Estudio de fase 1b, abierto, aleatorizado, con múltiples fármacos, dirigido por biomarcadores en pacientes con cáncer de vejiga con invasión muscular (BISCAY)

MEDI4736

• Durvalumab

MEDI4736 (durvalumab) + Selumetinib

AZD4547 will be given orally twice daily until disease progression.

Patients who receive AZD4547 as monotherapy will have the option to cross over to durvalumab as monotherapy at the point of objective progression, as long as the following criteria are met:

• The investigator believes it is in the patient's interest to receive durvalumab;
• The patient consents to the continued treatment;
• It is clinically appropriate for the patient to continue on durvalumab treatment;
• The patient satisfies the key eligibility criteria for receiving durvalumab treatment.

AZD4547 Monotherapy vs. MEDI4736 (durvalumab) + AZD4547 1:1 Randomization.

AZD4547 will be given orally twice daily until disease progression. Patients will also receive MEDI 4736 (durvalumab) by IV infusion once every 4 weeks.

AZD4547 Monotherapy vs. MEDI4736 (durvalumab) + AZD4547 1:1 Randomization.

MEDI4736

• Durvalumab

MEDI4736 (durvalumab) will be given by IV infusion once every 4 weeks. Olaparib will be given orally twice daily.

MEDI4736

• Durvalumab

MEDI4736 (durvalumab) + Olaparib

• Lynparza

MEDI4736 (durvalumab) will be given by IV infusion once every 4 weeks. AZD1775 will be given orally in approximate 12 hour intervals over 3 days (6 doses) on Days 1-3, 8-10, and 15-17 of 28 day cycles.

MEDI4736

• Durvalumab

MEDI4736 (durvalumab) + AZD1775

MEDI 4736 (durvalumab) will be given by IV infusion once every 4 weeks.

MEDI4736

• Durvalumab

MEDI4736 (durvalumab) will be given by IV infusion once every 4 weeks. Vistusertib will be given orally twice per day on an intermittent schedule (2 days on, 5 days off).

MEDI4736

• Durvalumab

MEDI4736 (durvalumab) + Vistusertib

AZD9150 will be given as monotherapy on Days -7, -5, and -3 of a one week lead-in period. Combination dosing with IV AZD9150 followed by IV MEDI4736 (durvalumab) begins on Day 1 of each 28 day cycle. Thereafter AZD9150 is given weekly and MEDI4736 is given once every 4 weeks.

MEDI4736

• Durvalumab

MEDI4736 (durvalumab) + AZD9150

The frequency and nature of adverse events will be assessed in order to determine the safety and tolerability of AZD4547 monotherapy given orally to selected patients with MIBC who have progressed following prior therapy.

The frequency and nature of adverse events will be assessed in order to determine the safety and tolerability of MEDI4736 (durvalumab) given intravenously in combination with AZD4547 given orally to selected patients with MIBC who have progressed following prior therapy.

The frequency and nature of adverse events will be assessed in order to determine the safety and tolerability of MEDI4736 (durvalumab) given intravenously in combination with olaparib given orally to selected patients with MIBC who have progressed following prior therapy.

The frequency and nature of adverse events will be assessed in order to determine the safety and tolerability of MEDI4736 (durvalumab) given intravenously in combination with AZD1775 given orally to selected patients with MIBC who have progressed following prior therapy.

The frequency and nature of adverse events will be assessed in order to determine the safety and tolerability of MEDI4736 (durvalumab) monotherapy given intravenously to selected patients with MIBC who have progressed following prior therapy.

The frequency and nature of adverse events will be assessed in order to determine the safety and tolerability of MEDI 4736 (durvalumab) given intravenously in combination with vistusertib given orally to selected patients with MIBC who have progressed following prior therapy.

The frequency and nature of adverse events will be assessed in order to determine the safety and tolerability of intravenous MEDI4736 (durvalumab) in combination with intravenous AZD9150 in selected patients with MIBC who have progressed following prior therapy.

The frequency and nature of adverse events will be assessed in order to determine the safety and tolerability of MEDI 4736 (durvalumab) given intravenously in combination with selumetinib given orally to selected patients with MIBC who have progressed following prior therapy.

Changes from baseline in clinical chemistry parameters will be assessed in order to determine the safety and tolerability of the drug regimen chosen in the sub study module for patients with MIBC who have progressed following prior therapy.

Changes from baseline in haemotology parameters will be assessed in order to determine the safety and tolerability of the drug regimen chosen in the sub study module for patients with MIBC who have progressed following prior therapy.

Changes from baseline in urinalysis findings will be assessed in order to determine the safety and tolerability of the drug regimen chosen in the sub study module for patients with MIBC who have progressed following prior therapy.

Changes from baseline in vital signs will be assessed in order to determine the safety and tolerability of the drug regimen chosen in the sub study module for patients with MIBC who have progressed following prior therapy.

Changes from baseline in physical examination findings will be assessed in order to determine the safety and tolerability of the drug regimen chosen in the sub study module for patients with MIBC who have progressed following prior therapy.

Changes from baseline in ECG findings will be assessed in order to determine the safety and tolerability of the drug regimen chosen in the sub study module for patients with MIBC who have progressed following prior therapy.

Changes from baseline in ejection fraction determined by assessing ECHO/MUGA scans will be assessed in order to determine the safety and tolerability of the drug regimen chosen in the sub study module for patients with MIBC who have progressed following prior therapy.

Changes from baseline in coagulation parameters will be assessed in order to determine the safety and tolerability of the drug regimen chosen in the sub study module for patients with MIBC who have progressed following prior therapy.

Changes from baseline in lipid profile will be assessed in order to determine the safety and tolerability of the drug regimen chosen in the sub study module for patients with MIBC who have progressed following prior therapy.

The percentage of patients who have a confirmed visit response of Complete Response (CR) or Partial Response (PR) as assessed by the investigator per RECIST 1.1.

Data obtained up until progression, or the last evaluable assessment in the absence of progression, will be included in the assessment of ORR.

Percentage of patients who have a confirmed visit response of CR or PR or stable disease (SD) ≥16 weeks as assessed by the investigator as per RECIST 1.1

The time from randomization until the date of objective disease progression or death (from any cause in the absence of progression) regardless of whether the patient withdraws from assigned therapy or receives another anticancer therapy prior to progression. Patients who have not progressed or died at the time of analysis will be censored at the time of the latest date of assessment from their last evaluable RECIST 1.1 assessment.

Duration of response is defined as the elapsed time from the date of first documented response (CR/PR) as per RECIST Version 1.1 as assessed by the investigator until the date of documented progression or death in the absence of disease progression. The time of the initial response is defined as the latest of the dates contributing towards the first visit response of PR or CR.

Defined as the proportion of patients surviving after 1 year from the start of treatment.

The timing of the PK samples may be adjusted during the study, dependent on emerging data, in order to ensure appropriate characterisation of the plasma concentration-time profiles.

The timing of the PK samples may be adjusted during the study, dependent on emerging data, in order to ensure appropriate characterisation of the plasma concentration-time profiles.

The timing of the PK samples may be adjusted during the study, dependent on emerging data, in order to ensure appropriate characterisation of the plasma concentration-time profiles.

The timing of the PK samples may be adjusted during the study, dependent on emerging data, in order to ensure appropriate characterisation of the plasma concentration-time profiles.

The timing of the PK samples may be adjusted during the study, dependent on emerging data, in order to ensure appropriate characterisation of the plasma concentration-time profiles.

The timing of the PK samples may be adjusted during the study, dependent on emerging data, in order to ensure appropriate characterisation of the plasma concentration-time profiles.

The timing of the PK samples may be adjusted during the study, dependent on emerging data, in order to ensure appropriate characterisation of the plasma concentration-time profiles.

The timing of the PK samples may be adjusted during the study, dependent on emerging data, in order to ensure appropriate characterisation of the plasma concentration-time profiles.

The timing of the PK samples may be adjusted during the study, dependent on emerging data, in order to ensure appropriate characterisation of the plasma concentration-time profiles.

The timing of the PK samples may be adjusted during the study, dependent on emerging data, in order to ensure appropriate characterisation of the plasma concentration-time profiles.

The formation of anti-drug antibodies and neutralizing antibodies will be assessed by validated methods.

Plasma and serum samples will be collected and assessed for circulating tumour DNA to explore the mutation status of cancer associated genes.

Biomarker analysis of blood and tissue to assess exploratory markers, which may include but is not limited to:

• immune cell gene expression profiles and cytokine profiles within the peripheral and tumoural compartments,
• the presence of IFN-γ, tumour necrosis factor-α, IL-2, IL-6, IL-10, IL-8, and IL-12 as well as antibodies against tumour, self, or viral antigens,
• expression of PD-L1,
• CD8 and the number and phenotype of immune cells such as T-cells.

Markers relevant to the targeted therapy, for example FGFR and ligand expression and PD markers, for example pErk, pS6 and γH2AX will also be measured in tumour paired biopsy samples.

Biomarker assessments that may have the potential to identify patients likely to respond to treatment with the agents studied in this modular protocol will be investigated to determine a patient's biomarker status and for possible correlation with efficacy endpoints.

To explore potential biomarkers in residual biological samples (e.g., tumour, plasma and/or serum) which may influence development of cancer (and associated clinical characteristics) and/or response.

To estimate the overall survival for patients have been pre-screened but do not enter the main part of the study.

The percentage of patients who have a confirmed response of CR or PR as assessed by the investigator using a modified RECIST 1.1. Modified RECIST 1.1 will be used for patients receiving MEDI4736 because of response may occur after progression has been initially determined. Patients receiving MEDI4736 may continue to receive treatment and be followed after an initial assessment of progression until subsequent confirmation. Confirmed progression is defined as ≥20% increase in sum of diameters of target lesions compared to the nadir at 2 consecutive visits; and/or significant progression (worsening) of non-target lesions (NTLs) or new lesions (NLs) at the confirmatory scan; and/or new unequivocal lesions at the confirmatory scan. If progression is not confirmed then the visit response is assessed as SD/PR or CR and the patient should continue scheduled scans. If progression is confirmed the visit response should be assessed as progressive disease.