Pacritinib in Patients With Endothelial Growth Factor (EGFR) Mutant Non-small Cell Lung Cancer (NSCLC) After EGFR Tyrosine Kinase Inhibitor (TKI)

Inclusion Criteria:

* Histologically or cytologically confirmed metastatic or unresectable locally advanced NSCLC with known sensitive EGFR mutations. Patients with mutations in T790M are eligible if they have progressed after treatment with a third generation EGFR tyrosine kinase inhibitor (osimertinib), but otherwise patients must have EGFR T790M negative or unknown status. Patients previously treated with third generation EGFR tyrosine kinase inhibitor must have achieved a treatment benefit of at least 4 months.
* Disease progression following therapy with erlotinib, afatinib, or gefitinib
* May have received one or more prior treatments with chemotherapy
* Measurable disease defined as lesions that can be accurately measured in at least one dimension (longest diameter to be recorded) as ≥ 10 mm with CT scan, as ≥ 20 mm by chest x-ray, or ≥ 10 mm with calipers by clinical exam.
* At least 18 years of age.
* ECOG performance status ≤ 1
* Normal bone marrow and organ function as defined below:

  * Absolute neutrophil count ≥ 1,500/mcl
  * Platelets ≥ 100,000/mcl
  * Hemoglobin ≥ 9.0 g/dL
  * Total bilirubin ≤ 2.0 x IULN
  * AST (SGOT) / ALT (SGPT) ≤ 3.0 x IULN; if liver metastases, ≤ 5.0 x IULN
  * Serum creatinine ≤ 1.5 x ULN
* Adequate cardiac function as demonstrated by LVEF ≥ 50% performed no more than 4 weeks prior to enrollment.
* Women of childbearing 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 participating in this study, she must inform her treating physician immediately.
* Able to swallow pills
* Able to understand and willing to sign a Human Research Protection Office (HRPO) approved written informed consent document (or that of legally authorized representative, if applicable).

Exclusion Criteria:

* Known pre-existing interstitial lung disease.
* Leptomeningeal carcinomatosis or other untreated or symptomatic central nervous system (CNS) metastases. Patients with asymptomatic CNS metastases, other than leptomeningeal disease, are eligible provided they have been clinically stable without requiring increase in steroid dose for at least 4 weeks.
* A history of other malignancy ≤ 5 years previous with the exception of basal cell or squamous cell carcinoma of the skin which were treated with local resection only or carcinoma in situ of the cervix.
* Received any chemotherapeutic or targeted agent (approved or investigational) for NSCLC within 2 weeks of initiation of pacritinib (with the exception of erlotinib).
* Currently receiving any other investigational agents.
* A history of allergic reactions attributed to compounds of similar chemical or biologic composition to pacritinib or other agents used in the study.
* Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
* Pregnant and/or breastfeeding: Patient must have a negative pregnancy test within 14 days of study entry.
* Known HIV-positivity on combination antiretroviral therapy because of the potential for pharmacokinetic interactions with pacritinib. In addition, these patients are at increased risk of lethal infections when treated with marrow-suppressive therapy. Appropriate studies will be undertaken in patients receiving combination antiretroviral therapy when indicated.
* Use of potent cytochrome P450 3A4 (CYP3A4) inducer within one week of pacritinib initiation
* Patients with CTCAE grade 2 cardiac arrhythmias may be considered for inclusion if the arrhythmias are stable, asymptomatic, and unlikely to affect patient safety. Patients will be excluded if they have ongoing cardiac dysrhythmias of CTCAE grade ≥ 3, corrected QT interval (QTc) prolongation \>450ms, or other factors that increase the risk for QT interval prolongation (eg, heart failure, hypokalemia \[defined as serum potassium \<3.0mEq/L that is persistent and refractory to correction\], or family history of long QT interval syndrome).
* Any gastrointestinal (GI) or metabolic condition that could interfere with absorption of oral medication such as ongoing grade 3 or higher diarrhea, constipation, nausea, or vomiting.
* Active viral hepatitis.