Open-Label, Randomised, Multi-Drug, Biomarker-Directed, Phase 1b Study in Pts w/ Muscle Invasive Bladder Cancer

NCT02546661 | Active Not Recruiting Phase 1 FDA Drug

• 4 other identifiers: D2615C00001GU 118BISCAY2015-002228-25
• Study Type: interventional
• Target: 117
• Locations: 5 countries
• Sites: 27

Brief Summary

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.

Conditions

Muscle Invasive Bladder Cancer

Keywords

Durvalumab; Olaparib; Vistusertib; Selumetinib; Muscle invasive bladder cancer; MIBC; BISCAY; MEDI4736; AZD4547; AZD2281; AZD1775; AZD2014; AZD9150; AZD6244

Outcome Measures

Primary Outcomes (17)

• Module A: The frequency and nature of adverse events related to AZD4547 monotherapy.

  The frequency and nature of adverse events will be assessed in order to determine the safety and tolerability of AZD4547 monotherapy given orally to selected patients with MIBC who have progressed following prior therapy.

  Adverse events will be assessed at each clinic visit, and at study discontinuation and 90 days after the end of treatment. Clinic visits are generally scheduled weekly.

• Module A: The frequency and nature of adverse events related to the combination of intravenous MEDI4736 (durvalumab) and oral AZD4547.

  The frequency and nature of adverse events will be assessed in order to determine the safety and tolerability of MEDI4736 (durvalumab) given intravenously in combination with AZD4547 given orally to selected patients with MIBC who have progressed following prior therapy.

  Adverse events will be assessed at each clinic visit, and at study discontinuation and 90 days after the end of treatment. Clinic visits are generally scheduled weekly.

• Module B: The frequency and nature of adverse events related to the combination of intravenous MEDI4736 (durvalumab) and oral olaparib.

  The frequency and nature of adverse events will be assessed in order to determine the safety and tolerability of MEDI4736 (durvalumab) given intravenously in combination with olaparib given orally to selected patients with MIBC who have progressed following prior therapy.

  Adverse events will be assessed at each clinic visit, and at study discontinuation and 90 days after the end of treatment. Clinic visits are generally scheduled weekly.

• Module C: The frequency and nature of adverse events related to intravenous MEDI4736 (durvalumab) when given in combination with oral AZD1775.

  The frequency and nature of adverse events will be assessed in order to determine the safety and tolerability of MEDI4736 (durvalumab) given intravenously in combination with AZD1775 given orally to selected patients with MIBC who have progressed following prior therapy.

  Adverse events will be assessed at each clinic visit, and at study discontinuation and 90 days after the end of treatment. Clinic visits are generally scheduled weekly.

• Module D: The frequency and nature of adverse events related to intravenous MEDI4736 (durvalumab) monotherapy.

  The frequency and nature of adverse events will be assessed in order to determine the safety and tolerability of MEDI4736 (durvalumab) monotherapy given intravenously to selected patients with MIBC who have progressed following prior therapy.

  Adverse events will be assessed at each clinic visit, and at study discontinuation and 90 days after the end of treatment. Clinic visits are generally scheduled weekly.

• Module E: The frequency and nature of adverse events related to intravenous MEDI4736 (durvalumab) when given in combination with oral vistusertib.

  The frequency and nature of adverse events will be assessed in order to determine the safety and tolerability of MEDI 4736 (durvalumab) given intravenously in combination with vistusertib given orally to selected patients with MIBC who have progressed following prior therapy.

  Adverse events will be assessed at each clinic visit, and at study discontinuation and 90 days after the end of treatment. Clinic visits are generally scheduled weekly.

• Module F: The frequency and nature of adverse events related to the combination of intravenous MEDI4736 (durvalumab) and intravenous AZD9150.

  The frequency and nature of adverse events will be assessed in order to determine the safety and tolerability of intravenous MEDI4736 (durvalumab) in combination with intravenous AZD9150 in selected patients with MIBC who have progressed following prior therapy.

  Adverse events will be assessed at each clinic visit, and at study discontinuation and 90 days after the end of treatment. Clinic visits are generally scheduled weekly.

• Module G: The frequency and nature of adverse events related to intravenous MEDI4736 (durvalumab) when given in combination with oral selumetinib.

  The frequency and nature of adverse events will be assessed in order to determine the safety and tolerability of MEDI 4736 (durvalumab) given intravenously in combination with selumetinib given orally to selected patients with MIBC who have progressed following prior therapy.

  Adverse events will be assessed at each clinic visit, and at study discontinuation and 90 days after the end of treatment. Clinic visits are generally scheduled weekly.

• All Modules: Change from baseline in clinical chemistry parameters.

  Changes from baseline in clinical chemistry parameters will be assessed in order to determine the safety and tolerability of the drug regimen chosen in the sub study module for patients with MIBC who have progressed following prior therapy.

  Days 1, 8, 15, and 22 of Cycle 1, Days 1, 15, and 22 of Cycles 2 and 3 and every 4 weeks thereafter, and at discontinuation.

• All Modules: Change from baseline in haematology parameters.

  Changes from baseline in haemotology parameters will be assessed in order to determine the safety and tolerability of the drug regimen chosen in the sub study module for patients with MIBC who have progressed following prior therapy.

  Days 1, 8, 15, and 22 of Cycle 1, Days 1, 15, and 22 of Cycles 2 and 3 and every 4 weeks thereafter, and at discontinuation.

• All Modules: Change from baseline in urinalysis results.

  Changes from baseline in urinalysis findings will be assessed in order to determine the safety and tolerability of the drug regimen chosen in the sub study module for patients with MIBC who have progressed following prior therapy.

  Days 1, 8, 15, and 22 of Cycle 1, Days 1, 15, and 22 of Cycles 2 and 3 and every 4 weeks thereafter, and at discontinuation.

• All Modules: Change from baseline in vital signs.

  Changes from baseline in vital signs will be assessed in order to determine the safety and tolerability of the drug regimen chosen in the sub study module for patients with MIBC who have progressed following prior therapy.

  Day 1 of Cycles 1, 2, 3, and 4 and every 4 weeks therafter, and at discontinuation.

• All Modules: Change from baseline in physical examination findings.

  Changes from baseline in physical examination findings will be assessed in order to determine the safety and tolerability of the drug regimen chosen in the sub study module for patients with MIBC who have progressed following prior therapy.

  Day 1 of Cycles 1, 2, 3, and 4 and every 4 weeks therafter, and at discontinuation.

• All Modules: Change from baseline in ECG findings.

  Changes from baseline in ECG findings will be assessed in order to determine the safety and tolerability of the drug regimen chosen in the sub study module for patients with MIBC who have progressed following prior therapy.

  ECGs will be collected at screening, Day 1, Cycle 1and then Day 1 of each cycle from Cycle 2 onwards.

• All Modules: Change from baseline in ejection fraction determined by assessing ECHO/MUGA scans.

  Changes from baseline in ejection fraction determined by assessing ECHO/MUGA scans will be assessed in order to determine the safety and tolerability of the drug regimen chosen in the sub study module for patients with MIBC who have progressed following prior therapy.

  Ejection fraction will be measured at screening, on Day 1, Cycle 1, and every 12 weeks thereafter (relative to the first dose of study drug) up to Cycle 7, and then every 16 weeks thereafter.

• All Modules: Change from baseline in coagulation parameters

  Changes from baseline in coagulation parameters will be assessed in order to determine the safety and tolerability of the drug regimen chosen in the sub study module for patients with MIBC who have progressed following prior therapy.

  Coagulation parameters will be measured at screening, on Day 1, Cycle 1, and every 12 weeks thereafter (relative to the first dose of study drug) up to Cycle 7, and then every 16 weeks thereafter.

• All Modules: Change from baseline in lipid profile

  Changes from baseline in lipid profile will be assessed in order to determine the safety and tolerability of the drug regimen chosen in the sub study module for patients with MIBC who have progressed following prior therapy.

  Lipid profile will be measured at screening, on Day 1, Cycle 1, and every 12 weeks thereafter (relative to the first dose of study drug) up to Cycle 7, and then every 16 weeks thereafter.

Secondary Outcomes (16)

• Objective response rate (ORR)

  16 weeks and 52 weeks

• Disease control rate (DCR)

  16 weeks and 52 weeks

• Progression free survival (PFS)

  up to 12 months

• Duration of response (DoR)

  up to 12 months

• Overall survival (OS) rate at 1 year

  1 year

Other Outcomes (5)

• Mutation status of cancer associated genes in circulating tumour DNA (ctDNA).

  Blood samples for assessment of ctDNA will be collected at screening, on Day 1 of Cycles 1, 2, 3, and 4 (up to 91 days) and at disease progression.

• Biomarker Analysis of Blood and Tissue

  Up to 12 months

• Correlation of biomarkers to response and/or development of cancer

  Throught out study (up to 18 months)

Study Arms (8)

Module A: AZD4547 Monotherapy

EXPERIMENTAL

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.

Drug: AZD4547

Module A: MEDI4736 (durvalumab) + AZD4547

EXPERIMENTAL

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

Drug: AZD4547; Drug: MEDI4736

Module B: MEDI4736 (durvalumab) + Olaparib

EXPERIMENTAL

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

Drug: MEDI4736; Drug: Olaparib

Module C: MEDI4736 (durvaluamb) + AZD1775

EXPERIMENTAL

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.

Drug: MEDI4736; Drug: AZD1775

Module D: MEDI4736 (durvalumab) monotherapy

EXPERIMENTAL

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

Drug: MEDI4736

Module E: MEDI4736 (durvalumab) + Vistusertib

EXPERIMENTAL

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).

Drug: MEDI4736; Drug: Vistusertib

Module F: MEDI4736 (durvaluamb) + AZD9150

EXPERIMENTAL

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.

Drug: MEDI4736; Drug: AZD9150

Module G: MEDI4736 + Selumetinib

EXPERIMENTAL

Drug: MEDI4736; Drug: Selumetinib

Interventions

AZD9150 DRUG

MEDI4736 (durvalumab) + AZD9150

Module F: MEDI4736 (durvaluamb) + AZD9150

Selumetinib DRUG

MEDI4736 (durvalumab) + Selumetinib

Module G: MEDI4736 + Selumetinib

AZD4547 DRUG

AZD4547 Monotherapy vs. MEDI4736 (durvalumab) + AZD4547 1:1 Randomization.

Module A: AZD4547 Monotherapy; Module A: MEDI4736 (durvalumab) + AZD4547

MEDI4736 DRUG

MEDI4736

Also known as: Durvalumab

Module A: MEDI4736 (durvalumab) + AZD4547; Module B: MEDI4736 (durvalumab) + Olaparib; Module C: MEDI4736 (durvaluamb) + AZD1775; Module D: MEDI4736 (durvalumab) monotherapy; Module E: MEDI4736 (durvalumab) + Vistusertib; Module F: MEDI4736 (durvaluamb) + AZD9150; Module G: MEDI4736 + Selumetinib

Olaparib DRUG

MEDI4736 (durvalumab) + Olaparib

Also known as: Lynparza

Module B: MEDI4736 (durvalumab) + Olaparib

AZD1775 DRUG

MEDI4736 (durvalumab) + AZD1775

Module C: MEDI4736 (durvaluamb) + AZD1775

Vistusertib DRUG

MEDI4736 (durvalumab) + Vistusertib

Module E: MEDI4736 (durvalumab) + Vistusertib

Eligibility Criteria

• Age: 18 Years - 130 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Metastatic MIBC
• nd/3rd line
• Failed adjuvant/neo-adjuvant chemotherapy \<1 yr
• lesion ≥10 mm at baseline in the longest diameter suitable for accurate repeated measurement
• WHO perf. status 0-1
• For Module A:
• M/F ≥25
• Confirmation of FGFR3 mutation or FGFR fusion
• For Module B:
• Hgb ≥10 g/dL
• Deleterious mutation, deletion or truncation in any HRR genes
• For Module C:
• \. Tumour harbours a deletion or inactivating mutation of the CDKN2A or RB1 genes and/or amplification of CCNE1, MYC, MYCL or MYCN genes
• For Module E:
• \. Contraception must be sustained throughout treatment with vistusertib and 16 wks after last dose

You may not qualify if:

• Immunotherapy, chemotherapy, anticancer agents, radiotherapy \<4 weeks, or radiotherapy for palliation \<2 weeks, any study drugs \<30 days.
• Major surgery \<4 weeks
• Unresolved toxicities from prior therapy
• Concurrent chemotherapy, immunotherapy, biologic or hormonal therapy
• Immunosuppressive drugs \<28 days
• Any of the following: Autoimmune disease ≤2 yr; IBD; primary immunodeficiency; organ transplant requiring immunosuppressives
• Spinal cord compression or brain metastases, treated and stable \& not requiring steroids for at least 4 weeks
• Severe or uncontrolled systemic disease
• Any of the following: Mean QTc ≥470 ms; abnormalities in resting ECG; factors that increase the risk of QTc prolongation or arrhythmia; uncontrolled hyper/hypotension; LVEF \<55%; atrial fibrillation; NYHA Grade II-IV; severe valvular disease; uncontrolled angina; stroke/TIA \<6 months; acute coronary syndrome \<6 months
• Any of the following laboratory values: ANC \<1.5x10(exp9)/L; Platelets \<100x10(exp9)/L; Hgb \<9.0 g/dL; ALT \>2.5xULN or \>5xULN with liver mets; Total bilirubin \>1.5 times ULN or with Gilbert's disease ≥2×ULN; Creatinine \>1.5xULN concurrent with creatinine clearance \<50 mL/min; Corrected Ca \>ULN, PO4 \>ULN
• Active infection including tuberculosis, hepatitis B (HBV), hepatitis C (HCV), or human immunodeficiency virus. Patients with a past or resolved HBV infection are eligible. Patients positive for HCV antibody are eligible only if polymerase chain reaction is negative for HCV RNA.
• Live attenuated vaccination \<30 days
• For Module A:
• Prior exposure to: Nitrosourea or mitomycin C \<6 weeks; any agent with FGFR inhibition as its primary pharmacology; AZD4547; potent inhibitors/inducers of CYP3A4, inhibitors of CYP2D6 or substrates of CYP3A4 \<2 wks
• Ophthalmological criteria: RPED; laser treatment or intraocular injection for macular degeneration; age-related macular degeneration; retinal vein occlusion; retinal degenerative disease; other clinically relevant chorioretinal defect

Sponsors & Collaborators

• AstraZeneca: lead

Study Sites (27)

Research Site

Los Angeles, California, 90095, United States

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Research Site

New Haven, Connecticut, 06510, United States

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Fort Myers, Florida, 33901, United States

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New York, New York, 10029, United States

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New York, New York, 10032, United States

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New York, New York, 10116, United States

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Cleveland, Ohio, 44195, United States

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Nashville, Tennessee, 37203, United States

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Edmonton, Alberta, T6G 1Z2, Canada

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Vancouver, British Columbia, V5Z 4E6, Canada

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Toronto, Ontario, M5G 2M9, Canada

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Montreal, Quebec, H3T 1E2, Canada

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Bordeaux, 33075, France

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Caen, 14000, France

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Lyon, 69373, France

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Marseille, 13273, France

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Saint-Herblain, 44805, France

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Toulouse, 31100, France

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Badalona, 08003, Spain

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Barcelona, 08035, Spain

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Barcelona, 08041, Spain

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Madrid, 28040, Spain

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Glasgow, G12 0YN, United Kingdom

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London, EC1M 6BQ, United Kingdom

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London, W1G 6AD, United Kingdom

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Manchester, M20 4BX, United Kingdom

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Southampton, SO16 6YD, United Kingdom

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Related Publications (2)

• Powles T, Carroll D, Chowdhury S, Gravis G, Joly F, Carles J, Flechon A, Maroto P, Petrylak D, Rolland F, Cook N, Balar AV, Sridhar SS, Galsky MD, Grivas P, Ravaud A, Jones R, Cosaert J, Hodgson D, Kozarewa I, Mather R, McEwen R, Mercier F, Landers D. An adaptive, biomarker-directed platform study of durvalumab in combination with targeted therapies in advanced urothelial cancer. Nat Med. 2021 May;27(5):793-801. doi: 10.1038/s41591-021-01317-6. Epub 2021 May 3.

  PMID: 33941921 BACKGROUND

• Maia MC, Salgia M, Pal SK. Harnessing cell-free DNA: plasma circulating tumour DNA for liquid biopsy in genitourinary cancers. Nat Rev Urol. 2020 May;17(5):271-291. doi: 10.1038/s41585-020-0297-9. Epub 2020 Mar 17.

  PMID: 32203306 DERIVED

Related Links

• Clinical Study Protocol Redacted
• Statistical Analysis Plan Redacted
• CSR Synopsis Redacted
• An adaptive, biomarker-directed platform study of durvalumab in combination with targeted therapies in advanced urothelial cancer

MeSH Terms

Interventions

AZD4547; durvalumab; olaparib; adavosertib; vistusertib; danvatirsen; AZD 6244

Study Officials

• Thomas Powles, MBBS, MRCP, MD

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

  PRINCIPAL INVESTIGATOR

• Hendrik-Tobias Arkenau, MD, PhD

  Sarah Cannon Research Institute, UK

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 27, 2015
• First Posted: September 11, 2015
• Study Start: December 28, 2016
• Primary Completion: March 18, 2020
• Study Completion: January 30, 2026
• Last Updated: December 29, 2025

Record last verified: 2025-12

Data Sharing

• IPD Sharing: Will share
• Time Frame: AstraZeneca will meet or exceed data availability as per the commitments made to the EFPIA Pharma Data Sharing Principles. For details of our timelines, please rerefer to our disclosure commitment at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
• Access Criteria: When a request has been approved AstraZeneca will provide access to the de-identified individual patient-level data in an approved sponsored tool . Signed Data Sharing Agreement (non-negotiable contract for data accessors) must be in place before accessing requested information. Additionally, all users will need to accept the terms and conditions of the SAS MSE to gain access. For additional details, please review the Disclosure Statements at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.

Locations

ES (4); GB (5); FR (6); US (8); CA (4)