Patient case: 45-year-old female with Melanoma. Genetic variant: BRAF (V600E), CDKN2A Deletion. Other conditions: None.

Clinical trial: 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

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:
  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

Relevance to patient case: not relevant