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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02546661
Recruitment Status : Active, not recruiting
First Posted : September 11, 2015
Last Update Posted : July 23, 2020
Sponsor:
Information provided by (Responsible Party):
AstraZeneca

Tracking Information
First Submitted Date  ICMJE August 27, 2015
First Posted Date  ICMJE September 11, 2015
Last Update Posted Date July 23, 2020
Actual Study Start Date  ICMJE October 3, 2016
Actual Primary Completion Date March 18, 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: March 25, 2019)
  • Module A: The frequency and nature of adverse events related to AZD4547 monotherapy. [ Time Frame: 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. ]
    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.
  • Module A: The frequency and nature of adverse events related to the combination of intravenous MEDI4736 (durvalumab) and oral AZD4547. [ Time Frame: 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. ]
    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.
  • Module B: The frequency and nature of adverse events related to the combination of intravenous MEDI4736 (durvalumab) and oral olaparib. [ Time Frame: 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. ]
    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.
  • Module C: The frequency and nature of adverse events related to intravenous MEDI4736 (durvalumab) when given in combination with oral AZD1775. [ Time Frame: 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. ]
    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.
  • Module D: The frequency and nature of adverse events related to intravenous MEDI4736 (durvalumab) monotherapy. [ Time Frame: 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. ]
    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.
  • Module E: The frequency and nature of adverse events related to intravenous MEDI4736 (durvalumab) when given in combination with oral vistusertib. [ Time Frame: 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. ]
    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.
  • Module F: The frequency and nature of adverse events related to the combination of intravenous MEDI4736 (durvalumab) and intravenous AZD9150. [ Time Frame: 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. ]
    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.
  • Module G: The frequency and nature of adverse events related to intravenous MEDI4736 (durvalumab) when given in combination with oral selumetinib. [ Time Frame: 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. ]
    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.
  • All Modules: Change from baseline in clinical chemistry parameters. [ Time Frame: 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. ]
    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.
  • All Modules: Change from baseline in haematology parameters. [ Time Frame: 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. ]
    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.
  • All Modules: Change from baseline in urinalysis results. [ Time Frame: 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. ]
    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.
  • All Modules: Change from baseline in vital signs. [ Time Frame: Day 1 of Cycles 1, 2, 3, and 4 and every 4 weeks therafter, and at discontinuation. ]
    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.
  • All Modules: Change from baseline in physical examination findings. [ Time Frame: Day 1 of Cycles 1, 2, 3, and 4 and every 4 weeks therafter, and at discontinuation. ]
    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.
  • All Modules: Change from baseline in ECG findings. [ Time Frame: ECGs will be collected at screening, Day 1, Cycle 1and then Day 1 of each cycle from Cycle 2 onwards. ]
    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.
  • All Modules: Change from baseline in ejection fraction determined by assessing ECHO/MUGA scans. [ Time Frame: 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. ]
    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.
  • All Modules: Change from baseline in coagulation parameters [ Time Frame: 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. ]
    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.
  • All Modules: Change from baseline in lipid profile [ Time Frame: 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. ]
    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.
Original Primary Outcome Measures  ICMJE
 (submitted: September 9, 2015)
  • Number of Patients Experiencing Adverse Events [ Time Frame: Up to 28 Days ]
    A Safety Review Committee (SRC) will consider the data from the combination arm (AZD4547 plus MEDI4736 IV infusion every 4 weeks) when patients have been treated for at least 28 days or less if ≥2 in 6 patients experience a dose limiting toxicity (DLT) (Cohort 1). If 1 in 6 patients has a DLT then the next 11 patients allocated to the combination arm will receive the same doses. If ≥2 in 6 patients have a DLT then the next 6 patients on the combination arm will receive a dose reduction (Cohort 2). If 1 in 6 patients in Cohort 2 has a DLT, then the next 11 patients allocated to the combination arm will receive the same doses. If ≥ 2 in 6 patients in Cohort 2 have a DLT then no more patients will be entered into the AZD4547 and MEDI4736 combination arm.
  • Change from Baseline in Clinical Chemistry Values [ Time Frame: Up to 28 Days ]
    The following chemistry parameters will be assessed: Albumin Alanine aminotransferase (ALT) Aspartate aminotransferase (AST) Alkaline phosphatase Bilirubin, total Calcium, corrected Creatinine Glucose (fasting on PK days only) Magnesium Phosphate Potassium Sodium Urea nitrogen Free T3 Free T4 Thyroid stimulating hormone (TSH) The investigator will make an assessment of the available results with regard to clinically relevant abnormalities.
  • Change from Baseline in Urinalysis [ Time Frame: Up to 28 Days ]
    The following urinalysis parameters will be assessed by dipstick: Glucose Protein Blood
  • Change from Baseline in Haemotology Values [ Time Frame: Up to 28 Days ]
    The following haematology values will be assessed: Haemoglobin Leukocytes Haematocrit Red Blood Cell (RBC) count Absolute leukocyte differential count: Neutrophils Lymphocytes Monocytes Basophils Eosinophils Platelet count Reticulocytes
  • Change from Baseline in Physical Examination [ Time Frame: Up to 28 Days ]
    A complete physical examination will be performed on Day 1 of each treatment cycle and will include an assessment of the following: General Appearance Respiratory Cardiovascular Abdomen Skin Head and neck (including ears, eyes, nose, and throat) Lymph nodes Thyroid Musculoskeletal (including spine and extremities) Neurological
  • Change from Baseline in World Health Organization (WHO) Performance Status [ Time Frame: Up to 28 Days ]
    Performance status will be assessed on Day 1 of each treatment cycle according to WHO criteria as follows: 0 = Fully active, able to carry out all pre-disease activities without restrictions
    1. = Restricted in physically strenuous activity but ambulatory and able to carry out any work of a light or sedentary nature e.g.., light housework or office work
    2. = Ambulatory and capable of self-care, but unable to carry out any work activities. Up and about more than 50% of waking hours.
    3. = Capable of only limited self-care, confined to bed or chair more than 50% of waking hours.
    4. = Completely disabled, cannot carry on self-care, totally confined to bed or chair.
  • Change in Baseline in Electrocardiogram (ECG) [ Time Frame: Up to 15 Days ]
    A 12-lead ECG will be performed at baseline and Days 1 and 15 of Cycle 1. Twelve-lead ECGs will be obtained after the patient has been resting semi-supine for at least 10 minutes prior to times indicated. For each on-study time point, triplicate ECG recordings should be taken. The investigator (or delegate) will review each of the ECGs and may refer to a local cardiologist if appropriate.
  • Change from Baseline in Left Ventricular Ejection Fraction (LVEF) [ Time Frame: Up to 12 Weeks ]
    LVEF will be assessed by echocardiography/multiple gated acquisition scan (MUGA)
  • Change from Baseline in Pulse and Blood Pressure [ Time Frame: Up to 28 Days ]
    Pulse and blood pressure will be assessed after a 10 minute rest.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: September 26, 2018)
  • Objective response rate (ORR) [ Time Frame: 16 weeks and 52 weeks ]
    The percentage of patients who have a confirmed visit response of Complete Response (CR) or Partial Response (PR) as assessed by the investigator per RECIST 1.1. Data obtained up until progression, or the last evaluable assessment in the absence of progression, will be included in the assessment of ORR.
  • Disease control rate (DCR) [ Time Frame: 16 weeks and 52 weeks ]
    Percentage of patients who have a confirmed visit response of CR or PR or stable disease (SD) ≥16 weeks as assessed by the investigator as per RECIST 1.1
  • Progression free survival (PFS) [ Time Frame: up to 12 months ]
    The time from randomization until the date of objective disease progression or death (from any cause in the absence of progression) regardless of whether the patient withdraws from assigned therapy or receives another anticancer therapy prior to progression. Patients who have not progressed or died at the time of analysis will be censored at the time of the latest date of assessment from their last evaluable RECIST 1.1 assessment.
  • Duration of response (DoR) [ Time Frame: up to 12 months ]
    Duration of response is defined as the elapsed time from the date of first documented response (CR/PR) as per RECIST Version 1.1 as assessed by the investigator until the date of documented progression or death in the absence of disease progression. The time of the initial response is defined as the latest of the dates contributing towards the first visit response of PR or CR.
  • Overall survival (OS) rate at 1 year [ Time Frame: 1 year ]
    Defined as the proportion of patients surviving after 1 year from the start of treatment.
  • Plasma concentration of AZD4547 (Module A) [ Time Frame: Blood samples will be taken pre-dose on Days 1 and 8 of Cycle 1; pre-dose and 2, 3, 4 and 6 hours post-dose on Day 1 of Cycle 2; and pre-dose and 2 to 4 hours post-dose on Day 1 of Cycle 3. ]
    The timing of the PK samples may be adjusted during the study, dependent on emerging data, in order to ensure appropriate characterisation of the plasma concentration-time profiles.
  • Plasma concentration of MEDI4736 (durvalumab) (Module A) [ Time Frame: Blood samples will be taken pre-dose and end of infusion for Day 1 of Cycles 1 to 7 and for the post-Cycle 7 8-weekly assessments, and pre-dose for Day 8 of Cycle 1. ]
    The timing of the PK samples may be adjusted during the study, dependent on emerging data, in order to ensure appropriate characterisation of the plasma concentration-time profiles.
  • Plasma concentration of olaparib (Module B) [ Time Frame: Blood samples will be taken on Day 3 of Cycles 1 and pre-dose and 4 hr post-dose. Serial samples on Day 3 of Cycle 3, pre-dose, 1, 2, 4, 6, 8, and 10 hr post-dose. ]
    The timing of the PK samples may be adjusted during the study, dependent on emerging data, in order to ensure appropriate characterisation of the plasma concentration-time profiles.
  • Plasma concentration of AZD1775 (Module C) [ Time Frame: Blood samples will be taken on Day 8 at steady state at the following time points: pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 12 hr post-dose. ]
    The timing of the PK samples may be adjusted during the study, dependent on emerging data, in order to ensure appropriate characterisation of the plasma concentration-time profiles.
  • Plasma concentration of MEDI4736 (durvalumab) (Module C) [ Time Frame: Blood samples will be taken on Days 1 and 8 of Cycle 1 pre-dose and at the end of infusion (1 hour). Samples will also be collected on Day 1 of Cycles 2 to 7 pre-dose and at the end of infusion. ]
    The timing of the PK samples may be adjusted during the study, dependent on emerging data, in order to ensure appropriate characterisation of the plasma concentration-time profiles.
  • Plasma concentration of MEDI4736 (durvalumab) (Module D) [ Time Frame: Blood samples will be taken on Days 1 and 8 of Cycle 1 ]
    The timing of the PK samples may be adjusted during the study, dependent on emerging data, in order to ensure appropriate characterisation of the plasma concentration-time profiles.
  • Plasma concentration of vistusertib (Module E) [ Time Frame: Blood samples will be collected pre-dose, and 2 and 4 hr post-dose on Day 1 of Cycle 1; and pre-dose and 2 to 6 hr post-dose (matched to biopsy) on Day 2 of Cycle 2. ]
    The timing of the PK samples may be adjusted during the study, dependent on emerging data, in order to ensure appropriate characterisation of the plasma concentration-time profiles.
  • Plasma concentration of Medi4736 (durvalumab) (Module E). [ Time Frame: Blood samples will be taken pre-dose and end of infusion for Day 1 of Cycles 1 to 7 and every 8 weeks thereafter and pre-dose for Day 8 of Cycle 1. ]
    The timing of the PK samples may be adjusted during the study, dependent on emerging data, in order to ensure appropriate characterisation of the plasma concentration-time profiles.
  • Plasma concentration of AZD9150 (Module F) [ Time Frame: Blood samples will be taken pre-dose of Days -7, -5, and -3 of the lead-in portion and thereafter prior to dosing and at the ned of infusion on Day 1 of Cycles 1, 2, 3, 4, 6, and 8 (approximately 8 months). ]
    The timing of the PK samples may be adjusted during the study, dependent on emerging data, in order to ensure appropriate characterisation of the plasma concentration-time profiles.
  • Plasma concentration of MEDI4736 (durvalumab) (Module F). [ Time Frame: Blood samples will be taken pre-dose and end of infusion for Day 1 of Cycles 1 to 7 and every 8 weeks thereafter and pre-dose for Day 8 of Cycle 1. ]
    The timing of the PK samples may be adjusted during the study, dependent on emerging data, in order to ensure appropriate characterisation of the plasma concentration-time profiles.
  • The presence of Anti-Drug Antibodies (ADA) and ADA neutralising antibodies to MEDI4736 will be assessed in patients receiving MEDI4736 in any sub-study module. [ Time Frame: Blood samples will be collected prior to MEDI4736 dosing on Day 1 of Cycles 1, 2 and 4 and every 12 weeks thereafter (up to 12 months). ]
    The formation of anti-drug antibodies and neutralizing antibodies will be assessed by validated methods.
Original Secondary Outcome Measures  ICMJE
 (submitted: September 9, 2015)
  • Area under the plasma concentration-time curve (AUC). [ Time Frame: Blood will be collected at the following times: Pre dose on Day 1/Cycle 1; pre dose on Day 8/Cycle 1; pre dose on Day 1/Cycle 2; and 2, 3, 4, and 6 hours post dose on Day1 /Cycle 2; pre dose on Day 1/Cycle 3; and 2 to 4 hours post dose on Day 1/Cycle 3. ]
    The multiple dose area under the plasma concentration-time curve will be calculated for both AZD4547 and MEDI4736 at steady state.
  • Apparent plasma clearance at steady state (CL). [ Time Frame: Blood will be collected at the following times: Pre dose on Day 1/Cycle 1; pre dose on Day 8/Cycle 1; pre dose on Day 1/Cycle 2; and 2, 3, 4, and 6 hours post dose on Day1 /Cycle 2; pre dose on Day 1/Cycle 3; and 2 to 4 hours post dose on Day 1/Cycle 3. ]
    The multiple dose apparent plasma clearance at steady state will be calculated for both AZD4547 and MEDI4736.
  • Maximum plasma concentration at steady state (Cmax) [ Time Frame: Blood will be collected at the following times: Pre dose on Day 1/Cycle 1; pre dose on Day 8/Cycle 1; pre dose on Day 1/Cycle 2; and 2, 3, 4, and 6 hours post dose on Day1 /Cycle 2; pre dose on Day 1/Cycle 3; and 2 to 4 hours post dose on Day 1/Cycle 3. ]
    The multiple dose Cmax will be calculated for both AZD4547 and MEDI4736.
  • Minimum plasma concentration at steady state (Cmin) [ Time Frame: Blood will be collected at the following times: Pre dose on Day 1/Cycle 1; pre dose on Day 8/Cycle 1; pre dose on Day 1/Cycle 2; and 2, 3, 4, and 6 hours post dose on Day1 /Cycle 2; pre dose on Day 1/Cycle 3; and 2 to 4 hours post dose on Day 1/Cycle 3. ]
    The multiple dose Cmin will be calculated for both AZD4547 and MEDI4736.
  • Time to maximum plasma concentration at steady state (tmax) [ Time Frame: Blood will be collected at the following times: Pre dose on Day 1/Cycle 1; pre dose on Day 8/Cycle 1; pre dose on Day 1/Cycle 2; and 2, 3, 4, and 6 hours post dose on Day1 /Cycle 2; pre dose on Day 1/Cycle 3; and 2 to 4 hours post dose on Day 1/Cycle 3. ]
    The time at which the maximum plasma concentration is reached after multiple dosing will be calculated.
  • Objective response rate (ORR) [ Time Frame: 12 weeks and 24 weeks ]
    The percentage of patients who have a confirmed visit response of Complete Response (CR) or Partial Response (PR) as assessed by the investigator per RECIST 1.1. Data obtained up until progression, or the last evaluable assessment in the absence of progression, will be included in the assessment of ORR.
  • Disease control rate (DCR) [ Time Frame: 2, 4, 6, and 12 months. ]
    The percentage of patients who have a confirmed visit response of CR or PR or stable disease (SD) as assessed by the investigator per RECIST 1.1.
  • Progression free survival (PFS) [ Time Frame: 1, 2, 3, and 4 months after the first dose of study drug. ]
    The time from randomization until the date of objective disease progression or death (from any cause in the absence of progression) regardless of whether the patient withdraws from assigned therapy or receives another anticancer therapy prior to progression. Patients who have not progressed or died at the time of analysis will be censored at the time of the latest date of assessment from their last evaluable RECIST 1.1 assessment.
  • Duration of response (DoR) [ Time Frame: up to 12 months ]
    Duration of overall response will be analysed using Kaplan-Meier methods, where patients who do not progress before dying will be censored at the time of death or at the administrative end of the study.
Current Other Pre-specified Outcome Measures
 (submitted: September 26, 2018)
  • Mutation status of cancer associated genes in circulating tumour DNA (ctDNA). [ Time Frame: 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. ]
    Plasma and serum samples will be collected and assessed for circulating tumour DNA to explore the mutation status of cancer associated genes.
  • Biomarker Analysis of Blood and Tissue [ Time Frame: Up to 12 months ]
    Biomarker analysis of blood and tissue to assess exploratory markers, which may include but is not limited to:
    • immune cell gene expression profiles and cytokine profiles within the peripheral and tumoural compartments,
    • the presence of IFN-γ, tumour necrosis factor-α, IL-2, IL-6, IL-10, IL-8, and IL-12 as well as antibodies against tumour, self, or viral antigens,
    • expression of PD-L1,
    • CD8 and the number and phenotype of immune cells such as T-cells.
    Markers relevant to the targeted therapy, for example FGFR and ligand expression and PD markers, for example pErk, pS6 and γH2AX will also be measured in tumour paired biopsy samples. Biomarker assessments that may have the potential to identify patients likely to respond to treatment with the agents studied in this modular protocol will be investigated to determine a patient's biomarker status and for possible correlation with efficacy endpoints.
  • Correlation of biomarkers to response and/or development of cancer [ Time Frame: Throught out study (up to 18 months) ]
    To explore potential biomarkers in residual biological samples (e.g., tumour, plasma and/or serum) which may influence development of cancer (and associated clinical characteristics) and/or response.
  • Estimate overall survival (OS) [ Time Frame: Up to 18 months ]
    To estimate the overall survival for patients have been pre-screened but do not enter the main part of the study.
  • Objective Response Rate (ORR) (by modified RECIST 1.1) [ Time Frame: 16 weeks and 52 weeks ]
    The percentage of patients who have a confirmed response of CR or PR as assessed by the investigator using a modified RECIST 1.1. Modified RECIST 1.1 will be used for patients receiving MEDI4736 because of response may occur after progression has been initially determined. Patients receiving MEDI4736 may continue to receive treatment and be followed after an initial assessment of progression until subsequent confirmation. Confirmed progression is defined as ≥20% increase in sum of diameters of target lesions compared to the nadir at 2 consecutive visits; and/or significant progression (worsening) of non-target lesions (NTLs) or new lesions (NLs) at the confirmatory scan; and/or new unequivocal lesions at the confirmatory scan. If progression is not confirmed then the visit response is assessed as SD/PR or CR and the patient should continue scheduled scans. If progression is confirmed the visit response should be assessed as progressive disease.
Original Other Pre-specified Outcome Measures
 (submitted: September 9, 2015)
  • Mutation status of cancer associated genes in circulating tumour DNA (ctDNA). [ Time Frame: 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). ]
    Plasma and serum samples will be collected and assessed for circulating tumour DNA to explore the mutation status of cancer associated genes
  • Biomarker Analysis of Blood and Tissue [ Time Frame: Up to 12 months ]
    Biological samples (including archived tumour samples) will be collected and may be analysed for exploratory biomarkers to assess correlations with disease activity, effects of study drug, clinical outcomes, and toxicity. Biomarker assessments that may have the potential to identify patients likely to respond to treatment with agents studied in this modular protocol will be investigated to determine a patient's biomarker status and for possible correlation with efficacy endpoints.
 
Descriptive Information
Brief Title  ICMJE Open-Label, Randomised, Multi-Drug, Biomarker-Directed, Phase 1b Study in Pts w/ Muscle Invasive Bladder Cancer
Official Title  ICMJE An Open-Label, Randomised, Multi-Drug, Biomarker-Directed, Multi-Centre, Multi-arm Phase 1b Study in Patients With Muscle Invasive Bladder Cancer (MIBC) Who Have Progressed on Prior Treatment (BISCAY).
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.

Detailed Description

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 in patients whose tumours express specific genomic alterations relevant to the molecules under investigation and whose disease has progressed following prior therapy. The allocation of patients to specific modules will depend on the specific eligible genomic alterations identified in their tumours.

Each module will determine the appropriate combination dose for further clinical evaluation based on safety, tolerability and efficacy profile. A maximum tolerated dose will be defined and each arm expanded appropriately to explore further the safety, tolerability, pharmacokinetics and biological activity at the selected combination doses.

Module A includes an AZD4547 monotherapy arm and a MEDI4736 (durvalumab) + AZD4547 combination therapy arm and will investigate the safety and tolerability of MEDI4736 given intravenously, in combination with AZD4547 given orally to selected patients with MIBC with tumours that have fibroblast growth factor receptor mutations or fibroblast growth factor receptor fusions.

Module B will investigate the safety and tolerability of MEDI4736 given intravenously in combination with olaparib (AZD2281, Lynparza) given orally to selected patients with MIBC whose tumors have mutations in a homologous recombination repair gene panel and whose disease had progressed following prior therapy.

Module C will investigate the safety and tolerability of MEDI4736 given intravenously, in combination with AZD1775 given orally to selected patients with MIBC whose tumours have mutations in genes involved in cell cycle regulation (e.g., loss of either retinoblastoma 1 or cyclin-dependent kinase inhibitor 2A or amplification of cyclin E1 or MYC family genes).

Module D will investigate the safety and tolerability of MEDI4736 given intravenously as monotherapy to patients with MIBC who do not qualify for Modules A, B or C.

Module E will investigate the safety and tolerability of MEDI4736 given intravenously, in combination with vistusertib (AZD2014) given orally to patients with MIBC whose tumours do not show genomic alterations that would be eligible for other study modules. Patients whose MIBC tumours harbour the following genomic alterations that have potential to respond to a mammalian target of rapamycin (mTOR) inhibitor will also be included in Module E: RICTOR amplification, or TSC1/1 mutations.

Module F will investigate the safety and tolerability of MEDI4736 given intravenously in combination with AZD9150 given intravenously to patients with MIBC whose tumours do not show genomic alterations that would be eligible for other modules.

Module G will investigate the safety and tolerability of MEDI4736 given intravenously in combination with selumetinib (AZD6244) given orally to patients with MIBC. Patients in this module will not be selected for any specific tumour genomic alteration.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Muscle Invasive Bladder Cancer
Intervention  ICMJE
  • Drug: AZD4547
    AZD4547 Monotherapy vs. MEDI4736 (durvalumab) + AZD4547 1:1 Randomization.
  • Drug: MEDI4736
    MEDI4736
    Other Name: Durvalumab
  • Drug: Olaparib
    MEDI4736 (durvalumab) + Olaparib
    Other Name: Lynparza
  • Drug: AZD1775
    MEDI4736 (durvalumab) + AZD1775
  • Drug: Vistusertib
    MEDI4736 (durvalumab) + Vistusertib
  • Drug: AZD9150
    MEDI4736 (durvalumab) + AZD9150
  • Drug: Selumetinib
    MEDI4736 (durvalumab) + Selumetinib
Study Arms  ICMJE
  • Experimental: Module A: AZD4547 Monotherapy

    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.
    Intervention: Drug: AZD4547
  • Experimental: Module A: MEDI4736 (durvalumab) + AZD4547
    AZD4547 will be given orally twice daily until disease progression. Patients will also receive MEDI 4736 (durvalumab) by IV infusion once every 4 weeks.
    Interventions:
    • Drug: AZD4547
    • Drug: MEDI4736
  • Experimental: Module B: MEDI4736 (durvalumab) + Olaparib
    MEDI4736 (durvalumab) will be given by IV infusion once every 4 weeks. Olaparib will be given orally twice daily.
    Interventions:
    • Drug: MEDI4736
    • Drug: Olaparib
  • Experimental: Module C: MEDI4736 (durvaluamb) + AZD1775
    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.
    Interventions:
    • Drug: MEDI4736
    • Drug: AZD1775
  • Experimental: Module D: MEDI4736 (durvalumab) monotherapy
    MEDI 4736 (durvalumab) will be given by IV infusion once every 4 weeks.
    Intervention: Drug: MEDI4736
  • Experimental: Module E: MEDI4736 (durvalumab) + Vistusertib
    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).
    Interventions:
    • Drug: MEDI4736
    • Drug: Vistusertib
  • Experimental: Module F: MEDI4736 (durvaluamb) + AZD9150
    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.
    Interventions:
    • Drug: MEDI4736
    • Drug: AZD9150
  • Experimental: Module G: MEDI4736 + Selumetinib
    Interventions:
    • Drug: MEDI4736
    • Drug: Selumetinib
Publications * Powles T, Carroll D, Chowdhury S, Gravis G, Joly F, Carles J, Fléchon 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.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Actual Enrollment  ICMJE
 (submitted: May 10, 2019)
156
Original Estimated Enrollment  ICMJE
 (submitted: September 9, 2015)
40
Estimated Study Completion Date  ICMJE February 14, 2022
Actual Primary Completion Date March 18, 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria for all Modules:

  1. Metastatic MIBC
  2. 2nd/3rd line
  3. Failed adjuvant/neo-adjuvant chemotherapy <1 yr
  4. 1 lesion ≥10 mm at baseline in the longest diameter suitable for accurate repeated measurement
  5. WHO perf. status 0-1

For Module A:

  1. M/F ≥25
  2. Confirmation of FGFR3 mutation or FGFR fusion

For Module B:

  1. Hgb ≥10 g/dL
  2. Deleterious mutation, deletion or truncation in any HRR genes

For Module C:

1. 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:

1. Contraception must be sustained throughout treatment with vistusertib and 16 wks after last dose

For Module F:

  1. Adequate organ and marrow function, defined as Leukocytes ≥3.0x10(exp9)/L; ANC ≥1.5x10(exp9)/L; platelets ≥100x10(exp9)/L
  2. Contraceptive measures must be sustained throughout treatment with AZD9150 and for 180 days after the last dose.

Exclusion Criteria for all Modules:

  1. Immunotherapy, chemotherapy, anticancer agents, radiotherapy <4 weeks, or radiotherapy for palliation <2 weeks, any study drugs <30 days.
  2. Major surgery <4 weeks
  3. Unresolved toxicities from prior therapy
  4. Concurrent chemotherapy, immunotherapy, biologic or hormonal therapy
  5. Immunosuppressive drugs <28 days
  6. Any of the following: Autoimmune disease ≤2 yr; IBD; primary immunodeficiency; organ transplant requiring immunosuppressives
  7. Spinal cord compression or brain metastases, treated and stable & not requiring steroids for at least 4 weeks
  8. Severe or uncontrolled systemic disease
  9. 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
  10. 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
  11. 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.
  12. Live attenuated vaccination <30 days

For Module A:

  1. 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
  2. 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
  3. Refractory nausea/vomiting, chronic GI diseases, or previous bowel resection

For Module B:

  1. Transfusion <120 days
  2. Concurrent medications that are strong inhibitors of cytochrome P450 (CYP) 3A (CYP3A) or strong inducers of CYP3A4.
  3. Previous treatment with PARP inhibitor, including olaparib
  4. Patients with history of MDS or AML

For Module C:

  1. Prior exposure to any of the following: Nitrosourea or mitomycin C <6 wks; any agent with Wee1 inhibition as its primary pharmacology; prior treatment with AZD1775
  2. Any drugs or products known to be sensitive to CYP3A4 substrates or CYP3A4 substrates with narrow therapeutic index, or moderate to strong inhibitors/inducers of CYP3A4
  3. Herbal preparations
  4. Refractory nausea and vomiting or chronic GI diseases
  5. Cardiac disease <6 months

For Module E:

  1. Minor surgery <14 days of first dose
  2. Exposure to specific substrates of OATP1B1, OATP1B3, MATE1 and MATE2K <5x half-life before treatment. Exposure to strong/moderate inhibitors/inducers of CYP3A4/5, Pgp (MDR1) and BRCP if taken within washout periods before the first dose
  3. Haemopoietic growth factors (filgrastim, sargramostim, GM-CSF) <14 days prior to treatment
  4. Other mTOR inhibitors
  5. Renal disease or renal tubular acidosis
  6. Uncontrolled Type 1 or 2 diabetes

For Module F:

1. AST ≤ 2.5xULN or ≤5xULN with liver metastases

For Module G:

  1. Have had prior treatment with a MEK, Ras or Raf inhibitor.
  2. Any of the following ophthalmic criteria: Current or past history of central serous retinopathy, detachment of retinal pigmented epithelium, or retinal vein occlusion; intraocular pressure (IOP) >21 mmHg; uncontrolled glaucoma (irrespective of IOP)
  3. Baseline left ventricular ejection fraction (LVEF) <55% measured by echocardiogram (ECHO) or, if allowed, a multigated acquisition (MUGA) scan. Appropriate correction to be used if a MUGA is performed.
  4. Previous moderate or severe impairment of LVEF (<45% on echocardiography or equivalent on MUGA) even if full recovery has occurred.
  5. Male or female patients with reproductive potential and, as judged by the investigator, are not employing an effective method of birth control and female patients who are breastfeeding.
  6. Past medical history of interstitial lung disease (ILD), drug-induced ILD, radiation pneumonitis which required steroid treatment, or any evidence of clinically active ILD.
  7. Receiving or have received systemic therapy with nitrosoureas, mitomycin or suramin within 6 weeks prior to starting study treatment.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 130 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Canada,   France,   Spain,   United Kingdom,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02546661
Other Study ID Numbers  ICMJE D2615C00001
GU 118 ( Other Identifier: Sarah Cannon Development Innovations, LLC )
BISCAY ( Other Identifier: Sponsor )
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: Yes
Plan Description: Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request portal. All request will be evaluated as per the AZ disclosure commitment: https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
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.
URL: https://astrazenecagroup-dt.pharmacm.com/DT/Home
Responsible Party AstraZeneca
Study Sponsor  ICMJE AstraZeneca
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: 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
PRS Account AstraZeneca
Verification Date July 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP