Phase 2 Study of Study of Tesevatinib in Subjects With NSCLC and Brain or Leptomeningeal Metastases
Condition: Non-Small Cell Lung Cancer; Leptomeningeal Metastases; Brain Metastases
MeSH terms: Lung Neoplasms; Carcinoma, Non-Small-Cell Lung; Neoplasm Metastasis; Neoplasms, Second Primary; Brain Neoplasms; Meningeal Carcinomatosis
Intervention: Tesevatinib
Intervention MeSH terms: XL647
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 36.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

Summary:

      A study to assess the activity of tesevatinib in subjects with non-small cell lung cancer
      (NSCLC) and activating epidermal growth factor receptor (EGFR) mutations who have disease
      progression with Brain Metastases (BM) or Leptomeningeal Metastases (LM) or who have either
      BM or LM at initial presentation (IP)
    

Eligibility criteria:

        Cohort A

        Inclusion Criteria:

          -  History of non-small cell lung cancer (NSCLC) with epidermal growth factor receptor
             (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 (≥ 10 mm in longest diameter).
             Target lesions must not have received stereotactic radiotherapy (SRS). If a 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 have been enrolled without prior radiation therapy to the brain.
             Subjects with minimally symptomatic brain metastases may have been 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 had asymptomatic LM detected by MRI. (Subjects with
             symptoms or signs attributed to LM were 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 able to comply with the study
             protocol for the duration of the study

          -  Women of childbearing potential (i.e., menstruating women) must have had a negative
             urine pregnancy test (positive urine tests confirmed by serum test)

        Exclusion Criteria:

          -  First day of dosing with tesevatinib 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 less than 4 weeks from the last radiotherapy of
             the brain or spinal cord/cauda equina

          -  First day of dosing with tesevatinib less than 2 weeks from treatment with another
             investigational agent

          -  Treatment with erlotinib must have been discontinued at least 3 days prior to first
             dose of tesevatinib and treatment with afatinib or other tyrosine kinase inhibitor
             must have been 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 selective serotonin
             uptake inhibitor (SSRI) class was 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

          -  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 were discussed with the medical monitor

          -  Had an active infectious process

          -  Female subject pregnant or lactating

          -  Known contraindication to MRI, such as cardiac pacemaker, shrapnel, or ocular foreign
             body

          -  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 interfering 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 had a clinical
             response to erlotinib, afatinib, or gefitinib in the subject 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 occurred after osimertinib, subjects were eligible.

          -  Presence of at least one CTCAE 4.03 symptom/sign of at least Grade 1 attributed by the
             investigator to LM

          -  Diagnosis of LM by:

               1. Cytological evidence in cerebrospinal fluid (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 were 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
             had not recurred

          -  Adequate organ and bone marrow functions

          -  Serum potassium and magnesium levels above the lower limit of normal (LLN)

          -  No coexisting medical problems of sufficient severity to limit compliance with the
             study

          -  Willing and able to sign written informed consent and able to comply with the study
             protocol for the duration of the study

          -  Women of childbearing potential (i.e., menstruating women) must have had a negative
             urine pregnancy test (positive urine tests confirmed by serum test)

        Exclusion Criteria:

          -  First day of dosing with tesevatinib 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 less than 4 weeks from the last radiotherapy of
             the brain or spinal cord/cauda equina

          -  First day of dosing with tesevatinib less than 2 weeks from treatment with another
             investigational agent

          -  Treatment with erlotinib must have been discontinued at least 3 days prior to first
             dose of tesevatinib and treatment with afatinib or other tyrosine kinase inhibitor
             must have been 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 was
             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

          -  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 were discussed with the medical monitor.

          -  Has an active infectious process

          -  Female subject pregnant or lactating

          -  Known contraindication to MRI, such as cardiac pacemaker, shrapnel, or ocular foreign
             body

          -  Marked prolongation of QTc(F) interval at screening or baseline (QTc[F] interval > 470
             msec) using the Fridericia method of correction for heart rate

          -  GI condition that would interfere with drug absorption

          -  Non-malignant neurological disease that would interfere with evaluation of symptoms or
             signs of leptomeningeal metastases

          -  Contraindications to lumbar puncture:

               1. International Normalized Ratio (INR) > 1.5

               2. Platelets < 50 × 10^9/L (Note that platelets are required to be ≥100× 10^9/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 was
                  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 was 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 (≥ 10 mm in longest diameter) in a
             subject with asymptomatic or minimally symptomatic brain metastases who did 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 had 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 able to comply with the study
             protocol for the duration of the study

          -  Women of childbearing potential (i.e., menstruating women) must have had a negative
             urine pregnancy test (positive urine tests are to be confirmed by serum test)

        Exclusion Criteria:

          -  Surgical procedures 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 was
             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

          -  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 were discussed with the medical monitor

          -  An active infectious process

          -  Female subject pregnant or lactating

          -  Known contraindication to MRI, such as cardiac pacemaker, shrapnel, or ocular foreign
             body

          -  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 interfering with drug absorption

          -  Non-malignant neurological disease that would interfere with evaluation of symptoms or
             signs of brain metastases