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)

This was a multicenter, phase 2, open-label study to assess the activity of tesevatinib, in subjects with non-small cell lung cancer (NSCLC) and activating epidermal growth factor receptor (EGFR) mutations, and brain metastases (BM) or leptomeningeal metastases (LM).

After completion of the screening assessments and confirmation of study eligibility, tesevatinib was orally administered to all subjects at a dose of 300 mg once daily (QD). Tumor response, both in the central nervous system (CNS) and outside the central nervous system (non-CNS), was assessed after the second cycle of treatment and then at the end of every two cycles of treatment thereafter. Subjects were treated with tesevatinib 300 mg QD until disease progression or the subject experienced unacceptable toxicity.

Subjects who discontinued tesevatinib therapy were followed for survival.

Subjects with NSCLC + EGFR mutations were assigned to one of three cohorts:

• Cohort A: Brain Metastases (BM). Subjects had progressed with BM.
• Cohort B: Leptomeningeal Metastases (LM). Subjects had initially presented or progressed with LM.
• Cohort C: Brain Metastases at Initial Presentation (BM-IP). Subjects had no prior systemic therapy.

Each of the three cohorts was to have 20 subjects, for a total of 60 subjects. All three cohorts were enrolled simultaneously.

The primary objectives were to include:

• Clinical activity of tesevatinib of subjects in Cohort A (BM) and Cohort C (BM-IP) as measured by Response Criteria in Solid Tumors (RECIST) version 1.1 which evaluated changes in BM size.
• Clinical activity of tesevatinib of subjects in Cohort B (LM) as measured by improvement in Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 symptoms and signs.

Efficacy assessments included response to treatment using RECIST criteria, progression-free survival (PFS), time to progression (TTP), overall survival (OS), and Quality of Life (QOL) questionnaires. Safety assessments included adverse event (AE) monitoring, electrocardiogram (ECG), Eastern Cooperative Oncology Group (ECOG) Performance Status, laboratory testing, physical examination, vital signs, and pregnancy testing. In addition, pharmacokinetic (PK) and pharmacodynamic (PD) assessments were performed.

An End of Treatment Visit occurred within 3 days after the subject's last dose of study drug. This could have occurred at the visit when disease progression was diagnosed. Subjects were continued to be followed for disease progression and survival.

A follow-up visit occurred 30 days (± 5 days) after the last dose of study drug. This visit may have occurred prior to 30 days if a new therapy was started within 30 days of last dose of study drug.

For long-term follow-up, after subjects withdrew from the active treatment portion of the study, they were contacted by telephone every 8 weeks to assess survival status and any subsequent anti-cancer treatment.

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