This phase Ib trial is to find out the best dose, possible benefits and/or side effects of osimertinib and tegavivint as first-line therapy in treating patients with EGFR-mutant non-small cell lung cancer that has spread to other places in the body (metastatic). Osimertinib and tegavivint may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.
Age >= 18 years. Children are excluded from this study because neither dosing nor safety data are currently available for AZD9291 or BC2059 in patients < 18 years of age
Pathology-confirmed metastatic NSCLC
A common activating mutation must be present in the EGFR gene, i.e., exon 19 deletion or L858R. The presence of uncommon EGFR mutations, e.g., G719X, S768I, or L861Q are also permitted if they co-occur with a common activating mutation. Mutation status must be determined using a tumor biopsy by local Clinical Laboratory Improvement Act (CLIA)-certified assessment. Mutations identified by blood-based testing can be provided, but must be verified by tumor biopsy
The presence of a concurrent T790M mutation, while uncommon in patients who are naïve to treatment with EGFR TKIs, is also permitted
Prior treatment with an EGFR TKI in any setting
Patients who have not recovered from adverse events (AEs) due to prior anti-cancer therapy (i.e., have residual toxicities > grade 1), with the exception of alopecia
Past medical history of interstitial lung disease, drug-induced interstitial lung disease, radiation pneumonitis requiring steroid treatment, or any evidence of clinically active interstitial lung disease
Patients who are receiving any other investigational agent or immunotherapy within five half-lives of the compound or 3 months, whichever is greater
Single group
Osimertinib
DrugGiven PO
Tegavivint
DrugGiven IV
Echocardiography Test
Procedure/SurgeryUndergo ECHO
Multigated Acquisition Scan
Procedure/SurgeryUndergo MUGA scan
Computed Tomography
Procedure/SurgeryUndergo CT
FDG-Positron Emission Tomography
Procedure/SurgeryUndergo 18F-FDG PET
Biospecimen Collection
Procedure/SurgeryUndergo blood and/or tissue sample collection
Maximum tolerated dose
Overall response rate (ORR)
Defined as patients with complete or partial response using Response Evaluation Criteria in Solid Tumors (RECIST) version (v)1.1. will be calculated as the proportion of patients who achieve a response to therapy divided by the total number of evaluable patients. An evaluable patient is defined as an eligible patient who has received at least one dose of therapy. All evaluable patients will be included in calculating the ORR for the study along with corresponding 95% binomial confidence intervals (CIs) (assuming that the number of patients who respond is binomially distributed).
Progression free survival
Survival will initially be modeled using Kaplan-Meier methods, resulting in median survival times with 95% CI, assuming sufficient events have occurred.
Duration of response
Overall survival
Survival will initially be modeled using Kaplan-Meier methods, resulting in median survival times with 95% CI, assuming sufficient events have occurred.
Tegavivint (BC2059) pharmacokinetics (PK)
Assessed by BC2059 drug levels following combination therapy with BC2059 and AZD9291 in patients with metastatic EGFR activating mutation positive non-small cell lung cancer (NSCLC).
Osimertinib (AZD9291) PK
Assessed by AZD9291 drug levels following combination therapy with BC2059 and AZD9291 in patients with metastatic EGFR activating mutation positive NSCLC.
Β-catenin pathway activity
Will be evaluated by measuring serum levels of the secreted transcriptional targets, PAI1 and MMP7 pre- and post-treatment. EGFR and Notch3/B-catenin expression, cellular localization, and pathway activity will also be assessed in voluntary serial tumor biopsies using immunohistochemical analysis.
Circulating tumor deoxyribonucleic acid (ctDNA)
Will be assessed pre- and posttreatment to evaluate for clearance, as well as at time of progression to assess for changes in EGFR mutation status.
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