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

Basic Trial Information

Phase Type Age Sponsor Protocol IDs Status
Phase 2 Interventional 18 Years and older Kadmon Corporation, LLC KD019-206
NCT02616393
Enrolling patients

Study Design:


Principal Investigator

Professor of Medicine
Chair, Data and Safety Monitoring Committee
Bonnie J. and Anthony Addario Endowed Chair in Thoracic Oncology
UCSF Helen Diller Family Comprehensive Cancer Center

Clinical Research Coordinator

UCSF Helen Diller Family Comprehensive Cancer Center
415) 353-9712 Phone
(415) 353-9721 Fax

Trial Summary

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.

Eligibility

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 either erlotinib or afatinib or
    gefitinib. Previous systemic treatment included erlotinib or afatinib or gefitinib
    for at least 14 days. Patients may have received osimertinib or rociletinib, or other
    agents inhibiting the T790M EGFR mutation, but only if they then receive at least 14
    days of treatment with erlotinib, afatinib, or gefitinib and have CNS but not
    peripheral progression
  • 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 either erlotinib or afatinib or
    gefitinib. Previous systemic treatment included erlotinib or afatinib or gefitinib
    for at least 14 days. Patients may have received osimertinib or rociletinib, or other
    agents inhibiting the T790M EGFR mutation, but only if they then receive at least 14
    days of treatment with erlotinib, afatinib, or gefitinib and have CNS but not
    peripheral progression
  • 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:
           Cytological evidence in CSF sample of LM due to NSCLC, and/or
           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:
           INR > 1.5
           Platelets < 50 × 109/L (Note that platelets are required to be ≥100× 109/L at
           screening)
           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.
           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

Important

Final eligibility is determined by the health professionals conducting the trial and the protocol approved by the Committee on Human Resources (CHR) at the University of California, San Francisco (UCSF). The Patient Consent Form for this trial is available upon request. For more information about this trial, please see the full posting at ClinicalTrials.gov.

Information about this trial was obtained from the NIH Clinical Trials website, http://clinicaltrials.gov on 1/26/2017. UCSF specific information including the PI (Principal Investigator), trial enrollment status, and UCSF Study ID, supplement the ClinicalTrials.gov study posting.
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