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

Prior treatment

• 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
• Spinal cord compression or brain metastases, treated and stable \& not requiring steroids for at least 4 weeks
• 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
• Refractory nausea/vomiting, chronic GI diseases, or previous bowel resection
  • For Module B:
• Concurrent medications that are strong inhibitors of cytochrome P450 (CYP) 3A (CYP3A) or strong inducers of CYP3A4.
• Previous treatment with PARP inhibitor, including olaparib
• 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
• 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
• Minor surgery \<14 days of first dose
• 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
• Haemopoietic growth factors (filgrastim, sargramostim, GM-CSF) \<14 days prior to treatment
• Other mTOR inhibitors
• Have had prior treatment with a MEK, Ras or Raf inhibitor.
• Receiving or have received systemic therapy with nitrosoureas, mitomycin or suramin within 6 weeks prior to starting study treatment.

Other illness

• Any of the following: Autoimmune disease ≤2 yr; IBD; primary immunodeficiency; organ transplant requiring immunosuppressives
• Severe or uncontrolled systemic disease
• 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.
• Patients with history of MDS or AML
  • For Module C:
• Refractory nausea and vomiting or chronic GI diseases
• Cardiac disease \<6 months
  • For Module E:
• Renal disease or renal tubular acidosis
• 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)
• Past medical history of interstitial lung disease (ILD), drug-induced ILD, radiation pneumonitis which required steroid treatment, or any evidence of clinically active ILD.

Lab values

• 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
• Uncontrolled Type 1 or 2 diabetes
  • For Module F:
  • 1\. AST ≤ 2.5xULN or ≤5xULN with liver metastases
  • For Module G:
• 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.
• Previous moderate or severe impairment of LVEF (\<45% on echocardiography or equivalent on MUGA) even if full recovery has occurred.

Age

• 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

Other

• Live attenuated vaccination \<30 days
  • For Module A:
• Transfusion \<120 days
• Herbal preparations
• 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.

• Metastatic MIBC
• 2nd/3rd line
• Failed adjuvant/neo-adjuvant chemotherapy \<1 yr
• 1 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:
  • 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:
• Adequate organ and marrow function, defined as Leukocytes ≥3.0x10(exp9)/L; ANC ≥1.5x10(exp9)/L; platelets ≥100x10(exp9)/L
• Contraceptive measures must be sustained throughout treatment with AZD9150 and for 180 days after the last dose.