Last updated on June 2018

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


Brief description of study

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

Detailed Study Description

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 (sub-studies), each evaluating the safety and tolerability of a specific agent or combination in patients whose tumours express specific mutations 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 mutations identified in their tumours.

Module A includes an AZD4547 monotherapy arm and a durvalumab + AZD4547 combination therapy arm. Patients who receive AZD4547 monotherapy will have the option to cross over to durvalumab as a monotherapy treatment at the point of objective progression. Module A will investigate the safety and tolerability of durvalumab 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 evaluate the durvalumab + AZD4547 combination dose(s) for further clinical evaluation and assess 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 by dose-limiting toxicity. An expansion cohort(s) in Module A will enroll additional patients to explore further the safety, tolerability, pharmacokinetics and biological activity at the selected AZD4547 plus durvalumab dose(s). 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 investigator believes it is in the patient's interest to continue MEDI4736 monotherapy.

Module B will evaluate durvalumab + olaparib combination dose(s) to confirm the safety and tolerability of durvalumab given intravenously in combination with olaparib (AZD2281). Olaparib will be given orally to selected patients with muscle invasion bladder cancer (MIBC) whose tumors have deleterious mutations, deletions or truncations in any one of a panel of homologous recombination repair (HRR) genes, and whose disease had progressed following prior therapy.

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

Module D will evaluate durvalumab monotherapy treatment to confirm the safety and tolerability of durvalumab given intravenously as monotherapy to patients with MIBC who do not qualify for Modules A, B or C. This sub-study will not be restricted to any PD-L1 defined sub-population and it is intended to perform retrospective analysis of PD-L1 so that patients with positive PD-L1 status are included in this monotherapy module.

Module E will evaluate the safety and tolerability of durvalumab given intravenously, in combination with vistusertib (AZD2014) given orally to patients with MIBC whose disease has progressed following prior therapy. Patients who enter this sub study will be those whose tumours do not show mutations that would be eligible for other study modules, with the exception of the following mutations that have potential to respond to an mTOR inhibitor: RICTOR amplification, or TSC1/2 mutations.

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

Clinical Study Identifier: NCT02546661

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AstraZeneca Clinical Study Information Center

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Baltimore, MD United States
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Kansas City, MO United States
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New York, NY United States
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Cincinnati, OH United States
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Cleveland, OH United States
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Nashville, TN United States
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Milwaukee, WI United States
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AstraZeneca Clinical Study Information Center

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Marseille Cedex 9, France
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Saint Herblain Cedex, France
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Los Angeles, CA United States
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New Haven, CT United States
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Detroit, MI United States
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