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).


Condition: Muscle Invasive Bladder Cancer

Intervention:

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

Purpose: 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.

Study Type: Interventional

Clinical Trials Identifier NCT 8-digits: NCT02546661

Sponsor: AstraZeneca

Primary Outcome Measures:

  • Measure: 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.
  • Safety Issue:
  • Measure: 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.
  • Safety Issue:
  • Measure: 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.
  • Safety Issue:
  • Measure: 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.
  • Safety Issue:
  • Measure: 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.
  • Safety Issue:
  • Measure: 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.
  • Safety Issue:
  • Measure: 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.
  • Safety Issue:
  • Measure: 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.
  • Safety Issue:
  • Measure: 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.
  • Safety Issue:
  • Measure: 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.
  • Safety Issue:
  • Measure: 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.
  • Safety Issue:
  • Measure: 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.
  • Safety Issue:
  • Measure: 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.
  • Safety Issue:
  • Measure: 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.
  • Safety Issue:
  • Measure: 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.
  • Safety Issue:
  • Measure: 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.
  • Safety Issue:
  • Measure: 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.
  • Safety Issue:

Secondary Outcome Measures:

  • Measure: Objective response rate (ORR)
  • Time Frame: 16 weeks and 52 weeks
  • Safety Issue:
  • Measure: Disease control rate (DCR)
  • Time Frame: 16 weeks and 52 weeks
  • Safety Issue:
  • Measure: Progression free survival (PFS)
  • Time Frame: up to 12 months
  • Safety Issue:
  • Measure: Duration of response (DoR)
  • Time Frame: up to 12 months
  • Safety Issue:
  • Measure: Overall survival (OS) rate at 1 year
  • Time Frame: 1 year
  • Safety Issue:
  • Measure: 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.
  • Safety Issue:
  • Measure: 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.
  • Safety Issue:
  • Measure: 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.
  • Safety Issue:
  • Measure: 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.
  • Safety Issue:
  • Measure: 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.
  • Safety Issue:
  • Measure: Plasma concentration of MEDI4736 (durvalumab) (Module D)
  • Time Frame: Blood samples will be taken on Days 1 and 8 of Cycle 1
  • Safety Issue:
  • Measure: 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.
  • Safety Issue:
  • Measure: 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.
  • Safety Issue:
  • Measure: 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).
  • Safety Issue:
  • Measure: 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.
  • Safety Issue:
  • Measure: 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).
  • Safety Issue:

Estimated Enrollment: 196

Study Start Date: October 3, 2016

Phase: Phase 1

Eligibility:

  • Age: minimum 18 Years maximum 130 Years
  • Gender: All

Inclusion Criteria:

  1. for all Modules:
  2. Metastatic MIBC
  3. 2nd/3rd line
  4. Failed adjuvant/neo-adjuvant chemotherapy <1 yr
  5. 1 lesion ≥10 mm at baseline in the longest diameter suitable for accurate repeated measurement
  6. WHO perf. status 0-1 For Module A:
  7. M/F ≥25
  8. Confirmation of FGFR3 mutation or FGFR fusion For Module B:
  9. Hgb ≥10 g/dL
  10. Deleterious mutation, deletion or truncation in any HRR genes For Module C:
  11. 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:
  12. Contraception must be sustained throughout treatment with vistusertib and 16 wks after last dose For Module F:
  13. Adequate organ and marrow function, defined as Leukocytes ≥3.0x10(exp9)/L; ANC ≥1.5x10(exp9)/L; platelets ≥100x10(exp9)/L
  14. Contraceptive measures must be sustained throughout treatment with AZD9150 and for 180 days after the last dose.

Exclusion Criteria:

  1. for all Modules:
  2. Immunotherapy, chemotherapy, anticancer agents, radiotherapy <4 weeks, or radiotherapy for palliation <2 weeks, any study drugs <30 days.
  3. Major surgery <4 weeks
  4. Unresolved toxicities from prior therapy
  5. Concurrent chemotherapy, immunotherapy, biologic or hormonal therapy
  6. Immunosuppressive drugs <28 days
  7. Any of the following: Autoimmune disease ≤2 yr; IBD; primary immunodeficiency; organ transplant requiring immunosuppressives
  8. Spinal cord compression or brain metastases, treated and stable & not requiring steroids for at least 4 weeks
  9. Severe or uncontrolled systemic disease
  10. 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
  11. 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
  12. 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.
  13. Live attenuated vaccination <30 days For Module A:
  14. 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
  15. 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
  16. Refractory nausea/vomiting, chronic GI diseases, or previous bowel resection For Module B:
  17. Transfusion <120 days
  18. Concurrent medications that are strong inhibitors of cytochrome P450 (CYP) 3A (CYP3A) or strong inducers of CYP3A
  19. Previous treatment with PARP inhibitor, including olaparib
  20. Patients with history of MDS or AML For Module C:
  21. 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
  22. 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
  23. Herbal preparations
  24. Refractory nausea and vomiting or chronic GI diseases
  25. Cardiac disease <6 months For Module E:
  26. Minor surgery <14 days of first dose
  27. 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
  28. Haemopoietic growth factors (filgrastim, sargramostim, GM-CSF) <14 days prior to treatment
  29. Other mTOR inhibitors
  30. Renal disease or renal tubular acidosis
  31. Uncontrolled Type 1 or 2 diabetes For Module F:
  32. AST ≤ 2.5xULN or ≤5xULN with liver metastases For Module G:
  33. Have had prior treatment with a MEK, Ras or Raf inhibitor.
  34. 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)
  35. 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.
  36. Previous moderate or severe impairment of LVEF (<45% on echocardiography or equivalent on MUGA) even if full recovery has occurred.
  37. 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.
  38. Past medical history of interstitial lung disease (ILD), drug-induced ILD, radiation pneumonitis which required steroid treatment, or any evidence of clinically active ILD.
  39. Receiving or have received systemic therapy with nitrosoureas, mitomycin or suramin within 6 weeks prior to starting study treatment.

Contact:

  • AstraZeneca Clinical Study Information Center
  • 1-877-240-9479

Locations:

  • Research Site
  • Los Angeles California 90033 United States
  • Research Site
  • Los Angeles California 90095 United States
  • Research Site
  • New Haven Connecticut 06510 United States
  • Research Site
  • Fort Myers Florida 33901 United States
  • Research Site
  • Baltimore Maryland 21231 United States
  • Research Site
  • Baltimore Maryland 21287-0013 United States
  • Research Site
  • Detroit Michigan 48202 United States
  • Research Site
  • Kansas City Missouri 64132 United States
  • Research Site
  • New York New York 10029 United States
  • Research Site
  • New York New York 10032 United States
  • Research Site
  • New York New York 10116 United States
  • Research Site
  • Cincinnati Ohio 45243 United States
  • Research Site
  • Cleveland Ohio 44195 United States
  • Research Site
  • Nashville Tennessee 37203 United States
  • Research Site
  • Milwaukee Wisconsin 53226 United States
  • Research Site
  • Edmonton Alberta T6G 1Z2 Canada
  • Research Site
  • Vancouver British Columbia V5Z 4E6 Canada
  • Research Site
  • Toronto Ontario M5G 2M9 Canada
  • Research Site
  • Montreal Quebec H3T 1E2 Canada
  • Research Site
  • Bordeaux 33075 France
  • Research Site
  • Caen 14000 France
  • Research Site
  • LYON cedex 08 69373 France
  • Research Site
  • Marseille Cedex 9 13273 France
  • Research Site
  • Saint Herblain Cedex 44805 France
  • Research Site
  • Toulouse Cedex 31100 France
  • Research Site
  • Badalona 08003 Spain
  • Research Site
  • Barcelona 08035 Spain
  • Research Site
  • Barcelona 08041 Spain
  • Research Site
  • Madrid 28040 Spain
  • Research Site
  • Cardiff CF14 2TL United Kingdom
  • Research Site
  • Edinburgh EH4 2XR United Kingdom
  • Research Site
  • Glasgow G12 0YN United Kingdom
  • Research Site
  • London EC1M 6BQ United Kingdom
  • Research Site
  • London W1G 6AD United Kingdom
  • Research Site
  • Manchester M20 4BX United Kingdom
  • Research Site
  • Plymouth PL6 8DH United Kingdom
  • Research Site
  • Southampton SO16 6YD United Kingdom

View trial on ClinicalTrials.gov


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