PRIMARY OBJECTIVE:
I. Evaluate the overall response rate of the TORC1/TORC2 inhibitor sapanisertib (MLN0128
[TAK-228]) in stage IV squamous cell lung cancers or KRAS mutant lung cancers harboring
NFE2L2 or KEAP1 mutations.
SECONDARY OBJECTIVES:
I. To evaluate the median progression free survival of patients in each cohort. II. To
explore the feasibility of performing reverse phase protein array analysis (RPPA) in paired
snap-frozen core biopsies from patients in this study prior to MLN0128 (TAK-228) dosing and
during week 2 of treatment.
III. To describe the effectiveness of MLN0128 (TAK-228) in suppressing activation of mTOR and
PI3K signaling through the exploratory RPPA analysis.
OUTLINE:
Patients receive sapanisertib orally (PO) once daily (QD) on days 1-28. Cycles repeat every
28 days in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up for 4 weeks.
Inclusion Criteria:
- Patients must have histologically or cytologically confirmed stage IV or recurrent
squamous cell lung cancer or KRAS mutant lung cancer that harbors any of the NFE2L2
mutations or KEAP1 mutations; any KEAP1 mutation will be eligible
- Patients must have measurable disease, defined as at least one lesion that can be
accurately measured in at least one dimension (longest diameter to be recorded for
non-nodal lesions and short axis for nodal lesions) as >= 20 mm (>= 2 cm) with
conventional techniques or as >= 10 mm (>= 1 cm) with spiral computed tomography (CT)
scan, magnetic resonance imaging (MRI), or calipers by clinical exam
- Patients must have completed at least 1 prior line of systemic therapy; patients who
have declined first line therapy or for whom first-line therapy would be clinically
inappropriate, will be considered eligible for the trial
- Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)
- Life expectancy of greater than 3 months
- Leukocytes >= 3,000/mcL
- Absolute neutrophil count >= 1,500/mcL
- Platelets >= 100,000/mcL
- Total bilirubin within normal institutional limits
- Fasting serum glucose =< 130 mg/dL or hemoglobin A1C (HBA1C) < 7.0%
- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase
[SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
=< 2.5 x institutional upper limit of normal
- Creatinine within normal institutional limits OR creatinine clearance >= 50
mL/min/1.73 m^2 for patients with creatinine levels above institutional normal
- Patients with controlled diabetes are allowed on study; controlled diabetes is defined
as fetal bovine serum (FBS) =< 130 mg/dL in the context of this study
- The effects of MLN0128 (TAK-228) on the developing human fetus are unknown; for this
reason women of child-bearing potential and men must agree to practice 1 highly
effective method of contraception and 1 additional effective (barrier) method, at the
same time, prior to study through 90 days (or longer, as mandated by local labeling
[e.g., United States Package Insert (USPI), Summary of Product Characteristics (SmPC),
etc;]) after the last dose of study drug; should a woman become pregnant or suspect
she is pregnant while she or her partner is participating in this study, she should
inform her treating physician immediately; any woman who becomes pregnant while
receiving MLN0128 (TAK-228) will be removed from the trial; men treated or enrolled on
this protocol must also agree to use highly effective barrier contraception prior to
the study, for the duration of study participation, and 120 days after completion of
MLN0128 (TAK-228) administration; men must agree not to donate sperm during the course
of this study or within 120 days after receiving their last dose of study drug
- Ability to understand and the willingness to sign a written informed consent document
- Ability to swallow oral medications
- 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
Exclusion Criteria:
- Patients who have had chemotherapy or radiotherapy within 2 weeks prior to the planned
start of study treatment or those who have not recovered to baseline or less than
grade 2 from adverse events from prior treatments
- Patients who are receiving any other investigational agents
- Patients with untreated central nervous system (CNS) metastases; patients with treated
CNS metastases who are off steroids are eligible
- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to MLN0128 (TAK-228)
- 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; no ischemic myocardial or cerebrovascular event, class III or IV
heart failure, placement of pacemaker, or pulmonary embolism within six months of
receiving first dose of MLN0128 (TAK-228)
- Baseline prolongation of the rate-corrected QT interval (QTc) > 480 milliseconds, or
history of congenital long QT syndrome, or torsades de pointes
- Pregnant women are excluded from this study because MLN0128 (TAK-228) is an mTOR agent
with the potential for teratogenic or abortifacient effects; because there is an
unknown but potential risk for adverse events in nursing infants secondary to
treatment of the mother with MLN0128 (TAK-228), breastfeeding should be discontinued
if the mother is treated with MLN0128 (TAK-228)
- Patients previously treated with an mammalian TOR (mTOR) or PI3K inhibitor
- Concomitant administration of any proton pump inhibitor (PPI) is not permitted during
the study; patients receiving PPI therapy before enrollment must stop using the PPI
for 7 days before their first dose of study drugs
- Uncontrolled diabetes mellitus (fasting plasma glucose > 130 mg/dL despite optimal
medical management of hyperglycemia)
- Known hepatitis B surface antigen-positive, or known or suspected active hepatitis C
infection
- Patients receiving histamine H2 receptor antagonists before enrollment must stop using
these medications for at least 24 hours before their first dose of study drug
