A Clinical Study to Assess Safety, Tolerability, and Anti-Tumour Activity of Multiple Drugs Given Alone or in Combination in Patients with Bladder Cancer that has Spread to the Muscle Tissue Surrounding the Bladder.
- Conditions
- Muscle-invasive bladder cancerTherapeutic area: Diseases [C] - Cancer [C04]
- Registration Number
- EUCTR2015-002228-25-GB
- Lead Sponsor
- AstraZeneca AB
- Brief Summary
Not available
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- Authorised-recruitment may be ongoing or finished
- Sex
- All
- Target Recruitment
- 160
FOR ALL PATIENTS IN ALL SUB-STUDY MODULES:
1. Male or female aged 18 years and older, except patients in Module A must be = 25 years of age.
2. Histological confirmation of advanced/metastatic (Stage IV) urothelial cancer (including any of the following: renal pelvis, ureters, urinary bladder, and/or urethra). Histological confirmation at initial diagnosis is acceptable. Patients must have received at least one prior platinum-containing regimen in a metastatic setting.
AND/OR
Patients must have failed an adjuvant or neo-adjuvant containing regimen within a period of one year prior to the commencement of screening for this study. Patients can have either radiological or histological confirmation of disease progression.
3. Willingness to provide consent for biopsy samples. Tumour biopsies will be required for all patients as described in the protocol. Tumour lesions used for biopsy must not be lesions used as RECIST target lesions (TLs).
Tumour sample requirements:
(i) Mandatory provision of an unstained, archived tumour tissue sample, taken within 3 years of entry into the study and in a quantity sufficient to allow for analysis. A copy of the pathology report related to the archival tissue must also be provided, if available. If no archival tumour sample is available. a fresh biopsy (formalin fixed and paraffin embedded), collected at the same time as the baseline serial tumour biopsies, may be submitted.
AND
(ii) Paired pre- and on-drug tumour biopsies resulting in adequate tissue for analysis will be required for all patients enrolled in each treatment arm in each module of the study. This tumour biopsy is mandatory except if associated with unacceptable clinical risk and after discussion with the Medical Monitor.
4. At least 1 lesion, not previously irradiated, 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 computerised tomography (CT) or magnetic resonance imaging (MRI) which is suitable for accurate repeated measurement.
5. WHO performance status of 0 to 1 with no deterioration between Screening and the first dose of study treatment, and a minimum life expectancy of 12 weeks.
6. Females must be using two highly effective contraceptive measures, must not be breast feeding and must have a negative pregnancy test prior to start of dosing if of child-bearing potential or must have evidence of non-child-bearing potential by fulfilling 1 of the following criteria at screening:
(i) Post-menopausal defined as aged more than 50 years and amenorrhoeic for at least 12 months following cessation of all exogenous hormonal treatments
(ii) Women under 50 years old would be considered postmenopausal if they have been amenorrhoeic for at least 12 months following the cessation of exogenous hormonal treatments, and have serum follicle-stimulating hormone and luteinising hormone levels in the postmenopausal range for the institution
(iii) Documentation of irreversible surgical sterilisation by hysterectomy, bilateral oophorectomy or bilateral salpingectomy but not tubal ligation
7. Male patients must use barrier contraception (ie, condoms).
MODULE A:
1. Male or females =25 years.
2. Central or local confirmation from a previous archival sample that the tumor harbours an FGFR3 mutation or FGFR fusion or local confirmation of tumour FGFR3 mutation or FGFR fusion status from a fresh biopsy taken during s
1. Prior exposure to: other immunotherapy (CTLA-4, PD-1 or PD-L1 inhibitor), other chemotherapy or anticancer agents <4 weeks before the first study dose, radiotherapy of the primary site with wide field <4 weeks or radiotherapy with a limited field for palliation <2weeks. 2. Major surgery<4 wks.3. Unresolved toxicities from prior therapy >CTCAE Grade1. 4.Concurrent chemotherapy, immunotherapy, biologic or hormonal therapy. 5. Immunosuppressive medication within 14 days of MEDI4736. 6. Autoimmune disease =2 yrs; inflammatory bowel disease or diverticulitis; systemic lupus erythematosus; sarcoidosis syndrome, or Wegener syndrome; primary immunodeficiency; organ transplant that requires use of immunosuppressives. 7. Spinal cord compression or brain metastases unless asymptomatic, treated and stable, not requiring steroids for at least 4 wks. 8.Severe or uncontrolled systemic disease. 9. Mean QTc =470 ms, abnormalities in rhythm, conduction or morphology of resting ECG, factors that increase the risk of QTc prolongation or arrhythmic events; uncontrolled hypertension or hypotension; atrial fibrillation with a ventricular rate>100 bpm on an ECG at rest; symptomatic heart failure NYHA Grade II-IV; cardiomyopathy; severe valvular heart disease; uncontrolled angina; stroke or TIA or acute coronary syndrome in the last 6 months 10. Inadequate bone marrow reserve or organ function. 11. Active infection including tuberculosis, hepatitis B, hepatitis C or HIV. 12.Other malignancies, except malignancy treated with curative intent with no active disease for =5 years and felt to be at low risk for recurrence, adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease or adequately treated carcinoma in situ without evidence of disease. 13. Substance abuse <12 months.14. Current refractory nausea/vomiting, malabsorption syndrome, disease significantly affecting gastrointestinal function, resection of the stomach or small bowel, symptomatic inflammatory bowel disease or ulcerative colitis, partial or complete bowel obstruction. 15.Vaccination with live attenuated vaccine<30 days. 16. Hypersensitivity to any drug in the study or drugs with a similar chemical structure. MODULE A 1. Prior exposure to nitrosourea or mitomycin C<6wks; any agent with FGFR inhibition as its primary pharmacology; prior treatment with AZD4547 or randomisation in a study in which included AZD4547. 2. Potent inhibitors or inducers of CYP3A4, inhibitors of CYP2D6 or substrates of CYP3A4 within 2wks (<3wks for St John’s Wort). 3. LVEF <55% by chemotherapy. 4. History of small localized retinal detachments, previous laser treatment or intra-ocular injection for treatment of macular degeneration, dry or wet AMD, retinal vein occlusion or retinal degenerative diseases, or any other clinically relevant chorioretinal defect. 5. Elevated calcium or phosphate.
MODULE B 1.Whole blood transfusions<120 days (packed RBC & platelet transfusions are acceptable, as long as not received <21 days). 2.Concomitant use of known strong or moderate CYP3A inhibitors or inducers. 3.Previous treatment with a PARP inhibitor. 4. MDS or AML and patients with baseline features suggestive of MDS or AML. 5. Creatinine clearance <40 mL/min.
MODULE C 1. Prior exposure to any of the following: nitrosourea or mitomycin C<6 wks before the first dose of study treatment; any agent with Wee1 inhibition as its primary pharmacology; prior treatment with AZD1775 or randomisation in a
Study & Design
- Study Type
- Interventional clinical trial of medicinal product
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method
- Secondary Outcome Measures
Name Time Method