Phase 2 Study of Study of Tesevatinib in Subjects With NSCLC and Brain or Leptomeningeal Metastases

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 toerlotinib, 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 BMprogression 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 subjecthad prior whole brain radiotherapy (WBRT), progression in any measurable BM lesionmust have occurred at least 3 months after the end of WBRT. Subjects with asymptomaticbrain metastases may have been enrolled without prior radiation therapy to the brain.Subjects with minimally symptomatic brain metastases may have been enrolled withoutprior radiation therapy to the brain if they do not require immediate surgical orradiation therapy in the opinion of the treating investigator and in the opinion of aradiation therapy or neurosurgical consultant
• Subjects in Cohort A may have had asymptomatic LM detected by MRI. (Subjects withsymptoms or signs attributed to LM were enrolled in Cohort B whether or not they havebrain metastases)
• No clinically significant progression outside of the CNS on most recent EGFR inhibitortherapy
• ECOG Score ≤ 2
• No history of another malignancy in the 5 years prior to study entry, except treatednon-melanoma skin cancer or superficial bladder cancer or carcinoma in situ of thecervix or Stage 1 or 2 cancers of other sites that have been treated surgically andhave 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 thestudy
• Willing and able to sign written informed consent and able to comply with the studyprotocol for the duration of the study
• Women of childbearing potential (i.e., menstruating women) must have had a negativeurine 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 ofcytotoxic chemotherapy, biological therapy, or immunotherapy, and less than 6 weeksfor nitrosoureas and mitomycin C. Surgical procedures must have been performed atleast 2 weeks prior to the start of study treatment. Subjects must have recovered fromthe reversible effects of prior lung cancer treatments, including surgery andradiation therapy (excluding alopecia).
• First day of dosing with tesevatinib less than 4 weeks from the last radiotherapy ofthe brain or spinal cord/cauda equina
• First day of dosing with tesevatinib less than 2 weeks from treatment with anotherinvestigational agent
• Treatment with erlotinib must have been discontinued at least 3 days prior to firstdose of tesevatinib and treatment with afatinib or other tyrosine kinase inhibitormust 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 orany drugs that are CYP3A4 inducers (including anti-epileptic agents such asphenytoin). A stable regimen (≥ 4 weeks) of antidepressants of the selective serotoninuptake 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 orseverely prolong the QTc(F) interval
• Evidence of active heart disease such as myocardial infarction within the 3 monthsprior to study entry; symptomatic coronary insufficiency congestive heart failure;moderate or severe pulmonary dysfunction
• History of torsades de pointes, ventricular tachycardia or fibrillation, pathologicsinus bradycardia (< 50 bpm), heart block (excluding first degree block, being PRinterval only), or congenital long QT syndrome. Subjects with a history of atrialarrhythmias 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 foreignbody
• Marked prolongation of QTc(F) interval at screening or baseline (QTc[F] interval > 470msec) 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 orsigns of brain metastases Cohort B Inclusion Criteria:
• History of NSCLC with EGFR mutation (either exon 19 deletion or L858R mutation) or, ifpreviously treated, history of an activating EGFR mutation that had a clinicalresponse to erlotinib, afatinib, or gefitinib in the subject being enrolled).
• Presentation with LM at initial presentation with no prior systemic treatment, oroccurrence 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 LMprogression occurred after osimertinib, subjects were eligible.
• Presence of at least one CTCAE 4.03 symptom/sign of at least Grade 1 attributed by theinvestigator 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 inhibitortherapy
• Concomitant brain metastases and brain metastases previously treated with radiationtherapy were allowed. (Subjects with symptoms or signs attributed to LM will beenrolled 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 treatednon-melanoma skin cancer or superficial bladder cancer or carcinoma in situ of thecervix or Stage 1 or 2 cancers of other sites that have been treated surgically andhad 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 thestudy
• Willing and able to sign written informed consent and able to comply with the studyprotocol for the duration of the study
• Women of childbearing potential (i.e., menstruating women) must have had a negativeurine 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 ofcytotoxic chemotherapy, biological therapy, or immunotherapy, and less than 6 weeksfor nitrosoureas and mitomycin C. Surgical procedures must have been performed atleast 2 weeks prior to the start of study treatment. Subjects must have recovered fromthe reversible effects of prior lung cancer treatments, including surgery andradiation therapy (excluding alopecia).
• First day of dosing with tesevatinib less than 4 weeks from the last radiotherapy ofthe brain or spinal cord/cauda equina
• First day of dosing with tesevatinib less than 2 weeks from treatment with anotherinvestigational agent
• Treatment with erlotinib must have been discontinued at least 3 days prior to firstdose of tesevatinib and treatment with afatinib or other tyrosine kinase inhibitormust 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 orany drugs that are CYP3A4 inducers (including anti-epileptic agents such asphenytoin). A stable regimen (≥ 4 weeks) of antidepressants of the SSRI class wasallowed (common SSRIs include escitalopram oxalate, citalopram, fluvoxamine,paroxetine, sertraline, and fluoxetine)
• Taking any drugs associated with torsades de pointes or known to moderately orseverely prolong the QTc(F) interval
• Evidence of active heart disease such as myocardial infarction within the 3 monthsprior to study entry; symptomatic coronary insufficiency congestive heart failure;moderate or severe pulmonary dysfunction
• History of torsades de pointes, ventricular tachycardia or fibrillation, pathologicsinus bradycardia (< 50 bpm), heart block (excluding first degree block, being PRinterval only), or congenital long QT syndrome. Subjects with a history of atrialarrhythmias 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 foreignbody
• Marked prolongation of QTc(F) interval at screening or baseline (QTc[F] interval > 470msec) 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 orsigns 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 atscreening)
3. Therapeutic anticoagulant treatment that can't be held for 24 hours. Low dose lowmolecular weight heparin given for deep vein thrombosis (DVT) prophylaxis wasallowed.
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 notconsidered 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 asubject with asymptomatic or minimally symptomatic brain metastases who did notrequire immediate surgical or radiation therapy in the opinion of the treatinginvestigator 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 treatednon-melanoma skin cancer or superficial bladder cancer or carcinoma in situ of thecervix or Stage 1 or 2 cancers of other sites that have been treated surgically andhave 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 thestudy.
• Willing and able to sign written informed consent and able to comply with the studyprotocol for the duration of the study
• Women of childbearing potential (i.e., menstruating women) must have had a negativeurine 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 orany drugs that are CYP3A4 inducers (including anti-epileptic agents such asphenytoin). A stable regimen (≥ 4 weeks) of antidepressants of the SSRI class wasallowed (common SSRIs include escitalopram oxalate, citalopram, fluvoxamine,paroxetine, sertraline, and fluoxetine)
• Taking any drugs associated with torsades de pointes or known to moderately orseverely prolong the QTc(F) interval
• Evidence of active heart disease such as myocardial infarction within the 3 monthsprior to study entry; symptomatic coronary insufficiency congestive heart failure;moderate or severe pulmonary dysfunction
• History of torsades de pointes, ventricular tachycardia or fibrillation, pathologicsinus bradycardia (< 50 bpm), heart block (excluding first-degree block, being PRinterval only), or congenital long QT syndrome. Subjects with a history of atrialarrhythmias 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 foreignbody
• 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 orsigns of brain metastases