AzTrials
AzTrials

Metastatic Lung Non-Small Cell CarcinomaPhase 1NCT02503722

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

A Phase 1 study testing Laboratory Biomarker Analysis, Osimertinib and Pharmacological Study in people with Metastatic Lung Non-Small Cell Carcinoma and Recurrent Lung Non-Small Cell Carcinoma, run by National Cancer Institute (NCI) at 5 sites in 2 countries.

Active, not recruiting

Under way, not looking for participants. Everyone needed has enrolled. The study is still running.

Official record
Search all trials

Trial summary

This phase I trial studies the side effects and best dose of sapanisertib when given together with osimertinib in treating patients with stage IV EGFR mutation positive non-small cell lung cancer that has progressed after treatment with an EGFR tyrosine kinase inhibitor. Read more about this study

Who is it for?
Ages 18 years and older
What is being tested?
Laboratory Biomarker Analysis, Osimertinib and Pharmacological Study
Could I receive a placebo?
No, everyone receives an active treatment
How many people
36 participants
Where
5 sitesin 2 countries
Study dates
23 Mar 2017to 28 Feb 2027
Phase
Phase 1
Are there results?
Not yet: the study is under way

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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)
  • Progressive disease on osimertinib (AZD9291) given first line
  • For the dose expansion portion ONLY, patient must: 1) have progression of disease with first line osimertinib administered for advanced or metastatic disease as the last previous systemic treatment, 2) be treatment naïve for other 3rd generation EGFR-TKI (CO-1686) 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
  • For the dose expansion, no other systemic therapies for advanced/metastatic disease is permissible after first line osimertinib
Show all 31Show fewer
  • 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; patients with small brain metastases for which radiation or surgery is not indicated, may be eligible on discussion with the study chair. Brain metastases that were managed with first line osimertinib is permissible, provided that the brain metastases are stable on a baseline MRI and for whom radiation or surgical resection is not indicated
  • The patient is asymptomatic from the brain metastases
  • Corticosteroids and anti-epileptic drugs 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 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) =< 7.0%
  • 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

Who cannot join

  • 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
Show all 43Show fewer
  • 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)
  • Pregnant women or women who are breast feeding are not eligible for the study; the effects of MLN0128 (TAK-228) and osimertinib (AZD9291) on the developing human fetus are unknown
  • 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)

Trial locations and contacts

5 sites in 2 countries.

5 sites in 2 countries

United States3 sites

  • Smilow Cancer Center/Yale-New Haven Hospital

    New Haven, Connecticut, 06510

  • Yale University

    New Haven, Connecticut, 06520

  • Moffitt Cancer Center

    Tampa, Florida, 33612

Other trials in United States

Canada2 sites

  • University Health Network-Princess Margaret Hospital

    Toronto, Ontario, M5G 2M9

  • BCCA-Vancouver Cancer Centre

    Vancouver, British Columbia, V5Z 4E6

Other trials in Canada

About this study

Official title: A Phase 1 Trial of MLN0128 (TAK-228) in Combination With Osimertinib (AZD9291) in Advanced EGFR Mutation Positive Non-Small Cell Lung Cancer (NSCLC) After Progression on a Previous EGFR Tyrosine Kinase Inhibitor

This phase I trial studies the side effects and best dose of sapanisertib when given together with osimertinib in treating patients with stage IV EGFR mutation positive non-small cell lung cancer that has progressed after treatment with an EGFR tyrosine kinase inhibitor. Sapanisertib and osimertinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Read the detailed description

PRIMARY OBJECTIVES:

  1. 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) and 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 who are resistant to previous EGFR-TKI therapy with first line osimertinib. (Dose expansion phase)

SECONDARY OBJECTIVES:

  1. 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 cycle 1). Patients also receive osimertinib PO 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 at 30 days, and then every 8 weeks thereafter.

Being tested
Laboratory Biomarker Analysis, Osimertinib, Pharmacological Study, Sapanisertib
Medical subject headings
Carcinoma, Non-Small-Cell Lung

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Laboratory Biomarker AnalysisOther

    Correlative studies

  • OsimertinibDrug

    Also called AZD 9291, AZD-9291, AZD9291, Mereletinib

    Given PO

  • Pharmacological StudyOther

    Correlative studies

  • SapanisertibDrug

    Also called INK-128, INK128, MLN-0128, MLN0128

    Given PO

Study groups in NCT02503722
Study groupRoleWhat they receive
Treatment (sapanisertib, osimertinib)ExperimentalPatients receive sapanisertib PO QD on days 1, 3, 5, 8, 10, 12, 15, 17, 19, 22, 24, and 26 (day 1 is omitted in cycle 1). Patients also receive osimertinib PO QD on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Receives: Other: Laboratory Biomarker Analysis; Drug: Osimertinib; Other: Pharmacological Study; Drug: Sapanisertib

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Maximum tolerated dose of sapanisertib in combination with osimertinib in patients with EGFRmutant (m) non-small cell lung cancer (NSCLC)

    Toxicities will be graded according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events version 4 (CTCAE v4). CTCAE version 5.0 will be utilized beginning April 1, 2018.

    Measured: 28 days

  2. Dose-limiting toxicity (DLT) of sapanisertib in combination with osimertinib in patients with EGFRm NSCLC

    Toxicities will be graded according to the NCI CTCAE v4. CTCAE version 5.0 will be utilized beginning April 1, 2018.

    Measured: 28 days

Secondary outcomes (9)

  1. Non-DLTs associated with the administration of sapanisertib and osimertinib

    Frequency and severity of adverse events will be tabulated using counts and proportions detailing frequently occurring, serious and severe events of interest. Adverse events will be summarized using all adverse events experienced, although a sub-analysis may be conducted including only those adverse events in which the treating physician deems possibly, probably or definitely attributable to one or both study treatments.

    Measured: Up to 30 days after completion of study treatment

  2. Pharmacokinetic (PK) profiles of sapanisertib in combination with osimertinib

    PK analyses will be descriptive and will permit the evaluation of the PK profile of Tsapanisertib when combined with osimertinib.

    Measured: Baseline, and at 1, 2, 4, 6, 8, and 24 hours post-sapanisertib administration, before administration and at 1, 2, 4, 6, 8, and 24 hours post-sapanisertib on day 26 of course 1; and day 1 of course 2

  3. Response rate

    Will be assessed using Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. Summary statistics such as the mean, median, counts and proportion, will be used to describe patients' clinical characteristics. Treatment administered will be reported including the number of cycles, dose modifications, reason off treatment, reason off study, whether a DLT was experienced, best response, and time to progression. These will be listed for each patient and summarized using standard descriptive methods.

    Measured: Up to 2 years

  4. Disease control rate

    Summary statistics such as the mean, median, counts and proportion, will be used to describe patients' clinical characteristics. Treatment administered will be reported including the number of cycles, dose modifications, reason off treatment, reason off study, whether a DLT was experienced, best response, and time to progression. These will be listed for each patient and summarized using standard descriptive methods.

    Measured: Up to 2 years

  5. Progression free survival

    Summary statistics such as the mean, median, counts and proportion, will be used to describe patients' clinical characteristics. Treatment administered will be reported including the number of cycles, dose modifications, reason off treatment, reason off study, whether a DLT was experienced, best response, and time to progression. These will be listed for each patient and summarized using standard descriptive methods.

    Measured: From start of treatment to time of progression or death, whichever occurs first, assessed up to 2 years

  6. Response rate of patients with T790M- NSCLC in an expansion cohort

    Will be assessed using RECIST 1.1. Summary statistics such as the mean, median, counts and proportion, will be used to describe patients' clinical characteristics. Treatment administered will be reported including the number of cycles, dose modifications, reason off treatment, reason off study, whether a DLT was experienced, best response, and time to progression. These will be listed for each patient and summarized using standard descriptive methods.

    Measured: Up to 2 years

  7. Disease control rate of patients with T790M- NSCLC in an expansion cohort

    Summary statistics such as the mean, median, counts and proportion, will be used to describe patients' clinical characteristics. Treatment administered will be reported including the number of cycles, dose modifications, reason off treatment, reason off study, whether a DLT was experienced, best response, and time to progression. These will be listed for each patient and summarized using standard descriptive methods.

    Measured: Up to 2 years

  8. Progression free survival of patients with T790M- NSCLC in an expansion cohort

    Summary statistics such as the mean, median, counts and proportion, will be used to describe patients' clinical characteristics. Treatment administered will be reported including the number of cycles, dose modifications, reason off treatment, reason off study, whether a DLT was experienced, best response, and time to progression. These will be listed for each patient and summarized using standard descriptive methods.

    Measured: At 6 months

  9. Biomarkers of response and resistance to the combination, explored by studying baseline biopsies, resistance biopsies, and serial plasma deoxyribonucleic acid specimens

    Predictors of clinical outcomes will be investigated using logistic regression, Cox proportional hazards regression and or generalized estimating equations as appropriate. Potential predictors include clinical predictors and molecular correlates analyzed in tumor and blood. Descriptive statistics and plotting of data will also be used to better understand potential relationships.

    Measured: Up to 2 years

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted21 Jul 2015 (estimated)
  2. Study start23 Mar 2017
  3. Primary completion28 Feb 2027 (estimated)
  4. Study completion28 Feb 2027 (estimated)

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
36 participants (estimated)
IDs, dates and publications
ClinicalTrials.gov ID
NCT02503722
Sponsor's protocol ID
NCI-2015-01139
Other IDs
NCI-2015-01139, PJC-020, 9910/PJC-020, 9910, 9910, UM1CA186644, UM1CA186689
Status last verified
Jun 2026
First submitted
20 Jul 2015
Last updated
11 Jun 2026
Results posted
No
Data monitoring committee
Yes
FDA-regulated drug
Yes
FDA-regulated device
No

Questions about this trial

What is this clinical trial studying?

A Phase 1 study testing Laboratory Biomarker Analysis, Osimertinib and Pharmacological Study in people with Metastatic Lung Non-Small Cell Carcinoma and Recurrent Lung Non-Small Cell Carcinoma, run by National Cancer Institute (NCI) at 5 sites in 2 countries.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 31 inclusion and 43 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: under way, not looking for participants, as of the sponsor's last update on 11 Jun 2026. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 5 sites in United States, Canada. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

This study is still under way. Results are not available in the source record yet.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Maximum tolerated dose of sapanisertib in combination with osimertinib in patients with EGFRmutant (m) non-small cell lung cancer (NSCLC) (time frame: 28 days). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT02503722.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 11 Jun 2026.

AzTrials uses cookies for analytics and advertising. You can accept or reject them; the site works either way. Privacy Policy.

Free account

Log in to keep searching

You’ve used your 3 free searches. AzTrials is free: log in or create a free account to keep searching clinical trials and save the ones you want to follow.

Create a free accountLog in