Clinical trial NCT02936102: A Study of FAZ053 Single Agent and in Combination With PDR001 in Patients With Advanced Malignancies.
Official title: 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
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
Conditions: Advanced Solid Tumors
Triple Negative Breast Cancer
Chordoma and Alveolar Soft Part Sarcoma
Keywords: Phase I
FAZ053
PDR001
Checkpoint inhibitor
PD-L1
PD-1
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2016-10-18
Enrollment: 154
Sex: ALL
Minimum age (years): 18
Maximum age (years): 100
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.


Eligibility criteria: 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.

Primary outcomes:
measure: Number of participants with Adverse Events (AEs) and Serious Adverse Events (SAEs)
timeFrame: throughout the study and up to 150 days after end of treatment (up to approximately 46 months)
measure: Incidence of Dose Limiting Toxicities (DLTs)
timeFrame: 21 days (single agent FAZ053) and 42 days (FAZ053+PDR001)
measure: Dose interruptions and reductions
timeFrame: Up to approximately 41 months
measure: Dose intensity
timeFrame: Up to approximately 41 months
Secondary outcomes:
measure: Serum concentration-time profiles of FAZ053 as single agent and FAZ053 in combination with PDR001.
timeFrame: 41 months
measure: Presence of anti-FAZ053 and anti-PDR001.
timeFrame: 41 months
measure: Concentration of anti-FAZ053 and anti-PDR001.
timeFrame: 41 months
measure: Receptor Occupancy (RO) profiles when FAZ053 is given as single agent.
timeFrame: 41 months
measure: Total soluble/shed PD-L1 concentration-time profiles when FAZ053 is given as single agent and for FAZ053 in combination with PDR001.
timeFrame: 41 months
measure: Histopathology of tumor infiltrating lymphocytes (TILs) by hematoxylin.
timeFrame: 41 months
measure: Histopathology of tumor infiltrating lymphocytes (TILs) by eosin (H&E) stain.
timeFrame: 41 months
measure: Overall response rate (ORR) per RECIST v1.1
timeFrame: 41 months
measure: Best overall response per RECIST v1.1
timeFrame: 41 months
measure: Disease control rate per RECIST 1.1
timeFrame: 41 months
measure: Progression free survival (PFS) per RECIST 1.1
timeFrame: 41 months
measure: Duration of response per RECIST 1.1
timeFrame: 41 months
measure: Overall response rate (ORR) per immune related Response Criteria (irRC).
timeFrame: 41 months
measure: Progression free survival (PFS) per immune related Response Criteria (irRC).
timeFrame: 41 months
measure: Characterization of Tumor Infiltrating Lymphocytes (TILs) by Immunohistochemistry (IHC)
timeFrame: 41 months
measure: Characterization of myeloid cell infiltrate by IHC.
timeFrame: 41 months
measure: Area under the curve (AUC) for FAZ053 as single agent and FAZ053 in combination with PDR001.
timeFrame: 41 months
measure: Cmax for FAZ053 as single agent and FAZ053 in combination with PDR001.
timeFrame: 41 months
measure: Tmax for FAZ053 as single agent and FAZ053 in combination with PDR001.
timeFrame: 41 months
measure: Half-life for FAZ053 as single agent and FAZ053 in combination with PDR001.
timeFrame: 41 months
measure: Clast for FAZ053 as single agent and FAZ053 in combination with PDR001.
timeFrame: 41 months
measure: Tlast for FAZ053 as single agent and FAZ053 in combination with PDR001.
timeFrame: 41 months
Other outcomes:
Locations:
city: New York
country: United States
facility: Memorial Sloan Kettering Cancer Ctr
state: New York
city: Houston
country: United States
facility: UT MD Anderson Cancer Center
state: Texas
city: Toronto
country: Canada
facility: Novartis Investigative Site
state: Ontario
city: Toulouse
country: France
facility: Novartis Investigative Site
city: Tel Aviv
country: Israel
facility: Novartis Investigative Site
city: Milano
country: Italy
facility: Novartis Investigative Site
state: MI
city: Modena
country: Italy
facility: Novartis Investigative Site
state: MO
city: Koto ku
country: Japan
facility: Novartis Investigative Site
state: Tokyo
city: Singapore
country: Singapore
facility: Novartis Investigative Site
city: Sevilla
country: Spain
facility: Novartis Investigative Site
state: Andalucia
city: Barcelona
country: Spain
facility: Novartis Investigative Site
state: Catalunya
city: Taipei
country: Taiwan
facility: Novartis Investigative Site
Study officials:
affiliation: Novartis Pharmaceuticals
name: Novartis Pharmaceuticals
role: STUDY_DIRECTOR
References: