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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02616393
Recruitment Status : Completed
First Posted : November 26, 2015
Results First Posted : November 23, 2021
Last Update Posted : March 16, 2022
Sponsor:
Information provided by (Responsible Party):
Kadmon Corporation, LLC

Brief Summary:
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)

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

Detailed Description:

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.

Layout table for study information
Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 36 participants
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
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
Study Start Date : November 2015
Actual Primary Completion Date : April 3, 2018
Actual Study Completion Date : April 3, 2018

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Cohort A: Brain Metastases (BM)
Tesevatinib 300 mg orally (PO) once daily (QD) administered to subjects with NSCLC who had progressed with brain metastases (BM)
Drug: Tesevatinib
Other Name: KD019, XL647

Experimental: Cohort B: Leptomeningeal Metastases (LM)
Tesevatinib 300 mg PO QD administered to subjects with NSCLC who had progressed with leptomeningeal metastases (LM)
Drug: Tesevatinib
Other Name: KD019, XL647

Experimental: Cohort C: Brain Metastases at Initial Presentation (BM-IP)
Tesevatinib 300 mg PO QD administered NSCLC who presented initially with BM at initial presentation
Drug: Tesevatinib
Other Name: KD019, XL647




Primary Outcome Measures :
  1. Best Overall Response Rate (ORR) of Subjects With BM [ Time Frame: Until disease progression, unacceptable toxicity, or up to 2 years, whichever occurred first ]
    The best overall response rates (ORRs) of subjects who had brain tumors and exhibited either a complete response (CR) or a partial responder (PR) to therapy divided by the total number of subjects treated with tesevatinib 300 mg PO QD. Response rates are in accordance with RECIST Version 1.1 criteria. Since such brain metastases (BM) tumors can either affect the central nervous system (CNS) or not affect the CNS (non-CNS), they were categorized into CNS and non-CNS subsets. Because leptomeningeal metastases (LM) only are considered cancer cell migration from the breast, lung, or some other part of the body to the cerebrospinal fluid (CSF), analysis of CNS are not appropriate, so Cohort B is excluded.

  2. Best ORR of Subjects With LM [ Time Frame: Until disease progression, unacceptable toxicity, or up to 2 years, whichever occurred first ]
    The best overall response rates (ORRs) of subjects who had leptomeningeal tumors and exhibited either a complete response (CR) or a partial responder (PR) to therapy divided by the total number of subjects treated with tesevatinib 300 mg PO QD. Response rates are in accordance with RECIST Version 1.1 criteria. Since leptomeningeal metastases (LM) are only considered cancer cell migration from the breast, lung, or some other part of the body to the cerebrospinal fluid (CSF), analysis of CNS are not appropriate, so Cohorts A and C are excluded.


Secondary Outcome Measures :
  1. Median Progression-free Survival (PFS) [ Time Frame: Until disease progression, unacceptable toxicity, or up to 2 years, whichever occurred first ]
    Median duration of survival without progression of subjects treated with tesevatinib 300 mg PO QD.

  2. Probability of PFS at 12 Weeks and 24 Weeks--Cohort A (BM Only) and Cohort B (LM Only) [ Time Frame: 24 weeks (6 months) ]
    Probability that subjects with brain metastases (BM) or leptomeningeal metastases (LM) would not progress, i.e., progression-free survival (PFS) after 12 weeks (3 months) and after 24 weeks (6 months) of treatment with tesevatinib 300 mg PO QD

  3. Probability of PFS at 24 Weeks--Cohort C (BM-IP Only) [ Time Frame: 24 weeks (6 months) ]
    Probability that subjects with brain metastases at initial presentation (BM-IP) would not progress, i.e., progression-free survival (PFS) after 24 weeks (6 months) of treatment with tesevatinib 300 mg PO QD

  4. Probability of OS at 12 Weeks and at 24 Weeks--Cohort A (BM Only) and Cohort B (LM Only) [ Time Frame: 24 weeks (6 months) ]
    Probability that subjects with brain metastases (BM) or leptomeningeal metastases (LM) survived (overall survival [OS]) after 12 weeks (3 months) and after 24 weeks (6 months) of treatment with tesevatinib 300 mg PO QD

  5. Median Time to Progression (TTP)--Cohort A (BM), Cohort B (LM), Cohort C (BM-IP) [ Time Frame: Until disease progression, death, unacceptable toxicity, or up to 2 years, whichever occurred first ]
    Median time to the development of disease progression (TTP) for subjects in Cohort A, Cohort B and Cohort C who were treated with tesevatinib 300 mg PO QD

  6. Probability of TTP at 12 Weeks and 24 Weeks--Non-CNS Cohort A (BM Only) and Cohort B (LM Only) [ Time Frame: 24 weeks (6 months) ]
    Probability that the time to progression (TTP) for subjects with no metastases to the central nervous system (non-CNS) in Cohort A (brain metastases only) or Cohort B (leptomeningeal metastases only) would be at 12 weeks (3 months) and at 24 weeks (6 months) of therapy with tesevatinib 300 mg PO QD. There were an insufficient number of subjects in Cohort C (brain metastases at initial presentation) who had events.

  7. Probability of TTP at 24 Weeks--CNS [ Time Frame: 24 weeks (6 months) ]
    Probability that the time to progression (TTP) for subjects with metastases to the central nervous system (CNS) would be at 24 weeks (6 months) of therapy with tesevatinib 300 mg PO QD.

  8. Quality of Life (QoL): Mean Change From Baseline in EORTC-QLQ-C30 Questionnaire Scores [ Time Frame: Until disease progression, unacceptable toxicity, or up to 2 years, whichever occurred first ]
    The European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ) Cancer 30 (C30) is a 30-question assessment composed of both multi-item scales and single-item measures: 5 functional scales, 3 symptom scales, 1 global QoL scale, and 6 single items. Ratings are on a 4-point scale (not at all, a little quite a bit, very much), with scoring from 0 to 100. A high scale score represents a higher response level. A high score for a functional scale represents a high/healthy level of functioning, a high score for the global health status/QoL represents a high QoL, but a high score for a symptom scale/item represents a high level of symptomatology/problems. The outcome measure is the mean change in the EORTC-QLQ-C30 from baseline to a visit.

  9. Quality of Life (QoL): Mean Change From Baseline in EORTC-QLQ-BN20 Questionnaire Scores [ Time Frame: Until disease progression, unacceptable toxicity, or up to 2 years, whichever occurred first ]
    The European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ) Cancer BN20 Questionnaire is a 20-question assessment of symptomatology based on a categorical scale (Not at all = 1; A little = 2; Quite a bit = 3; and Very much = 4). For 20 questions: minimum score = 20 and maximum score = 80. Higher scores indicate greater level of symptomatology/problems. The outcome measure is the mean change in the EORTC-QLQ-BN20 from baseline to a visit.



Information from the National Library of Medicine

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Layout table for eligibility information
Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02616393


Locations
Layout table for location information
United States, California
Beverly Hills Cancer Center
Beverly Hills, California, United States, 90211
USC Norris Oncology/Hematology Newport Beach
Newport Beach, California, United States, 92663
John Wayne Cancer Institute
Santa Monica, California, United States, 90404
United States, Colorado
University of Colorado Cancer Center
Aurora, Colorado, United States, 80045
United States, District of Columbia
Georgetown University Medical Center
Washington, District of Columbia, United States, 20007
United States, Tennessee
Sarah Cannon Research Institute
Nashville, Tennessee, United States, 37203
United States, Texas
UT M.D. Anderson Cancer Center
Houston, Texas, United States, 77030
Sponsors and Collaborators
Kadmon Corporation, LLC
  Study Documents (Full-Text)

Documents provided by Kadmon Corporation, LLC:
Study Protocol  [PDF] October 3, 2017
Statistical Analysis Plan  [PDF] October 5, 2018

Layout table for additonal information
Responsible Party: Kadmon Corporation, LLC
ClinicalTrials.gov Identifier: NCT02616393    
Other Study ID Numbers: KD019-206
First Posted: November 26, 2015    Key Record Dates
Results First Posted: November 23, 2021
Last Update Posted: March 16, 2022
Last Verified: March 2022
Additional relevant MeSH terms:
Layout table for 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
XL647
Antineoplastic Agents
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action