PBF-1129 and Nivolumab for the Treatment of Recurrent or Metastatic Non-Small Cell Lung Cancer

Study Overview
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Brief Summary
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This phase I trial studies the side effects and best dose of PBF-1129 in combination with nivolumab in treating patients with non-small cell lung cancer that has come back (recurrent) or spread to other places in the body (metastatic). Immunotherapy with monoclonal antibodies, such as PBF-1129 and nivolumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread.

Detailed Description
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PRIMARY OBJECTIVE: I. To determine the safety and tolerability of the combination of adenosine A2B receptor antagonist PBF-1129 (PBF-1129) and nivolumab in patients with advanced non-small cell lung cancer (NSCLC) based upon the Common Terminology Criteria for Adverse Events (CTCAE) version 5 criteria. SECONDARY OBJECTIVE: I. To determine the efficacy of the combination of PBF-1129 and nivolumab in patients with advanced NSCLC, including progression-free survival (PFS), objective response (ORR), disease control rate (DCR), and overall survival (OS) based on Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. EXPLORATORY OBJECTIVES: I. To study the effect of PBF-1129 on the levels of myeloid-derived suppressor cells (MDSC) within the tumor microenvironment (TME) and in peripheral blood of study patients. II. To evaluate correlative biomarkers that might predict disease response to treatment with PBF-1129 and nivolumab therapy in previously treated NSCLC patients including STK11 genetic alterations and a transcriptional signature of LKB1 functional status developed by the Carbone lab. OUTLINE: This is a dose-escalation study of PBF-1129 given in combination with immune checkpoint blockade. Patients receive adenosine A2B receptor antagonist PBF-1129 (PBF-1129) orally (PO) once daily (QD) and nivolumab intravenously (IV) on day 1. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up every 12 weeks for up to 1 year.

Official Title
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A Phase Ib Trial of PBF-1129 and Nivolumab in Patients With Advanced Non-Small Cell Lung Cancer

Conditions
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Metastatic Lung Non-Small Cell Carcinoma, Recurrent Lung Non-Small Cell Carcinoma, Stage IV Lung Cancer AJCC v8, Stage IVA Lung Cancer AJCC v8, Stage IVB Lung Cancer AJCC v8

Intervention / Treatment
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* Drug: Adenosine A2B Receptor Antagonist PBF-1129
* Procedure: Biospecimen Collection
* Biological: Nivolumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age >= 18 years Confirmed recurrent or metastatic non-small cell carcinoma of the lung of any histology without curative options Measurable disease based on RECIST 1.1 Patients must have received standard of care chemotherapy and immunotherapy. No limits to prior lines of therapy. Prior PD-1 and/or PD-L1 directed therapies are required. Prior CTLA4 therapy is permitted. Patients may have received no more than 3 prior lines of therapy in the metastatic setting Patients with known actionable mutations with Food and Drug Administration (FDA)-approved treatment options must have received all approved and standard of care treatment options (ie osimertinib for EGFR, alectinib for ALK, etc) Eastern Cooperative Oncology Group (ECOG) performance status of 0-1 Absolute neutrophil count (ANC) >= 1,500 /mcL Platelets >= 100,000 / mcL Serum creatinine OR measured or calculated creatinine clearance (glomerular filtration rate [GFR] can also be used in place of creatinine or creatinine clearance [CrCl]) =< 1.5 X upper limit of normal (ULN) OR >= 60 mL/min for subject with creatinine levels > 1.5 X institutional ULN Serum total bilirubin =< 1.5 X ULN OR direct bilirubin =< ULN for subjects with total bilirubin levels > 1.5 ULN AAspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 X ULN OR =< 5 X ULN for subjects with liver metastases Albumin >= 2.5 mg/dL International normalized ratio (INR) or prothrombin time (PT) or activated partial thromboplastin time (aPTT) =< 1.5 X ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants =< 1.5 X ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants Anticipated life expectancy of >= 3 months Willing to comply with study procedures Must be able to swallow pills Female subjects of childbearing potential must be willing to use an adequate method of contraception For female patients of childbearing potential, a negative serum pregnancy test within 7 days prior to first dose of protocol therapy is required Be willing and able to understand and sign the written informed consent document Availability of a recent formalin-fixed, paraffin-embedded (FFPE) tumor tissue block. A recently obtained archival FFPE tumor tissue block (if an FFPE tissue block cannot be provided, 15 unstained slides (10 minimum) will be acceptable) from a primary or metastatic tumor resection or biopsy can be provided if it was obtained within 1 year of trial screening For patients in dose expansion cohort: Be willing to provide tissue from a pre-treatment and on-treatment fin needle aspirate (FNA) or core biopsy of a tumor lesion. Subjects must consent to pre-treatment and on-treatment biopsy prior to initiation of clinical trial, however subjects for whom newly-obtained samples cannot be provided (e.g. inaccessible or subject safety concern) may still continue on study Be willing to provide peripheral blood samples for correlative studies Exclusion Criteria: Has active autoimmune disease, including myasthenic syndrome, which has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy (at a dose > 10 mg prednisone or equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment Known active chronic infections - human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS), known active (ie with detectable polymerase chain reaction [PCR]) Hepatitis B or C Cirrhosis (Child-Pugh B or worse) or cirrhosis with history of hepatic encephalopathy or clinically meaningful ascites resulting from cirrhosis. Clinically meaningful ascites is defined as ascites from cirrhosis requiring diuretics or paracentesis Untreated central nervous system (CNS) metastases. Patients with treated brain metastases are eligible if they are clinically stable with regard to neurologic function, on stable dose of steroids after cranial irradiation with maximum of 10 mg prednisone equivalent. Treatment (whole brain radiation therapy, focal radiation therapy, and stereotactic radiosurgery) must be completed at least 2 weeks prior to randomization, or after surgical resection performed at least 28 days prior to treatment initiation Pregnancy or breastfeeding Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject's participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator Any of the following cardiac criteria: Mean resting corrected QT interval (corrected QT [QTc] using Fredericia's formula [QTcF]) > 470 msec (Fridericia's Criteria for Corrected QT interval [QTc] Calculation: Fridericia's formula QTcF = (QT/RR0.33). RR is the time from the interval of 1 QRS complex to the next measured in seconds and is commonly calculated as (60/heart rate [HR]) Any clinically important abnormalities in rhythm, conduction or morphology of resting electrocardiogram (ECG) (e.g., complete left bundle branch block, third degree heart block, second degree heart block Any patient who experience unacceptable toxicity on prior checkpoint inhibitor therapy: >= grade 3 adverse event (AE) related to checkpoint inhibitor Ongoing >= grade 2 immune-related AE associated with checkpoint inhibitor with the exception of endocrine toxicities as detailed below CNS, ocular or cardiac AE of any grade related to checkpoint inhibitor NOTE: Patients with a prior endocrine AE are permitted to enroll if they are stably maintained on appropriate replacement therapy and are asymptomatic

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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (PBF-1129, nivolumab)<br>Patients receive PBF-1129 PO QD and nivolumab IV on day 1. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. | Drug: Adenosine A2B Receptor Antagonist PBF-1129<br>* Given PO<br>* Other names: PBF1129;Procedure: Biospecimen Collection<br>* Correlative studies<br>* Other names: Biospecimen Collected;Biological: Nivolumab<br>* Given IV<br>* Other names: Opdivo;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of adverse events | Safety will be measured by the occurrence of dose-limited toxicities as well as any other adverse events as defined in Common Terminology Criteria for Adverse Events version 5. Frequency and severity of adverse events and tolerability of the regimen will be collected and summarized by descriptive statistics. The maximum grade for each type of toxicity will be recorded for each patient, and frequency tables will be reviewed to determine toxicity patterns. All patients who have received at least one dose of the therapeutic agents will be evaluable for toxicity and tolerability. | Up to 30 days after the last dose of study treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall objective response rate | Will be calculated and exact binomial 95% confidence interval (CI) will be provided. | Up to 1 year after treatment discontinuation | 
| Disease control rate | Will be calculated and exact binomial 95% CI will be provided. | Up to 1 year after treatment discontinuation | 
| Overall survival | Will be defined as time from initiation of therapy to death, or censored at last follow-up date if the subject is alive. Kaplan-Meier methods will be used to estimate overall survival with 95% CI. | Up to 1 year after treatment discontinuation | 
| Progression free survival | Will be defined as the time from initiation of therapy to the time of Response Evaluation Criteria in Solid Tumors progression or death. Kaplan-Meier methods will be used to estimate progression free survival with 95% CI. | Up to 1 year after treatment discontinuation |