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

Study Type: Interventional

Clinical Trials Identifier NCT 8-digits: NCT02546661

Sponsor: AstraZeneca

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.

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