Multiple Drugs for Bladder Cancer

(BISCAY Trial)

Recruiting at 22 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: AstraZeneca

Must not be taking: Immunosuppressives, CYP3A4 inhibitors

Disqualifiers: Autoimmune disease, IBD, severe disease, others

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

Compensation: Varies

Number of Visits: 94

Duration: up to 12 months

117 Participants Needed

Trial Summary

What is the purpose of this trial?

This is an open label, multi-drug, biomarker-directed, multi-centre, multi-arm, Phase 1b study in patients with muscle invasive bladder cancer (MIBC) (urothelial) who have progressed on prior treatment. This study is modular in design, allowing evaluation of the safety, tolerability, pharmacokinetics and anti-tumour activity of multiple agents as monotherapy and as combinations of different novel anti-cancer agents. The study will consist of a number of study modules (sub-studies), each evaluating the safety and tolerability of a specific agent or combination.

Will I have to stop taking my current medications?

The trial requires that you stop taking certain medications before participating. Specifically, you must not have had immunotherapy, chemotherapy, anticancer agents, or radiotherapy within 4 weeks, and you cannot be on concurrent chemotherapy, immunotherapy, biologic, or hormonal therapy. Additionally, certain modules have specific restrictions on medications that affect liver enzymes or are used for other treatments.

What data supports the effectiveness of the drugs used in the Multiple Drugs for Bladder Cancer trial?

The research mentions that atezolizumab, a drug similar to some in the trial, has shown antitumor activity in patients with advanced bladder cancer. Additionally, the study on systemic therapy highlights the potential of immunotherapies, like PD-1/PD-L1 antibodies, which are related to some drugs in the trial, in treating bladder cancer. ^{1 2 3 4 5}

What makes the drug combination AZD1775, AZD4547, AZD9150, MEDI4736, Olaparib, Selumetinib, and Vistusertib unique for bladder cancer?

This drug combination is unique because it targets specific genetic mutations and pathways (like FGFR2, EGFR/HER2, VEGF, MET, and PI3/AKT/mTOR) in bladder cancer, offering a personalized treatment approach rather than the traditional one-size-fits-all chemotherapy. This approach aims to improve outcomes by matching the treatment to the tumor's genetic profile, which is a novel strategy compared to standard platinum-based therapies. ^{1 2 6 7 8}

Research Team

Hendrik-Tobias Arkenau, MD

Principal Investigator

Sarah Cannon Research Institute, UK

Thomas Powles, MBBS, MRCP, MD

Principal Investigator

Barts Cancer Center, Barts and The London School of Medicine and Denistry

Eligibility Criteria

This trial is for adults over 25 with muscle invasive bladder cancer who've had prior treatment fail within a year. They must have at least one measurable lesion, be in good physical condition (WHO performance status 0-1), and not have certain genetic mutations or severe organ dysfunction. Participants need to use effective contraception during and after the study for specified periods.

Inclusion Criteria

WHO perf. status 0-1

My treatment is in the 2nd or 3rd round.

Hgb ≥10 g/dL

Exclusion Criteria

You have been diagnosed with an autoimmune disease, inflammatory bowel disease (IBD), primary immunodeficiency, or have had an organ transplant that requires medication to suppress your immune system within the past two years.

I haven't taken immunosuppressive drugs in the last 28 days.

My brain or spinal cancer is stable and I haven't needed steroids for 4 weeks.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive various combinations of MEDI4736 and other agents based on genomic alterations in a modular design

up to 12 months

Weekly visits for adverse event assessment and every 4 weeks for treatment administration

Follow-up

Participants are monitored for safety and effectiveness after treatment

90 days post-treatment

Visits at study discontinuation and 90 days after end of treatment

Open-label extension (optional)

Participants may opt into continuation of treatment long-term if they benefit from the therapy

Long-term

Treatment Details

Interventions

• AZD1775
• AZD4547
• AZD9150
• MEDI4736
• Olaparib
• Selumetinib
• Vistusertib

Trial Overview The trial tests multiple drugs (MEDI4736, Olaparib, AZD1775, etc.) alone or in combination against bladder cancer. It's an early-phase study assessing safety, tolerability, how the body processes these drugs, and their effectiveness against tumors.

Participant Groups

Group I: Module G: MEDI4736 + Selumetinib Experimental Treatment 2 Interventions

Group II: Module F: MEDI4736 (durvaluamb) + AZD9150 Experimental Treatment 2 Interventions

AZD9150 will be given as monotherapy on Days -7, -5, and -3 of a one week lead-in period. Combination dosing with IV AZD9150 followed by IV MEDI4736 (durvalumab) begins on Day 1 of each 28 day cycle. Thereafter AZD9150 is given weekly and MEDI4736 is given once every 4 weeks.

Group III: Module E: MEDI4736 (durvalumab) + Vistusertib Experimental Treatment 2 Interventions

MEDI4736 (durvalumab) will be given by IV infusion once every 4 weeks. Vistusertib will be given orally twice per day on an intermittent schedule (2 days on, 5 days off).

Group IV: Module D: MEDI4736 (durvalumab) monotherapy Experimental Treatment 1 Intervention

MEDI 4736 (durvalumab) will be given by IV infusion once every 4 weeks.

Group V: Module C: MEDI4736 (durvaluamb) + AZD1775 Experimental Treatment 2 Interventions

MEDI4736 (durvalumab) will be given by IV infusion once every 4 weeks. AZD1775 will be given orally in approximate 12 hour intervals over 3 days (6 doses) on Days 1-3, 8-10, and 15-17 of 28 day cycles.

Group VI: Module B: MEDI4736 (durvalumab) + Olaparib Experimental Treatment 2 Interventions

MEDI4736 (durvalumab) will be given by IV infusion once every 4 weeks. Olaparib will be given orally twice daily.

Group VII: Module A: MEDI4736 (durvalumab) + AZD4547 Experimental Treatment 2 Interventions

AZD4547 will be given orally twice daily until disease progression. Patients will also receive MEDI 4736 (durvalumab) by IV infusion once every 4 weeks.

Group VIII: Module A: AZD4547 Monotherapy Experimental Treatment 1 Intervention

AZD4547 will be given orally twice daily until disease progression. Patients who receive AZD4547 as monotherapy will have the option to cross over to durvalumab as monotherapy at the point of objective progression, as long as the following criteria are met: * The investigator believes it is in the patient's interest to receive durvalumab; * The patient consents to the continued treatment; * It is clinically appropriate for the patient to continue on durvalumab treatment; * The patient satisfies the key eligibility criteria for receiving durvalumab treatment.

Who Is Running the Clinical Trial?

AstraZeneca

Lead 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

In a study of 115 patients with metastatic urothelial carcinoma treated with atezolizumab (ATZ) after failing first-line chemotherapy, the objective response rate was 28.7%, indicating that ATZ is effective in this patient population.

The treatment was well tolerated, with 98% of patients experiencing adverse events, but only 21.2% had severe (grade 3-4) treatment-related adverse events, suggesting a manageable safety profile similar to previous clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Atezolizumab in Patients with Metastatic Urothelial Carcinoma Who Have Progressed After First-line Chemotherapy: Results of Real-life Experiences. Tural, D., Ölmez, ÖF., Sümbül, AT., et al.[2022]

Neoadjuvant chemotherapy has been shown to improve overall survival in patients with locally advanced muscle-invasive bladder cancer, but its use in clinical practice remains low due to ongoing controversies regarding adjuvant chemotherapy.

Recent advancements include the approval of atezolizumab, a checkpoint inhibitor, for metastatic bladder cancer, alongside other promising therapies targeting mutational signatures, such as VEGF and HER2-directed agents.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Systemic therapy in muscle-invasive and metastatic bladder cancer: current trends and future promises. Aragon-Ching, JB., Trump, DL.[2017]

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]

Cisplatin and gemcitabine are the most commonly used first-line treatment for advanced bladder cancer, showing comparable efficacy and better tolerance than the traditional four-drug regimen, especially for patients who cannot receive cisplatin due to comorbidities.

Recent advancements in molecular characterization of advanced bladder cancer have revealed actionable genetic alterations, leading to the development of targeted therapies that may significantly improve treatment outcomes by matching specific mutations with appropriate treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The role of genomics in the management of advanced bladder cancer. Guancial, EA., Rosenberg, JE.[2018]

References

1. Netherlands pubmed.ncbi.nlm.nih.gov

Atezolizumab in Patients with Metastatic Urothelial Carcinoma Who Have Progressed After First-line Chemotherapy: Results of Real-life Experiences. [2022]

2. England pubmed.ncbi.nlm.nih.gov

Systemic therapy in muscle-invasive and metastatic bladder cancer: current trends and future promises. [2017]

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

Pazopanib synergizes with docetaxel in the treatment of bladder cancer cells. [2021]

4. England pubmed.ncbi.nlm.nih.gov

Integrative multi-omics analysis of muscle-invasive bladder cancer identifies prognostic biomarkers for frontline chemotherapy and immunotherapy. [2022]

5. Germany pubmed.ncbi.nlm.nih.gov

New drugs and new approaches for the treatment of metastatic urothelial cancer. [2022]

6. England pubmed.ncbi.nlm.nih.gov

Therapy of metastatic bladder carcinoma. [2020]

7. England pubmed.ncbi.nlm.nih.gov

Molecular classification of patients with NMIBC predicts the efficacy of intravesical chemotherapy with pirarubicin, pharmorubicin and gemcitabine-immunohistochemistry-based classification. [2022]

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

The role of genomics in the management of advanced bladder cancer. [2018]