A Phase 1b Safety and Pharmacodynamic Study of MER Tyrosine Kinase Inhibitor, MRX-2843, in Combination With Osimertinib in Advanced EGFR Mutant Non-Small Cell Lung Cancer
Overview
- Phase
- Phase 1
- Status
- Recruiting
- Sponsor
- Emory University
- Enrollment
- 69
- Locations
- 1
- Primary Endpoint
- Maximum tolerated dose (MTD)
Overview
Brief Summary
This phase Ib trial evaluates the best dose and side effects of MRX-2843 when given in combination with osimertinib in treating patients with EGFR gene mutant non-small cell lung cancer that has spread to other places in the body (advanced). MRX-2843 and osimertinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.
Detailed Description
PRIMARY OBJECTIVES:
I. Assess the safety and tolerability of MRX-2843 (MRX-2843) when administered along with osimertinib.
II. Establish the recommended phase 2 dose (RP2D) of the tested combinations.
SECONDARY OBJECTIVES:
I. To observe and record anti-tumor activity. II. To perform biomarker profiling in order to identify potential predictive biomarker to optimize treatment efficacy.
OUTLINE: This is a dose-escalation study of MRX-2843.
Patients receive osimertinib orally (PO) once daily (QD) and MRX-2843 PO QD on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up for minimum of 30 days, or until resolution of treatment-related toxicity to =< grade 1, whichever is longer after removal from study.
Study Design
- Study Type
- Interventional
- Allocation
- Na
- Intervention Model
- Single Group
- Primary Purpose
- Treatment
- Masking
- None
Eligibility Criteria
- Ages
- 18 Years to — (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- •Patients must have histologically confirmed metastatic non-small cell lung cancer (NSCLC) with activating EGFR mutation including typical and atypical mutations in egfr exons 19 and 21
- •Eastern Cooperative Oncology Group (ECOG) performance status of 0-2
- •Patients in the expansion cohort must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded for non-nodal lesions and short axis for nodal lesions) as \>= 20 mm (\>= 2 cm) by chest x-ray or as \>= 10 mm (\>= 1 cm) with computed tomography (CT) scan, magnetic resonance imaging (MRI), or calipers by clinical exam
- •Ability to safely swallow oral medication
- •Absolute neutrophil count \>= 1500/mm\^3
- •Platelet count \>= 100,000/mm\^3
- •Hemoglobin \>= 8.5 g/dL (must be \> 2 weeks post-red blood cell transfusion)
- •Bilirubin =\< 1.5 x the upper limit of normal (ULN). For subjects with documented Gilbert's disease, bilirubin =\< 3.0 mg/dL. For subjects with documented liver metastases, bilirubin =\< 2.5 x ULN
- •Serum creatinine =\< 1.5 x the ULN or creatinine clearance (CrCl) \>= 50 mL/min. For creatinine clearance estimation, the Cockcroft and Gault equation should be used
- •Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =\< 3 x the ULN (=\< 5 x the ULN for subjects with liver metastases)
Exclusion Criteria
- •Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study
- •Patients who have not recovered from adverse events due to prior anti-cancer therapy (i.e., have residual toxicities \> grade 1)
- •Patients who are receiving any other investigational agents
- •Patients with symptomatic untreated brain metastases would be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events. Patient with treated or asymptomatic untreated brain metastasis is allowed on study
- •History of allergic reactions attributed to compounds of similar chemical or biologic composition to MRX-2843 or osimertinib
- •Patients with known diagnosis of interstitial lung disease/pneumonitis
- •Patients with corrected QT (QTc) interval prolongation \> 500 msec (average of 3 readings), family history of congenital long QTc syndrome or torsades
- •Patients with known cardiomyopathy or decreased left ventricular ejection fraction (LVEF) \< 50%
- •Patient with known history of keratitis or symptoms suggestive of keratitis (such as eye inflammation, lacrimation, light sensitivity, blurred vision, eye pain and/or red eye)
- •Patients receiving any medications or substances that are inhibitors or inducers of CYP450 enzyme(s) are ineligible. Because the lists of these agents are constantly changing, it is important to regularly consult a frequently-updated medical reference. As part of the enrollment/informed consent procedures, the patient will be counseled on the risk of interactions with other agents, and what to do if new medications need to be prescribed or if the patient is considering a new over-the-counter medicine or herbal product
Arms & Interventions
Treatment (osimertinib, MRX-2843)
Patients receive osimertinib PO QD and MRX-2843 PO QD on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Intervention: Flt3/MerTK Inhibitor MRX-2843 (Drug)
Treatment (osimertinib, MRX-2843)
Patients receive osimertinib PO QD and MRX-2843 PO QD on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Intervention: Osimertinib (Drug)
Outcomes
Primary Outcomes
Maximum tolerated dose (MTD)
Time Frame: Up to 3.5 years after study start
The computation of the dose to be administered to each patient and the 95% highest posterior density credible interval estimate of the MTD will be carried out using computer program escalation with overdose control (EWOC) version 3.1 and R. Upon completion of the trial, the MTD will be estimated as the median of the marginal posterior distribution of the MTD.
Recommended phase 2 dose (RP2D) of the tested combination (dose escalation)
Time Frame: Up to 3.5 years after study start
The highest dose level of the combination that is under-toxic and safely tolerated would be considered the RP2D.
Secondary Outcomes
- Predictive Protein Biomarkers(Up to 3.5 years after study start)
- Overall response rate (ORR) (dose expansion)(Baseline up to the time measurement criteria are met for complete response or partial response (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented, assessed up to 3.5 years)
- 1-year progression free survival rate (dose expansion)(From start of treatment to time of progression or death, whichever occurs first, assessed at 1 year)
Investigators
Conor Steuer
Principal Investigator
Emory University