Durvalumab + Chemo/Radiation for Bladder Cancer

Recruiting at 247 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: National Cancer Institute (NCI)

Must not be taking: Immunosuppressive medications

Disqualifiers: Pregnancy, Active infection, 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: 12

Duration: 6.5-8 weeks

95 Participants Needed

Trial Summary

What is the purpose of this trial?

This phase II trial studies the benefit of adding an immunotherapy drug called MEDI4736 (durvalumab) to standard chemotherapy and radiation therapy in treating bladder cancer which has spread to the lymph nodes. Drugs used in standard chemotherapy work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Cisplatin is in a class of medications known as platinum-containing compounds. It works by killing, stopping or slowing the growth of tumor cells. Radiation therapy uses high-energy x-rays to kill tumor cells and shrink tumors. Immunotherapy with durvalumab may help the body's immune system attack the cancer and may interfere with the ability of tumor cells to grow and spread. Giving chemotherapy and radiation therapy with the addition of durvalumab may work better in helping tumors respond to treatment compared to chemotherapy and radiation therapy alone. Patients with limited regional lymph node involvement may benefit from attempt at bladder preservation, and use of immunotherapy and systemic chemotherapy.

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. However, it mentions that you must not have used immunosuppressive medication within 14 days before starting durvalumab, with some exceptions like certain steroids. It's best to discuss your specific medications with the trial team.

What data supports the effectiveness of the drugs used in the Durvalumab + Chemo/Radiation for Bladder Cancer trial?

Research shows that combinations of drugs like cisplatin, doxorubicin, vinblastine, and methotrexate are effective against metastatic bladder cancer, with response rates up to 40%. Additionally, combining gemcitabine and cisplatin is a standard regimen due to lower toxicity, and combining chemotherapy with radiotherapy is promising for bladder cancer treatment. ^{1 2 3 4 5}

Is the combination of Durvalumab with chemotherapy and radiation therapy safe for treating bladder cancer?

The combination of chemotherapy drugs like cisplatin, doxorubicin, vinblastine, and methotrexate with radiation therapy has been used to treat bladder cancer, and while it can cause side effects like nausea, vomiting, and low blood cell counts, these are generally mild and patients recover. Additionally, combining paclitaxel and carboplatin with radiation therapy has been well-tolerated, showing no severe acute or late toxicity. Cisplatin with radiation therapy also showed mild side effects such as anorexia and diarrhea, with patients recovering spontaneously. ^{1 6 7 8 9}

How is the treatment with Durvalumab and chemotherapy/radiation unique for bladder cancer?

This treatment combines Durvalumab, an immunotherapy drug that helps the immune system attack cancer cells, with chemotherapy and radiation, which are standard treatments for bladder cancer. The combination aims to enhance the effectiveness of treatment by using multiple approaches to target the cancer, potentially improving outcomes compared to using chemotherapy or radiation alone. ^{1 4 5 10 11}

Research Team

Monika Joshi

Principal Investigator

ECOG-ACRIN Cancer Research Group

Eligibility Criteria

This trial is for adults with bladder cancer that has spread to lymph nodes but not elsewhere. They must have good physical function, no prior pelvic radiation, and acceptable blood counts and organ function. HIV-positive patients on effective therapy can join. Those with a history of certain cancers or autoimmune diseases, active infections like tuberculosis or hepatitis, or who are pregnant cannot participate.

Inclusion Criteria

I agree to have a CT scan for treatment planning.

I have never had radiation therapy to my pelvic area.

I meet the criteria for adjuvant durvalumab treatment.

Exclusion Criteria

I haven't had any live vaccines in the last 30 days.

You have a history of a weak immune system from birth.

I do not have serious liver disease.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants undergo chemoradiation with or without durvalumab for bladder cancer

6.5-8 weeks

Multiple visits for radiation and chemotherapy administration

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 years

Every 12 weeks for 1 year, every 6 months for year 2, then annually for years 3-4

Extension

Participants who achieve clinical CR or benefit may receive additional durvalumab treatment

6 cycles of 28 days each

Treatment Details

Interventions

• Carboplatin
• Cisplatin
• Doxorubicin Hydrochloride
• Durvalumab
• Fluorouracil
• Gemcitabine Hydrochloride
• Methotrexate
• Mitomycin
• Radiation Therapy
• Vinblastine Sulfate

Trial Overview The INSPIRE study is testing if adding the immunotherapy drug Durvalumab to standard chemotherapy (Cisplatin) and radiation improves treatment response in bladder cancer that's reached lymph nodes. The goal is to see if this combination helps shrink tumors better than chemo and radiation alone.

Participant Groups

Group I: Step 2, Arm E (durvalumab) Experimental Treatment 6 Interventions

Patients previously randomized to Arm C (chemoradiation and durvalumab) who achieve clinical CR or clinical benefit receive durvalumab IV over 60 minutes on day 1 of each cycle. Treatment repeats every 28 days for 6 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo bladder biopsy on study, cystoscopy on study and during follow-up, as well as CT or MRI throughout the trial. Patients may also undergo tumor tissue and blood sample collection on study.

Group II: Step 1, Arm C (durvalumab, radiation therapy, chemotherapy) Experimental Treatment 11 Interventions

Patients undergo radiation therapy for 6.5-8 weeks. Beginning 4 days before or after starting radiation therapy, patients receive durvalumab IV over 60 minutes on day 1 of each cycle. Treatment repeats every 21 days for up to 3 cycles in the absence of disease progression or unacceptable toxicity. Beginning 4 days before or after starting radiation therapy, patients also receive gemcitabine hydrochloride IV over 30-60 minutes BIW for 6 weeks; or cisplatin IV over 30-60 minutes QW for 6 weeks; or mitomycin IV over 30 minutes on day 1 of radiation and fluorouracil IV continuous infusion on days 1-5 and 16-20 of radiation in the absence of disease progression or unacceptable toxicity. Patients also undergo bladder biopsy on study, cystoscopy on study and during follow-up, as well as CT or MRI throughout the trial. Patients may also undergo tumor tissue and blood sample collection on study.

Group III: Step 1, Arm D (radiation therapy, chemotherapy) Active Control 10 Interventions

Patients undergo radiation therapy for 6.5-8 weeks. Beginning 4 days before or after starting radiation therapy, patients also receive gemcitabine hydrochloride IV over 30-60 minutes BIW for 6 weeks; or cisplatin IV over 30-60 minutes QW for 6 weeks; or mitomycin IV over 30 minutes on day 1 of radiation and fluorouracil IV continuous infusion on days 1-5 and 16-20 of radiation in the absence of disease progression or unacceptable toxicity. Patients also undergo bladder biopsy on study, cystoscopy on study and during follow-up, as well as CT or MRI throughout the trial. Patients may also undergo tumor tissue and blood sample collection on study.

Group IV: Step 2, Arm F (observation) Active Control 6 Interventions

Patients previously randomized to Arm D (chemoradiation) who achieve clinical CR or clinical benefit undergo observation undergo observation. Patients also undergo bladder biopsy on study, cystoscopy on study and during follow-up, as well as CT or MRI throughout the trial. Patients may also undergo tumor tissue and blood sample collection on study.

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

Approved in United States as Paraplatin for:

• Ovarian cancer
• Testicular cancer
• Lung cancer
• Head and neck cancer
• Brain cancer

Approved in European Union as Carboplatin for:

• Ovarian cancer
• Small cell lung cancer

Approved in Canada as Carboplatin for:

• Ovarian cancer
• Small cell lung cancer
• Testicular cancer

Who Is Running the Clinical Trial?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

Findings from Research

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]

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 45 patients with high-risk bladder cancer, the combination of transurethral resection of the bladder tumor (TURB) with concurrent cisplatin, 5-fluorouracil (5-FU), and radiation therapy resulted in an impressive 87% complete response rate, with 64% of patients remaining tumor-free after treatment.

The treatment protocol demonstrated acceptable safety, with only 10% experiencing severe hematologic toxicity and a 5-year survival rate of 54% with preserved bladder, indicating its efficacy and potential as a viable option for bladder cancer management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Organ preservation in patients with invasive bladder cancer: initial results of an intensified protocol of transurethral surgery and radiation therapy plus concurrent cisplatin and 5-fluorouracil. Rödel, C., Grabenbauer, GG., Kühn, R., et al.[2019]

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]

Urothelial carcinoma, the most common urological cancer, is primarily treated with Bacillus Calmette-Guerin (BCG) immunotherapy for superficial cases and cisplatin-based chemotherapy for metastatic disease, with vinflunine as the standard second-line option in Europe.

Novel PD-1/PD-L1 inhibitors like atezolizumab, nivolumab, and pembrolizumab have shown promise in treating bladder cancer, particularly for patients who cannot tolerate cisplatin, and are generally well tolerated with manageable side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Immunotherapy for Bladder Cancer]. Büchler, T.[2019]

References

1. France pubmed.ncbi.nlm.nih.gov

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

2. Germany pubmed.ncbi.nlm.nih.gov

[Neoadjuvant or Adjuvant Chemotherapy for Bladder Cancer?]. [2016]

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

Chemotherapy in advanced urinary bladder cancer. [2019]

4. France pubmed.ncbi.nlm.nih.gov

[Radiotherapy and chemotherapy in infiltrating bladder tumors]. [2006]

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

Organ preservation in patients with invasive bladder cancer: initial results of an intensified protocol of transurethral surgery and radiation therapy plus concurrent cisplatin and 5-fluorouracil. [2019]

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

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

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

Radiation therapy and concomitant paclitaxel/carboplatin chemotherapy for muscle invasive transitional cell carcinoma of the bladder: a well-tolerated combination. [2016]

9. Japan pubmed.ncbi.nlm.nih.gov

[Treatment using CDDP and radiation therapy in treating bladder tumor]. [2013]

10. Czech Republic pubmed.ncbi.nlm.nih.gov

[Immunotherapy for Bladder Cancer]. [2019]

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

Bladder Preservation With Twice-a-Day Radiation Plus Fluorouracil/Cisplatin or Once Daily Radiation Plus Gemcitabine for Muscle-Invasive Bladder Cancer: NRG/RTOG 0712-A Randomized Phase II Trial. [2022]