Osimertinib in Combination With Alisertib or Sapanisertib for the Treatment of Osimertinib-Resistant EGFR Mutant Stage IIIB or IV Non-Small Cell Lung Cancer

ALISERTIB ARM: Radiation therapy to more than 25% of the bone marrow. Whole pelvic radiation is considered to be over 25%

ALISERTIB ARM: Prior allogeneic bone marrow or organ transplantation

Known gastrointestinal (GI) disease or GI procedures that could interfere with the oral absorption or tolerance of study drugs. Examples include, but are not limited to partial gastrectomy, history of small intestine surgery, and celiac disease. In addition, patients with enteric stomata are also excluded

Inability to swallow oral medication or inability or unwillingness to comply with the administration requirements related to study drugs

ALISERTIB ARM: Known history of uncontrolled sleep apnea syndrome and other conditions that could result in excessive daytime sleepiness, such as severe chronic obstructive pulmonary disease; requirement for supplemental oxygen

Requirement for constant administration of proton pump inhibitor, H2 antagonist, or pancreatic enzymes throughout the study. The intermittent use of proton pump inhibitor (PPI), H2-antagonists and antacids (including carafate) is only allowed within the following guidelines:

* H2 receptor antagonists until 24 hours (h) of the first dose of study drug

* Antacid formulations until 2 hours before dosing and after 2 hours following dosing.

* PPI is allowed until 5 days before the first study treatment dose. PPIs are prohibited throughout the study

SAPANISERTIB ARM: Patients receiving systemic corticosteroids (either intravenous \[IV\] or oral steroids, excluding inhalers or low-dose hormone replacement therapy) within 1 week before administration of the first dose of study drug

History of any of the following within the last 6 months before administration of the first dose of the drug:

* New York Heart Association (NYHA) class III or IV heart failure, ischemic myocardial event, including angina requiring therapy and artery revascularization procedures

* Ischemic cerebrovascular event, including transient ischemic attack and artery revascularization procedures

* Pulmonary embolism

Any of the following cardiac criteria

* Mean resting corrected QT interval (QTc using Fridericia's formula) \> 470 msec or torsades de pointes

* Any clinically important abnormalities in rhythm, conduction or morphology of resting electrocardiogram (ECG) e.g., complete left bundle branch block, third degree heart block, second degree heart block, PR interval \> 250 msec. Prior to study entry, any ECG abnormality at Screening has to be documented by the investigator as not medically relevant.

* Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as 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

SAPANISERTIB ARM: Significant active cardiovascular or pulmonary disease including:

* Uncontrolled hypertension (i.e., systolic blood pressure \> 180 mm Hg, diastolic blood pressure \> 95 mm Hg). Use of anti-hypertensive agents to control hypertension before cycle 1 day 1 is allowed

* Pulmonary hypertension

* Uncontrolled asthma or oxygen (O2) saturation \< 90% by arterial blood gas analysis or pulse oximetry on room air

* Significant valvular disease; severe regurgitation or stenosis by imaging independent of symptom control with medical intervention, or history of valve replacement

Past medical history of interstitial lung disease (ILD), drug-induced ILD, radiation pneumonitis which required steroid treatment, or any evidence of clinically active interstitial lung disease

Patients with uncharacterized eye disorders

Unstable central nervous system (CNS) metastasis (as defined by need for steroids in last 14 days)

Patients who are currently receiving treatment with contraindicated QTc prolonging medications (list provided https://crediblemeds.org/pdftemp/pdf/CombinedList.pdf) or potent CYP3A4 inducers/inhibitors (list provided https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers), if that treatment cannot be either discontinued or switched to a different medication prior to first day of study treatment

Known leptomeningeal carcinomatosis

SAPANISERTIB ARM: Known hepatitis B surface antigen-positive, or known or suspected active hepatitis C infection

ALISERTIB ARM: Known human immunodeficiency virus (HIV) positive patients who meet the following criteria will be considered eligible:

* CD4 count \> 350 cells/mm\^3

* Undetectable viral load

* Maintained on modern therapeutic regimens utilizing non-CYP-interactive agents

* No history of acquired immunodeficiency syndrome (AIDS)-defining opportunistic infections

SAPANISERTIB ARM: Known HIV positive patients

Use of investigational drugs within 30 days or 5 half-lives of enrollment (whichever was greater)

ALISERTIB ARM: Previous treatment with aurora kinase inhibitors

SAPANISERTIB ARM: Previous treatment with PI3K, AKT, dual PI3K/mTOR inhibitors, TORC1/2 inhibitors or TORC1 inhibitors

Diagnosed or treated for another malignancy within 2 years of enrollment, with the exception of complete resection of basal cell carcinoma or squamous cell carcinoma of the skin, an in situ malignancy, or low-risk prostate cancer after curative therapy

Other severe acute or chronic medical or psychiatric condition, or laboratory abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the patient inappropriate for enrollment in this study

Female subject who is pregnant or breast-feeding.

* Confirmation that the subject is not pregnant must be established by a negative serum beta-human chorionic gonadotropin (beta-hCG) pregnancy test result obtained during screening. Pregnancy testing is not required for post-menopausal or surgically sterilized women.

Female patient who intend to donate eggs (ova) during the course of this study or 180 days after receiving their last dose of study drug(s)

Male patients who intend to donate sperm during the course of this study or 4 months after receiving their last dose of study drug(s)

What this study is about