Testing the Combination of MLN0128 (TAK-228) and AZD9291 in Advanced EGFR (Epidermal Growth Factor Receptor) Mutation Positive Non-small Cell Lung Cancer

Exclusion Criteria

• •Any serious intercurrent or psychiatric illness that could, in the investigator's opinion, potentially interfere with the completion of treatment according to this protocol including but not limited to:
• •* Uncontrolled diabetes mellitus (fasting plasma glucose \> 130 mg/dL or 7.2 mmol/L)
• •* Past medical history of interstitial lung disease, drug-induced interstitial lung disease, radiation pneumonitis which required steroid treatment, or any evidence of clinically active interstitial lung disease
• •* Active infections
• •* Gastrointestinal disease limiting the ability to swallow oral medications or absorb oral medications including refractory nausea and vomiting, chronic gastrointestinal diseases, inflammatory bowel disease; malabsorption syndromes
• •* Patients with enteric stomata or significant bowel resection
• •* Prior history of corneal ulceration
• •* Patients with any evidence of severe or uncontrolled systemic liver disease including those with known hepatitis B and hepatitis C (excluding treated hepatitis C that has been cured)
• •* Active bleeding diatheses
• •Significant active cardiovascular or pulmonary disease including:
• •* Uncontrolled hypertension (i.e., systolic blood pressure \> 180 mmHg, diastolic blood pressure \> 95 mmHg); 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
• •* Any clinically important abnormalities in rhythm, conduction or morphology of resting electrocardiogram (ECG) e.g. medically significant (symptomatic) bradycardia, complete left bundle branch block, third degree heart block and second-degree heart block or history of arrhythmia requiring an implantable cardiac defibrillator; or within the last 6 months before administration of the first dose of drug:
• •* Requirement for inotropic support (excluding digoxin) or serious (uncontrolled) cardiac arrhythmia (including atrial flutter/fibrillation, ventricular fibrillation or ventricular tachycardia)
• •* Placement of a pacemaker for control of rhythm
• •* Ischemic myocardial event, including angina requiring therapy and artery revascularization procedures
• •* Ischemic cerebrovascular event, including transient ischemic attack and artery revascularization procedures
• •* New York Heart Association (NYHA) class III or IV heart failure
• •* Symptomatic pulmonary embolism or asymptomatic pulmonary emboli within the last 3 months
• •* Baseline prolongation of the rate-corrected QT interval (QTc) (e.g., repeated demonstration of QTcF \>= 470 msec (mean value) obtained from 3 ECGs, using the screening clinic ECG machine derived QTc value, or history of congenital long QT syndrome, or torsades de pointes); any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalaemia, 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
• •* Left ventricular ejection fraction (LVEF) by either multigated acquisition (MUGA) or echocardiography (ECHO) less than lower limit of normal
• •Patients with active malignancies other than NSCLC or prior curatively treated malignancy at high risk of relapse during the study period with the exception of localized squamous or basal cell skin cancers
• •Concurrent anti-cancer therapy
• •History of hypersensitivity attributed to compounds of similar chemical or biologic composition to MLN0128 (TAK-228) or osimertinib (AZD9291)
• •Women of non-child bearing potential must be:
• •* Women more than 50 years must be post-menopausal for at least 12 months following the end of all exogenous hormonal treatments OR
• •* Women under 50 years must be postmenopausal for at least 12 months following the end of exogenous hormonal treatments and with LH and FSH levels in the post-menopausal range for the institution OR
• •* Documentation of irreversible surgical sterilization by hysterectomy, bilateral oophorectomy or bilateral salpingectomy but not tubal ligation
• •Women of child bearing potential must have a negative serum or urine pregnancy test within 7 days of registration and must agree to:
• •* Practice 1 highly effective method of contraception and 1 additional effective (barrier) method, at the same time, from the time of signing the informed consent through 120 days (or longer, as mandated by local labeling \[e.g., United Surgical Partners International (USPI), Summary of Product Characteristics (SmPC), etc.;\]) after the last dose of study drug, OR
• •* Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the patient; NOTE: Periodic abstinence (e.g., calendar, ovulation, symptothermal, postovulation methods), withdrawal, spermicides only, and lactational amenorrhea are not acceptable methods of contraception; female and male condoms should not be used together
• •Male patients, even if surgically sterilized (i.e., status postvasectomy) must agree to:
• •* Practice highly effective barrier contraception during the entire study treatment period and through 120 days after the last dose of study drug, OR
• •* Practice true abstinence, when this is in line with the preferred and usual lifestyle of the patient; NOTE: Periodic abstinence (e.g., calendar, ovulation, symptothermal, postovulation methods for the female partner), withdrawal, spermicides only, and lactational amenorrhea are not acceptable methods of contraception; female and male condoms should not be used together
• •* Not to donate sperm during the course of this study or within 120 days after receiving their last dose of study drug
• •Inability to discontinue drugs that are strong cytochrome P450 3A4 (CYP3A4) or P450 3A5 (CYP3A5), cytochrome P450 2C19 (CYP2C19), and cytochrome P450 2C9 (CYP 2C9) inhibitors and/or inducers; and substrates of CYP 3A4/5 or CYP1A2 that are sensitive or have a narrow therapeutic window at least three weeks prior to study registration
• •Patients receiving systemic corticosteroids (either IV or oral steroids, excluding inhalers or low-dose hormone replacement therapy) within 1 week before administration of the first dose of study drug
• •Consumption of grapefruit or grapefruit juice is not permitted during the study; patients should not consume food or beverages containing the fruit or juice of grapefruits or Seville oranges within 7 days before the first dose of study drug and throughout the study
• •Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with MLN0128 (TAK-228) and osimertinib (AZD9291)
• •No concomitant use of proton pump inhibitors (PPI) is allowed; any prior PPI must be discontinued at least one week before receiving MLN0128 (TAK-228)