| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Muscle-invasive bladder cancer |
|
| E.1.1.1 | Medical condition in easily understood language |
| Cancer of the bladder which has spread to the muscle tissue surrounding the bladder. |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To assess the safety and tolerability of study treatments given to selected patients with muscle invasive bladder cancer who have progressed following prior therapy, and confirm the dose(s) for further clinical evaluation. |
|
| E.2.2 | Secondary objectives of the trial |
(1) To characterise the pharmacokinetic (PK) profile(s) of study treatments in selected patients in the muscle invasive bladder cancer population.
(2) To investigate the immunogenicity of MEDI4736 (durvalumab) and module specific treatments.
(3) To estimate the overall clinical activity of study treatments in selected patients with muscle invasive bladder cancer progressing on prior therapy using RECIST v1.1 (Response Evaluation Criteria In Solid Tumours). |
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
There are 6 sub-studies (referred to as Modules A, B, C, D, E, and F) currently planned, as follows:
Module A sub-study. AZD4547 and durvalumab + AZD4547. Patients who receive AZD4547 as monotherapy will have the option to cross over to durvalumab as monotherapy at the point of objective progression.
Primary Objective (1): To assess the safety and tolerability of durvalumab given intravenously in combination with AZD4547 given orally to selected patients with MIBC who have progressed following prior therapy, and confirm the combination dose(s) for further clinical evaluation.
Primary Objective (2): To confirm the safety and tolerability of AZD4547 given orally to selected patients with MIBC who have progressed following prior therapy.
Module B sub-study. Durvalumab + olaparib.
Primary Objective: To assess the safety and tolerability of durvalumab given intravenously in combination with olaparib given orally to selected patients with MIBC who have progressed following prior therapy, and confirm the combination dose(s) for further clinical evaluation.
Module C sub-study. Durvalumab + AZD1775
Primary Objective: To assess the safety and tolerability of durvalumab given intravenously in combination with AZD1775 given orally to selected patients with MIBC who have progressed following prior therapy, and confirm the combination dose(s) for further clinical evaluation.
Module C will not be initiated until further information is available from an ongoing clinical study to confirm the dose and schedule appropriate for use with the AZD1775 + MEDI4736 combination.
Module D sub-study. Durvalumab Monotherapy
Primary Objective: To assess the safety and tolerability of durvalumab given intravenously to selected patients with MIBC who have progressed following prior therapy.
Module E sub-study. Durvalumab + vistusertib
Primary Objective: To assess the safety and tolerability of durvalumab given intravenously in combination with vistusertib given orally to selected patients with MIBC who have progressed following prior therapy, and to confirm the combination doses(s) for further clinical evaluation.
Module F sub-study. Durvalumab + AZD9150
Primary Objective: To assess the safety and tolerability of intravenous durvalumab in combination with intravenous AZD9150 to selected patients with MIBC who have progressed following prior therapy, and to confirm the combination doses(s) for further clinical evaluation. |
|
| E.3 | Principal inclusion criteria |
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 screening.
MODULE B:
- For biomarker selected patients, central confirmation that the tumour harbours a deleterious mutation, deletion or truncation in any one of a panel of HRR genes, either from a previous archival or a fresh tumour sample.
MODULE C:
- Central confirmation from either a previous archival tumour biopsy sample or fresh tumour biopsy taken during screening, that the tumour harbours a deletion or inactivating mutation of the CDKN2A or RB1 genes and/or amplification of CCNE1, MYC, MYCL, or MYCN genes.
NO INCLUSION CRITERIA SPECIFIC TO MEDI4736 MONOTHERAPY IN MODULE D.
MODULE E:
1. Patients may be unselected for any biomarkers or may have central confirmation from either a previous archival tumour biopsy sample or fresh tumour biopsy taken during screening, that the tumour harbours amplification of the RICTOR gene or deleterious/loss of function alteration in TSC1 and TSC2 genes.
2. Contraceptive measures must be sustained throughout treatment with vistusertib and for 16-weeks post last dose.
MODULE F:
1. Adequate organ and marrow function as defined below. Transfusions intended to elevate any parameters solely for the intent of meeting study eligibility criteria are not permitted.
-Leukocytes ≥ 3.0 x 10(exp9)/L
-Absolute neutrophil count ≥ 1.5 x 10(exp9)/L
-Platelet count ≥ 100 x 10(exp9)/L.
2. Contraceptive measures must be sustained throughout treatment with AZD9150 and for 180 after the last dose. |
|
| E.4 | Principal exclusion criteria |
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 which included AZD1775. 2. Patient has received another product known to be sensitive to CYP3A4 substrates or CYP3A4 substrates with a narrow therapeutic index, or to be moderate to strong inhibitors/inducers of CYP3A4 which cannot be discontinued 2 wks prior to study start. Co-administration of aprepitant or fosaprepitant during this study is prohibited. 3. Herbal products are not allowed throughout the stud and must be discontinued 7 days prior to first dose.
4. Leptomeningeal carcinomatosis. 5.Cardiac diseases ongoing or in the past 6 months.
THERE ARE NO EXCLUSION CRITERIA SPECIFIC TO MODULE D.
MODULE E. 1. Minor surgery <14 days. 2.Exposure to specific substrates of the drug transporters OATP1B1, OATP1B3, MATE1 and MATE2K.Exposure to strong/moderate inhibitors or inducers of CYP3A4/5, Pgp (MDR1) and BRCP if taken within the stated washout periods. 3. Any haematopoietic growth factors <14 days. 4. Prior treatment with other mTOR inhibitors. 5. Pre-existing renal disease. 6.Any of the following procedures or conditions currently or in the preceding 6 months; coronary artery bypass graft, angioplasty, vascular stent, myocardial infarction, abnormal echocardiogram at baseline.7. Patients with uncontrolled Type 1 or 2 diabetes.
MODULE F 1. AST≥ 2.5 x ULN if no liver metastases or≥ 5 xULN in the presence of liver metastases. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
(1): Number of participants with Adverse Events and/or Dose Limiting Toxicities as a measure of safety and tolerability of durvalumab when given as monotherapy or in combination with AZD4547, AZD1775, olaparib, vistusertib, or AZD9150.
(2): Number of participants with Adverse Events and/or Dose Limiting Toxicities as a measure of safety and tolerability of AZD4547 when given as monotherapy
(3): Changes from baseline in clinical chemistry, haematology and urinalysis parameters
(4): Changes from baseline in vital signs and physical examination
(5): Changes from baseline in ECG findings
(6): Change from baseline in ejection fraction determined by assessing ECHO/MUGA scans. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
(1): 28 Days (35 Days in Module F)
(2): 28 Days
(3): 28 Days
(4): 28 Days
(5): 28 Days
(6): 28 Days |
|
| E.5.2 | Secondary end point(s) |
Module A: (1) AZD4547 plasma PK parameters AUC(0-6), Cmax(ss), Cmin(ss), tmax(ss) for AZD4547; and Cmax(ss), and Cmin(ss), for durvalumab will be derived.
Module A: (2) Anti-drug antibodies (ADA) from confirmatory results: positive or negative; titres (ADA neutralizing antibodies will also be assessed).
Module A: (3) Objective Response Rate (ORR), Disease Control Rate (DCR), Progression-Free Survival (PFS), and Duration of Response (DoR).
Module B: (1) PK parameters for olaparib and metabolites of olaparib: AUC(ss), CL(ss)/F, Cmax(ss), Cmin(ss), tmax(ss),MRAUC(ss), MRCmax(ss). Serum concentration of durvalumab, including Cmax(ss) and Cmin(ss).
Module B: (2) Anti-drug antibodies (ADA) from confirmatory results: positive or negative; titres (ADA neutralizing antibodies will also be assessed).
Module B: (3) Objective Response Rate (ORR), Disease Control Rate (DCR), Progression-Free Survival (PFS), and Duration of Response (DoR).
Module C: (1) PK parameters for AZD1775: AUC, AUC(ss), CL(ss)/F, Cmax(ss), Cmin(ss), tmax(ss). Serum concentrations of durvalumab, including Cmax(ss) and Cmin(ss).
Module C: (2) Anti-drug antibodies (ADA) from confirmatory results: positive or negative; titres (ADA neutralizing antibodies will also be assessed).
Module C: (3) Objective Response Rate (ORR), Disease Control Rate (DCR), Progression-Free Survival (PFS), and Duration of Response (DoR).
Module D: (1) Serum concentration of durvalumab, including Cmax(ss) and Cmin(ss).
Module D: (2) Anti-drug antibodies (ADA) from confirmatory results: positive or negative; titres (ADA neutralizing antibodies will also be assessed).
Module D: (3) Objective Response Rate (ORR), Disease Control Rate (DCR), Progression-Free Survival (PFS), and Duration of Response (DoR).
Module E: (1) Plasma vistusertib concentrations following multiple dosing. Serum concentration of durvalumab, including Cmax(ss) and Cmin(ss).
Module E: (2) Anti-drug antibodies (ADA) from confirmatory results: positive or negative; titres (ADA neutralizing antibodies will also be assessed).
Module E: (3) Objective Response Rate (ORR), Disease Control Rate (DCR), Progression-Free Survival (PFS), and Duration of Response (DoR).
Module F: (1) Plasma AZD9150 concentrations following multiple dosing. Serum concentration of durvalumab, including Cmax(ss) and Cmin(ss).
Module F: (2) Anti-drug antibodies (ADA) from confirmatory results: positive or negative; titres (ADA neutralizing antibodies will also be assessed).
Module F: (3) Objective Response Rate (ORR), Disease Control Rate (DCR), Progression-Free Survival (PFS), and Duration of Response (DoR). |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
All modules: (1) Samples will be collected from subjects at pre-specified times on Cycle 1 - Days 1 and 8, Cycle 2 - Day 1, and Cycle 3 - Day 1.
All modules: (2) Samples will be collected on Day 1 of Cycles 1 and 2, and at the 90 Day follow-up.
All modules: (3) ORR and DCR will be assessed at 16 and 24 wks. PFS and DoR will evaluated up to 12 months. |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| E.7.1.3.1 | Other trial type description |
|
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.1.7.1 | Other trial design description |
|
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 7 |
| E.8.3 |
The trial involves single site in the Member State concerned
| Information not present in EudraCT |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Information not present in EudraCT |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 7 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 21 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Canada |
| France |
| Spain |
| United Kingdom |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| Last Subject Last Visit (LSLV) |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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