Chemotherapy + Durvalumab for Bladder Cancer

Recruiting in Palo Alto (17 mi)

Overseen by Matthew Campbell, MD

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 2

Recruiting

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

No Placebo Group

Prior Safety Data

Breakthrough Therapy

Trial Summary

What is the purpose of this trial?

This trial is testing if adding durvalumab to standard chemotherapy improves outcomes for bladder cancer patients whose cancer has spread to pelvic lymph nodes. Durvalumab helps the immune system attack cancer cells, potentially making the treatment more effective.

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.

What evidence supports the effectiveness of the drug combination used in the Chemotherapy + Durvalumab for Bladder Cancer trial?

Research shows that combinations of cisplatin, methotrexate, vinblastine, and doxorubicin (known as MVAC) have been effective in treating bladder cancer, with some patients experiencing complete or partial remission. Although these combinations can be toxic, they have shown a response rate of up to 52% in some studies, indicating potential effectiveness in managing advanced bladder cancer. ^{1 2 3 4 5}

Is the combination of chemotherapy drugs including cisplatin, methotrexate, vinblastine, doxorubicin, and durvalumab safe for humans?

The combination of chemotherapy drugs like cisplatin, methotrexate, vinblastine, and doxorubicin has been used in treating bladder cancer, but it can cause significant side effects, including blood-related issues like low white blood cell counts. Managing these side effects is important to avoid reducing or stopping treatment. Durvalumab, a newer drug, is generally considered safe, but its combination with these chemotherapy drugs should be monitored closely for safety. ^{5 6 7 8 9}

What makes the drug combination of Chemotherapy + Durvalumab unique for bladder cancer?

This treatment combines chemotherapy drugs with Durvalumab, an immunotherapy drug that helps the immune system attack cancer cells, potentially offering a novel approach by enhancing the body's natural defenses alongside traditional chemotherapy. ^{1 10 11 12 13}

Research Team

Matthew Campbell, MD

Principal Investigator

M.D. Anderson Cancer Center

Eligibility Criteria

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

I am 18 years old or older.

Your heart is pumping blood normally.

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

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.

Trial Timeline

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

Treatment Details

Interventions

• Cisplatin (Alkylating agents)
• Doxorubicin Hydrochloride (Anti-tumor antibiotic)
• Durvalumab (Checkpoint Inhibitor)
• Methotrexate (Anti-metabolites)
• Vinblastine (Anti-metabolites)

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.

Participant Groups

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 Canada, Japan for the following indications:

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+

Dr. Peter WT Pisters

M.D. Anderson Cancer Center

Chief Executive Officer since 2017

MD from University of Western Ontario

Dr. Jeffrey E. Lee

M.D. Anderson Cancer Center

Chief Medical Officer

MD from Stanford University School of Medicine

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

Findings from Research

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]

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 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 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]

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 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 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 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]

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]

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]

References

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

Chemotherapy in the management of bladder tumours. [2018]

2. France pubmed.ncbi.nlm.nih.gov

[Current chemotherapy of locally advanced or metastatic bladder tumors]. [2006]

3. Germany pubmed.ncbi.nlm.nih.gov

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

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

M-VAC or MVC for the treatment of advanced transitional cell carcinoma: metastatic, induction, and adjuvant. [2019]

5. United States 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. [2018]

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

Management of cisplatin-associated toxicities in bladder cancer patients. [2021]

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

Combination cisplatin and dichloromethotrexate in patients with advanced bladder cancer. Phase 2. A Southwest Oncology Group study. [2019]

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. Japan pubmed.ncbi.nlm.nih.gov

Adverse events of MVAC chemotherapy in patients with advanced urothelial cancer of the bladder. [2013]

10. France pubmed.ncbi.nlm.nih.gov

[Why use chemotherapy in cancer of the bladder? What are the initial limitations]. [2013]

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

Chemotherapy of Metastatic Bladder Cancer. [2019]

12. Germany pubmed.ncbi.nlm.nih.gov

Chemotherapy of advanced transitional-cell carcinoma of the bladder. [2019]

13. England pubmed.ncbi.nlm.nih.gov

Therapy of metastatic bladder carcinoma. [2020]