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

Trial Summary

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.

What data supports the effectiveness of the drug combination including Etrumadenant, AB928, Pemetrexed, Alimta, Pemfexy, Ciambra, Pemetrexed, Zimberelimab, AB122 for bladder cancer?

Research shows that Pemetrexed, one of the drugs in the combination, has shown promise in treating advanced bladder cancer, with studies indicating it can be effective when used alone or with other drugs like gemcitabine. ^{1 2 3 4 5}

Is the triple therapy for bladder cancer safe for humans?

Pemetrexed, one of the drugs in the triple therapy, has shown minimal toxicity when used alone for advanced bladder cancer. Studies have evaluated its safety in combination with other drugs, indicating it is generally safe for humans. ^{1 2 3 6 7}

What makes the drug combination of Etrumadenant, Pemetrexed, and Zimberelimab unique for bladder cancer?

This drug combination is unique because it includes Etrumadenant, a novel agent not typically used in standard bladder cancer treatments, alongside Pemetrexed and Zimberelimab, which may offer a new approach by combining chemotherapy with targeted therapy and immunotherapy, potentially improving efficacy and reducing toxicity compared to traditional regimens. ^{1 2 8 9 10}

What is the purpose of this trial?

This is a Phase 2 open-label, single-arm trial for patients with MTAP-deficient advanced urothelial cancer who had received prior immunotherapy. This is a single site study at the University of Texas MD Anderson Cancer Center. This study will allow patients in second line of treatment for advanced urothelial ca or beyond. All patients must have been previously treated with immune checkpoint inhibitor (ICI) therapy as per current standard of care.

Research Team

Omar Alhalabi, MD

Principal Investigator

M.D. Anderson Cancer Center

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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 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]

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]

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]

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 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]

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]

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]

References

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

Pemetrexed in transitional cell carcinoma of the urothelium. [2022]

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

Phase II study of pemetrexed for second-line treatment of transitional cell cancer of the urothelium. [2022]

3. England 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. [2022]

4. England pubmed.ncbi.nlm.nih.gov

Organ-Specific Therapeutic Effect of Paclitaxel and Carboplatin Chemotherapy After Platinum-Based Chemotherapy and Pembrolizumab for Metastatic Urothelial Carcinoma. [2022]

5. United States 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. [2021]

6. England 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). [2018]

7. Netherlands pubmed.ncbi.nlm.nih.gov

Cost-effectiveness of Pembrolizumab for Patients with Advanced, Unresectable, or Metastatic Urothelial Cancer Ineligible for Cisplatin-based Therapy. [2022]

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

Neoadjuvant Dose Dense MVAC versus Gemcitabine and Cisplatin in Patients with cT3-4aN0M0 Bladder Cancer Treated with Radical Cystectomy. [2022]

9. India pubmed.ncbi.nlm.nih.gov

External beam radiation plus concurrent intra-arterial chemotherapy with low dose cisplatin for muscle invasive bladder cancer. [2020]

10. Australia pubmed.ncbi.nlm.nih.gov

Chemotherapeutic and targeted biological agents for metastatic bladder cancer: a comprehensive review. [2014]