Critères d'inclusion : Inclusion Criteria for all Modules:
- M/F ≥18
- Metastatic MIBC
- 2nd/3rd line
- Failed adjuvant/neo-adjuvant chemotherapy <1 year
- 1 lesion ≥10 mm at baseline in the longest diameter suitable for accurate repeated measurement
- WHO perf. status 0-1
Specific to Module A:
- M/F ≥25
- Confirmation of FGFR3 mutation or FGFR fusion
Specific to Module B:
- Hgb ≥ 10 g/dL
- Deleterious mutation, deletion or truncation in any HRR genes
Specific to Module C:
- Tumour harbours a deletion or inactivating mutation of the CDKN2A or RB1 genes and/or amplification of CCNE1, MYC, MYCL or MYCN genes
Specific to Module E:
- Contraception must be sustained throughout treatment with vistusertib and 16 wks after last dose
Critères de non-inclusion : Exclusion Criteria for all Modules:
- Immunotherapy, chemotherapy, anticancer agents, radiotherapy <4 wks, or radiotherapy for palliation <2 wks, any study drugs <30 days.
- Major surgery <4 wk
- Unresolved toxicities from prior therapy
- Concurrent chemotherapy, immunotherapy, biologic or hormonal therapy
- Immunosuppressive drugs <28 days
- Any of the following:
1) Autoimmune disease ≤2 yr
2) IBD
3) Primary immunodeficiency
4) Organ transplant requiring immunosuppressives
- Spinal cord compression or brain metastases, treated and stable & not requiring steroids for at least 4 weeks
- Severe or uncontrolled systemic disease
- Any of the following:
1) Mean QTc ≥470 ms
2) Abnormalities in resting ECG
3) Factors that increase the risk of QTc prolongation or arrhythmia
4) Uncontrolled hypertension or hypotension
5) LVEF <55%
6) Atrial fibrillation
7) NYHA Grade II-IV
8) Severe valvular disease
9) Uncontrolled angina
10) Stroke/TIA <6 months
11) Acute coronary syndrome <6 months
- Any of the following laboratory values:
1) ANC <1.5x10(exp9)/L
2) Platelets <100x10(exp9)/L
3) Hgb <9.0 g/dL
4) ALT >2.5xULN or >5xULN with liver mets
5) Total bilirubin >1.5 times ULN or with Gilbert's disease ≥2×ULN
6) Creatinine >1.5xULN concurrent with creatinine clearance <50 mL/min
7) Corrected CA >ULN
8) PO4 >ULN
- History of tuberculosis
- Live attenuated vaccination <30 days
For Module A:
- Prior exposure to:
1) Nitrosourea or mitomycin C <6 weeks
2) Agent with FGFR inhibition as its primary pharmacology
3)AZD4547
4) Potent inhibitors/inducers of CYP3A4, inhibitors of CYP2D6 or substrates of CYP3A4 <2 wks
- Ophthalmological criteria:
1) RPED
2) Laser treatment or intra-ocular injection for macular degeneration
3) Age-related macular degeneration
4) Retinal vein occlusion
5) Retinal degenerative disease
6) Any other clinically relevant chorioretinal defect
- Refractory nausea/vomiting, chronic GI diseases, or previous bowel resection
For Module B:
- Transfusion <120 days
- Concurrent medications that are strong inhibitors of cytochrome P450 (CYP) 3A (CYP3A) or strong inducers of CYP3A4.
- Previous treatment with PARP inhibitor, including olaparib
- Patients with history of MDS or AML
For Module C:
- Prior exposure to any of the following:
1) Nitrosourea or mitomycin C <6 wks
2) Any agent with Wee1 inhibition as its primary pharmacology
3) 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
- Herbal preparations
- Refractory nausea and vomiting or chronic GI diseases
- Cardiac disease <6 months
For Module E:
- 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 of 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 receiving treatment
- Other mTOR inhibitors
- Renal disease or renal tubular acidosis
- Uncontrolled Type 1 or 2 diabetes