Durvalumab + Chemotherapy for Urothelial Carcinoma

Recruiting at 230 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 2 & 3

Sponsor: National Cancer Institute (NCI)

Must not be taking: Immunosuppressants, Anthracyclines

Disqualifiers: Pregnancy, Metastatic disease, Autoimmune disease, 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: 7

Duration: 8-12 weeks

249 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests whether adding durvalumab, an immunotherapy drug, to chemotherapy is more effective than chemotherapy alone in shrinking tumors before surgery for upper urinary tract cancer. Immunotherapy helps the body's immune system attack cancer cells, while chemotherapy stops cancer growth and spread. The study compares different combinations of these treatments across three groups. Individuals with high-grade upper tract urothelial carcinoma who are eligible for surgery might be suitable for this trial. As a Phase 2 trial, this research measures the treatment's effectiveness in an initial, smaller group, offering participants a chance to contribute to important advancements in cancer treatment.

Will I have to stop taking my current medications?

The trial protocol does not specify whether you need to stop taking your current medications. However, you must not be on immunosuppressive medication within 14 days before starting durvalumab, except for certain low-dose steroids and specific types of steroid use.

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

Research has shown that combining durvalumab with chemotherapy is generally safe for patients with urothelial carcinoma, a type of bladder cancer. Studies indicate that patients tolerate durvalumab well, experiencing side effects similar to those of other immune system treatments. These side effects can include tiredness, nausea, and diarrhea, but they are usually not severe.

For the combination of durvalumab and gemcitabine, earlier research in patients with similar conditions found that the treatment was generally well-tolerated. Common side effects included fatigue and mild skin reactions.

The FDA has already approved durvalumab for use in other cancer treatments, confirming its safety for patients. While no treatment is without risks, evidence suggests that durvalumab, both alone and with chemotherapy drugs like gemcitabine, is well-tolerated by most patients. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments for urothelial carcinoma because they incorporate durvalumab, an immune checkpoint inhibitor, which offers a fresh approach by helping the immune system recognize and attack cancer cells. Unlike standard chemotherapy, which broadly targets rapidly dividing cells, durvalumab specifically blocks the PD-L1 protein, potentially enhancing the body's immune response against the cancer. In Arm A, the combination of durvalumab with a multi-drug chemotherapy regimen potentially offers a more potent anti-cancer effect by combining immune activation with traditional chemo agents. Meanwhile, Arm C focuses on a less intensive combination of durvalumab with gemcitabine, which might offer a favorable balance between efficacy and tolerability. These innovative approaches could lead to improved outcomes for patients with this challenging condition.

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

Research has shown that adding durvalumab to chemotherapy might benefit patients with urothelial carcinoma. Durvalumab boosts the immune system, enabling it to attack cancer cells more effectively. In this trial, participants in Arm A will receive durvalumab combined with a chemotherapy regimen of methotrexate, vinblastine sulfate, doxorubicin, and cisplatin. Studies have found that patients receiving both durvalumab and chemotherapy achieved better results than those receiving only chemotherapy, which is being tested in Arm B. Meanwhile, Arm C will evaluate the combination of durvalumab with gemcitabine hydrochloride, which has shown promise in shrinking tumors before surgery. These findings suggest that combining durvalumab with chemotherapy could be a more effective treatment for upper urinary tract cancer. ^{1 3 6 7 8}

Who Is on the Research Team?

Jean H Hoffman-Censits

Principal Investigator

ECOG-ACRIN Cancer Research Group

Are You a Good Fit for This Trial?

Adults with high-grade upper urinary tract cancer who are fit for chemotherapy and surgery. They must have a life expectancy of at least 12 weeks, adequate organ function, no severe hearing loss or neuropathy, not be pregnant or breastfeeding, and willing to use contraception. Excluded if they have small cell/neuroendocrine carcinoma components in their cancer, other active cancers (with some exceptions), uncontrolled illnesses, recent major surgeries, certain autoimmune diseases or treatments.

Inclusion Criteria

I was diagnosed with a severe type of urinary tract cancer within the last 12 weeks.

Your blood platelet count must be at least 100,000 per microliter, and this should be checked no more than 14 days before participating in the study.

I understand a biopsy is necessary for my participation in the study.

Exclusion Criteria

Patients of childbearing potential and sexually active patients must not expect to conceive or father children, either by using accepted and effective method(s) of contraception or by abstaining from sexual intercourse from the time of registration, while on study treatment and for at least 6 months after the last dose of protocol treatment

I have never been treated with anthracycline drugs.

I've been cancer-free for over 2 years after treatment and haven't had immune therapy.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive durvalumab and chemotherapy or chemotherapy alone for up to 4 cycles

8-12 weeks

4 visits (in-person) every 14 or 21 days depending on the arm

Surgery

Participants undergo surgery within 21-60 days after completion of systemic treatment if no metastatic or unresectable disease is present

3-8 weeks post-treatment

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 5 years

Every 3-6 months

What Are the Treatments Tested in This Trial?

Interventions

• Doxorubicin Hydrochloride
• Durvalumab
• Gemcitabine Hydrochloride
• Methotrexate
• Pegfilgrastim
• Therapeutic Conventional Surgery
• Vinblastine Sulfate

Trial Overview The trial is testing the addition of Durvalumab (an immunotherapy drug) to standard chemotherapy before surgery compared to chemotherapy alone. The goal is to see if combining Durvalumab with chemo can better shrink tumors before they're surgically removed.

How Is the Trial Designed?

Group I: Arm C (durvalumab, gemcitabine hydrochloride) Experimental Treatment 7 Interventions

Patients receive durvalumab IV over 60 minutes on day 1 and gemcitabine hydrochloride IV over 30 minutes on days 1 and 8. Treatment repeats every 21 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity. Within 21- 60 days after completion of systemic treatment, patients with continued lack of radiographic presence of metastatic or unresectable disease undergo surgery. Patients also undergo tissue biopsy and blood sample collection on study, and CT or MRI throughout the trial.

Group II: Arm A (durvalumab, chemotherapy) Experimental Treatment 11 Interventions

Patients receive durvalumab IV over 60 minutes on day 1 of chemotherapy cycles 1 and 3. Patients also receive methotrexate IV over 2-3 minutes, vinblastine sulfate IV, doxorubicin IV, cisplatin IV over at least 2 hours on day 1. Treatments repeat every 14 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity. Within 21- 60 days after completion of systemic treatment, patients with continued lack of radiographic presence of metastatic or unresectable disease undergo surgery. Patients also undergo tissue biopsy and blood sample collection on study, and CT or MRI throughout the trial.

Group III: Arm B (chemotherapy) Active Control 10 Interventions

Patients also receive methotrexate IV over 2-3 minutes, vinblastine sulfate IV, doxorubicin IV, cisplatin IV over at least 2 hours on day 1. Treatments repeat every 14 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity. Within 21- 60 days after completion of systemic treatment, patients with continued lack of radiographic presence of metastatic or unresectable disease undergo surgery. Patients also undergo tissue biopsy and blood sample collection on study, and CT or MRI throughout the trial.

Doxorubicin Hydrochloride is already approved in United States, European Union for the following indications:

Approved in United States as Adriamycin for:

• Breast cancer
• Ovarian cancer
• Bladder cancer
• Leukemia
• Lymphoma

Approved in European Union as Doxorubicin Hydrochloride for:

• Breast cancer
• Ovarian cancer
• Bladder cancer
• Leukemia
• Lymphoma

Who Is Running the Clinical Trial?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

In a phase 3 trial involving 1032 patients with metastatic urothelial carcinoma, durvalumab alone showed a median overall survival of 14.4 months in patients with high PD-L1 expression, compared to 12.1 months with standard chemotherapy, although this difference was not statistically significant.

The combination of durvalumab and tremelimumab resulted in a median overall survival of 15.1 months in the overall patient population, compared to 12.1 months for chemotherapy, but again, this did not meet the primary endpoint for significance, highlighting the need for further research into which patients may benefit from these treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Durvalumab alone and durvalumab plus tremelimumab versus chemotherapy in previously untreated patients with unresectable, locally advanced or metastatic urothelial carcinoma (DANUBE): a randomised, open-label, multicentre, phase 3 trial. Powles, T., van der Heijden, MS., Castellano, D., et al.[2021]

Recent phase II clinical trials have shown that combination therapies using cis-diamminedichloride platinum II, Adriamycin, and methotrexate are effective in treating advanced transitional cell carcinoma of the urothelial tract.

While combination regimens appear to lead to higher remission rates compared to single-agent treatments, further prospective randomized trials are necessary to confirm these benefits and address challenges in patient selection and response criteria.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Chemotherapy of Metastatic Bladder Cancer. Yagoda, A.[2019]

In a study of 277 patients with muscle-invasive bladder cancer or locally advanced upper tract urothelial cancer, both high dose-intensity combination chemotherapy (HD MVAC) and gemcitabine plus cisplatin (GC) showed similar oncologic outcomes, with no significant differences in pathologic complete response rates or overall survival after 3 years.

However, HD MVAC was associated with a higher risk of febrile neutropenia compared to GC, indicating that while both treatments are effective, HD MVAC may pose additional safety concerns.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparison of clinical outcomes in patients with localized or locally advanced urothelial carcinoma treated with neoadjuvant chemotherapy involving gemcitabine-cisplatin and high dose-intensity MVAC. Lee, Y., Kim, YS., Hong, B., et al.[2022]

In a study of 109 patients with muscle-invasive bladder cancer, both gemcitabine and cisplatin (GC) and dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin (ddMVAC) showed similar rates of pathologic complete response (pCR), with 25% for GC and 21% for ddMVAC, indicating that both regimens are equally effective as neoadjuvant chemotherapy.

Switching between GC and ddMVAC after 1 or 2 cycles may benefit patients with poor initial responses, as 4 out of 7 patients in the switch therapy group experienced downstaging, suggesting a potential strategy for improving treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Downstaging of Muscle-Invasive Bladder Cancer Using Neoadjuvant Gemcitabine and Cisplatin or Dose-Dense Methotrexate, Vinblastine, Doxorubicin, and Cisplatin as Single Regimens or as Switch Therapy Modalities. Ruplin, AT., Spengler, AMZ., Montgomery, RB., et al.[2022]

Both chemotherapy regimens, gemcitabine and cisplatin (GC) and methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC), are well-tolerated in patients with locally advanced urothelial cancer after radical cystectomy, with 56% of subjects completing all planned cycles.

Despite similar efficacy between the two regimens, patients who received adjuvant chemotherapy had a shorter survival after recurrence compared to those who developed metastases without prior treatment, indicating potential resistance to subsequent therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adjuvant chemotherapy for locally advanced urothelial carcinoma: an overview of the USC experience. Dorff, TB., Tsao-Wei, D., Miranda, G., et al.[2022]

In a phase II study involving 61 patients with muscle-invasive urothelial carcinoma, the addition of neoadjuvant durvalumab to standard chemotherapy resulted in a high event-free survival (EFS) rate of 76% at 2 years, indicating promising efficacy in this treatment approach.

The study also reported an overall survival (OS) rate of 85% at 2 years, although 42% of patients experienced grade 3 or 4 treatment-related adverse events during the neoadjuvant phase, highlighting the need to balance efficacy with safety in treatment planning.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Perioperative Chemoimmunotherapy With Durvalumab for Muscle-Invasive Urothelial Carcinoma: Primary Analysis of the Single-Arm Phase II Trial SAKK 06/17. Cathomas, R., Rothschild, SI., Hayoz, S., et al.[2023]

The dose dense Methotrexate, vinblastine, doxorubicin, and cisplatin (ddMVAC) regimen shows a significantly better complete response rate and downstaging rate compared to the gemcitabine and cisplatin (GC) regimen in treating bladder cancer, based on a meta-analysis of five studies involving 1,206 patients.

Patients receiving ddMVAC also experienced longer overall survival compared to those treated with the GC regimen, indicating that ddMVAC may be a more effective neoadjuvant chemotherapy option for bladder cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A systematic review and meta-analysis of neoadjuvant chemotherapy for bladder cancer between ddMVAC and GC regimen. Liu, T., Jiang, G.[2022]

In a study of 39 patients with muscle-invasive urothelial cancer, neoadjuvant treatment with dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin (ddMVAC) achieved a significant pathologic response rate of 49%, indicating its efficacy in downstaging the cancer before surgery.

The treatment was well tolerated, with only 10% of patients experiencing high-grade toxicities, and no cases of neutropenic fever or treatment-related deaths, highlighting its safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neoadjuvant dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin with pegfilgrastim support in muscle-invasive urothelial cancer: pathologic, radiologic, and biomarker correlates. Choueiri, TK., Jacobus, S., Bellmunt, J., et al.[2022]

The combination of durvalumab and cabozantinib was found to be safe in a phase 2 study with 16 patients, showing no severe treatment-related adverse events in the first two cycles, although common mild side effects included fatigue and diarrhea.

Preliminary results indicated that 37.5% of patients experienced objective responses, including two complete responses, suggesting that this combination therapy may be effective for patients with advanced metastatic urothelial carcinoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cabozantinib Plus Durvalumab in Patients With Advanced Urothelial Carcinoma After Platinum Chemotherapy: Safety and Preliminary Activity of the Open-Label, Single-Arm, Phase 2 ARCADIA Trial. Marandino, L., Raggi, D., Calareso, G., et al.[2021]

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]

Neoadjuvant chemotherapy (NACT) in patients with urothelial cancer showed improved survival rates, pathologic complete response (pCR), and downstaging (pDS), with 9% of radical cystectomy patients receiving this treatment.

Among the chemotherapy regimens compared, MVAC resulted in higher downstaging compared to gemcitabine/cisplatin, although it did not lead to a significant increase in pathologic complete response.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neoadjuvant chemotherapy in urothelial bladder cancer: impact of regimen and variant histology. Kaimakliotis, HZ., Monn, MF., Cho, JS., et al.[2022]

In a phase III trial with 405 patients, the gemcitabine/cisplatin (GC) regimen showed comparable effectiveness to the standard MVAC regimen for advanced bladder cancer, with similar response rates and overall survival.

The GC regimen demonstrated significantly better safety and tolerability, with much lower rates of severe side effects like mucositis and neutropenic fever, suggesting it should be preferred as the standard treatment for advanced bladder cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Gemcitabine in advanced bladder cancer. von der Maase, H.[2022]

Gemcitabine, a newer chemotherapy agent, has shown promising activity against bladder cancer, both as a single agent and in combination with cisplatin, offering a favorable toxicity profile compared to traditional treatments.

The standard treatment for advanced bladder cancer in the US remains the M-VAC regimen, but ongoing trials are exploring the effectiveness of gemcitabine combined with other agents, which may lead to improved treatment options.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Gemcitabine in the treatment of bladder cancer. Ryan, CW., Vogelzang, NJ.[2022]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT05137262

Study Details | NCT05137262 | A Phase II Multicenter ... A Phase II Multicenter Study of Chemotherapy Versus Chemotherapy Plus Durvalumab (MEDI 4736) in Patients With Lymph Node Positive Urothelial Carcinoma of the ...

2. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/29517083/

Durvalumab for the treatment of urothelial carcinoma Currently, the only FDA-approved indication for the anti-PD-L1 monoclonal antibody durvalumab (MEDI-4736) is locally advanced or metastatic urothelial carcinoma ...

3. imfinzihcp.com imfinzihcp.com/bladder-cancer/muscle-invasive/efficacy.html

Efficacy and Clinical Trial Data for IMFINZI® (durvalumab) Healthcare professionals can review efficacy data for IMFINZI and clinical trial results in FDA-approved indications.

4. fda.gov fda.gov/drugs/resources-information-approved-drugs/fda-approves-durvalumab-muscle-invasive-bladder-cancer

FDA approves durvalumab for muscle invasive bladder ... On March 28, 2025, the Food and Drug Administration approved durvalumab (Imfinzi, AstraZeneca) with gemcitabine and cisplatin as neoadjuvant treatment.

5. s3.amazonaws.com s3.amazonaws.com/ctr-med-7111/D933RC00001/64fb18ca-1077-46c8-987e-4a5df41ef046/06c1e6cf-2b80-41ab-8913-a877eb4ea7e7/D933RC00001_CSP_Redacted-v1.pdf

Clinical Study Protocol Efficacy and safety of durvalumab in locally advanced or metastatic urothelial carcinoma: updated results from a phase 1/2 open-label study ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9983117/

Upper Tract Urinary Carcinoma: A Unique Immuno-Molecular ... Urothelial carcinoma (UC) is the most frequent malignancy of the urinary tract, which consists of bladder cancer (BC) for 90%, while 5% to 10%, of urinary ...

7. prohealthcare.org prohealthcare.org/medical-services/clinical-trials/details/?id=136

EA8192: A Phase II/III Trial of MED14736 (Durvalumab) ... This phase III trial compares the effect of adding durvalumab to chemotherapy versus chemotherapy alone before surgery in treating patients with upper urinary ...

8. ema.europa.eu ema.europa.eu/en/documents/variation-report/imfinzi-h-c-004771-ii-0073-epar-assessment-report-variation_en.pdf

Imfinzi, INN-durvalumab - EMA Durvalumab. DCO. Data cut-off dd-MVAC. Dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin. DFS. Disease-free survival. DoR.