Clinical Trials /

Study of Tesevatinib in Subjects With Non-Small Cell Lung Cancer, EGFR Activating Mutation, Prior Treatment With a Tyrosine Kinase Inhibitor, and Brain Metastases or Leptomeningeal Metastases

NCT02616393

Description:

A study to assess the activity of tesevatinib in subjects with NSCLC and activating EGFR mutations who have disease progression with Brain Metastases (BM) or Leptomeningeal Metastases (LM) or who heave either BM or LM at initial presentation.

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

Completed

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Study of Tesevatinib in Subjects With Non-Small Cell Lung Cancer, EGFR Activating Mutation, Prior Treatment With a Tyrosine Kinase Inhibitor, and Brain Metastases or Leptomeningeal Metastases
  • Official Title: A Phase 2, Multicenter Study of Tesevatinib in Subjects With Non-Small Cell Lung Cancer, EGFR Activating Mutation, Prior Treatment With a Tyrosine Kinase Inhibitor, and Brain Metastases or Leptomeningeal Metastases

Clinical Trial IDs

  • ORG STUDY ID: KD019-206
  • NCT ID: NCT02616393

Conditions

  • Non-Small Cell Lung Cancer
  • Leptomeningeal Metastases
  • Brain Metastases

Interventions

DrugSynonymsArms
TesevatinibKD019, XL647Cohort A - Brain Metastases

Purpose

A study to assess the activity of tesevatinib in subjects with NSCLC and activating EGFR mutations who have disease progression with Brain Metastases (BM) or Leptomeningeal Metastases (LM) or who heave either BM or LM at initial presentation.

Trial Arms

NameTypeDescriptionInterventions
Cohort A - Brain MetastasesExperimentalTesevatinib will be orally administered with a dose of 300 mg once daily to subjects with NSCLC who have progressed with BM
  • Tesevatinib
Cohort B - Leptomeningeal MetastasesExperimentalTesevatinib will be orally administered with a dose of 300 mg once daily to subjects with NSCLC who have progressed with LM
  • Tesevatinib
Cohort C - Brain Metastases at initial presentationExperimentalTesevatinib will be orally administered with a dose of 300 mg once daily to subjects with NSCLC with BM at initial presentation
  • Tesevatinib

Eligibility Criteria

        Cohort A

        Inclusion Criteria:

          -  History of NSCLC with EGFR mutation or an EGFR activating mutation that has had a
             clinical response to erlotinib, afatinib, or gefitinib in the patient being enrolled.

          -  Occurrence or progression of BM while receiving first line therapy (either erlotinib,
             afatinib, or gefitinib) for at least 14 days. Patients may have received osimertinib
             (or other agents inhibiting the T790M EGFR mutation) as second line therapy. If BM
             progression occurs after osimertinib, patient will be eligible.

          -  At least one measurable BM by RECIST 1.1 criteria (≥ 10mm in longest diameter). Target
             lesions must not have received stereotactic radiotherapy (SRS). If subject had prior
             whole brain radiotherapy (WBRT), progression in any measurable BM lesion must have
             occurred at least 3 months after the end of WBRT. Subjects with asymptomatic brain
             metastases may be enrolled without prior radiation therapy to the brain. Subjects with
             minimally symptomatic brain metastases may be enrolled without prior radiation therapy
             to the brain if they do not require immediate surgical or radiation therapy in the
             opinion of the treating investigator and in the opinion of a radiation therapy or
             neurosurgical consultant

          -  Subjects in Cohort A may have asymptomatic LM detected by MRI. (Subjects with symptoms
             or signs attributed to LM will be enrolled in Cohort B whether or not they have brain
             metastases)

          -  No clinically significant progression outside of the CNS on most recent EGFR inhibitor
             therapy

          -  ECOG Score ≤2

          -  No history of another malignancy in the 5 years prior to study entry, except treated
             non-melanoma skin cancer or superficial bladder cancer or carcinoma-in-situ of the
             cervix or Stage 1 or 2 cancers of other sites that have been treated surgically and
             have not recurred

          -  Adequate organ and bone marrow functions

          -  Serum potassium and magnesium levels above the lower limit of normal

          -  No coexisting medical problems of sufficient severity to limit compliance with the
             study

          -  Willing and able to sign written informed consent and be able to comply with the study
             protocol for the duration of the study

          -  Women of childbearing potential (i.e., menstruating women) must have a negative urine
             pregnancy test (positive urine tests are to be confirmed by serum test)

        Exclusion Criteria:

          -  First day of dosing with tesevatinib is less than 2 weeks from the last treatment of
             cytotoxic chemotherapy, biological therapy, or immunotherapy, and less than 6 weeks
             for nitrosoureas and mitomycin C. Surgical procedures must have been performed at
             least 2 weeks prior to the start of study treatment. Subjects must have recovered from
             the reversible effects of prior lung cancer treatments, including surgery and
             radiation therapy (excluding alopecia)

          -  First day of dosing with tesevatinib is less than 4 weeks from the last radiotherapy
             of the brain or spinal cord/cauda equina

          -  First day of dosing with tesevatinib is less than 2 weeks from treatment with another
             investigational agent

          -  Treatment with erlotinib must be discontinued at least 3 days prior to first dose of
             tesevatinib and treatment with afatinib or other tyrosine kinase inhibitor must be
             discontinued at least 3 days prior to first dose of tesevatinib

          -  Any concurrent therapy for BM other than the specified treatment in this study

          -  Taking any medication known to moderately or severely inhibit the CYP3A4 isozyme or
             any drugs that are CYP3A4 inducers (including anti-epileptic agents such as
             phenytoin). A stable regimen (≥ 4 weeks) of antidepressants of the SSRI class is
             allowed (common SSRIs include escitalopram oxalate, citalopram, fluvoxamine,
             paroxetine, sertraline, and fluoxetine)

          -  Taking any drugs associated with torsades de pointes or known to moderately or
             severely prolong the QTc(F) interval

          -  Has evidence of active heart disease such as myocardial infarction within the 3 months
             prior to study entry; symptomatic coronary insufficiency congestive heart failure;
             moderate or severe pulmonary dysfunction

          -  History of torsades de pointes, ventricular tachycardia or fibrillation, pathologic
             sinus bradycardia (< 50 bpm), heart block (excluding first degree block, being PR
             interval only), or congenital long QT syndrome. Subjects with a history of atrial
             arrhythmias should be discussed with the medical monitor

          -  Has an active infectious process

          -  Female subject who is pregnant or lactating

          -  Known contraindication to MRI, such as cardiac pacemaker, shrapnel, or ocular foreign
             body

          -  Has marked prolongation of QTc(F) interval at screening or baseline (QTc[F] interval >
             470 msec) using the Fridericia method of correction for heart rate

          -  Gastrointestinal (GI) condition that interferes with drug absorption

          -  Non-malignant neurological disease that would interfere with evaluation of symptoms or
             signs of brain metastases

        Cohort B

        Inclusion Criteria:

          -  History of NSCLC with EGFR mutation (either exon 19 deletion or L858R mutation) or, if
             previously treated, history of an activating EGFR mutation that has had a clinical
             response to erlotinib, afatinib, or gefitinib in the patient being enrolled).

          -  Presentation with LM at initial presentation with no prior systemic treatment, or
             occurrence or progression of LM while receiving first line therapy (either erlotinib,
             afatinib, or gefitinib) for at least 14 days. Patients may have received osimertinib
             (or other agents inhibiting the T790M EGFR mutation) as second line therapy. If LM
             progression occurs after osimertinib, patient will be eligible.

          -  Presence of at least one CTCAE 4.03 symptom/sign of at least Grade 1 attributed by the
             investigator to leptomeningeal metastases

          -  Diagnosis of LM by:

               1. Cytological evidence in CSF sample of LM due to NSCLC, and/or

               2. Findings on gadolinium-enhanced MRI

          -  No clinically significant progression outside of the CNS on most recent EGFR inhibitor
             therapy

          -  Concomitant brain metastases and brain metastases previously treated with radiation
             therapy are allowed. (Subjects with symptoms or signs attributed to LM will be
             enrolled in Cohort B whether or not they have brain metastases)

          -  ECOG Score ≤2

          -  No history of another malignancy in the 5 years prior to study entry, except treated
             non-melanoma skin cancer or superficial bladder cancer or carcinoma-in-situ of the
             cervix or Stage 1 or 2 cancers of other sites that have been treated surgically and
             have not recurred.

          -  Adequate organ and bone marrow functions

          -  Serum potassium and magnesium levels above the lower limit of normal

          -  No coexisting medical problems of sufficient severity to limit compliance with the
             study

          -  Willing and able to sign written informed consent and be able to comply with the study
             protocol for the duration of the study

          -  Women of childbearing potential (i.e., menstruating women) must have a negative urine
             pregnancy test (positive urine tests are to be confirmed by serum test)

        Exclusion Criteria:

          -  First day of dosing with tesevatinib is less than 2 weeks from the last treatment of
             cytotoxic chemotherapy, biological therapy, or immunotherapy, and less than 6 weeks
             for nitrosoureas and mitomycin C. Surgical procedures must have been performed at
             least 2 weeks prior to the start of study treatment. Subjects must have recovered from
             the reversible effects of prior lung cancer treatments, including surgery and
             radiation therapy (excluding alopecia)

          -  First day of dosing with tesevatinib is less than 4 weeks from the last radiotherapy
             of the brain or spinal cord/cauda equina

          -  First day of dosing with tesevatinib is less than 2 weeks from treatment with another
             investigational agent

          -  Treatment with erlotinib must be discontinued at least 3 days prior to first dose of
             tesevatinib and treatment with afatinib or other tyrosine kinase inhibitor must be
             discontinued at least 3 days prior to first dose of tesevatinib

          -  Any concurrent therapy for LM other than the specified treatment in this study

          -  Taking any medication known to moderately or severely inhibit the CYP3A4 isozyme or
             any drugs that are CYP3A4 inducers (including anti-epileptic agents such as
             phenytoin). A stable regimen (≥ 4 weeks) of antidepressants of the SSRI class is
             allowed (common SSRIs include escitalopram oxalate, citalopram, fluvoxamine,
             paroxetine, sertraline, and fluoxetine)

          -  Taking any drugs associated with torsades de pointes or known to moderately or
             severely prolong the QTc(F) interval

          -  Has evidence of active heart disease such as myocardial infarction within the 3 months
             prior to study entry; symptomatic coronary insufficiency congestive heart failure;
             moderate or severe pulmonary dysfunction

          -  History of torsades de pointes, ventricular tachycardia or fibrillation, pathologic
             sinus bradycardia (< 50 bpm), heart block (excluding first degree block, being PR
             interval only), or congenital long QT syndrome. Subjects with a history of atrial
             arrhythmias should be discussed with the medical monitor

          -  Has an active infectious process

          -  Female subject who is pregnant or lactating

          -  Known contraindication to MRI, such as cardiac pacemaker, shrapnel, or ocular foreign
             body

          -  Has marked prolongation of QTc(F) interval at screening or baseline (QTc[F] interval >
             470 msec) using the Fridericia method of correction for heart rate

          -  Gastrointestinal (GI) condition that interferes with drug absorption

          -  Non-malignant neurological disease that would interfere with evaluation of symptoms or
             signs of leptomeningeal metastases

          -  Contraindications to lumbar puncture:

               1. INR > 1.5

               2. Platelets < 50 × 109/L (Note that platelets are required to be ≥100× 109/L at
                  screening)

               3. Therapeutic anticoagulant treatment that can't be held for 24 hours. Low dose low
                  molecular weight heparin given for deep vein thrombosis (DVT) prophylaxis is
                  allowed.

               4. CNS lesions considered to be at risk for cerebral herniation, myelocompression,
                  or conus/cauda compression

        Cohort C

        Inclusion Criteria:

          -  NSCLC with EGFR activating mutation

          -  No prior systemic treatment for NSCLC. Treatment with systemic steroids is not
             considered systemic treatment for NSCLC

          -  No prior radiation therapy to the CNS (brain or spinal cord)

          -  At least one measurable BM by RECIST 1.1 criteria (≥ 10mm in longest diameter) in a
             subject with asymptomatic or minimally symptomatic brain metastases who does not
             require immediate surgical or radiation therapy in the opinion of the treating
             investigator and in the opinion of a radiation therapy or neurosurgical consultant.

          -  Subjects in Cohort C may have asymptomatic LM detected by MRI

          -  ECOG Score ≤2

          -  No history of another malignancy in the 5 years prior to study entry, except treated
             non-melanoma skin cancer or superficial bladder cancer or carcinoma-in-situ of the
             cervix or Stage 1 or 2 cancers of other sites that have been treated surgically and
             have not recurred

          -  Adequate organ and bone marrow functions

          -  Serum potassium and magnesium levels above the LLN

          -  No coexisting medical problems of sufficient severity to limit compliance with the
             study.

          -  Willing and able to sign written informed consent and be able to comply with the study
             protocol for the duration of the study

          -  Women of childbearing potential (i.e., menstruating women) must have a negative urine
             pregnancy test (positive urine tests are to be confirmed by serum test)

        Exclusion Criteria:

          -  Surgical procedures that were performed less than 2 weeks prior to the start of study
             treatment

          -  Any concurrent therapy for BM other than the specified treatment in this study

          -  Taking any medication known to moderately or severely inhibit the CYP3A4 isozyme or
             any drugs that are CYP3A4 inducers (including anti-epileptic agents such as
             phenytoin). A stable regimen (≥ 4 weeks) of antidepressants of the SSRI class is
             allowed (common SSRIs include escitalopram oxalate, citalopram, fluvoxamine,
             paroxetine, sertraline, and fluoxetine)

          -  Taking any drugs associated with torsades de pointes or known to moderately or
             severely prolong the QTc(F) interval

          -  Has evidence of active heart disease such as myocardial infarction within the 3 months
             prior to study entry; symptomatic coronary insufficiency congestive heart failure;
             moderate or severe pulmonary dysfunction

          -  History of torsades de pointes, ventricular tachycardia or fibrillation, pathologic
             sinus bradycardia (< 50 bpm), heart block (excluding first degree block, being PR
             interval only), or congenital long QT syndrome. Subjects with a history of atrial
             arrhythmias should be discussed with the medical monitor

          -  Has an active infectious process

          -  Female subject who is pregnant or lactating

          -  Known contraindication to MRI, such as cardiac pacemaker, shrapnel, or ocular foreign
             body

          -  Has marked prolongation of QTc(F) interval at screening or Cycle 1 Day 1 (QTc[F]
             interval > 470 msec) using the Fridericia method of correction for heart rate

          -  GI condition that interferes with drug absorption

          -  Non-malignant neurological disease that would interfere with evaluation of symptoms or
             signs of brain metastases
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Clinical Activity of tesevatinib against BM using RECIST 1.1
Time Frame:12 months
Safety Issue:
Description:The primary objective is to evaluate the clinical activity of tesevatinib in subjects with non-small cell lung cancer (NSCLC), activating EGFR mutations, and BM as measured by RECIST 1.1 evaluated changes in BM size (Cohort A)

Secondary Outcome Measures

Measure:Quality of Life in Subjects Receiving tesevatinib for BM
Time Frame:12 months
Safety Issue:
Description:To evaluate changes in Quality of Life (QOL) in subjects receiving tesevatinib for BM using the EORTC QLQ-C30 and EORTC QLQ-BN20 Questionnaires
Measure:Quality of Life in Subjects Receiving tesevatinib for LM
Time Frame:12 months
Safety Issue:
Description:To evaluate changes in QOL in subjects receiving tesevatinib for LM using the EORTC QLQ-C30 and EORTC QLQ-BN20 Questionnaires
Measure:Quality of Life in Subjects Receiving tesevatinib for BM at initial presentation
Time Frame:12 months
Safety Issue:
Description:To evaluate changes in QOL in subjects receiving tesevatinib for BM at initial presentation using the EORTC QLQ-C30 and EORTC QLQ-BN20 Questionnaires
Measure:Median Progression-Free Survival in Cohort A
Time Frame:12 months
Safety Issue:
Description:To determine the median progression-free survival (PFS) in Cohort A by assessing the median number of days from Cycle 1, Day 1 until disease progression or death
Measure:Rate of CNS Non-Progression in Cohort A
Time Frame:12 months
Safety Issue:
Description:To determine the rate of CNS non-progression at 3 and 6 months Cohort A by assessing the percentage of subjects in Cohort A without CNS disease progression 3 and 6 months after Cycle 1, Day 1
Measure:Non-CNS Time to Progression in Cohort A
Time Frame:12 months
Safety Issue:
Description:To determine the rate of Non-CNS time to progression in Cohort A by assessing the median number of days in Cycle 1, Day 1 until non-CNS disease progression
Measure:CNS TTP in Cohort A
Time Frame:12 months
Safety Issue:
Description:To determine the rate of CNS TTPin Cohort A by assessing the median number of days in Cycle 1, Day 1 to disease progression
Measure:Median Progression-Free Survival in Cohort B
Time Frame:12 months
Safety Issue:
Description:To determine the median progression-free survival (PFS) in Cohort B by assessing the median number of days from Cycle 1, Day 1 until disease progression or death
Measure:Rate of CNS Non-Progression in Cohort B
Time Frame:12 months
Safety Issue:
Description:To determine the rate of CNS non-progression at 3 and 6 months Cohort B by assessing the percentage of subjects in Cohort A without CNS disease progression 3 and 6 months after Cycle 1, Day 1
Measure:Non-CNS Time to Progression in Cohort B
Time Frame:12 months
Safety Issue:
Description:To determine the rate of Non-CNS time to progression in Cohort B by assessing the median number of days in Cycle 1, Day 1 until non-CNS disease progression
Measure:CNS TTP in Cohort B
Time Frame:12 months
Safety Issue:
Description:To determine the rate of CNS TTP in Cohort B by assessing the median number of days in Cycle 1, Day 1 to disease progression
Measure:Median Overall Survival in Cohort A
Time Frame:12 months
Safety Issue:
Description:To determine the median overall survival (OS) in Cohort A by measuring the median number of days from Cycle 1, Day 1 until death
Measure:Median Overall Survival in Cohort B
Time Frame:12 months
Safety Issue:
Description:To determine the median OS in Cohort B by measuring the median number of days from Cycle 1, Day 1 until death
Measure:Clinical Activity of tesevatinib against LM using Standard Cytology
Time Frame:12 months
Safety Issue:
Description:Evaluate the activity of tesevatinib in subjects with NSCLC as measured by decreases in NSCLC cells in the CSF using standard cytology as assessed by the percent change in the number of NSCLC cells in the CSF for each patient in cohort B from screening to Cycle 1, Day 14, from Day 14 to Cycle 3, Day 1, and from screening to Cycle 3, Day 1 (Cohort B)
Measure:Clinical Activity of tesevatinib against LM using Improvement in MRI Findings
Time Frame:12 months
Safety Issue:
Description:Evaluate the activity of tesevatinib in subjects with NSCLC as measured by changes in MRI findings consistent with leptomeningeal metastases (absent or present) for each patient in Cohort B from Cycle 1, Day 1 to Cycle 3, Day 1 and from Cycle 1, Day 1 to Cycle 5 Day 1 (Cohort B)
Measure:Pharmacokinetics
Time Frame:12 months
Safety Issue:
Description:To evaluate the concentration of tesevatinib in CSF versus plasma (Cohort B)
Measure:Median Progression-Free Survival in Cohort C
Time Frame:12 months
Safety Issue:
Description:To determine the median progression-free survival (PFS) in Cohort C by assessing the median number of days from Cycle 1, Day 1 until disease progression or death
Measure:Rate of CNS Non-Progression in Cohort C
Time Frame:12 months
Safety Issue:
Description:To determine the rate of CNS non-progression at 3 and 6 months Cohort C by assessing the percentage of subjects in Cohort C without CNS disease progression 3 and 6 months after Cycle 1, Day 1
Measure:Non-CNS Time to Progression in Cohort C
Time Frame:12 months
Safety Issue:
Description:To determine the rate of Non-CNS time to progression in Cohort C by assessing the median number of days in Cycle 1, Day 1 until non-CNS disease progression
Measure:CNS TTP in Cohort C
Time Frame:12 months
Safety Issue:
Description:To determine the rate of CNS TTPin Cohort C by assessing the median number of days in Cycle 1, Day 1 to disease progression
Measure:Median Overall Survival in Cohort C
Time Frame:12 months
Safety Issue:
Description:To determine the median overall survival (OS) in Cohort C by measuring the median number of days from Cycle 1, Day 1 until death

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Active, not recruiting
Lead Sponsor:Kadmon Corporation, LLC

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