Clinical Trials /

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

NCT02503722

Description:

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.

Related Conditions:
  • Non-Small Cell Lung Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: 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
  • 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

Clinical Trial IDs

  • ORG STUDY ID: NCI-2015-01139
  • SECONDARY ID: NCI-2015-01139
  • SECONDARY ID: 9910/PJC-020
  • SECONDARY ID: PJC-020
  • SECONDARY ID: 9910
  • SECONDARY ID: 9910
  • SECONDARY ID: UM1CA186644
  • SECONDARY ID: UM1CA186689
  • NCT ID: NCT02503722

Conditions

  • 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 Lung Non-Small Cell Carcinoma
  • Stage III Lung Non-Small Cell Cancer AJCC v7
  • Stage IIIA Lung Non-Small Cell Cancer AJCC v7
  • Stage IIIB Lung Non-Small Cell Cancer AJCC v7
  • Stage IV Lung Non-Small Cell Cancer AJCC v7

Interventions

DrugSynonymsArms
OsimertinibAZD-9291, AZD9291, Mereletinib, TagrissoTreatment (sapanisertib, osimertinib)
SapanisertibINK-128, INK128, MLN-0128, MLN0128, TAK-228Treatment (sapanisertib, osimertinib)

Purpose

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.

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. 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.
    

Trial Arms

NameTypeDescriptionInterventions
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 course 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.
  • Osimertinib
  • Sapanisertib

Eligibility 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; 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

          -  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)
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

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
Safety Issue:
Description: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.

Secondary Outcome Measures

Measure:Non-DLTs associated with the administration of sapanisertib and osimertinib
Time Frame:Up to 30 days after completion of study treatment
Safety Issue:
Description: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.
Measure: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
Safety Issue:
Description:PK analyses will be descriptive and will permit the evaluation of the PK profile of Tsapanisertib when combined with osimertinib.
Measure:Response rate
Time Frame:Up to 2 years
Safety Issue:
Description: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.
Measure:Disease control rate
Time Frame:Up to 2 years
Safety Issue:
Description: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.
Measure:Progression free survival
Time Frame:From start of treatment to time of progression or death, whichever occurs first, assessed up to 2 years
Safety Issue:
Description: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.
Measure:Response rate of patients with T790M- NSCLC in an expansion cohort
Time Frame:Up to 2 years
Safety Issue:
Description: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.
Measure:Disease control rate of patients with T790M- NSCLC in an expansion cohort
Time Frame:Up to 2 years
Safety Issue:
Description: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.
Measure:Progression free survival of patients with T790M- NSCLC in an expansion cohort
Time Frame:At 6 months
Safety Issue:
Description: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.
Measure: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
Safety Issue:
Description: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.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:National Cancer Institute (NCI)

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