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

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.

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 in patients whose tumours express specific genomic alterations relevant to the molecules under investigation and whose disease has progressed following prior therapy. The allocation of patients to specific modules will depend on the specific eligible genomic alterations identified in their tumours.

Each module will determine the appropriate combination dose for further clinical evaluation based on safety, tolerability and efficacy profile. A maximum tolerated dose will be defined and each arm expanded appropriately to explore further the safety, tolerability, pharmacokinetics and biological activity at the selected combination doses.

Module A includes an AZD4547 monotherapy arm and a MEDI4736 (durvalumab) + AZD4547 combination therapy arm and will investigate the safety and tolerability of MEDI4736 given intravenously, in combination with AZD4547 given orally to selected patients with MIBC with tumours that have fibroblast growth factor receptor mutations or fibroblast growth factor receptor fusions.

Module B will investigate the safety and tolerability of MEDI4736 given intravenously in combination with olaparib (AZD2281, Lynparza) given orally to selected patients with MIBC whose tumors have mutations in a homologous recombination repair gene panel and whose disease had progressed following prior therapy.

Module C will investigate the safety and tolerability of MEDI4736 given intravenously, in combination with AZD1775 given orally to selected patients with MIBC whose tumours have mutations in genes involved in cell cycle regulation (e.g., loss of either retinoblastoma 1 or cyclin-dependent kinase inhibitor 2A or amplification of cyclin E1 or MYC family genes).

Module D will investigate the safety and tolerability of MEDI4736 given intravenously as monotherapy to patients with MIBC who do not qualify for Modules A, B or C.

Module E will investigate the safety and tolerability of MEDI4736 given intravenously, in combination with vistusertib (AZD2014) given orally to patients with MIBC whose tumours do not show genomic alterations that would be eligible for other study modules. Patients whose MIBC tumours harbour the following genomic alterations that have potential to respond to a mammalian target of rapamycin (mTOR) inhibitor will also be included in Module E: RICTOR amplification, or TSC1/1 mutations.

Module F will investigate the safety and tolerability of MEDI4736 given intravenously in combination with AZD9150 given intravenously to patients with MIBC whose tumours do not show genomic alterations that would be eligible for other modules.

Module G will investigate the safety and tolerability of MEDI4736 given intravenously in combination with selumetinib (AZD6244) given orally to patients with MIBC. Patients in this module will not be selected for any specific tumour genomic alteration.

Eligibility Criteria:
Inclusion Criteria for all Modules:

1. Metastatic MIBC
2. 2nd/3rd line
3. Failed adjuvant/neo-adjuvant chemotherapy \<1 yr
4. 1 lesion ≥10 mm at baseline in the longest diameter suitable for accurate repeated measurement
5. WHO perf. status 0-1

For Module A:

1. M/F ≥25
2. Confirmation of FGFR3 mutation or FGFR fusion

For Module B:

1. Hgb ≥10 g/dL
2. 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:

1. Adequate organ and marrow function, defined as Leukocytes ≥3.0x10(exp9)/L; ANC ≥1.5x10(exp9)/L; platelets ≥100x10(exp9)/L
2. Contraceptive measures must be sustained throughout treatment with AZD9150 and for 180 days after the last dose.

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.