Osimertinib and Tegavivint as First-Line Therapy for the Treatment of Metastatic EGFR-Mutant Non-small Cell Lung Cancer

A Phase Ib Study of AZD9291 (Osimertinib) and BC2059 (Tegavivint) as First-Line Therapy in Patients With Metastatic EGFR-Mutant Non-Small Cell Lung Cancer (NSCLC)

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.

Study Overview

• Status: Recruiting
• Conditions: Metastatic Lung Non-Small Cell Carcinoma; Stage IVA Lung Cancer AJCC v8; Stage IVB Lung Cancer AJCC v8; Stage IV Lung Cancer AJCC v8
• Intervention / Treatment: Drug: Osimertinib; Drug: Tegavivint

Detailed Description

PRIMARY OBJECTIVE:

I. Assess the safety and tolerability of osimertinib (AZD9291) in combination with tegavivint (BC2059) in patients with metastatic EGFR-mutant non-small lung cancer (NSCLC) and determine the recommended phase 2 dose (RP2D).

SECONDARY OBJECTIVES:

I. Determine the objective response rate (ORR) in patients with metastatic EGFR-mutant NSCLC treated with the combination of AZD9291 and BC2059.

II. Determine the progression free survival (PFS) in patients with metastatic EGFR-mutant NSCLC treated with the combination of AZD9291 and BC2059.

III. Determine the duration of response (DOR) in patients with metastatic EGFR-mutant NSCLC treated with the combination of AZD9291 and BC2059.

IV. Determine the overall survival (OS) in patients with metastatic EGFR-mutant NSCLC treated with the combination of AZD9291 and BC2059.

CORRELATIVE/EXPLORATORY OBJECTIVES:

I. Evaluate biomarkers of EGFR, Notch3, and beta-catenin pathway activity in tumor biopsies and blood samples.

II. Assess the pharmacokinetics (PK) of AZD9291 and BC2059 in patients with metastatic EGFR-mutant NSCLC.

III. Assess circulating tumor deoxyribonucleic acid (DNA) (ctDNA) at baseline, following 2 and 4 weeks of treatment to evaluate for clearance, and at time of progression to assess for changes in EGFR mutation status.

IV. Measure response using computed tomography (CT) tumor volumetry and dynamic positron emission tomography (PET)/CT.

V. Identify a gene signature that may be predictive of treatment response or resistance using ribonucleic acid (RNA) sequencing of tumor tissue.

OUTLINE:

Patients receive osimertinib orally (PO) once daily (QD) on days 1-28 and tegavivint intravenously (IV) on day 1. Treatment repeats every 28 days for 4 cycles in the absence of disease progression or unacceptable toxicity. Patients then receive osimertinib PO QD on days 1-28. Treatment repeats every 28 days for 4 cycles in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 30 days and then for 4 years.

• Study Type: Interventional
• Enrollment (Estimated): 18
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: The Ohio State University Comprehensive Cancer Center; Phone Number: 800-293-5066; Email: OSUCCCClinicaltrials@osumc.edu

Study Locations

• United States
  • Ohio
    • Columbus, Ohio, United States, 43210
      • Recruiting
      • Ohio State University Comprehensive Cancer Center
      • Contact: Regan M. Memmott, M.D., Ph.D; Phone Number: 614-366-1618; Email: regan.memmott@osumc.edu
      • Principal Investigator: Regan M. Memmott, M.D., Ph.D

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• 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
• Measurable disease as defined by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 criteria
• Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)
• The patient must be able to swallow pills
• Life expectancy > 3 months
• Leukocytes >= 3,000/mcL
• Absolute neutrophil count >= 1,500/mcL
• Platelets >= 100,000/mcL
• Hemoglobin >= 90 g/L
• Total bilirubin =< 1.5 x institutional upper limit normal (ULN) and up to 3 mg/dL for patients with Gilbert's
• Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase ALT (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x institutional ULN and =< 5 x institutional ULN for patients with liver metastases
• Creatinine within 1.5 x ULN OR glomerular filtration rate (GFR) >= 50 mL/min/1.73 m^2 (measured or calculated by Cockcroft and Gault equation) -confirmation of creatinine clearance is only required for patients with creatinine levels above institutional upper limit of normal
• If evidence of chronic hepatitis B virus (HBV) infection, HBV viral load must be undetectable on suppressive therapy if indicated
• If history of hepatitis C virus (HCV) infection, it must be treated and have an undetectable viral load
• Patients with treated brain metastases are asymptomatic and not requiring ongoing treatment
• Patients with new or progressive brain metastases (active brain metastases) or leptomeningeal disease are eligible if the treating physician determines that immediate central nervous system (CNS)-specific treatment is not required and is unlikely to be required during the first cycle of therapy. Clinical stability on a stable dose of decadron is permitted
• Patients with a prior or concurrent malignancy whose natural history or treatment will not interfere with the safety or efficacy assessment of the investigational drugs are eligible for this trial
• Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. To be eligible for this trial, patients must be class 2B or better
• Ability to understand and sign a written informed consent document

Exclusion Criteria:

• 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
• Patients with an uncontrolled intercurrent illness
• Patients with psychiatric illness/social situations that would limit compliance with study requirements
• History of allergic reactions attributed to compounds of similar chemical or biologic composition as BC2059 or AZD9291. Patients with hypersensitivity to any of the inactive excipients should also be excluded
• Currently receiving (or unable to stop use prior to receiving the first dose of study treatment) medications or herbal supplements known to be potent inducers of CYP3A4 (wash-out periods vary. All patients must try to avoid concomitant use of any medications, herbal supplements and/or ingestion of foods with known inducer effects on CYP3A4
• Pregnant women are excluded from this study because BC2059 has the potential for teratogenic or abortifacient effects. There is also an unknown but potential risk for AEs in nursing infants secondary to treatment of the mother with AZD9291 or BC2059. Breastfeeding patients will be excluded
• Patients with a significant history of cardiovascular disease (e.g., myocardial infarction [MI], thrombotic or thromboembolic event in the last 6 months)

• Any of the following cardiac criteria:

  • Mean resting corrected QT interval (corrected QT [QTc] using Fredericia's formula [QTcF]) > 470 msec. RR is the time from the interval of 1 QRS complex to the next measured in seconds and is commonly calculated as (60/HR)
  • Any clinically important abnormalities in rhythm, conduction or morphology of resting ECG (e.g., complete left bundle branch block, third degree heart block, second degree heart block)
  • Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as decompensated heart failure, hypokalemia, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years of age in first degree relatives, or any concomitant medication known to prolong the QT interval
  • Left ventricular ejection fraction (LVEF) < lower limit of normal (LLN) as assessed by either multigated acquisition (MUGA) scan or echocardiogram (ECHO)
• Patients with active malignancies other than NSCLC or patients with prior curatively treated malignancy at high risk of relapse during the study period with the exception of localized squamous or basal cell skin cancers, ductal carcinoma in-situ (DCIS), or indolent cancer currently on observation (i.e. chronic lymphocytic leukemia [CLL] or low-risk prostate cancer)
• Any evidence of severe or uncontrolled systemic disease, including uncontrolled hypertension and active bleeding diatheses, which in the investigator's opinion makes it undesirable for the patient to participate in the trial or which would jeopardize compliance with the protocol, or active infection with human immunodeficiency virus (HIV). Screening for chronic conditions is not required
• Patients who are at risk for impaired absorption of oral medication including, but not limited to, refractory nausea and vomiting, chronic gastrointestinal diseases, inability to swallow the formulated product or previous significant bowel resection that would preclude adequate absorption of AZD9291
• Judgment by the investigator that the patient should not participate in the study if the patient is unlikely to comply with study procedures, restrictions, or requirements
• Involvement in the planning and/or conduct of the study (applies to both investigator staff and/or staff at the study site)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Treatment (osimertinib, tegavivint); Patients receive osimertinib PO QD on days 1-28 and tegavivint IV on day 1. Treatment repeats every 28 days for 4 cycles in the absence of disease progression or unacceptable toxicity. Patients then receive osimertinib PO QD on days 1-28. Treatment repeats every 28 days for 4 cycles in the absence of disease progression or unacceptable toxicity.	Drug: Osimertinib; Given PO; Other Names: AZD-9291; AZD9291; Mereletinib; Tagrisso; Drug: Tegavivint; Given IV; Other Names: BC 2059; BC-2059; BC2059; Tegatrabetan

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Maximum tolerated dose	Up to 28 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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).	Up to 4 years
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.	From initiation of therapy to disease progression or death, assessed up to 4 years
Duration of response		From objective response to disease progression or death, assessed up to 4 years
Overall survival	Survival will initially be modeled using Kaplan-Meier methods, resulting in median survival times with 95% CI, assuming sufficient events have occurred.	From start of treatment until death of any cause, assessed up to 4 years

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
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).	Pre-dose on day 1 of cycles 1, 8, and 15 and day 22 of cycle 1, 96 hours after treatment on days 5 and 19 of cycle 1 and, 4 hours after treatment on day 15 cycle 1
Osimertinib (AZD9291) PK	Assessed by AZD9291 drug levels following combination therapy with BC2059 and AZD9291 in patients with metastatic EGFR activating mutation positive NSCLC.	Pre-dose on day 1 of cycles 1, 8, and 15 and day 22 of cycle 1 and 30 minutes, 1.5 hours, and 4 hours on day 15 cycle 1
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.	Up to 4 years
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.	Up to 4 years
Fludeoxyglucose F 18 (18F-FDG) positron emission tomography (PET) imaging	Assessed by static (standardized uptake value [SUV]max, average SUV, tumor-to-background ratio, metabolic tumor volume, total lesion glycolysis) and dynamic (net influx rate constant and glucose metabolic rate at 30 and 60 minutes) parameters will be assessed in patients with metastatic EGFR activating mutation positive NSCLC. 18F-FDG-PET parameters will also be summarized at baseline and after treatment using mean +/- SEM, range, and median. The changes in the FDG-PET/computed tomography parameter measurements from baseline to after treatment will be compared between responders and non-responders using two sample t-test or Wilcoxon test, whichever is appropriate. Logistics regression model might also be used to identify potential predictive and prognostic biomarkers beyond any genomic alteration with response to study drugs.	Baseline to 4 years

Collaborators and Investigators

• Sponsor: Ohio State University Comprehensive Cancer Center
• Investigators: Principal Investigator: Regan M Memmott, M.D., Ph.D, Ohio State University Comprehensive Cancer Center

Publications and helpful links

Helpful Links

• The Jamesline

Study record dates

Study Major Dates

• Study Start (Actual): January 18, 2022
• Primary Completion (Estimated): December 31, 2024
• Study Completion (Estimated): December 31, 2024

Study Registration Dates

• First Submitted: February 28, 2021
• First Submitted That Met QC Criteria: February 28, 2021
• First Posted (Actual): March 3, 2021

Study Record Updates

• Last Update Posted (Estimated): December 11, 2023
• Last Update Submitted That Met QC Criteria: December 7, 2023
• Last Verified: December 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Neoplasms; Lung Diseases; Neoplasms by Site; Respiratory Tract Neoplasms; Thoracic Neoplasms; Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Carcinoma, Non-Small-Cell Lung; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Protein Kinase Inhibitors; Osimertinib
• Other Study ID Numbers: OSU-20298; NCI-2021-01360 (Registry Identifier: CTRP (Clinical Trial Reporting Program))

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No