PBF-1129 in Patients With NSCLC

Study Overview
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Brief Summary
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Phase I clinical trial in Eastern Cooperative Oncology Group (ECOG) 0-1 patients with locally advanced or metastatic NSCLC to evaluate safety and tolerability of the compound PBF-1129, an Adenosine A2b receptor antagonist. The phase I dose escalation will be conducted 3+3 method. Pharmacokinetic (PK) data will be also obtained.

Official Title
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Phase I Trial of PBF-1129 in Patients With Advanced Non-Small Cell Lung Cancer (NSCLC)

Conditions
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Locally Advanced or Metastatic NSCLC

Intervention / Treatment
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* Drug: PBF-1129


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histological or cytological diagnosis of metastatic squamous or non-squamous NSCLC. Life expectancy greater or equal to 3 months, as determined by the investigator -Patients must have progressed on the standard therapy, including platinum based - chemotherapy. Patients with epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), or ROS-1 mutations must have progressed on standard treatment options including EGFR, ALK, or ROS-1-directed therapies. No limits to the prior lines of treatment ECOG performance status of 0/1 Measurable Disease by RECIST v1.1 Age greater than 18 years. Adequate bone marrow, renal and hepatic function: Absolute neutrophil count (ANC) ≥ 1500 /µL White blood cell count (WBC) t ≥ 2.5 x 109/L (2500/µL) Lymphocyte count ≥ 0.5 x 109/L (500/µL) Platelet count ≥ 100 x 109/L (100,000/µL) without transfusion Hemoglobin ≥ (9.0 g/dL) - patients may be transfused to meet this criterion. Aspartate aminotransferase AST, alanine aminotransferase (ALT), and alkaline phosphatase (ALP) ≤ 2.5 x upper limit of normal (ULN) Serum bilirubin ≤ 1.5 x ULN, with the exception of patients with known Gilbert disease: serum bilirubin level ≤ 3 x ULN Creatinine clearance >60 mL/min (calculated using the Cockcroft-Gault formula) or by 24-hours urine collection Written informed consent and any locally-required authorization obtained from the subject prior to performing any protocol-related procedures, including screening evaluations Subject is willing and able to comply with the protocol for the duration of the study Exclusion Criteria: Participation in another clinical study with an investigational product during the last 4 weeks or 5 half-lives prior to starting on treatment. Symptomatic and/or untreated or actively progressing central nervous system (CNS) metastases or leptomeningeal disease. Patients with a history of treated CNS metastases are eligible, provided that all of the following criteria are met: The patient has not received stereotactic radiotherapy within 7 days prior to initiation of study treatment or whole-brain radiotherapy within 14 days prior to initiation of study treatment. The patient has no ongoing requirement for corticosteroids as therapy for CNS disease. Anti-convulsant therapy at a stable dose is permitted. Serious uncontrolled medical disorder or active infection that would impair the patient's ability to receive study treatment. Concurrent use of other anticancer approved or investigational agents is not allowed. Autoimmune disorder Prior malignancy in past 2 years or as identified in Section 7.2 of this protocol Active or prior documented autoimmune disease within the past 2 years. NOTE: Patients with vitiligo, Grave's disease, or psoriasis not requiring systemic treatment (within the past 2 years) are not excluded. Patients receiving systemic steroids ≥ 10mg/day of prednisone or the equivalent Smoking (cigarettes, cigars or pipes) must be discontinued at least 7 days prior to initiating study drug administration; smoking cessation products (transdermal nicotine patches or chewing gum may be used. Pregnancy or breastfeeding, or intention of becoming pregnant during the study. Female subjects must either be of non-reproductive potential or have a negative serum pregnancy test result within 14 days prior to initiation of study treatment

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: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: PBF-1129_40mg<br> | Drug: PBF-1129<br>* PBF-1129 once a day by oral administration<br>|
| Experimental: PBF-1129_80mg<br> | Drug: PBF-1129<br>* PBF-1129 once a day by oral administration<br>|
| Experimental: PBF-1129_160mg<br> | Drug: PBF-1129<br>* PBF-1129 once a day by oral administration<br>|
| Experimental: PBF-1129_320mg<br> | Drug: PBF-1129<br>* PBF-1129 once a day by oral administration<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Tolerated Dose (MTD) of PBF-1129 | The MTD evaluation will be based on the Dose-limiting Toxicity (DLT) of the treated Population, which includes all subjects who receive any dose of PBF-1129, and will include Adverse events (AEs), Serious Adverse events (SAEs), laboratory evaluations and electrocardiogram (ECG) results | 28 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to PBF-1129 peak concentration in plasma Tmax | The parameter will be calculated from plasma samples collected at days 1 and 29 after drug administration.It will consist in the time (in minutes) to reach the maximum PBF-1129 concentration in plasma samples of patients after oral administration of PBF-1129. | days 1 and 29 | 
| Time to PBF-1129 peak concentration in plasma at steady state Tmax,ss | The parameter will be calculated from plasma samples collected at days 1 and 29 after drug administration. It will consist in the time (in minutes) to reach the maximum PBF-1129 concentration in plasma samples of patients during a dosing interval at steady state. | days 1 and 29 | 
| PBF-1129 peak concentration in plasma Cmax | The parameter will be calculated from plasma samples collected at days 1 and 29 after drug administration. It will consist in the maximum plasma concentration (ng/mL) of PBF-1129 observed after administration. | days 1 and 29 | 
| PBF-1129 peak concentration in plasma at steady stateCmax,ss | The parameter will be calculated from plasma samples collected at days 1 and 29 after drug administration.It will consist in the maximum plasma concentration (ng/mL) of PBF-1129 observed during a dosing interval at steady state. | days 1 and 29 | 
| The area under PBF-1129 plasma concentration-time curve to infinite time AUC(0-inf) | The parameter will be calculated from plasma samples collected at days 1 and 29 after drug administration. It will consist in the area under the concentration-time curve from zero up to ∞ with extrapolation of the terminal phase. AUC(0-inf) will be given in Amount·time/ volume units | days 1 and 29 | 
| The area under PBF-1129 plasma concentration-time curve up to time 't' AUC(0-t) | The parameter will be calculated from plasma samples collected at days 1 and 29 after drug administration.It will consist in the area under the concentration-time curve from zero up to a definite time t. AUC(0-t) will be given in Amount·time/ volume units. | days 1 and 29 | 
| The area under PBF-1129 plasma concentration-time curve over the dosing interval AUC(0-τ) | The parameter will be calculated from plasma samples collected at days 1 and 29 after drug administration. It will consist in the area under the concentration-time curve over the dosing interval. AUC(0-τ) will be given in Amount·time/ volume units. | days 1 and 29 | 
| PBF-1129 half-life in plasma  t½ | The parameter will be calculated from plasma samples collected at days 1 and 29 after drug administration. It will consist in the terminal half-life of PBF-1129 in plasma. t½ will be given in hours (h) | days 1 and 29 | 
| Efficacy as measured by Objective response rate (ORR) | ORR: Response and progression will be evaluated in this study using the new international criteria proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1).ORR is defined as confirmed complete response (CR) or partial response (PR) based on modified RECIST v1.1. | 2 years | 
| Efficacy as measured by Disease control rate (DCR) | The disease control rate (DCR) will be estimated considering the following variables: Complete response (CR), Partial response (PR) and stable disease (SD) as described by Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1). These variables will be assessed based on Imaging-based evaluation methods as chest x-ray, conventional computed tomography (CT) and magnetic resonance imaging (MRI) that will be performed every 2 cycles of 28 days administration. | 2 years | 
| Efficacy as measured by duration of response (DoR) | Duration of response (DoR) is defined as the duration from the first documentation of OR to the first documented disease progression or death due to any cause, whichever occurs first | 2 years | 
| Efficacy as measured by progression-free survival (PFS) | Progression-free survival (PFS) will be measured from the start of treatment until the documentation of disease progression or death due to any cause, whichever occurs first. For subjects who are alive and progression-free at the time of data cut-off for analysis, PFS will be censored at the last tumor assessment date. | 2 years | 
| Efficacy as measured by overall survival (OS) | Overall survival (OS) will be determined as the time from the start of treatment until death due to any cause. | 2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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immune system activator, adenosine receptors, checkpoint inhibitors