A Study of FAZ053 Single Agent and in Combination With PDR001 in Patients With Advanced Malignancies.

Study Overview
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Brief Summary
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The purpose of this first-in-human study of FAZ053 is to characterize the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD) and antitumor activity of FAZ053 administered Intravenously (i.v.)as a single agent or in combination with PDR001 in adult patients with advanced solid tumors. By blocking the interaction between Programmed Death Ligand-1 (PD-L1) and its receptors, Programmed Death-1 (PD-1) and B7.1, FAZ053 inhibits the PD-L1 immune checkpoint, resulting in activation of an antitumor immune response by activating effector T-cells and inhibiting regulatory T-cells. This study has been designed as a Phase I, open-label, multi-center study with a dose escalation part of FAZ053 as single agent and in combination with PDR001, followed by a dose expansion part of FAZ053 as single agent. FAZ053 will initially be dosed every three weeks. A less frequent dosing regimen such as every 6 weeks may be evaluated in parallel. A patient may continue treatment with FAZ053 single agent or in combination with PDR001 until the patient experiences unacceptable toxicity, confirmed disease progression per immune related Response Criteria and/or treatment is discontinued at the discretion of the investigator or the patient.

Official Title
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A Phase I, Open-label, Multi-center Dose Escalation Study of FAZ053 as Single Agent and in Combination With PDR001 in Adult Patients With Advanced Malignancies

Conditions
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Advanced Solid Tumors, Triple Negative Breast Cancer, Chordoma and Alveolar Soft Part Sarcoma

Intervention / Treatment
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* Drug: FAZ053
* Drug: PDR001


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Written informed consent prior to any procedure. Dose escalation cohorts of FAZ053 single agent and FAZ053 in combination with PDR001: Patients with advanced/metastatic solid tumors with measurable or non-measurable disease as determined by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 who may or may not have received prior treatment with an immune checkpoint inhibitor, who have progressed despite standard therapy, or for whom no standard therapy is available. Dose expansion groups of FAZ053 single agent: Patients with advanced/metastatic solid tumors with at least one measurable lesion as determined by RECIST version 1.1 who may or may not have received prior treatment with an immune checkpoint inhibitor (for FAZ053 single agent no treatment with an anti-PD-L1 inhibitor is permitted), who have progressed despite standard therapy, or for whom no standard therapy is available and fit into one of the following groups: FAZ053 single agent: TNBC/ Chordoma/ ASPS Performance Status (PS) ≤ 2: Patient must have a site of disease amenable to biopsy and be a candidate for tumor biopsy according to the treating institution's guidelines. Patient must be willing to undergo a new tumor biopsy at screening/ baseline and during therapy on this study. Exclusion Criteria: Presence of symptomatic central nervous system (CNS) metastases or CNS metastases that require local CNS-directed therapy (e.g. radiotherapy or surgery) or increasing doses of corticosteroids within the prior 2 weeks. Patients with treated brain metastases should be neurologically stable (for 4 weeks post-treatment and prior to study enrollment) and off of steroids for at least 2 weeks before administration of any study treatment. History of severe hypersensitivity to study treatment excipients and additives or other monoclonal antibodies (mAbs) and/or their excipients. Active, known or suspected autoimmune disease. Patients with vitiligo, residual hypothyroidism only requiring hormone replacement, psoriasis not requiring systemic treatment or conditions not expected to recur in the absence of an external trigger should not be excluded. Patients previously exposed to anti-PD-1/PD-L1 treatment who are adequately treated for skin rash or with replacement therapy for endocrinopathies should not be excluded. Treatment with cytotoxic or targeted antineoplastics within 3 weeks of initiation of study treatment. For cytotoxic agents that have major delayed toxicity a washout period of one cycle is indicated (examples are nitrosoureas and mitomycin C which typically require a 6 week washout). Prior antibodies or immunotherapies require a 6 week washout. Patients receiving systemic chronic steroid therapy or any immunosuppressive therapy (≥ 10mg/day prednisone or equivalent). Topical, inhaled, nasal and ophthalmic steroids are allowed. Active infection requiring systemic antibiotic therapy. Other protocol-defined inclusion/exclusion criteria may apply.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: FAZ053 single agent<br> | Drug: FAZ053<br>* Anti-PD-L1 Antibody<br>|
| Experimental: FAZ053 + PDR001<br> | Drug: FAZ053<br>* Anti-PD-L1 Antibody<br>Drug: PDR001<br>* Anti-PD-1 Antibody<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants with Adverse Events (AEs) as a measure of safety and tolerability |  | throughout the study up to 150 days after end of treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Serum concentration-time profiles of FAZ053 as single agent and FAZ053 in combination with PDR001. |  | 41 months | 
| Presence of anti-FAZ053 and anti-PDR001. |  | 41 months | 
| Concentration of anti-FAZ053 and anti-PDR001. |  | 41 months | 
| Receptor Occupancy (RO) profiles when FAZ053 is given as single agent. |  | 41 months | 
| Total soluble/shed PD-L1 concentration-time profiles when FAZ053 is given as single agent and for FAZ053 in combination with PDR001. |  | 41 months | 
| Histopathology of tumor infiltrating lymphocytes (TILs) by hematoxylin. |  | 41 months | 
| Histopathology of tumor infiltrating lymphocytes (TILs) by eosin (H&E) stain. |  | 41 months | 
| Overall response rate (ORR) per RECIST v1.1 |  | 41 months | 
| Best overall response per RECIST v1.1 |  | 41 months | 
| Disease control rate per RECIST 1.1 |  | 41 months | 
| Progression free survival (PFS) per RECIST 1.1 |  | 41 months | 
| Duration of response per RECIST 1.1 |  | 41 months | 
| Overall response rate (ORR) per immune related Response Criteria (irRC). |  | 41 months | 
| Progression free survival (PFS) per immune related Response Criteria (irRC). |  | 41 months | 
| Characterization of Tumor Infiltrating Lymphocytes (TILs) by Immunohistochemistry (IHC) |  | 41 months | 
| Characterization of myeloid cell infiltrate by IHC. |  | 41 months | 
| Area under the curve (AUC) for FAZ053 as single agent and FAZ053 in combination with PDR001. |  | 41 months | 
| Cmax for FAZ053 as single agent and FAZ053 in combination with PDR001. |  | 41 months | 
| Tmax for FAZ053 as single agent and FAZ053 in combination with PDR001. |  | 41 months | 
| Half-life for FAZ053 as single agent and FAZ053 in combination with PDR001. |  | 41 months | 
| Clast for FAZ053 as single agent and FAZ053 in combination with PDR001. |  | 41 months | 
| Tlast for FAZ053 as single agent and FAZ053 in combination with PDR001. |  | 41 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Phase I, FAZ053, PDR001, Checkpoint inhibitor, PD-L1, PD-1