Sapanisertib and Osimertinib in Treating Patients With Stage IV EGFR Mutation Positive Non-small Cell Lung Cancer After Progression on a Previous EGFR Tyrosine Kinase Inhibitor

PRIMARY OBJECTIVES:

I. To determine the safety and recommended phase II dose (RP2D) of sapanisertib (MLN0128)
(TAK-228) in combination with osimertinib (AZD9291) in patients with advanced epidermal
growth factor receptor mutation positive (EGFRm) non-small cell lung cancer (NSCLC) who are
resistant to previous EGFR-tyrosine kinase inhibitor (TKI) therapy. (Dose escalation phase)
II. To evaluate the safety and preliminary efficacy of MLN0128(TAK-228) in combination with
osimertinib (AZD9291) in patients with advanced EGFRm NSCLC that is negative for the
resistance mutation T790M (T790M negative [-]) and who are resistant to previous EGFR-TKI
therapy. (Dose expansion phase)

SECONDARY OBJECTIVES:

I. To evaluate pharmacokinetic profiles of MLN0128 (TAK-228) in combination with osimertinib
(AZD9291).

II. To evaluate the response rate, disease control rate and progression free survival of the
combination.

III. To explore biomarkers of response and resistance to the combination by studying baseline
biopsies, resistance biopsies, and serial plasma deoxyribonucleic acid (DNA) specimens.

OUTLINE: This is a dose-escalation study of sapanisertib.

Patients receive sapanisertib orally (PO) once daily (QD) on days 1, 3, 5, 8, 10, 12, 15, 17,
19, 22, 24, and 26 (day 1 is omitted in course 1). Patients also receive osimertinib PO QD on
days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable
toxicity.

After completion of study treatment, patients are followed up at 30 days, and then every 8
weeks thereafter.

Inclusion Criteria:

- Patients with stage IV or recurrent/metastatic histologically or cytologically
confirmed non-squamous NSCLC

- NSCLC must harbor an EGFR activating mutation (Exon 21 L858R, Exon 19 deletion, Exon
18 G719X, Exon 21 L861Q)

- Progressive disease on at least one prior EGFR-TKI (previous treatment with 3rd
generation EGFR-TKI including osimertinib [AZD9291] allowed for dose escalation only)

- Adequate archival tissue from a biopsy performed after progression of disease on
previous EGFR-TKI or willing to consent to a fresh tumor biopsy (mandatory for dose
expansion cohort only; optional for dose escalation)

- For the dose expansion portion ONLY, patient must: 1) have progression of disease with
erlotinib, gefitinib or afatinib as last previous systemic treatment, 2) tumors must
be EGFR T790M negative confirmed by central testing prior to treatment (If EGFR-T790M
status is unknown, patient may consent for trial for biopsy and testing for EGFR T790M
will be performed as part of the initial biopsy for the trial: patients who test
positive for EGFR T790M by central testing will be ineligible for the dose expansion),
3) be treatment naive for 3rd generation EGFR-TKI (CO-1686 and osimertinib [AZD9291])
and mTOR inhibitors

- Patients must have measurable disease by Response Evaluation Criteria in Solid Tumors
(RECIST) 1.1, defined as at least one lesion that can be accurately measured in at
least one dimension >= 10 mm (>= 1 cm) by computed tomography (CT) imaging or magnetic
resonance imaging (MRI) within 28 days prior to start of protocol therapy; the CT from
a combined positron emission tomography (PET)/CT may be used if it is of diagnostic
quality; laboratory parameters are not acceptable as the only evidence of disease

- Any number of prior therapies are allowed

- Eastern Cooperative Oncology Group (ECOG) performance status =< 1 (Karnofsky >= 70%)

- Patients with a prior history of brain metastases are eligible provided:

- The brain metastases have been treated

- The patient is asymptomatic from the brain metastases

- Corticosteroids prescribed for the management of brain metastases have been
discontinued at least 7 days prior to registration

- The brain metastases are stable on pre-registration imaging

- Absolute neutrophil count (ANC) >= 1.5 x 10^9/L

- Hemoglobin >= 90 g/L (or >= 9 g/dL)

- Platelets >= 100 x 10^9/L

- Calculated creatinine clearance of > 50 mL/min using Cockcroft Gault equation equation
or 24-hour urine sampling

- Total bilirubin =< 1.5 institutional upper limit of normal

- Aspartate transaminase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) and
alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x
institutional upper limit of normal

- Fasting plasma glucose =< 130 mg/dL (or 7.2 mmol/L)

- Glycosylated hemoglobin (Hb A1c) =< 7%

- Fasting triglycerides =< 300 mg/dL (3.42 mmol/L)

- Cholesterol =< 300 mg/dL (7.75 mmol/L)

- Fridericia's correction formula (QTcF) =< 470 msec

- Patients must have had sufficient time between a prior therapy and resolution of
toxicities from the prior therapies prior to registration as follows:

- Prior EGFR inhibitor: A minimum of 7 days must have elapsed from the last dose of
the prior EGFR inhibitor and resolution of any drug-related toxicity to =< grade
1 except for alopecia

- Chemotherapy: A minimum of 21 days must have elapsed from the last dose and
resolution of toxicity to =< grade 1 excluding =< grade 2 peripheral neuropathy
or alopecia

- Surgery: A minimum of 21 days must have elapsed following major surgery and
resolution of toxicity to < grade 1 and complete wound healing must have occurred

- Radiation: A minimum of 14 days must have elapsed following radiation therapy and
resolution of all radiation induced toxicity excluding alopecia

- Treatment with an investigational drug: A minimum of 3 months or five half-lives
of the compound, whichever is greater, must have elapsed from last treatment date

- Ability to understand and the willingness to sign a written informed consent document

- Available for follow-up of their disease after treatment until progressive disease is
documented and resolution of related adverse events until < grade 2

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

- History of arrhythmia requiring an implantable cardiac defibrillator

- 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

- Pulmonary embolism

- 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)

- Pregnant women or women who are breast feeding are not eligible for the study

- 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

- 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)