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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

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ClinicalTrials.gov Identifier: NCT02503722
Recruitment Status : Recruiting
First Posted : July 21, 2015
Last Update Posted : July 31, 2018
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)

Brief 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. Sapanisertib and osimertinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Condition or disease Intervention/treatment Phase
EGFR Activating Mutation EGFR Exon 19 Deletion Mutation EGFR NP_005219.2:p.G719X EGFR NP_005219.2:p.L858R EGFR NP_005219.2:p.L861Q EGFR T790M Mutation Negative Recurrent Non-Small Cell Lung Carcinoma Stage III Non-Small Cell Lung Cancer AJCC v7 Stage IIIA Non-Small Cell Lung Cancer AJCC v7 Stage IIIB Non-Small Cell Lung Cancer AJCC v7 Stage IV Non-Small Cell Lung Cancer AJCC v7 Other: Laboratory Biomarker Analysis Drug: Osimertinib Other: Pharmacological Study Drug: Sapanisertib Phase 1

Detailed Description:

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.


Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 36 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : October 13, 2016
Estimated Primary Completion Date : August 31, 2019

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Lung Cancer
Drug Information available for: Osimertinib

Arm Intervention/treatment
Experimental: Treatment (sapanisertib, osimertinib)
Patients receive sapanisertib PO 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.
Other: Laboratory Biomarker Analysis
Correlative studies

Drug: Osimertinib
Given PO
Other Names:
  • AZD-9291
  • AZD9291
  • Mereletinib
  • Tagrisso

Other: Pharmacological Study
Correlative studies

Drug: Sapanisertib
Given PO
Other Names:
  • INK-128
  • INK128
  • MLN-0128
  • MLN0128
  • TAK-228




Primary Outcome Measures :
  1. Maximum tolerated dose of sapanisertib in combination with osimertinib in patients with EGFRmutant (m) non-small cell lung cancer (NSCLC) [ Time Frame: 28 days ]
    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.

  2. Dose-limiting toxicity (DLT) of sapanisertib in combination with osimertinib in patients with EGFRm NSCLC [ Time Frame: 28 days ]
    Toxicities will be graded according to the NCI CTCAE v4. CTCAE version 5.0 will be utilized beginning April 1, 2018.


Secondary Outcome Measures :
  1. Non-DLTs associated with the administration of sapanisertib and osimertinib [ Time Frame: Up to 30 days after completion of study treatment ]
    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.

  2. Pharmacokinetic (PK) profiles of sapanisertib in combination with osimertinib [ Time Frame: 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 ]
    PK analyses will be descriptive and will permit the evaluation of the PK profile of Tsapanisertib when combined with osimertinib.

  3. Response rate, assessed using Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 [ Time Frame: Up to 2 years ]
    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.

  4. Disease control rate [ Time Frame: Up to 2 years ]
    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.

  5. Progression free survival [ Time Frame: From start of treatment to time of progression or death, whichever occurs first, assessed up to 2 years ]
    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.

  6. Response rate of patients with T790M- NSCLC in an expansion cohort, assessed using RECIST 1.1 [ Time Frame: Up to 2 years ]
    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.

  7. Disease control rate of patients with T790M- NSCLC in an expansion cohort [ Time Frame: Up to 2 years ]
    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.

  8. Progression free survival of patients with T790M- NSCLC in an expansion cohort [ Time Frame: At 6 months ]
    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.

  9. Biomarkers of response and resistance to the combination, explored by studying baseline biopsies, resistance biopsies, and serial plasma deoxyribonucleic acid specimens [ Time Frame: Up to 2 years ]
    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.



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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)

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02503722


Locations
United States, Connecticut
Smilow Cancer Center/Yale-New Haven Hospital Recruiting
New Haven, Connecticut, United States, 06510
Contact: Site Public Contact    203-785-5702    canceranswers@yale.edu   
Principal Investigator: Sarah B. Goldberg         
Yale University Recruiting
New Haven, Connecticut, United States, 06520
Contact: Site Public Contact    203-785-5702    canceranswers@yale.edu   
Principal Investigator: Sarah B. Goldberg         
United States, Florida
Moffitt Cancer Center Recruiting
Tampa, Florida, United States, 33612
Contact: Site Public Contact    800-456-7121    canceranswers@moffitt.org   
Principal Investigator: Eric B. Haura         
Canada, British Columbia
BCCA-Vancouver Cancer Centre Recruiting
Vancouver, British Columbia, Canada, V5Z 4E6
Contact: Site Public Contact    888-939-3333      
Principal Investigator: Cheryl Ho         
Canada, Ontario
University Health Network-Princess Margaret Hospital Recruiting
Toronto, Ontario, Canada, M5G 2M9
Contact: Site Public Contact    416-946-4501    clinical.trials@uhn.on.ca   
Principal Investigator: Penelope A. Bradbury         
Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
Principal Investigator: Penelope Bradbury University Health Network Princess Margaret Cancer Center LAO

Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT02503722     History of Changes
Other Study ID Numbers: NCI-2015-01139
NCI-2015-01139 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
9910/PJC-020
PJC-020
9910 ( Other Identifier: University Health Network Princess Margaret Cancer Center LAO )
9910 ( Other Identifier: CTEP )
UM1CA186644 ( U.S. NIH Grant/Contract )
UM1CA186689 ( U.S. NIH Grant/Contract )
First Posted: July 21, 2015    Key Record Dates
Last Update Posted: July 31, 2018
Last Verified: July 2018

Additional relevant MeSH terms:
Lung Neoplasms
Carcinoma, Non-Small-Cell Lung
Respiratory Tract Neoplasms
Thoracic Neoplasms
Neoplasms by Site
Neoplasms
Lung Diseases
Respiratory Tract Diseases
Carcinoma, Bronchogenic
Bronchial Neoplasms
Osimertinib
Antineoplastic Agents
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action