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

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.