Sapanisertib in Treating Patients With Stage IV or Recurrent Lung Cancer

Study Overview
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Brief Summary
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This phase II trial studies how well sapanisertib works in treating patients with lung cancer that is stage IV or has come back (recurrent) and has a mutation in the NFE2L2, KEAP-1, or KRAS gene. Damage to these genes may cause the cancer to grow. Sapanisertib may stop this from happening by blocking enzymes.

Detailed Description
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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.

Official Title
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A Phase 2 Study of MLN0128 (TAK-228) in Patients With Advanced Non-Small Cell Lung Cancers Harboring NFE2L2 and KEAP1 Mutations

Conditions
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Recurrent Lung Squamous Cell Carcinoma, Stage IV Lung Squamous Cell Carcinoma AJCC v7

Intervention / Treatment
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* Other: Laboratory Biomarker Analysis
* Other: Pharmacological Study
* Drug: Sapanisertib


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (sapanisertib)<br>Patients receive sapanisertib PO QD on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. | Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Other: Pharmacological Study<br>* Correlative studies<br>Drug: Sapanisertib<br>* Given PO<br>* Other names: TAK-228;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate (Complete Response [CR] + Partial Response [PR]) | Overall response rate (CR+PR) will be calculated separately for each cohort, including exact 95% confidence intervals. Duration of overall response and duration of stable disease will be calculated and summarized. Overall response rate was determined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1). Complete Response (CR): disappearance of all target lesions; Partial Response (PR): at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters. | CT imaging was obtained after every 2 cycles, or 8 weeks, starting from cycle 1 day 1 until end of study treatment, up to 1 year. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival | Median progression-free survival will be estimated using the Kaplan-Meier method with a two-sided 95% confidence interval. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), as a 20% increase in the sum of the longest diameter of target lesions, or a unequivocal increase in a non-target lesion, or the appearance of new lesions | From start of treatment (cycle 1 day 1) until the date of first documented progression or death, over the trial enrollment period, up to 1 year. | 
| Feasibility of Reverse Phase Protein Array Analysis, Defined as the Ability to Procure Sufficient Quantity and Quality of Tumor Protein for Sample | Single target signaling changes will be reported as percentages relative to the baseline pre-treatment tumor sample. Larger scale pathway changes will qualitatively represented through heatmaps. | Up to week 2 |