This is an open label, multi-drug, biomarker-directed, multi-centre, multi-arm, randomised
Phase 1b study in patients with muscle invasive bladder cancer (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 in patients with
muscle invasive bladder cancer.
The study will consist of a number of study modules (substudies), each evaluating the safety
and tolerability of a specific agent or combination. The initial module (Module A)
incorporates an AZD4547 monotherapy arm and MEDI4736+AZD4547 combination therapy arm. Module
A will investigate the safety and tolerability of MEDI4736 given intravenously, in
combination with AZD4547 given orally to selected patients with muscle invasive bladder
cancer with tumours that have fibroblast growth factor receptor mutations or fibroblast
growth factor receptor fusions and whose disease has progressed following prior therapy.
Specifically the following fibroblast growth factor receptor 3 activating mutations are
eligible, R248C, S249C, G370C, Y373C, S371C, G3780R, as are fibroblast growth factor
receptor 1, 2, 3 gene fusions resulting in removal of the c-terminal of the fibroblast
growth factor receptor while encoding an intact tyrosine kinase domain, an example being the
fibroblast growth factor receptor 3-transforming acidic coiled-coil 3 fusions identified in
bladder cancer and glioblastoma.
Module A will determine the MEDI4736+AZD4547 combination dose(s) for further clinical
evaluation and confirm the safety, tolerability and efficacy of AZD4547 given orally to
selected patients with muscle invasive bladder cancer who have progressed following prior
therapy. In the combination arm, a maximum tolerated dose will be defined in patients with
muscle invasive bladder cancer, as defined by dose-limiting toxicity. An expansion cohort(s)
in Module A will enrol additional patients to explore further the safety, tolerability,
pharmacokinetics and biological activity at the selected AZD4547 plus MEDI4736 dose(s).
Inclusion Criteria:
1. Fibroblast growth factor receptor (FGFR3) mutation fusion
2. Histological confirmation of metastatic muscle invasive bladder cancer
3. Second- or third-line treatment
4. Failed adjuvant or neo-adjuvant chemotherapy within 1 year
5. Willingness to provide consent for biopsy samples.
6. At least 1 lesion that can be accurately measured at baseline as 10 mm in the
longest diameter (except lymph nodes which must have short axis 15 mm) with CT or
MRI which is suitable for accurate repeated measurement
7. WHO performance status of 0-1
Exclusion Criteria:
1. Prior exposure to other immunotherapy [e.g., a cytotoxic T-lymphocyte-associated
protein 4 (CTLA4), PD-1 or PD-L1 inhibitor] before the first dose, any chemotherapy
or anticancer agents within 4 weeks, radiotherapy of the primary site with a wide
field of radiation within 4 weeks, or radiotherapy with a limited field of radiation
for palliation within 2 weeks, any investigational or study drugs from a previous
study within 30 days.
2. Major surgery within 4 weeks.
3. Unresolved toxicities (except alopecia) from prior therapy > CTCAE Grade 1, any prior
Grade 3 immune-related adverse event (irAE) while receiving immunotherapy, or any
unresolved irAE >Grade 1
4. Any concurrent chemotherapy, immunotherapy, biologic or hormonal therapy
5. Current or prior immunosuppressive medication within 28 days, with the exceptions of
intranasal, topical, and inhaled corticosteroids or systemic corticosteroids at
physiologic doses not to exceed 10 mg/day of prednisone or equivalent
6. Any of the following immune related criteria:
- Active or prior documented autoimmune disease within the past 2 years prior to
screening
- Active or prior documented inflammatory bowel disease (eg, Crohn's disease,
ulcerative colitis)
- History of primary immunodeficiency
- History of organ transplant that requires use of immunosuppressives
7. Spinal cord compression or brain metastases unless asymptomatic, treated and stable
and not requiring steroids for at least 4 weeks
8. As judged by the investigator, any evidence of severe or uncontrolled systemic
diseases, including uncontrolled hypertension, active bleeding diatheses, or active
infection including hepatitis B, hepatitis C and human immunodeficiency virus
9. Any of the following cardiac criteria:
- Mean QTc 470 ms
- Abnormalities in rhythm, conduction or morphology of resting ECG
- Any factors that increase the risk of QT interval, corrected (QTc) prolongation
or risk of arrhythmic events
- Uncontrolled hypertension - BP 150/95 mmHg despite medical therapy
- Uncontrolled hypotension - systolic BP <90 mmHg and/or diastolic BP <50 mmHg
- LVEF <55% measured by echocardiography
- Atrial fibrillation with a ventricular rate >100 bpm on an ECG at rest
- Symptomatic heart failure - New York Heart Association Grade II-IV
- Prior or current cardiomyopathy
- Severe valvular heart disease
- Uncontrolled angina
- Stroke or transient ischemic attack in the last 6 months
- Acute coronary syndrome in the last 6 months
10. Inadequate bone marrow reserve or organ function as demonstrated by any of the
following laboratory values:
- Absolute neutrophil count (ANC) <1.5 x 109/L
- Platelets <100 x 109/L
- Hgb <9.0 g/dL
- Alanine aminotransferase >2.5 times the upper limit of normal (ULN) if no
demonstrable liver metastases or >5 times ULN in the presence of liver
metastases
- Total bilirubin >1.5 times ULN or for patients with documented/suspected
Gilbert's disease, bilirubin 2 ULN
- Creatinine >1.5 times ULN concurrent with creatinine clearance <50 mL/min;
confirmation of creatinine clearance is only required when creatinine is >1.5
times ULN
- Corrected calcium >ULN
- Phosphate >ULN
11. Known history of tuberculosis
12. Receipt of any live attenuated vaccination within 30 days prior to study entry or
within 30 days of receiving MEDI4736.
Minimum Eligible Age: 18 Years
Maximum Eligible Age: 130 Years
Eligible Gender: Both
