Chemotherapy + Durvalumab for Bladder Cancer

Recruiting at 1 trial location

Overseen By Matthew Campbell

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: M.D. Anderson Cancer Center

Must not be taking: Immunosuppressants, Anti-PD-1, Anti-PD-L1, others

Disqualifiers: Metastatic disease, Neuropathy, Hearing loss, Heart failure, 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)

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

Compensation: Varies

Number of Visits: 14

Duration: 12 weeks

60 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new treatment approach for bladder cancer by adding durvalumab, an immune-boosting drug, to the usual chemotherapy regimen. The goal is to determine if this combination benefits patients with urothelial carcinoma of the bladder, particularly those with cancerous lymph nodes in the pelvic area. Participants will be divided into two groups: one will receive only the standard chemotherapy, while the other will receive chemotherapy plus durvalumab. This trial may suit individuals diagnosed with bladder cancer that has spread to pelvic lymph nodes and who can undergo a biopsy procedure. As a Phase 2 trial, this research focuses on measuring the treatment's effectiveness in an initial, smaller group of people.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, if you are on immunosuppressive medication, you must stop it 28 days before the first dose of the study drug, unless it's a low-dose corticosteroid. 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 durvalumab is generally safe for patients with bladder cancer. In earlier studies, it provided significant benefits, especially for those with a specific protein called PD-L1. Some serious side effects, such as blood in the urine, lung infections, and rashes, have been reported, but these are rare.

Cisplatin, doxorubicin hydrochloride, methotrexate, and vinblastine are often used together in a treatment known as MVAC. These drugs are well-known in cancer treatment and are usually effective, but they can cause side effects like nausea, hair loss, and low blood cell counts. Such side effects are common with chemotherapy but can usually be managed with medical care.

Researchers are studying the combination of durvalumab with MVAC to see if it leads to better results. So far, safety data suggests it is well-tolerated, but like any treatment, there are potential risks. Discuss these with the trial team if considering participation. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about combining Durvalumab with chemotherapy for bladder cancer because it brings a fresh approach to treatment. Unlike standard chemotherapy options, such as cisplatin-based regimens, Durvalumab is an immunotherapy drug that boosts the body's immune system to recognize and attack cancer cells more effectively. Another exciting aspect is that Durvalumab is given prior to and alongside chemotherapy, aiming to enhance the overall treatment response. This combination may offer a more powerful attack on the cancer, potentially leading to better outcomes for patients.

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

Research has shown that adding durvalumab to chemotherapy may help treat bladder cancer. In this trial, participants in Arm B will receive durvalumab combined with a chemotherapy plan called MVAC. This combination has demonstrated strong results, particularly in patients with high levels of a protein called PD-L1. Specifically, one study found a 25% lower risk of death compared to standard treatment alone, indicating that patients lived longer with durvalumab. The treatment began working in about six weeks, showing a quick effect. These findings suggest that durvalumab could be a valuable addition to current bladder cancer treatments. Participants in Arm A will receive the standard dose-dense MVAC chemotherapy without durvalumab. ^{1 2 3 6 7}

Who Is on the Research Team?

Matthew Campbell, MD

Principal Investigator

M.D. Anderson Cancer Center

Are You a Good Fit for This Trial?

This trial is for adults with bladder cancer that has spread to pelvic lymph nodes but not beyond. They must be in good physical condition, have a life expectancy of at least 12 weeks, weigh over 30 kg, and have proper heart and organ function. Women who can bear children need a negative pregnancy test and agree to use contraception.

Inclusion Criteria

Your heart is pumping blood normally.

I agree to provide tissue samples for biopsy before starting treatment.

My doctor confirmed a lymph node in my pelvis can be biopsied.

Exclusion Criteria

I have not had a stroke, heart attack, or severe chest pain in the last 6 months.

I have had an organ transplant from another person.

I have another cancer that is getting worse or needs treatment.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive neo-adjuvant cisplatin chemotherapy (NAC) or NAC plus durvalumab. Durvalumab is administered one week prior to the initial cycle and then with each additional cycle of dose-dense MVAC.

12 weeks

Every 14 days for up to 6 cycles

Surgery

Patients undergo radical cystectomy or biopsy if no longer surgical candidates.

Within 90 days post-treatment

Follow-up

Participants are monitored for safety and effectiveness after treatment, with blood and urine collected at baseline, week 2, week 6, week 16, and at the 6-week post-surgery visit.

6 weeks post-surgery

Maintenance

Durvalumab is continued as maintenance every 4 weeks until either relapse or 1 year.

Up to 1 year

What Are the Treatments Tested in This Trial?

Interventions

• Cisplatin
• Doxorubicin Hydrochloride
• Durvalumab
• Methotrexate
• Vinblastine

Trial Overview The study compares standard chemotherapy (cisplatin) with or without Durvalumab in patients with urothelial carcinoma of the bladder. Participants will be randomly assigned to receive either just chemotherapy or chemotherapy plus Durvalumab, which continues as maintenance for up to one year.

How Is the Trial Designed?

Group I: Arm B: Intervention with dose-dense MVAC plus Durvalumab Experimental Treatment 6 Interventions

Durvalumab will be administered one week prior to the initial cycle of dose-dense MVAC and then with each additional cycle of dose-dense MVAC on Arm B

Group II: Arm A: Standard of Care with dose-dense MVAC Experimental Treatment 6 Interventions

The patient will receive treatment every 14 days for up to 6 cycles in the neoadjuvant setting.

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

Approved in European Union as Platinol for:

• Testicular cancer
• Ovarian cancer
• Cervical cancer
• Bladder cancer
• Head and neck cancer
• Esophageal cancer
• Lung cancer
• Mesothelioma
• Brain tumors
• Neuroblastoma

Approved in United States as Platinol for:

• Testicular cancer
• Ovarian cancer
• Cervical cancer
• Bladder cancer
• Head and neck cancer
• Esophageal cancer
• Lung cancer
• Mesothelioma
• Brain tumors
• Neuroblastoma

Approved in Canada as Platinol for:

• Testicular cancer
• Ovarian cancer
• Cervical cancer
• Bladder cancer
• Head and neck cancer
• Esophageal cancer
• Lung cancer
• Mesothelioma
• Brain tumors
• Neuroblastoma

Approved in Japan as Platinol for:

• Testicular cancer
• Ovarian cancer
• Cervical cancer
• Bladder cancer
• Head and neck cancer
• Esophageal cancer
• Lung cancer
• Mesothelioma
• Brain tumors
• Neuroblastoma

Who Is Running the Clinical Trial?

M.D. Anderson Cancer Center

Lead Sponsor

Trials

3,107

Recruited

1,813,000+

AstraZeneca

Industry 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

Published Research Related to This Trial

Combination chemotherapy for metastatic bladder cancer, particularly the MVAC regimen, shows the highest effectiveness with complete response rates of 30-40%.

Chemotherapy is primarily used for palliative care in metastatic cases, but it can also serve as neoadjuvant treatment to shrink tumors before surgery, potentially preserving the bladder.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Why use chemotherapy in cancer of the bladder? What are the initial limitations]. Maraninchi, D., Viens, P.[2013]

Cisplatin-based combination chemotherapy has shown greater efficacy in treating advanced transitional-cell carcinoma of the bladder compared to older regimens based on Adriamycin or methotrexate, with significant patient responses reported in trials.

While regimens like CMV (cisplatin, methotrexate, and vinblastine) and M-VAC (methotrexate, vinblastine, Adriamycin, and cisplatin) demonstrate improved response rates and survival, they also come with significant toxicity, prompting ongoing phase III studies to further evaluate their safety and effectiveness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Chemotherapy of advanced transitional-cell carcinoma of the bladder. Miller, RS., Torti, FM.[2019]

Standard chemotherapy for transitional cell carcinoma of the bladder, known as MVAC (cisplatin, methotrexate, vinblastine, and doxorubicin), shows a high response rate but rarely leads to long-term survival, indicating a need for more effective and less toxic treatments.

Alternative agents like paclitaxel, gemcitabine, and gallium nitrate have demonstrated significant activity, either alone or in combination with cisplatin or carboplatin, achieving response rates of 40% to 70% in patients with advanced disease, although the best treatment regimen is still not established.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Current chemotherapy of locally advanced or metastatic bladder tumors]. Dourthe, LM., Ceccaldi, B., Fournier, R., et al.[2006]

Cisplatin is a key treatment for bladder cancer, but managing its side effects, like nausea and acute kidney injury, is crucial to maintain treatment effectiveness and avoid dose reductions.

An effective strategy for preventing cisplatin-associated nausea and vomiting involves a four-drug prophylactic regimen, while intensive hydration is essential for preventing acute kidney injury.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Management of cisplatin-associated toxicities in bladder cancer patients. Desilets, A., Adam, JP., Soulières, D.[2021]

The gemcitabine and cisplatin (CG) combination has emerged as the new standard of care for metastatic bladder carcinoma, showing similar effectiveness to the previous standard M-VAC regimen but with less toxicity.

Novel treatments like pemetrexed and vinflunine are showing promise in clinical trials, with pemetrexed demonstrating a 28% response rate and vinflunine providing an 18% response rate in pretreated patients, indicating potential for improved outcomes in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Therapy of metastatic bladder carcinoma. Iaffaioli, RV., Milano, A., Caponigro, F.[2020]

In a randomized phase III trial involving 220 patients with inoperable or metastatic urothelial carcinoma, the MVAC regimen demonstrated superior response rates (54.2% vs. 37.4%) and longer median time to progression (9.4 months vs. 6.1 months) compared to the docetaxel and cisplatin (DC) combination.

While MVAC was more effective, it also resulted in higher rates of severe side effects, such as neutropenia and neutropenic sepsis, although the toxicity was lower than previously reported for MVAC without G-CSF support, suggesting that G-CSF makes MVAC a safer option for first-line treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Docetaxel and cisplatin with granulocyte colony-stimulating factor (G-CSF) versus MVAC with G-CSF in advanced urothelial carcinoma: a multicenter, randomized, phase III study from the Hellenic Cooperative Oncology Group. Bamias, A., Aravantinos, G., Deliveliotis, C., et al.[2018]

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]

Intravesical treatments with thiotepa, doxorubicin, mitomycin C, or Bacillus Calmette-Guerin have proven beneficial for managing superficial bladder tumors, although the specific indications for each treatment need further clarification.

For metastatic bladder cancer, cisplatin combined with doxorubicin or methotrexate shows significant efficacy, achieving complete remission in 20-35% of cases and partial remission in an additional 20-40%, with some patients maintaining complete remission for over 10 years.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Chemotherapy in the management of bladder tumours. Whitmore, WF., Yagoda, A.[2018]

Cisplatin and methotrexate are the most effective chemotherapy agents for metastatic transitional cell carcinoma, and their inclusion in polychemotherapy regimens, particularly MVAC, improves complete remission rates.

Despite the improved remission rates with polychemotherapy, only about 10-15% of patients achieve a durable response, and the treatment is associated with significant toxicity, highlighting the need for further research on optimal treatment strategies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Chemotherapy of bladder carcinoma. Current status and trends]. Block, T.[2007]

In a study of 97 patients with metastatic bladder cancer, the combination of cisplatin and dichloromethotrexate resulted in a 42% response rate, with 14% of patients achieving a complete response, indicating its potential efficacy in patients with good renal function.

The study found that dichloromethotrexate alone did not produce any responses in patients with impaired renal function, and the overall response rate was not high enough to justify further studies with this agent, suggesting a need for new treatments for metastatic bladder cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combination cisplatin and dichloromethotrexate in patients with advanced bladder cancer. Phase 2. A Southwest Oncology Group study. Meyers, FJ., Blumenstein, B., Crawford, ED., et al.[2019]

In a study of 59 patients with advanced bladder cancer receiving MVAC chemotherapy, over 90% experienced hematological adverse events, particularly leukocytopenia and neutropenia, with severe cases (grade 3 or 4) affecting 60-75% of patients.

Despite the high incidence of adverse events, including nausea in 70-80% of patients and a small number of severe complications like febrile neutropenia, the overall adverse events were considered tolerable, especially for those undergoing 2 courses of treatment in the neoadjuvant or adjuvant settings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adverse events of MVAC chemotherapy in patients with advanced urothelial cancer of the bladder. Maeda, T., Takahashi, A., Hirobe, M., et al.[2013]

In a study of 25 patients with metastatic urothelial carcinoma, the cisplatin-based chemotherapy regimens M-VAC and MVC resulted in a 48% overall response rate, with 20% achieving a complete response and 28% a partial response.

While these combination therapies showed improved efficacy compared to cisplatin alone, they also had significant toxicity, leading to two deaths, highlighting the need to balance treatment effectiveness with safety.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

M-VAC or MVC for the treatment of advanced transitional cell carcinoma: metastatic, induction, and adjuvant. Soloway, MS., Ishikawa, S., Taylor, T., et al.[2019]

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]

Citations

1. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/27269937/

Safety and Efficacy of Durvalumab (MEDI4736), an ... - PubMed Durvalumab demonstrated a manageable safety profile and evidence of meaningful clinical activity in PD-L1-positive patients with UBC, ...

2. ascopubs.org ascopubs.org/doi/10.1200/JCO.2016.67.9761

Safety and Efficacy of Durvalumab (MEDI4736), an Anti– ... Durvalumab demonstrated a manageable safety profile and evidence of meaningful clinical activity in PD-L1–positive patients with UBC, many of whom were heavily ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC6452813/

Durvalumab for the management of urothelial carcinoma The median time to response was 6.3 weeks (95% CI, 5.6–12.1 weeks) in the 13 responding patients, and median duration of response has not been reached (range, ...

4. clinicaltrials.gov clinicaltrials.gov/study/NCT02516241

NCT02516241 | Study of MEDI4736 (Durvalumab) With or ... This is a randomized, open-label, controlled, multi-center, global Phase III study to determine the efficacy and safety of MEDI4736 (Durvalumab) monotherapy

5. ascopubs.org ascopubs.org/doi/10.1200/JCO.2025.43.5_suppl.778

Feasibility and safety results from RAD-IO Recent phase 3 results with peri-operative durvalumab show a 25% reduction in the risk of death compared to standard of care. Methods: RADIO is ...

6. annalsofoncology.org annalsofoncology.org/article/S0923-7534(24)04349-7/fulltext

273MO DURANCE: A phase Ib/II study to assess the safety ... Three serious AEs (haematuria, lung infection, and maculopapular rash) were observed in 1/14 patients (7.1%) during DLT period, all of which were considered ...

7. clinicaltrials.gov clinicaltrials.gov/study/NCT03528694

Study Details | NCT03528694 | Assessment of Efficacy and ... Assessment of Efficacy and Safety of Durvalumab Plus BCG Compared to the Standard Therapy With BCG in Non-muscle Invasive Bladder Cancer (POTOMAC).