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

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