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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

This study is currently recruiting participants.
See Contacts and Locations
Verified March 2017 by Kadmon Corporation, LLC
Sponsor:
Information provided by (Responsible Party):
Kadmon Corporation, LLC
ClinicalTrials.gov Identifier:
NCT02616393
First received: November 20, 2015
Last updated: March 1, 2017
Last verified: March 2017
  Purpose
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.

Condition Intervention Phase
Non-Small Cell Lung Cancer Leptomeningeal Metastases Brain Metastases Drug: Tesevatinib Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: No masking
Primary Purpose: Treatment
Official Title: A Phase 2, Multicenter 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

Resource links provided by NLM:


Further study details as provided by Kadmon Corporation, LLC:

Primary Outcome Measures:
  • Clinical Activity of tesevatinib against BM using RECIST 1.1 [ Time Frame: 12 months ]
    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)

  • Clinical Activity of tesevatinib against LM using Symptom Resolution [ Time Frame: 12 months ]
    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)

  • Clinical Activity of tesevatinib against BM at initial presentation using RECIST 1.1 [ Time Frame: 12 months ]
    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)


Secondary Outcome Measures:
  • Quality of Life in Subjects Receiving tesevatinib for BM [ Time Frame: 12 months ]
    To evaluate changes in Quality of Life (QOL) in subjects receiving tesevatinib for BM using the EORTC QLQ-C30 and EORTC QLQ-BN20 Questionnaires

  • Quality of Life in Subjects Receiving tesevatinib for LM [ Time Frame: 12 months ]
    To evaluate changes in QOL in subjects receiving tesevatinib for LM using the EORTC QLQ-C30 and EORTC QLQ-BN20 Questionnaires

  • Quality of Life in Subjects Receiving tesevatinib for BM at initial presentation [ Time Frame: 12 months ]
    To evaluate changes in QOL in subjects receiving tesevatinib for BM at initial presentation using the EORTC QLQ-C30 and EORTC QLQ-BN20 Questionnaires

  • Median Progression-Free Survival in Cohort A [ Time Frame: 12 months ]
    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

  • Rate of CNS Non-Progression in Cohort A [ Time Frame: 12 months ]
    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

  • Non-CNS Time to Progression in Cohort A [ Time Frame: 12 months ]
    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

  • CNS TTP in Cohort A [ Time Frame: 12 months ]
    To determine the rate of CNS TTPin Cohort A by assessing the median number of days in Cycle 1, Day 1 to disease progression

  • Median Progression-Free Survival in Cohort B [ Time Frame: 12 months ]
    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

  • Rate of CNS Non-Progression in Cohort B [ Time Frame: 12 months ]
    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

  • Non-CNS Time to Progression in Cohort B [ Time Frame: 12 months ]
    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

  • CNS TTP in Cohort B [ Time Frame: 12 months ]
    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

  • Median Overall Survival in Cohort A [ Time Frame: 12 months ]
    To determine the median overall survival (OS) in Cohort A by measuring the median number of days from Cycle 1, Day 1 until death

  • Median Overall Survival in Cohort B [ Time Frame: 12 months ]
    To determine the median OS in Cohort B by measuring the median number of days from Cycle 1, Day 1 until death

  • Clinical Activity of tesevatinib against LM using Standard Cytology [ Time Frame: 12 months ]
    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)

  • Clinical Activity of tesevatinib against LM using Improvement in MRI Findings [ Time Frame: 12 months ]
    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)

  • Pharmacokinetics [ Time Frame: 12 months ]
    To evaluate the concentration of tesevatinib in CSF versus plasma (Cohort B)

  • Median Progression-Free Survival in Cohort C [ Time Frame: 12 months ]
    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

  • Rate of CNS Non-Progression in Cohort C [ Time Frame: 12 months ]
    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

  • Non-CNS Time to Progression in Cohort C [ Time Frame: 12 months ]
    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

  • CNS TTP in Cohort C [ Time Frame: 12 months ]
    To determine the rate of CNS TTPin Cohort C by assessing the median number of days in Cycle 1, Day 1 to disease progression

  • Median Overall Survival in Cohort C [ Time Frame: 12 months ]
    To determine the median overall survival (OS) in Cohort C by measuring the median number of days from Cycle 1, Day 1 until death


Estimated Enrollment: 60
Study Start Date: November 2015
Estimated Primary Completion Date: June 2017 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Cohort A - Brain Metastases
Tesevatinib will be orally administered with a dose of 300 mg once daily to subjects with NSCLC who have progressed with BM
Drug: Tesevatinib
Other Name: KD019, XL647
Experimental: Cohort B - Leptomeningeal Metastases
Tesevatinib will be orally administered with a dose of 300 mg once daily to subjects with NSCLC who have progressed with LM
Drug: Tesevatinib
Other Name: KD019, XL647
Experimental: Cohort C - Brain Metastases at initial presentation
Tesevatinib will be orally administered with a dose of 300 mg once daily to subjects with NSCLC with BM at initial presentation
Drug: Tesevatinib
Other Name: KD019, XL647

  Eligibility

Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT02616393

Locations
United States, California
Beverly Hills Cancer Center Recruiting
Beverly Hills, California, United States, 90211
Contact: Jordan Garst, CRC    310-432-8932    Clinicaltrials@bhcancercenter.com   
Principal Investigator: David Berz, MD         
UC San Diego Moores Cancer Center Recruiting
La Jolla, California, United States, 92093
Contact: Nisha R Parikh, MSCR    858-822-4171    nrparikh@ucsd.edu   
Principal Investigator: Hatim Husain, MD         
USC/Norris Comprehensive Cancer Center Recruiting
Los Angeles, California, United States, 90033
Contact: Gina Tse, RN    323-865-0514    tse_g@med.usc.edu   
Contact: Laurie de Oliveira    323-226-6397    Laurie.DeOliveira@med.usc.edu   
USC Norris Oncology/Hematology Newport Beach Recruiting
Newport Beach, California, United States, 92663
Contact: Kristy Massopust, CCRP    949-474-5733    massopust_k@med.usc.edu   
University of California San Francisco Recruiting
San Francisco, California, United States, 94115
Contact: Eduardo Sosa    415-514-6241    Eduardo.sosa@ucsf.edu   
Principal Investigator: Thierry Jahan, MD         
John Wayne Cancer Institute Recruiting
Santa Monica, California, United States, 90404
Contact: Annie Heng, RN    310-582-7457    henga@jwci.org   
Principal Investigator: Santosh Kesari, MD         
United States, Colorado
University of Colorado Cancer Center Recruiting
Aurora, Colorado, United States, 80045
Contact: Paula Fisk    720-848-0676    PAULA.FISK@UCDENVER.EDU   
Principal Investigator: David Ross Camidge, MD, PhD         
United States, District of Columbia
Georgetown University Medical Center Recruiting
Washington, District of Columbia, United States, 20007
Contact: Jenny Crawford       crawfojg@georgetown.edu   
Principal Investigator: Deepa Subramaniam, MD         
United States, Tennessee
Sarah Cannon Research Institute Recruiting
Nashville, Tennessee, United States, 37203
Contact: Misty Moore    615-524-4025    Misty.Moore@scresearch.net   
Principal Investigator: Melissa Johnson, MD         
United States, Texas
UT M.D. Anderson Cancer Center Recruiting
Houston, Texas, United States, 77030
Contact: Kathy Hunter, RN    713-745-5769    kuhunter@mdanderson.org   
Principal Investigator: Barbara J O'Brien, MD         
Sponsors and Collaborators
Kadmon Corporation, LLC
  More Information

Responsible Party: Kadmon Corporation, LLC
ClinicalTrials.gov Identifier: NCT02616393     History of Changes
Other Study ID Numbers: KD019-206
Study First Received: November 20, 2015
Last Updated: March 1, 2017

Additional relevant MeSH terms:
Lung Neoplasms
Carcinoma, Non-Small-Cell Lung
Neoplasm Metastasis
Neoplasms, Second Primary
Brain Neoplasms
Meningeal Carcinomatosis
Respiratory Tract Neoplasms
Thoracic Neoplasms
Neoplasms by Site
Neoplasms
Lung Diseases
Respiratory Tract Diseases
Carcinoma, Bronchogenic
Bronchial Neoplasms
Neoplastic Processes
Pathologic Processes
Central Nervous System Neoplasms
Nervous System Neoplasms
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Meningeal Neoplasms

ClinicalTrials.gov processed this record on June 22, 2017