MRX-2843 and Osimertinib for the Treatment of Advanced EGFR Mutant Non-small Cell Lung Cancer

Inclusion Criteria:

• Patients must have histologically confirmed metastatic non-small cell lung cancer (NSCLC) with activating EGFR mutation including typical and atypical mutations inegfr 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 leastone lesion that can be accurately measured in at least one dimension (longestdiameter 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 documentedGilbert's disease, bilirubin =< 3.0 mg/dL. For subjects with documented livermetastases, bilirubin =< 2.5 x ULN

• Serum creatinine =< 1.5 x the ULN or creatinine clearance (CrCl) >= 50 mL/min. Forcreatinine 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)

• 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 adequatecontraception (hormonal or barrier method of birth control; abstinence) prior tostudy entry and for the duration of study participation. Should a woman becomepregnant or suspect she is pregnant while she or her partner is participating inthis study, she should inform her treating physician immediately. Men treated orenrolled on this protocol must also agree to use adequate contraception prior to thestudy, for the duration of study participation, and 4 months after completion ofstudy drug administration

• Females of childbearing potential who are sexually active with a non-sterilized malepartner agree to use 2 methods of effective contraception from screening, and agreeto 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 responsiblephysician. Females of childbearing potential are defined as those who are notsurgically sterile (i.e., bilateral tubal ligation, bilateral oophorectomy, orcomplete hysterectomy) or postmenopausal (defined as 12 months with no menseswithout an alternative medical cause)

• Non-sterilized males who are sexually active with a female of childbearing potentialmust agree to use an acceptable method of effective contraception from Day 1 and for 90 days after the final dose of study drug

• Female subjects of childbearing potential must be nonpregnant, and have a negativepregnancy test result at screening and day 1 of cycles 1-6

• Ability to understand and the willingness to sign a written informed consentdocument

• COHORT SPECIFIC ELIGIBILITY REQUIREMENTS

• Dose Escalation Cohort: Patients with progressive EGFR (+) NSCLC disease; previouslytreated or naive to EGFR-tyrosine kinase inhibitor (TKI) (previous treatment with 3rd generation EGFR-TKI including osimertinib allowed

• 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 treatmentprior to disease recurrence and be free of recurrence for at least 12 months (+1 day) while off treatment

• Dose Expansion Cohort B (EGFR TKI resistant):

• Have progression of disease on osimertinib, erlotinib, gefitinib or afatinib aslast previous systemic treatment,

• If not previously treated with osimertinib, must be EGFR-T790M negative asconfirmed using a standard testing platform (circulating tumor deoxyribonucleicacid [ctDNA] or tissue based testing) prior to study treatment

• Backfill Cohort C: This cohort will be open to candidates who are not able to getinto any of the dose escalation or expansion cohorts. Examples will be a patientalready on osimertinib but without disease progression or an otherwise eligiblepatient who is unable to wait for new cohorts to open due to disease burden andsymptoms.

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 cohortspecific requirements,

• If currently on osimertinib, must have tolerated the standard dose of 80 mg for atleast 2 cycles without any grade > 2 adverse events,

• Will be treated at a dose previously established to be safe from the dose escalationcohort,

• Will not be included in the dose limiting toxicity (DLT) or maximum tolerated dose (MTD) determination,

• Approval by the study sponsor

Exclusion Criteria:

• Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks fornitrosoureas 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 thisclinical trial because of their poor prognosis and because they often developprogressive neurologic dysfunction that would confound the evaluation of neurologicand other adverse events. Patient with treated or asymptomatic untreated brainmetastasis is allowed on study

• History of allergic reactions attributed to compounds of similar chemical orbiologic 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 3readings), 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 aseye inflammation, lacrimation, light sensitivity, blurred vision, eye pain and/orred eye)

• Patients receiving any medications or substances that are inhibitors or inducers ofCYP450 enzyme(s) are ineligible. Because the lists of these agents are constantlychanging, it is important to regularly consult a frequently-updated medicalreference. As part of the enrollment/informed consent procedures, the patient willbe counseled on the risk of interactions with other agents, and what to do if newmedications need to be prescribed or if the patient is considering a newover-the-counter medicine or herbal product

• Uncontrolled intercurrent illness including, but not limited to, ongoing or activeinfection, symptomatic congestive heart failure, unstable angina pectoris, cardiacarrhythmia, or psychiatric illness/social situations that would limit compliancewith study requirements

• Pregnant women are excluded from this study because osimertinib is an agent with thepotential for teratogenic or abortifacient effects. Because there is an unknown butpotential risk for adverse events in nursing infants secondary to treatment of themother with osimertinib and MRX-2843, breastfeeding should be discontinued if themother is treated with the study agents

• Human immunodeficiency virus (HIV)-positive patients on combination antiretroviraltherapy are ineligible because of the potential for pharmacokinetic interactionswith osimertinib and MRX-2843. In addition, these patients are at increased risk oflethal infections when treated with marrow-suppressive therapy. Appropriate studieswill be undertaken in patients receiving combination antiretroviral therapy whenindicated

• Subject has known or suspected history of retinitis pigmentosa or known or suspectedfamilial history of retinitis pigmentosa

• Subject has a history of type 1 diabetes (T1D) or is considered at high risk forT1D, where high risk is defined as

• Subject has one first-degree relative (defined as parents, offspring orsiblings) with T1D and A1C value > 6.5% or subject with two or morefirst-degree relatives with T1D