Immunotherapy + Chemotherapy for Bladder Cancer

(ADAPT-BLADDER Trial)

Recruiting at 7 trial locations

Overseen By Gabrielle Tiggs

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Noah Hahn, M.D.

Must be taking: BCG therapy

Must not be taking: Immunosuppressants, PD-1, PD-L1, CTLA-4

Disqualifiers: Muscle-invasive cancer, Active second malignancy, others

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

Compensation: Varies

Number of Visits: Unknown

Duration: 6 months

55 Participants Needed

Trial Summary

What is the purpose of this trial?

Upon successful screening and registration, enrollment to durvalumab monotherapy (cohort 1) will begin. If DLT criteria outlined in the protocol are exceeded with durvalumab monotherapy (cohort 1), the study will close. Provided the safety of durvalumab monotherapy is established, enrollment to combination regimen cohorts will proceed. Cohorts will simultaneously enroll in parallel to each other with patients assigned to cohorts based on patient slot availability and study site choice of radiation arm participation. Patient assignment to future phase 1 arms would proceed similarly. Within BCG-containing cohorts, treatment will begin at full-dose BCG. If DLT criteria outlined in Section 5.1.4 are exceeded with full-dose BCG, a one level dose reduction of BCG will be implemented. If DLT criteria outlined in Section 5.1.4 are exceeded with reduced-dose BCG, the BCG-containing cohort will not proceed to Phase 2 of the study. Similarly, if DLT criteria outlined in Section 5.1.4 are exceeded within non-BCG containing cohorts, the non-BCG containing cohort will not proceed to phase 2 of the study. Due to the prolonged half-life of antibody therapies, no dose adjustments are planned for durvalumab in any of the cohorts.

Will I have to stop taking my current medications?

The trial protocol does not specify if you need to stop taking your current medications. However, you cannot use immunosuppressive medication within 14 days before starting the study drug, except for certain exceptions like low-dose steroids or NSAIDs. It's best to discuss your specific medications with the study team.

What data supports the effectiveness of this treatment for bladder cancer?

Research shows that using gemcitabine and docetaxel together can help patients with bladder cancer who did not respond to BCG treatment, providing a durable remission. Additionally, BCG is a standard treatment for bladder cancer, and efforts to enhance its effectiveness with other therapies like immunotherapy are ongoing. ^{1 2 3 4 5}

Is the combination of immunotherapy and chemotherapy for bladder cancer safe?

Studies have shown that while Bacillus Calmette-Guérin (BCG) is effective for bladder cancer, it can have significant side effects. Alternatives like gemcitabine and docetaxel have been evaluated for safety and are considered tolerable, offering a potential option for those who cannot tolerate BCG. ^{1 5 6 7 8}

How is the Immunotherapy + Chemotherapy treatment for bladder cancer different from other treatments?

This treatment combines immunotherapy and chemotherapy, using a mix of drugs like Bacillus Calmette-Guérin (BCG), Docetaxel, Durvalumab, Gemcitabine, and Tremelimumab, which is unique because it targets the cancer in multiple ways, potentially offering a more comprehensive approach compared to traditional single-drug therapies. ^{3 4 5 9 10}

Research Team

Noah M. Hahn, MD

Principal Investigator

Hoosier Cancer Research Network

Eligibility Criteria

Adults with non-muscle invasive bladder cancer confirmed within the last 60 days, who are generally healthy and have good organ function. They must not have other active cancers (except certain skin or prostate cancers), severe medical conditions, or be pregnant/breastfeeding. Participants need to use contraception and agree to follow study rules.

Inclusion Criteria

Subjects who give a written informed consent obtained according to local guidelines

My bladder cancer is confirmed and not muscle-invasive.

I am 18 years old or older.

Exclusion Criteria

I have another cancer besides non-melanoma skin cancer or prostate cancer that is not actively growing.

I haven't had cancer treatment in the last 4 weeks or still have side effects.

My bladder cancer cannot be removed by surgery and has spread.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive durvalumab monotherapy or combination regimens, including BCG, radiation, or chemotherapy, depending on cohort assignment

6 months

Follow-up

Participants are monitored for safety and effectiveness after treatment, including assessments for recurrence-free survival and adverse events

12 months

Extension

Optional continuation of treatment for further monitoring and assessment of long-term outcomes

12 months

Treatment Details

Interventions

• Bacillus Calmette-Guérin (BCG)
• Docetaxel
• Durvalumab
• External Beam Radiotherapy (EBRT)
• Gemcitabine
• Tremelimumab

Trial Overview The trial is testing Durvalumab alone or in combination with treatments like EBRT, Gemcitabine, Docetaxel, Tremelimumab, and BCG for bladder cancer. It starts with Durvalumab; if safe, it adds other treatments. Patients join different groups based on availability and choice of radiation participation.

Participant Groups

Group I: Phase 2: Cohort 4 Expansion Experimental Treatment 3 Interventions

Durvalumab + Gemcitabine/Intravesical Docetaxel (Gem/Doc) The sequence of administration is flexible to allow for scheduling of both the infusion and intravesical treatments.

Group II: Phase 1: Cohort 6 Experimental Treatment 1 Intervention

Additional Regimens (to be determined)

Group III: Phase 1: Cohort 5 Experimental Treatment 4 Interventions

NOTE: Cohort 5 was abandoned prior to any patients enrolled. Durvalumab + Tremelimumab + Gem/Doc The sequence of administration is flexible to allow for scheduling of both the infusion and intravesical treatments. For the intravenous medications, durvalumab should be administered first followed by tremelimumab.

Group IV: Phase 1: Cohort 4 Experimental Treatment 3 Interventions

Durvalumab + Gemcitabine/Intravesical Docetaxel (Gem/Doc) The sequence of administration is flexible to allow for scheduling of both the infusion and intravesical treatments.

Group V: Phase 1: Cohort 3 Experimental Treatment 2 Interventions

Durvalumab plus External Beam Radiotherapy (EBRT) (BCG re-treatment) - Cross-over to Durvalumab Monotherapy

Group VI: Phase 1: Cohort 2 Experimental Treatment 2 Interventions

Durvalumab plus BCG

Group VII: Phase 1: Cohort 1 Experimental Treatment 1 Intervention

Durvalumab monotherapy

Bacillus Calmette-Guérin (BCG) is already approved in United States, Canada, European Union for the following indications:

Approved in United States as TheraCys for:

• Non-muscle invasive bladder cancer
• Upper tract urothelial carcinoma

Approved in Canada as Immun BCG for:

• Non-muscle invasive bladder cancer

Approved in European Union as TICE BCG for:

• Non-muscle invasive bladder cancer

Who Is Running the Clinical Trial?

Noah Hahn, M.D.

Lead Sponsor

Trials

5

Recruited

280+

Hoosier Cancer Research Network

Collaborator

Trials

69

Recruited

3,800+

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

Sequential intravesical gemcitabine/docetaxel (gem/doce) treatment for patients with BCG-unresponsive high-risk nonmuscle invasive bladder cancer showed promising efficacy, with 6-, 12-, and 24-month high-grade recurrence-free survival rates of 78%, 65%, and 49%, respectively, over a median follow-up of 18 months.

The treatment was generally well-tolerated, with mild to moderate adverse effects reported in 57% of patients, and only a small percentage (6.9%) experiencing treatment delays, indicating that gem/doce could be a safe alternative to radical cystectomy for these patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sequential intravesical gemcitabine/docetaxel provides a durable remission in recurrent high-risk NMIBC following BCG therapy. Yim, K., Melnick, K., Mott, SL., et al.[2023]

Bacillus Calmette-Guérin (BCG) is an effective immunotherapy for treating nonmuscle-invasive urothelial carcinoma, but about 30% of patients may still progress to more severe muscle-invasive disease.

Research is ongoing to enhance the immune response against urothelial carcinoma through various innovative therapies, including recombinant BCG, nonlive Mycobacterium agents, and adoptive T-cell therapies, aiming to improve patient outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Evolving immunotherapy strategies in urothelial cancer. Brancato, SJ., Lewi, K., Agarwal, PK.[2019]

In a study of 35 patients with non-muscle-invasive bladder cancer who experienced BCG treatment failure, sequential intravesical gemcitabine and docetaxel (gem/doce) showed a promising 60% progression-free survival rate at two years, indicating its efficacy as a salvage therapy.

The treatment was generally safe and well-tolerated, with only 37% of patients experiencing adverse events, and a high overall survival rate of 94% at two years, suggesting that gem/doce could be a viable option for patients who are not candidates for radical cystectomy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Salvage therapy for BCG failure with intravesical sequential gemcitabine and docetaxel in patients with recurrent NMIBC. Garneau, CA., Marcotte, N., Lacombe, L., et al.[2023]

In a study comparing the efficacy of BCG plus interferon a-2b (BCG/IFN) and Gemcitabine/Docetaxel (Gem/Doce) in patients with recurrent non-muscle invasive bladder cancer (NMIBC) after one prior BCG course, both treatments showed similar recurrence-free survival rates, with 1-year rates of 61% for BCG/IFN and 68% for Gem/Doce.

Despite differences in patient characteristics, such as age and disease severity, neither treatment was associated with a significantly increased risk of failure, indicating that Gem/Doce can be a viable alternative to BCG/IFN for these patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Intravesical sequential gemcitabine and docetaxel versus bacillus calmette-guerin (BCG) plus interferon in patients with recurrent non-muscle invasive bladder cancer following a single induction course of BCG. Steinberg, RL., Packiam, VT., Thomas, LJ., et al.[2022]

Intravesical gemcitabine and docetaxel therapy shows promising efficacy for high-risk nonmuscle invasive bladder cancer, with 1-year and 2-year recurrence-free survival rates of 86% and 84% in BCG-naive patients, and 80%, 66%, and 51% in BCG-unresponsive patients at 6 months, 1 year, and 2 years, respectively.

The treatment is generally well tolerated, with only 2.3% of patients unable to complete induction therapy and 6.9% experiencing delays or dose reductions due to adverse events, suggesting it could be a viable alternative to BCG therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sequential intravesical gemcitabine and docetaxel therapy in patients with nonmuscle invasive bladder cancer: a systematic review and meta-analysis. Kawada, T., Yanagisawa, T., Araki, M., et al.[2023]

In a study of 60 patients with non-muscle invasive bladder cancer (NMIBC), the combination of intravesical gemcitabine and docetaxel (Gem/Doce) demonstrated better quality of life outcomes compared to the traditional BCG treatment after 6 months of maintenance therapy.

The Gem/Doce treatment also resulted in fewer side effects than BCG, suggesting it could be a safer and effective alternative for NMIBC patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Quality of Life, Efficacy, and Safety of Sequential Intravesical Gemcitabine + Docetaxel versus BCG for Non-Muscle Invasive Urinary Bladder Cancer: A Pilot Study. Pareek, T., Parmar, K., Sharma, AP., et al.[2022]

In a study of 35 patients with BCG failure, intravesical gemcitabine demonstrated a 60% success rate in preventing tumor recurrences over an 18-month follow-up period, indicating its efficacy as an alternative treatment.

The treatment was well tolerated with low and mild adverse events, suggesting that gemcitabine is a safe option for patients who do not respond to BCG therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Intravesicle gemcitabine in management of BCG refractory superficial TCC of urinary bladder-our experience. Mohanty, NK., Nayak, RL., Vasudeva, P., et al.[2022]

In a study of 592 patients receiving intravesical therapy for non-muscle invasive bladder cancer, 78% reported side effects, with bladder symptoms and fatigue being the most common.

Reduced-dose BCG was associated with the lowest prevalence and severity of fatigue, while gemcitabine led to the highest prevalence of body aches, indicating significant differences in tolerability among the treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparison of Side Effects and Tolerability Between Intravesical Bacillus Calmette-Guerin, Reduced-Dose BCG and Gemcitabine for Non-Muscle Invasive Bladder Cancer. Kuperus, JM., Busman, RD., Kuipers, SK., et al.[2022]

Immunotherapy with Bacillus Calmette Guerin (BCG) is an effective long-term treatment for high-grade superficial bladder cancer, with a 35% recurrence rate and 74% of patients alive after a median follow-up of 71 months.

The study suggests that BCG therapy is a viable conservative option, as only 9% of patients required cystectomy, indicating that aggressive surgical intervention may not be necessary as a first-line treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

High grade superficial (G3t1) transitional cell carcinoma of the bladder treated with intravesical Bacillus Calmette-Guerin (BCG). Pansadoro, V., Emiliozzi, P., depaula, F., et al.[2006]

In a study involving 236 patients with recurrent bladder tumors, monthly BCG treatment was found to be significantly more effective than a combination of interferon-alpha2b and BCG, showing better results in time to initial recurrence and overall recurrence rates.

The treatment regimen, which included initial mitomycin C followed by monthly BCG for up to a year, was well tolerated with limited side effects, demonstrating its efficacy in controlling bladder tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Weekly mitomycin C followed by monthly bacillus Calmette-Guerin or alternating monthly interferon-alpha2B and bacillus Calmette-Guerin for prophylaxis of recurrent papillary superficial bladder carcinoma. Kaasinen, E., Rintala, E., Pere, AK., et al.[2018]

References

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

Sequential intravesical gemcitabine/docetaxel provides a durable remission in recurrent high-risk NMIBC following BCG therapy. [2023]

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

Evolving immunotherapy strategies in urothelial cancer. [2019]

3. Canada pubmed.ncbi.nlm.nih.gov

Salvage therapy for BCG failure with intravesical sequential gemcitabine and docetaxel in patients with recurrent NMIBC. [2023]

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

Intravesical sequential gemcitabine and docetaxel versus bacillus calmette-guerin (BCG) plus interferon in patients with recurrent non-muscle invasive bladder cancer following a single induction course of BCG. [2022]

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

Sequential intravesical gemcitabine and docetaxel therapy in patients with nonmuscle invasive bladder cancer: a systematic review and meta-analysis. [2023]

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

Quality of Life, Efficacy, and Safety of Sequential Intravesical Gemcitabine + Docetaxel versus BCG for Non-Muscle Invasive Urinary Bladder Cancer: A Pilot Study. [2022]

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

Intravesicle gemcitabine in management of BCG refractory superficial TCC of urinary bladder-our experience. [2022]

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

Comparison of Side Effects and Tolerability Between Intravesical Bacillus Calmette-Guerin, Reduced-Dose BCG and Gemcitabine for Non-Muscle Invasive Bladder Cancer. [2022]

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

High grade superficial (G3t1) transitional cell carcinoma of the bladder treated with intravesical Bacillus Calmette-Guerin (BCG). [2006]

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

Weekly mitomycin C followed by monthly bacillus Calmette-Guerin or alternating monthly interferon-alpha2B and bacillus Calmette-Guerin for prophylaxis of recurrent papillary superficial bladder carcinoma. [2018]