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.
Name: Tesevatinib
Type: DrugCohort A - Brain Metastases Cohort B - Leptomeningeal Metastases Cohort C - Brain Metastases at initial presentation
Description: The primary objective is to evaluate the clinical activity of tesevatinib in subjects with non-small cell lung cancer (NSCLC), activating EGFR mutations, and BM as measured by RECIST 1.1 evaluated changes in BM size (Cohort A)
Measure: Clinical Activity of tesevatinib against BM using RECIST 1.1 Time: 12 monthsDescription: The primary objective is to evaluate the clinical activity of tesevatinib in subjects with NSCLC, activating EGFR mutations and/or LM as measured by improvement in CTCAE v4.03 symptoms and signs (Cohort B)
Measure: Clinical Activity of tesevatinib against LM using Symptom Resolution Time: 12 monthsDescription: The primary objective is to evaluate the clinical activity of tesevatinib in subjects with non-small cell lung cancer (NSCLC), activating EGFR mutations, and BM at initial presentation as measured by RECIST 1.1 evaluated changes in BM size (Cohort C)
Measure: Clinical Activity of tesevatinib against BM at initial presentation using RECIST 1.1 Time: 12 monthsDescription: To evaluate changes in Quality of Life (QOL) in subjects receiving tesevatinib for BM using the EORTC QLQ-C30 and EORTC QLQ-BN20 Questionnaires
Measure: Quality of Life in Subjects Receiving tesevatinib for BM Time: 12 monthsDescription: To evaluate changes in QOL in subjects receiving tesevatinib for LM using the EORTC QLQ-C30 and EORTC QLQ-BN20 Questionnaires
Measure: Quality of Life in Subjects Receiving tesevatinib for LM Time: 12 monthsDescription: To evaluate changes in QOL in subjects receiving tesevatinib for BM at initial presentation using the EORTC QLQ-C30 and EORTC QLQ-BN20 Questionnaires
Measure: Quality of Life in Subjects Receiving tesevatinib for BM at initial presentation Time: 12 monthsDescription: To determine the median progression-free survival (PFS) in Cohort A by assessing the median number of days from Cycle 1, Day 1 until disease progression or death
Measure: Median Progression-Free Survival in Cohort A Time: 12 monthsDescription: To determine the rate of CNS non-progression at 3 and 6 months Cohort A by assessing the percentage of subjects in Cohort A without CNS disease progression 3 and 6 months after Cycle 1, Day 1
Measure: Rate of CNS Non-Progression in Cohort A Time: 12 monthsDescription: To determine the rate of Non-CNS time to progression in Cohort A by assessing the median number of days in Cycle 1, Day 1 until non-CNS disease progression
Measure: Non-CNS Time to Progression in Cohort A Time: 12 monthsDescription: To determine the rate of CNS TTPin Cohort A by assessing the median number of days in Cycle 1, Day 1 to disease progression
Measure: CNS TTP in Cohort A Time: 12 monthsDescription: To determine the median progression-free survival (PFS) in Cohort B by assessing the median number of days from Cycle 1, Day 1 until disease progression or death
Measure: Median Progression-Free Survival in Cohort B Time: 12 monthsDescription: To determine the rate of CNS non-progression at 3 and 6 months Cohort B by assessing the percentage of subjects in Cohort A without CNS disease progression 3 and 6 months after Cycle 1, Day 1
Measure: Rate of CNS Non-Progression in Cohort B Time: 12 monthsDescription: To determine the rate of Non-CNS time to progression in Cohort B by assessing the median number of days in Cycle 1, Day 1 until non-CNS disease progression
Measure: Non-CNS Time to Progression in Cohort B Time: 12 monthsDescription: To determine the rate of CNS TTP in Cohort B by assessing the median number of days in Cycle 1, Day 1 to disease progression
Measure: CNS TTP in Cohort B Time: 12 monthsDescription: To determine the median overall survival (OS) in Cohort A by measuring the median number of days from Cycle 1, Day 1 until death
Measure: Median Overall Survival in Cohort A Time: 12 monthsDescription: To determine the median OS in Cohort B by measuring the median number of days from Cycle 1, Day 1 until death
Measure: Median Overall Survival in Cohort B Time: 12 monthsDescription: Evaluate the activity of tesevatinib in subjects with NSCLC as measured by decreases in NSCLC cells in the CSF using standard cytology as assessed by the percent change in the number of NSCLC cells in the CSF for each patient in cohort B from screening to Cycle 1, Day 14, from Day 14 to Cycle 3, Day 1, and from screening to Cycle 3, Day 1 (Cohort B)
Measure: Clinical Activity of tesevatinib against LM using Standard Cytology Time: 12 monthsDescription: Evaluate the activity of tesevatinib in subjects with NSCLC as measured by changes in MRI findings consistent with leptomeningeal metastases (absent or present) for each patient in Cohort B from Cycle 1, Day 1 to Cycle 3, Day 1 and from Cycle 1, Day 1 to Cycle 5 Day 1 (Cohort B)
Measure: Clinical Activity of tesevatinib against LM using Improvement in MRI Findings Time: 12 monthsDescription: To evaluate the concentration of tesevatinib in CSF versus plasma (Cohort B)
Measure: Pharmacokinetics Time: 12 monthsDescription: To determine the median progression-free survival (PFS) in Cohort C by assessing the median number of days from Cycle 1, Day 1 until disease progression or death
Measure: Median Progression-Free Survival in Cohort C Time: 12 monthsDescription: To determine the rate of CNS non-progression at 3 and 6 months Cohort C by assessing the percentage of subjects in Cohort C without CNS disease progression 3 and 6 months after Cycle 1, Day 1
Measure: Rate of CNS Non-Progression in Cohort C Time: 12 monthsDescription: To determine the rate of Non-CNS time to progression in Cohort C by assessing the median number of days in Cycle 1, Day 1 until non-CNS disease progression
Measure: Non-CNS Time to Progression in Cohort C Time: 12 monthsDescription: To determine the rate of CNS TTPin Cohort C by assessing the median number of days in Cycle 1, Day 1 to disease progression
Measure: CNS TTP in Cohort C Time: 12 monthsDescription: To determine the median overall survival (OS) in Cohort C by measuring the median number of days from Cycle 1, Day 1 until death
Measure: Median Overall Survival in Cohort C Time: 12 monthsAllocation: Non-Randomized
Single Group Assignment
There are 2 SNPs
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). --- L858R ---
Patients may have received osimertinib (or other agents inhibiting the T790M EGFR mutation) as second line therapy. --- T790M ---