, and cisplatin) or the two-drug combination GC (gemcitabine and cisplatin).

New studies suggest that pemetrexed, either alone or in combination with gemcitabine, shows promise for improved efficacy and reduced toxicity, indicating a need for further research into these new treatment options.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pemetrexed in transitional cell carcinoma of the urothelium. von der Maase, H.[2022]

In a study of 37 patients with muscle invasive bladder cancer, trimodality therapy (including surgery, radiation, and low-dose cisplatin) resulted in impressive 5-year survival rates: 86.4% for cause-specific survival and 69.6% for overall survival, indicating its efficacy.

Patients who achieved a complete response to the therapy had significantly better outcomes, with 100% cause-specific survival, while those who did not respond had a 0% survival rate, highlighting the importance of achieving complete cancer remission for better long-term results.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

External beam radiation plus concurrent intra-arterial chemotherapy with low dose cisplatin for muscle invasive bladder cancer. Matsumoto, Y., Samma, S., Fukui, S., et al.[2020]

Pemetrexed, used as a second-line chemotherapy, showed an overall response rate of 27.7% in 47 patients with advanced transitional cell carcinoma (TCC) of the urothelium, indicating its efficacy in this setting.

The treatment was found to be safe, with manageable side effects, including some grade 3 or 4 hematologic events, suggesting that pemetrexed could be a viable option for patients who have already undergone prior chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II study of pemetrexed for second-line treatment of transitional cell cancer of the urothelium. Sweeney, CJ., Roth, BJ., Kabbinavar, FF., et al.[2022]

In a study of 64 patients with advanced bladder cancer, the combination of pemetrexed and gemcitabine showed an overall response rate of 20%, indicating some effectiveness but not superior to single-agent gemcitabine.

The treatment had a manageable safety profile, with significant hematologic toxicities observed in some patients, including neutropenia (38%) and anemia (19%), but overall, the combination did not demonstrate improved efficacy compared to gemcitabine alone.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase II trial of pemetrexed plus gemcitabine in locally advanced and/or metastatic transitional cell carcinoma of the urothelium. von der Maase, H., Lehmann, J., Gravis, G., et al.[2022]

In a phase II clinical trial involving 42 patients with advanced urothelial carcinoma, the combination of pemetrexed and cisplatin resulted in a high objective response rate of 64.3%, indicating significant efficacy as a first-line treatment.

The treatment was well tolerated, with manageable toxicity; while 28.6% of patients experienced grade 3 or 4 neutropenia, there were no cases of febrile neutropenia reported.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II study of pemetrexed in combination with cisplatin in patients with advanced urothelial cancer: the PECULIAR study (KCSG 10-17). Choi, YJ., Lee, SH., Lee, JL., et al.[2018]

In a study of 8 patients with metastatic urothelial carcinoma who had previously failed platinum-based chemotherapy and pembrolizumab, TC chemotherapy resulted in a median overall survival of 10.9 months and a 25% objective response rate, indicating some efficacy in this challenging patient population.

TC chemotherapy showed promising results specifically for lymph node, lung, and liver metastases, with partial responses observed in 40% of lymph node cases, 50% of lung cases, and 66.7% of liver cases, suggesting that TC may be a viable treatment option even after prior therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Organ-Specific Therapeutic Effect of Paclitaxel and Carboplatin Chemotherapy After Platinum-Based Chemotherapy and Pembrolizumab for Metastatic Urothelial Carcinoma. Furubayashi, N., Negishi, T., Miura, A., et al.[2022]

Cisplatin-based regimens, particularly the M-VAC combination therapy, significantly improve complete response rates and overall survival in patients with advanced and metastatic bladder cancer compared to single-agent cisplatin.

For patients ineligible for cisplatin due to health issues, alternative therapies like paclitaxel, gemcitabine, and carboplatin have shown benefits, while new targeted therapies require further research to establish their effectiveness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Chemotherapeutic and targeted biological agents for metastatic bladder cancer: a comprehensive review. Sio, TT., Ko, J., Gudena, VK., et al.[2014]

Pembrolizumab significantly improves survival and quality of life for patients with advanced urothelial cancer who cannot tolerate cisplatin-based chemotherapy, offering an increase of approximately 2.11 to 2.16 years in overall survival and 1.71 to 1.75 quality-adjusted life years (QALYs) compared to standard treatments like carboplatin plus gemcitabine and gemcitabine monotherapy.

Despite being associated with higher costs (an increase of €90,520 compared to carboplatin plus gemcitabine), pembrolizumab is considered cost-effective at a threshold of €100,000/QALY, making it a viable first-line treatment option for this patient population in Sweden.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cost-effectiveness of Pembrolizumab for Patients with Advanced, Unresectable, or Metastatic Urothelial Cancer Ineligible for Cisplatin-based Therapy. Patterson, K., Prabhu, V., Xu, R., et al.[2022]

In the KEYNOTE-045 study involving 542 patients with advanced urothelial cancer, pembrolizumab significantly prolonged overall survival compared to standard chemotherapy, demonstrating its efficacy as a treatment option.

Patients receiving pembrolizumab experienced a longer time to deterioration in health-related quality of life (3.5 months) compared to those on chemotherapy (2.3 months), indicating that pembrolizumab not only improves survival but also maintains or enhances quality of life.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Health-Related Quality-of-Life Analysis From KEYNOTE-045: A Phase III Study of Pembrolizumab Versus Chemotherapy for Previously Treated Advanced Urothelial Cancer. Vaughn, DJ., Bellmunt, J., Fradet, Y., et al.[2021]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT05335941

NCT05335941 | A Phase 2 Study to Evaluate the Triplet ... All patients will receive combination therapy of pemetrexed and ZIMBERELIMAB (AB122) intravenously every 3 weeks as well as ETRUMADENANT (AB928) orally daily.

2. cancer.gov cancer.gov/research/participate/clinical-trials-search/v?id=NCI-2022-02708

Pemetrexed, Etrumadenant, and Zimberelimab for the ... Giving pemetrexed, etrumadenant, and zimberelimab may help to control urothelial cancer (bladder, urethra, and/or ureters) that has spread or cannot be ...

3. clinicaltrials.gov clinicaltrials.gov/study/NCT05335941?term=AREA%5BBasicSearch%5D(AREA%5BBasicSearch%5D(AREA%5BBasicSearch%5D(AB928)))&rank=2

A Phase 2 Study to Evaluate the Triplet Combination of ... Types of outcome measures include primary outcome measure and secondary outcome measure. ... A type of intervention model describing a clinical trial in which two ...

4. mdanderson.org mdanderson.org/patients-family/diagnosis-treatment/clinical-trials/clinical-trials-index/clinical-trials-detail.ID2021-0774.html

A Phase 2 Study to evaluate the triplet combination of ... This is a Phase 2 open-label, single-arm trial for patients with MTAP-deficient advanced urothelial cancer who had received prior immunotherapy.

5. checkorphan.org checkorphan.org/clinicaltrial/a-phase-2-study-to-evaluate-the-triplet-combination-of-pemetrexed-plus-ab928-etrumadenant-ab122-zimberelimab-in-patients-with-previously-treated-advanced-or-metastatic-mtap-deficient-urothelial/

A Phase 2 Study to Evaluate the Triplet Combination of ... A Phase 2 Study to Evaluate the Triplet Combination of Pemetrexed Plus AB928 (Etrumadenant) + AB122 (Zimberelimab) in Patients With Previously ...

6. arcusbio.com arcusbio.com/wp-content/uploads/2020/09/AB928_ESMO_Poster_FINAL.pdf

Phase 1 Evaluation of AB928, a Novel Dual Adenosine ... Four global phase 1/1b disease-specific platform studies are assessing the safety, tolerability, PK, PD, and preliminary clinical activity of AB928 in ...