Durvalumab + Tremelimumab + Enfortumab Vedotin for Bladder Cancer

(VOLGA Trial)

Recruiting at 188 trial locations

Overseen By AstraZeneca Clinical Study Information Center

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: AstraZeneca

Must not be taking: Immunosuppressants

Disqualifiers: Metastatic disease, Active infection, others

Stay on Your Current Meds You can continue your current medications while participating

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

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

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

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

Compensation: Varies

Number of Visits: Unknown

Duration: Approximately 12 months

712 Participants Needed

Trial Summary

What is the purpose of this trial?

This trial tests a new combination of cancer treatments for bladder cancer patients who can't use standard chemotherapy. It uses drugs that help the immune system fight cancer and a drug that targets and kills cancer cells directly.

Do I need to stop my current medications for this trial?

The trial protocol does not specify if you need to stop your current medications. However, you cannot use immunosuppressive medication within 14 days before the first dose of the investigational products.

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 use immunosuppressive medication within 14 days before starting the trial treatment.

What data supports the idea that Durvalumab + Tremelimumab + Enfortumab Vedotin for Bladder Cancer is an effective drug?

The available research does not provide any data on the effectiveness of Durvalumab + Tremelimumab + Enfortumab Vedotin for Bladder Cancer. The studies listed focus on treatments for rheumatoid arthritis, not bladder cancer. ^{1 2 3 4 5}

What safety data is available for the combination of Durvalumab, Tremelimumab, and Enfortumab Vedotin in bladder cancer treatment?

The combination of Durvalumab and Tremelimumab has been studied for safety in various cancers. A systematic review and meta-analysis of 9 randomized controlled trials with 3060 patients showed that adverse events of Grade 3 or higher were more common with the combination (32.6%) compared to Durvalumab alone (23.8%). Common side effects included reduced appetite and diarrhea. Durvalumab has been approved for urothelial carcinoma and is under investigation in combination with Tremelimumab in phase III trials. Tremelimumab has been studied in combination with Durvalumab in phase I trials for safety and tolerability. Enfortumab Vedotin, also known as Padcev, is not specifically mentioned in the provided studies, so its safety data in combination with the other two drugs is not detailed here. ^{6 7 8 9 10}

Is the combination of Durvalumab, Tremelimumab, and Enfortumab Vedotin safe for humans?

The combination of Durvalumab and Tremelimumab has been studied for safety in various cancers, showing a higher rate of serious side effects like reduced appetite and diarrhea compared to Durvalumab alone. Durvalumab has been approved for certain cancers and is being tested in others, indicating it has been deemed safe enough for clinical use, but the combination with Enfortumab Vedotin specifically needs more research to fully understand its safety. ^{6 7 8 9 10}

Is the drug combination of Durvalumab, Enfortumab Vedotin, and Tremelimumab promising for bladder cancer?

The combination of Durvalumab, Enfortumab Vedotin, and Tremelimumab is promising for bladder cancer because it brings together powerful drugs that can work together to fight the disease. Durvalumab and Tremelimumab are known to help the immune system attack cancer cells, while Enfortumab Vedotin targets and delivers a cancer-killing agent directly to the cancer cells. This multi-faceted approach can potentially improve treatment effectiveness. ^{11 12 13 14 15}

What makes the drug combination of Durvalumab, Tremelimumab, and Enfortumab Vedotin unique for bladder cancer?

This drug combination is unique because it combines two immune checkpoint inhibitors, Durvalumab and Tremelimumab, which help the immune system attack cancer cells, with Enfortumab Vedotin, an antibody-drug conjugate that delivers chemotherapy directly to cancer cells. This multi-faceted approach aims to enhance the body's ability to fight bladder cancer more effectively than traditional treatments. ^{11 12 13 14 15}

Eligibility Criteria

This trial is for adults with muscle invasive bladder cancer who can't use or refuse cisplatin, haven't had chemo or immunotherapy for it, and are fit enough for cystectomy surgery. They must have a life expectancy of at least 12 weeks and be able to provide a tumor sample.

Inclusion Criteria

I have not had chemotherapy or immunotherapy for my bladder cancer.

My bladder cancer is at a specific stage but hasn't spread far.

I have not had chemotherapy or immunotherapy for bladder cancer.

Exclusion Criteria

My cancer has spread to lymph nodes or is metastatic.

I currently have an infection.

I have not been treated with immune therapies, except for BCG.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Safety Run-In

Initial phase to assess safety and tolerability of treatment combinations

Up to 84 months

Treatment

Participants receive 3 preoperative cycles of treatment followed by radical cystectomy and postoperative cycles

Approximately 12 months

Multiple visits for each cycle

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 5 years

Treatment Details

Interventions

• Durvalumab
• Enfortumab Vedotin
• Radical Cystectomy
• Tremelimumab

Trial Overview The study tests Durvalumab combined with Tremelimumab and Enfortumab Vedotin versus Durvalumab with Enfortumab Vedotin alone in patients undergoing surgery. It's randomized, meaning treatment is assigned by chance, aiming to improve current treatments.

Participant Groups

Group I: Durvalumab + Tremelimumab + Enfortumab vedotin Experimental Treatment 4 Interventions

Participants will receive 3 preoperative 21-day cycles of Durvalumab + Tremelimumab + Enfortumab Vedotin, followed by radical cystectomy, followed by 1 cycle of postoperative Tremelimumab and 9 cycles of Durvalumab. Each postoperative cycle is 28 days.

Group II: Durvalumab + Enfortumab vedotin Experimental Treatment 3 Interventions

Participants will receive 3 preoperative 21-day cycles of Durvalumab + Enfortumab Vedotin, followed by radical cystectomy, followed by 9 cycles of Durvalumab. Each postoperative cycle is 28 days.

Group III: Cystectomy with or without approved Adjuvant Therapy. Active Control 1 Intervention

Participants may receive SoC (nivolumab approved as adjuvant treatment for MIBC based on high risk criteria) per approved label in the country OR Participants receive standard of care surgery (radical cystectomy) alone.

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

Approved in European Union as Imfinzi for:

• Locally advanced, unresectable non-small cell lung cancer (NSCLC)

Approved in United States as Imfinzi for:

• Extensive-stage small cell lung cancer (ES-SCLC)
• Limited-stage small cell lung cancer (LS-SCLC)
• Locally advanced or metastatic urothelial carcinoma

Approved in Japan as Imfinzi for:

• Not specified in provided sources

Who Is Running the Clinical Trial?

AstraZeneca

Lead Sponsor

Trials

4,491

Recruited

290,540,000+

Sir Pascal Soriot

AstraZeneca

Chief Executive Officer since 2012

Veterinary Medicine from École nationale vétérinaire d'Alfort, MBA from HEC Paris

Dr. Cristian Massacesi

AstraZeneca

Chief Medical Officer since 2021

MD from Marche Polytechnic University, Oncology training at Royal Marsden Hospital, Kaplan Comprehensive Cancer Center, and European Institute of Oncology

Pascal Soriot

AstraZeneca

Chief Executive Officer since 2012

Veterinary Medicine from École nationale vétérinaire d'Alfort, MBA from HEC Paris

Cristian Massacesi

AstraZeneca

Chief Medical Officer since 2021

MD from Marche Polytechnic University, Medical Oncology training at Royal Marsden Hospital, Kaplan Comprehensive Cancer Center, and European Institute of Oncology

Findings from Research

In a study of 254 adult patients with active rheumatoid arthritis, etanercept, either alone or in combination with sulfasalazine, significantly improved disease activity compared to sulfasalazine alone, with 74% of etanercept patients achieving a 20% response at 24 weeks versus only 28% for sulfasalazine.

While etanercept was generally well tolerated, it had a higher incidence of infections and injection site reactions compared to sulfasalazine, but fewer common adverse events like headache and nausea when used alone.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Etanercept and sulfasalazine, alone and combined, in patients with active rheumatoid arthritis despite receiving sulfasalazine: a double-blind comparison. Combe, B., Codreanu, C., Fiocco, U., et al.[2022]

Tofacitinib, an oral Janus kinase inhibitor, shows comparable efficacy and tolerability to biological DMARDs in treating moderate-to-severe rheumatoid arthritis, based on a systematic review of 45 randomized clinical trials.

Both the 5 mg and 10 mg doses of tofacitinib, whether used alone or in combination with DMARDs, had similar rates of discontinuation due to adverse events compared to other treatment options, indicating it is a safe alternative.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tofacitinib versus Biologic Treatments in Moderate-to-Severe Rheumatoid Arthritis Patients Who Have Had an Inadequate Response to Nonbiologic DMARDs: Systematic Literature Review and Network Meta-Analysis. Bergrath, E., Gerber, RA., Gruben, D., et al.[2022]

In a 30-week trial involving 72 adults with active rheumatoid arthritis, the combination of infliximab and leflunomide was found to be safe, with only 17.1% of patients withdrawing due to treatment-related adverse events.

Significant clinical improvements were observed, with 19.4% of patients showing good improvement in disease activity scores and 47.1% achieving at least a 20% improvement according to the American College of Rheumatology criteria.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combination treatment with infliximab and leflunomide in patients with active rheumatoid arthritis: safety and efficacy in an open-label clinical trial. Kalden, JR., Nüsslein, HG., Wollenhaupt, J., et al.[2018]

In a study involving 2,965 patients with rheumatoid arthritis who did not respond adequately to disease-modifying antirheumatic drugs (DMARDs), mavrilimumab 150 mg combined with methotrexate (MTX) was found to be the most effective treatment, significantly improving ACR20 response rates compared to placebo.

Both mavrilimumab and tofacitinib treatments did not show a significant increase in serious adverse events, indicating that these interventions are safe options for patients with inadequate responses to DMARDs.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparison of the efficacy and safety of tofacitinib and mavrilimumab in patients with active rheumatoid arthritis: A Bayesian network meta-analysis of randomized controlled trials. Sung, YK., Lee, YH.[2021]

Leflunomide is an effective oral DMARD for treating active rheumatoid arthritis, showing significant improvements in symptoms and slowing disease progression compared to placebo and is equivalent to other treatments like sulfasalazine and methotrexate over 26 to 52 weeks.

It works by inhibiting the synthesis of pyrimidine nucleotides in immune cells, leading to reduced inflammation and has a rapid onset of action within 4 weeks, with mild to moderate side effects that are generally well-tolerated.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Leflunomide: a novel DMARD for the treatment of rheumatoid arthritis. Alldred, A., Emery, P.[2019]

The combination of durvalumab and tremelimumab in cancer treatment is associated with a higher incidence of severe adverse events (32.6%) compared to durvalumab alone (23.8%), indicating increased safety concerns with the combination therapy.

Patients receiving the combination therapy also experienced higher rates of specific side effects such as diarrhea (15.6% vs. 8.1%), rash (11.1% vs. 6.5%), and treatment discontinuation (18% vs. 3%), highlighting the need for careful monitoring and patient counseling regarding these risks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adverse Events and Tolerability of Combined Durvalumab and Tremelimumab versus Durvalumab Alone in Solid Cancers: A Systematic Review and Meta-Analysis. Fahmy, O., Ahmed, OAA., Khairul-Asri, MG., et al.[2023]

Durvalumab is an FDA-approved monoclonal antibody that enhances T-cell responses against cancer by blocking the PD-L1 pathway, specifically for patients with advanced urothelial carcinoma who have progressed after platinum-based chemotherapy.

The drug is currently being tested in phase III trials for various cancers, including lung and head and neck cancers, indicating its potential broad application in oncology beyond urothelial carcinoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Durvalumab: First Global Approval. Syed, YY.[2022]

In a phase I trial involving Japanese patients with advanced cancer, tremelimumab was found to be safe and well-tolerated, with no dose-limiting toxicities observed in the initial dosing phase, although 75% of patients reported treatment-related adverse events.

When combined with durvalumab, tremelimumab showed a manageable safety profile, with only two instances of serious adverse events (Grade 4 myasthenia gravis and hyperglycemia), indicating that the combination therapy can be administered with careful monitoring.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I Study of Tremelimumab Monotherapy or in Combination With Durvalumab in Japanese Patients With Advanced Solid Tumors or Malignant Mesothelioma. Fujiwara, Y., Takahashi, Y., Okada, M., et al.[2022]

In a study involving 867 patients with previously treated urinary tract carcinoma, fixed-dose durvalumab administered every four weeks demonstrated an acceptable safety profile, with 51% of patients experiencing adverse events and only 11% having immune-mediated adverse events.

The treatment showed clinical activity with a median overall survival of 7.0 months and an objective response rate of 18%, indicating that durvalumab can be an effective option for patients who have progressed after chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Primary results of STRONG: An open-label, multicenter, phase 3b study of fixed-dose durvalumab monotherapy in previously treated patients with urinary tract carcinoma. Sonpavde, GP., Sternberg, CN., Loriot, Y., et al.[2022]

Durvalumab, a PD-L1 inhibitor, has been shown to be safe for patients with various solid tumors, with common side effects including pruritus and fatigue, based on a meta-analysis of 17 studies involving 1,529 patients.

Higher levels of PD-L1 expression in tumors are linked to better treatment responses to durvalumab, indicating that PD-L1 could serve as a useful biomarker for predicting the drug's efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and efficacy of durvalumab (MEDI4736) in various solid tumors. Yang, H., Shen, K., Zhu, C., et al.[2022]

In a review of 16 trials involving 5345 patients with Crohn's disease (CD) and ulcerative colitis (UC), adalimumab demonstrated a consistent safety profile, with adverse event rates similar to previous analyses, indicating its long-term safety for these conditions.

The incidence of serious adverse events and malignancies was comparable to the general population, and the rate of opportunistic infections was notably low, suggesting that adalimumab is a safe treatment option for patients with moderate to severe CD and UC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-term safety of adalimumab in clinical trials in adult patients with Crohn's disease or ulcerative colitis. Colombel, JF., Sandborn, WJ., Reinisch, W., et al.[2019]

Leflunomide is an effective oral treatment for rheumatoid arthritis, working by inhibiting dihydroorotate dehydrogenase, which helps suppress inflammation and retard joint damage as seen in radiographic studies.

The side effects of leflunomide are generally mild, and it has been shown to be safe when used in combination with methotrexate, despite concerns about liver toxicity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Leflunomide for the treatment of rheumatoid arthritis and autoimmunity. Sanders, S., Harisdangkul, V.[2019]

In a study of elderly patients with overactive bladder, both solifenacin and mirabegron significantly reduced the frequency of incontinence episodes after 6 weeks of treatment, demonstrating their effectiveness as individual therapies.

Combining solifenacin and mirabegron resulted in even greater improvements in symptoms without increasing side effects, suggesting that this combination therapy may be more effective for managing severe overactive bladder symptoms in older adults.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A randomized, controlled trial of effectiveness and safety of management of OAB symptoms in elderly men and women with standard-dosed combination of solifenacin and mirabegron. Kosilov, K., Loparev, S., Ivanovskaya, M., et al.[2018]

In a study involving 1306 patients with overactive bladder, combination therapy of solifenacin and mirabegron significantly improved mean volume voided per micturition and reduced micturition frequency and urgency compared to solifenacin 5 mg alone.

The combination therapy was well tolerated, showing no significant additional safety concerns compared to monotherapy or placebo, although there was a slight increase in constipation with the combination treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combination treatment with mirabegron and solifenacin in patients with overactive bladder: efficacy and safety results from a randomised, double-blind, dose-ranging, phase 2 study (Symphony). Abrams, P., Kelleher, C., Staskin, D., et al.[2015]

In a study of 104 patients with moderate ulcerative colitis, both tofacitinib and adalimumab significantly improved quality of life and psychoemotional status more than budesonide, as measured by various questionnaires.

Tofacitinib showed the most substantial improvement in quality of life scores, with patients experiencing significant enhancements in both psychological and physical health components after treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

EFFECTS OF BIOLOGICAL THERAPY ON QUALITY OF LIFE AND PSYCHOEMOTIONAL STATUS OF PATIENTS WITH ULCERATIVE COLITIS. Varvarynets, AV.[2021]

References

1. England pubmed.ncbi.nlm.nih.gov

Etanercept and sulfasalazine, alone and combined, in patients with active rheumatoid arthritis despite receiving sulfasalazine: a double-blind comparison. [2022]

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

Tofacitinib versus Biologic Treatments in Moderate-to-Severe Rheumatoid Arthritis Patients Who Have Had an Inadequate Response to Nonbiologic DMARDs: Systematic Literature Review and Network Meta-Analysis. [2022]

3. Italy pubmed.ncbi.nlm.nih.gov

Combination treatment with infliximab and leflunomide in patients with active rheumatoid arthritis: safety and efficacy in an open-label clinical trial. [2018]

4. Germany pubmed.ncbi.nlm.nih.gov

Comparison of the efficacy and safety of tofacitinib and mavrilimumab in patients with active rheumatoid arthritis: A Bayesian network meta-analysis of randomized controlled trials. [2021]

5. England pubmed.ncbi.nlm.nih.gov

Leflunomide: a novel DMARD for the treatment of rheumatoid arthritis. [2019]

6. Switzerland pubmed.ncbi.nlm.nih.gov

Adverse Events and Tolerability of Combined Durvalumab and Tremelimumab versus Durvalumab Alone in Solid Cancers: A Systematic Review and Meta-Analysis. [2023]

7. New Zealand pubmed.ncbi.nlm.nih.gov

Durvalumab: First Global Approval. [2022]

8. England pubmed.ncbi.nlm.nih.gov

Phase I Study of Tremelimumab Monotherapy or in Combination With Durvalumab in Japanese Patients With Advanced Solid Tumors or Malignant Mesothelioma. [2022]

9. England pubmed.ncbi.nlm.nih.gov

Primary results of STRONG: An open-label, multicenter, phase 3b study of fixed-dose durvalumab monotherapy in previously treated patients with urinary tract carcinoma. [2022]

10. New Zealand pubmed.ncbi.nlm.nih.gov

Safety and efficacy of durvalumab (MEDI4736) in various solid tumors. [2022]

11. England pubmed.ncbi.nlm.nih.gov

Long-term safety of adalimumab in clinical trials in adult patients with Crohn's disease or ulcerative colitis. [2019]

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

Leflunomide for the treatment of rheumatoid arthritis and autoimmunity. [2019]

13. Netherlands pubmed.ncbi.nlm.nih.gov

A randomized, controlled trial of effectiveness and safety of management of OAB symptoms in elderly men and women with standard-dosed combination of solifenacin and mirabegron. [2018]

14. Switzerland pubmed.ncbi.nlm.nih.gov

Combination treatment with mirabegron and solifenacin in patients with overactive bladder: efficacy and safety results from a randomised, double-blind, dose-ranging, phase 2 study (Symphony). [2015]

15. Poland pubmed.ncbi.nlm.nih.gov

EFFECTS OF BIOLOGICAL THERAPY ON QUALITY OF LIFE AND PSYCHOEMOTIONAL STATUS OF PATIENTS WITH ULCERATIVE COLITIS. [2021]