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.

Objectives

PRIMARY OBJECTIVES:
I. Assess the safety and tolerability of Flt3/MerTK inhibitor 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.

Eligibility

1. 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
2. Eastern Cooperative Oncology Group (ECOG) performance status of 0-2
3. 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
4. Age >= 18 years. Because no dosing or adverse event data are currently available on the use of osimertinib in combination with MRX-2843 in patients <18 years of age, children are excluded from this study, but will be eligible for future pediatric trials
5. Ability to safely swallow oral medication
6. Absolute neutrophil count >= 1500/mm^3
7. Platelet count >= 100,000/mm^3
8. Hemoglobin >= 8.5 g/dL (must be > 2 weeks post-red blood cell transfusion)
9. 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
10. 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
11. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 3 x the ULN (=< 5 x the ULN for subjects with liver metastases)
12. The effects of MRX-2843 and osimertinib on the developing human fetus are unknown. For this reason, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 4 months after completion of study drug administration
13. Females of childbearing potential who are sexually active with a non-sterilized male partner agree to use 2 methods of effective contraception from screening, and agree to continue using such precautions for 90 days after the final dose of study drug; cessation of birth control after this point should be discussed with a responsible physician. Females of childbearing potential are defined as those who are not surgically sterile (i.e., bilateral tubal ligation, bilateral oophorectomy, or complete hysterectomy) or postmenopausal (defined as 12 months with no menses without an alternative medical cause)
14. Non-sterilized males who are sexually active with a female of childbearing potential must agree to use an acceptable method of effective contraception from Day 1 and for 90 days after the final dose of study drug
15. Female subjects of childbearing potential must be nonpregnant, and have a negative pregnancy test result at screening and day 1 of cycles 1-6
16. Ability to understand and the willingness to sign a written informed consent document
17. COHORT SPECIFIC ELIGIBILITY REQUIREMENTS
18. Dose Escalation Cohort: Patients with progressive EGFR (+) NSCLC disease; previously treated or naive to EGFR-tyrosine kinase inhibitor (TKI) (previous treatment with 3rd generation EGFR-TKI including osimertinib allowed
19. Dose Expansion Cohort A (Treatment naive): * Be treatment naive to osimertinib or any other EGFR TKI, * If treated with an EGFR TKI in the adjuvant, must have discontinued treatment prior to disease recurrence and be free of recurrence for at least 12 months (+1 day) while off treatment
20. Dose Expansion Cohort B (EGFR TKI resistant): * Previously treated and progressed on osimertinib, erlotinib, gefitinib or afatinib, * if previously treated with 1st or 2dn generation TKI but not previously treated with osimertinib, must be EGFR-T790M negative as confirmed using a standard testing platform (circulating tumor deoxyribonucleic acid [ctDNA] or tissue based testing) prior to study treatment
21. Backfill Cohort C: This cohort will be open to candidates who are not able to get into any of the dose escalation or expansion cohorts. Examples will be a patient already on osimertinib but without disease progression or an otherwise eligible patient who is unable to wait for new cohorts to open due to disease burden and symptoms. Such patients may be enrolled into the backfill cohort if they meet the following criteria: * Patients must meet the general eligibility requirements but do not meet cohort specific requirements, * If currently on osimertinib, must have tolerated the standard dose of 80 mg for at least 2 cycles without any grade > 2 adverse events, * Will be treated at a dose previously established to be safe from the dose escalation cohort, * Will not be included in the dose limiting toxicity (DLT) or maximum tolerated dose (MTD) determination, * Approval by the study sponsor