Brief Summary
This study will determine the safety and maximum tolerated dose of ONO-7579 in patients with advanced solid tumors, and evaluate efficacy of ONO-7579 in patients with advanced solid tumors harboring NTRK gene fusions.
Brief Title
Study of ONO-7579 in Patients With Advanced Solid Tumors/ NTRK Gene Fusion Positive Advanced Solid Tumors
Detailed Description
The trial was designed to be a Phase 1/2 trial, but was terminated without progressing to Phase 2.
Completion Date
Completion Date Type
Actual
Conditions
Solid Tumor
Eligibility Criteria
Inclusion Criteria (Parts A and B):
1. Male or female aged at least 18 years or older, at the time of signing the informed consent form.
2. The patient (or their legal representative) has provided written informed consent, which signifies an agreement to enter the study and comply with the restrictions and requirements listed in the informed consent form.
3. ECOG performance status ≤ 2
4. Life expectancy of at least 3 months
5. Patients must have measurable disease, according to RECIST 1.1 (defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded for non-nodal lesions and short axis for nodal lesions) as ≥ 20 mm (≥2 cm) with conventional techniques or as ≥10 mm (≥1 cm) with spiral CT scan), or RANO criteria for Glioma.
6. Patients must have received at least one prior line of therapy appropriate for their tumor type and stage of disease. For glioma, patient must have received at least one prior treatment with radiotherapy and temozolomide. Prior treatment of any Trk inhibitor(s) is not an exclusion.
7. Adequate hematologic, hepatic and renal function as defined by the following criteria:
* Absolute Neutrophil count ≥ 1.5x109
* Platelet count ≥ 75,000 / mm3
* Hemoglobin level ≥ 9.0 g/dL
* Total Bilirubin level ≤ 1.5 X ULN
* AST and ALT ≤ 3 X ULN
* Creatinine clearance\* ≥50 mL/min \*estimated CLcr by the Cockcroft-Gault equation
8. Women of:
1. Childbearing potential must have a negative serum pregnancy test documented within 14 days prior to enrollment, and must agree to use two adequate methods of contraception from Day 1 of the study until 3 months after the end of treatment. Acceptable forms of effective contraception include;
* Established use of oral, injected or implanted hormonal methods of contraception.
* Placement of an intrauterine device or intrauterine system.
* Barrier methods of contraception: condom or occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/suppository.
* Male sterilization (with the appropriate post-vasectomy documentation of the absence of sperm in the ejaculate).
2. Non-childbearing potential, defined as females with a documented history of a clinically recognized procedure (e.g. hysterectomy, tubal ligation, bilateral salpingo-/oophorectomy) ; or postmenopausal defined as 12 months of spontaneous amenorrhea with follicle-stimulating hormone (FSH) \>40 MlU/mL). Females on hormone replacement therapy (HRT) will be required to use one of the contraception methods in Inclusion criteria 8a or must discontinue HRT to allow confirmation of post-menopausal status prior to being enrolled in the study. Following confirmation of their post-menopausal status, they can resume HRT during the study and will not be required to use contraception.
9. A male patient is eligible to participate if he is not trying to father a child and is willing to use one of the relevant contraception methods as in inclusion criterion 8a from Day 1 of the study until 3 months after the end of treatment.
10. Able to swallow tablets
11. Patients must be recovered to Grade 1 from the effects (excluding alopecia) of any prior therapy for their malignancies.
Additional Criterion for Part A only
12. Patients with histologically/cytologically confirmed advanced solid tumors, and documented tumor progression for whom no further standard anticancer treatment is available.
13. Patients must be able to comply with the protocol requirements regarding fasting, as determined by the investigator (excluding patients in food assessment cohort(s)).
Additional Criteria for Part B only
14. Patients with histologically/cytologically confirmed advanced solid tumors and documented tumor progression for whom no further standard anticancer treatment exists or where, in the opinion of the investigator, the existing standard anticancer treatment options available are not expected to provide a reasonable benefit to the patient.
15. Patients must have NTRK1, NTRK2 or NTRK3 gene fusion confirmed locally prior to first dose.
Exclusion Criteria:
1. Radiotherapy within two weeks prior to study entry
2. Major surgery (excluding placement of vascular access) within 4 weeks before the first dose of study treatment
3. Spinal cord compression or brain metastases unless treated and radiologically stable for \>6 weeks post treatment and not requiring steroids for at least 4 weeks prior to start of study treatment
4. As judged by the Investigator, any evidence of severe or uncontrolled psychiatric disease or systemic diseases, including history of suicide attempt or current suicidal ideation or behavior, active infection including hepatitis B, hepatitis C and human immunodeficiency virus (HIV). Screening for chronic conditions is not required.
5. Concurrent treatment with another investigational agent or participated in another investigational trial within 30 days of study entry
6. Diagnosed or treated for a malignancy other than the tumor under investigation in the study within 5 years, or who were previously diagnosed with a malignancy other than that required for the study and have any radiographic or biochemical marker evidence of that malignancy. Patients with completely resected basal cell carcinoma, squamous cell carcinoma of the skin, or in situ malignancy are not excluded.
7. Clinically significant cardiovascular disease, including:
* History of myocardial infarction, acute coronary syndromes (including unstable angina), or coronary angioplasty/stenting/bypass grafting within the past 6 months.
* History of Class III or IV heart failure as defined by the New York Heart Association (NYHA) functional classification system
* Severe cardiac arrhythmia requiring medication or other severe conduction abnormalities (e.g. clinically significant QT prolongation or Torsade de pointes)
* Uncontrolled hypertension
* Clinically significant valvular disease, cardiomegaly, ventricular hypertrophy, or cardiomyopathy
8. QT prolongation defined as a QTcF interval \>470 msec or other significant ECG abnormalities including 2nd degree (type II) or 3rd degree AV block or bradycardia (ventricular rate \<50 beats/min) on 12-lead ECG at screening
9. Serious concurrent medical conditions, including serious active infection, in the opinion of the investigator
10. Female patients who are pregnant or breast feeding
1. Male or female aged at least 18 years or older, at the time of signing the informed consent form.
2. The patient (or their legal representative) has provided written informed consent, which signifies an agreement to enter the study and comply with the restrictions and requirements listed in the informed consent form.
3. ECOG performance status ≤ 2
4. Life expectancy of at least 3 months
5. Patients must have measurable disease, according to RECIST 1.1 (defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded for non-nodal lesions and short axis for nodal lesions) as ≥ 20 mm (≥2 cm) with conventional techniques or as ≥10 mm (≥1 cm) with spiral CT scan), or RANO criteria for Glioma.
6. Patients must have received at least one prior line of therapy appropriate for their tumor type and stage of disease. For glioma, patient must have received at least one prior treatment with radiotherapy and temozolomide. Prior treatment of any Trk inhibitor(s) is not an exclusion.
7. Adequate hematologic, hepatic and renal function as defined by the following criteria:
* Absolute Neutrophil count ≥ 1.5x109
* Platelet count ≥ 75,000 / mm3
* Hemoglobin level ≥ 9.0 g/dL
* Total Bilirubin level ≤ 1.5 X ULN
* AST and ALT ≤ 3 X ULN
* Creatinine clearance\* ≥50 mL/min \*estimated CLcr by the Cockcroft-Gault equation
8. Women of:
1. Childbearing potential must have a negative serum pregnancy test documented within 14 days prior to enrollment, and must agree to use two adequate methods of contraception from Day 1 of the study until 3 months after the end of treatment. Acceptable forms of effective contraception include;
* Established use of oral, injected or implanted hormonal methods of contraception.
* Placement of an intrauterine device or intrauterine system.
* Barrier methods of contraception: condom or occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/suppository.
* Male sterilization (with the appropriate post-vasectomy documentation of the absence of sperm in the ejaculate).
2. Non-childbearing potential, defined as females with a documented history of a clinically recognized procedure (e.g. hysterectomy, tubal ligation, bilateral salpingo-/oophorectomy) ; or postmenopausal defined as 12 months of spontaneous amenorrhea with follicle-stimulating hormone (FSH) \>40 MlU/mL). Females on hormone replacement therapy (HRT) will be required to use one of the contraception methods in Inclusion criteria 8a or must discontinue HRT to allow confirmation of post-menopausal status prior to being enrolled in the study. Following confirmation of their post-menopausal status, they can resume HRT during the study and will not be required to use contraception.
9. A male patient is eligible to participate if he is not trying to father a child and is willing to use one of the relevant contraception methods as in inclusion criterion 8a from Day 1 of the study until 3 months after the end of treatment.
10. Able to swallow tablets
11. Patients must be recovered to Grade 1 from the effects (excluding alopecia) of any prior therapy for their malignancies.
Additional Criterion for Part A only
12. Patients with histologically/cytologically confirmed advanced solid tumors, and documented tumor progression for whom no further standard anticancer treatment is available.
13. Patients must be able to comply with the protocol requirements regarding fasting, as determined by the investigator (excluding patients in food assessment cohort(s)).
Additional Criteria for Part B only
14. Patients with histologically/cytologically confirmed advanced solid tumors and documented tumor progression for whom no further standard anticancer treatment exists or where, in the opinion of the investigator, the existing standard anticancer treatment options available are not expected to provide a reasonable benefit to the patient.
15. Patients must have NTRK1, NTRK2 or NTRK3 gene fusion confirmed locally prior to first dose.
Exclusion Criteria:
1. Radiotherapy within two weeks prior to study entry
2. Major surgery (excluding placement of vascular access) within 4 weeks before the first dose of study treatment
3. Spinal cord compression or brain metastases unless treated and radiologically stable for \>6 weeks post treatment and not requiring steroids for at least 4 weeks prior to start of study treatment
4. As judged by the Investigator, any evidence of severe or uncontrolled psychiatric disease or systemic diseases, including history of suicide attempt or current suicidal ideation or behavior, active infection including hepatitis B, hepatitis C and human immunodeficiency virus (HIV). Screening for chronic conditions is not required.
5. Concurrent treatment with another investigational agent or participated in another investigational trial within 30 days of study entry
6. Diagnosed or treated for a malignancy other than the tumor under investigation in the study within 5 years, or who were previously diagnosed with a malignancy other than that required for the study and have any radiographic or biochemical marker evidence of that malignancy. Patients with completely resected basal cell carcinoma, squamous cell carcinoma of the skin, or in situ malignancy are not excluded.
7. Clinically significant cardiovascular disease, including:
* History of myocardial infarction, acute coronary syndromes (including unstable angina), or coronary angioplasty/stenting/bypass grafting within the past 6 months.
* History of Class III or IV heart failure as defined by the New York Heart Association (NYHA) functional classification system
* Severe cardiac arrhythmia requiring medication or other severe conduction abnormalities (e.g. clinically significant QT prolongation or Torsade de pointes)
* Uncontrolled hypertension
* Clinically significant valvular disease, cardiomegaly, ventricular hypertrophy, or cardiomyopathy
8. QT prolongation defined as a QTcF interval \>470 msec or other significant ECG abnormalities including 2nd degree (type II) or 3rd degree AV block or bradycardia (ventricular rate \<50 beats/min) on 12-lead ECG at screening
9. Serious concurrent medical conditions, including serious active infection, in the opinion of the investigator
10. Female patients who are pregnant or breast feeding
Inclusion Criteria
Inclusion Criteria (Parts A and B):
1. Male or female aged at least 18 years or older, at the time of signing the informed consent form.
2. The patient (or their legal representative) has provided written informed consent, which signifies an agreement to enter the study and comply with the restrictions and requirements listed in the informed consent form.
3. ECOG performance status ≤ 2
4. Life expectancy of at least 3 months
5. Patients must have measurable disease, according to RECIST 1.1 (defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded for non-nodal lesions and short axis for nodal lesions) as ≥ 20 mm (≥2 cm) with conventional techniques or as ≥10 mm (≥1 cm) with spiral CT scan), or RANO criteria for Glioma.
6. Patients must have received at least one prior line of therapy appropriate for their tumor type and stage of disease. For glioma, patient must have received at least one prior treatment with radiotherapy and temozolomide. Prior treatment of any Trk inhibitor(s) is not an exclusion.
7. Adequate hematologic, hepatic and renal function as defined by the following criteria:
* Absolute Neutrophil count ≥ 1.5x109
* Platelet count ≥ 75,000 / mm3
* Hemoglobin level ≥ 9.0 g/dL
* Total Bilirubin level ≤ 1.5 X ULN
* AST and ALT ≤ 3 X ULN
* Creatinine clearance\* ≥50 mL/min \*estimated CLcr by the Cockcroft-Gault equation
8. Women of:
1. Childbearing potential must have a negative serum pregnancy test documented within 14 days prior to enrollment, and must agree to use two adequate methods of contraception from Day 1 of the study until 3 months after the end of treatment. Acceptable forms of effective contraception include;
* Established use of oral, injected or implanted hormonal methods of contraception.
* Placement of an intrauterine device or intrauterine system.
* Barrier methods of contraception: condom or occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/suppository.
* Male sterilization (with the appropriate post-vasectomy documentation of the absence of sperm in the ejaculate).
2. Non-childbearing potential, defined as females with a documented history of a clinically recognized procedure (e.g. hysterectomy, tubal ligation, bilateral salpingo-/oophorectomy) ; or postmenopausal defined as 12 months of spontaneous amenorrhea with follicle-stimulating hormone (FSH) \>40 MlU/mL). Females on hormone replacement therapy (HRT) will be required to use one of the contraception methods in Inclusion criteria 8a or must discontinue HRT to allow confirmation of post-menopausal status prior to being enrolled in the study. Following confirmation of their post-menopausal status, they can resume HRT during the study and will not be required to use contraception.
9. A male patient is eligible to participate if he is not trying to father a child and is willing to use one of the relevant contraception methods as in inclusion criterion 8a from Day 1 of the study until 3 months after the end of treatment.
10. Able to swallow tablets
11. Patients must be recovered to Grade 1 from the effects (excluding alopecia) of any prior therapy for their malignancies.
Additional Criterion for Part A only
12. Patients with histologically/cytologically confirmed advanced solid tumors, and documented tumor progression for whom no further standard anticancer treatment is available.
13. Patients must be able to comply with the protocol requirements regarding fasting, as determined by the investigator (excluding patients in food assessment cohort(s)).
Additional Criteria for Part B only
14. Patients with histologically/cytologically confirmed advanced solid tumors and documented tumor progression for whom no further standard anticancer treatment exists or where, in the opinion of the investigator, the existing standard anticancer treatment options available are not expected to provide a reasonable benefit to the patient.
15. Patients must have NTRK1, NTRK2 or NTRK3 gene fusion confirmed locally prior to first dose.
1. Male or female aged at least 18 years or older, at the time of signing the informed consent form.
2. The patient (or their legal representative) has provided written informed consent, which signifies an agreement to enter the study and comply with the restrictions and requirements listed in the informed consent form.
3. ECOG performance status ≤ 2
4. Life expectancy of at least 3 months
5. Patients must have measurable disease, according to RECIST 1.1 (defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded for non-nodal lesions and short axis for nodal lesions) as ≥ 20 mm (≥2 cm) with conventional techniques or as ≥10 mm (≥1 cm) with spiral CT scan), or RANO criteria for Glioma.
6. Patients must have received at least one prior line of therapy appropriate for their tumor type and stage of disease. For glioma, patient must have received at least one prior treatment with radiotherapy and temozolomide. Prior treatment of any Trk inhibitor(s) is not an exclusion.
7. Adequate hematologic, hepatic and renal function as defined by the following criteria:
* Absolute Neutrophil count ≥ 1.5x109
* Platelet count ≥ 75,000 / mm3
* Hemoglobin level ≥ 9.0 g/dL
* Total Bilirubin level ≤ 1.5 X ULN
* AST and ALT ≤ 3 X ULN
* Creatinine clearance\* ≥50 mL/min \*estimated CLcr by the Cockcroft-Gault equation
8. Women of:
1. Childbearing potential must have a negative serum pregnancy test documented within 14 days prior to enrollment, and must agree to use two adequate methods of contraception from Day 1 of the study until 3 months after the end of treatment. Acceptable forms of effective contraception include;
* Established use of oral, injected or implanted hormonal methods of contraception.
* Placement of an intrauterine device or intrauterine system.
* Barrier methods of contraception: condom or occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/suppository.
* Male sterilization (with the appropriate post-vasectomy documentation of the absence of sperm in the ejaculate).
2. Non-childbearing potential, defined as females with a documented history of a clinically recognized procedure (e.g. hysterectomy, tubal ligation, bilateral salpingo-/oophorectomy) ; or postmenopausal defined as 12 months of spontaneous amenorrhea with follicle-stimulating hormone (FSH) \>40 MlU/mL). Females on hormone replacement therapy (HRT) will be required to use one of the contraception methods in Inclusion criteria 8a or must discontinue HRT to allow confirmation of post-menopausal status prior to being enrolled in the study. Following confirmation of their post-menopausal status, they can resume HRT during the study and will not be required to use contraception.
9. A male patient is eligible to participate if he is not trying to father a child and is willing to use one of the relevant contraception methods as in inclusion criterion 8a from Day 1 of the study until 3 months after the end of treatment.
10. Able to swallow tablets
11. Patients must be recovered to Grade 1 from the effects (excluding alopecia) of any prior therapy for their malignancies.
Additional Criterion for Part A only
12. Patients with histologically/cytologically confirmed advanced solid tumors, and documented tumor progression for whom no further standard anticancer treatment is available.
13. Patients must be able to comply with the protocol requirements regarding fasting, as determined by the investigator (excluding patients in food assessment cohort(s)).
Additional Criteria for Part B only
14. Patients with histologically/cytologically confirmed advanced solid tumors and documented tumor progression for whom no further standard anticancer treatment exists or where, in the opinion of the investigator, the existing standard anticancer treatment options available are not expected to provide a reasonable benefit to the patient.
15. Patients must have NTRK1, NTRK2 or NTRK3 gene fusion confirmed locally prior to first dose.
Gender
All
Gender Based
false
Keywords
TRK
TRKA
TRKB
TRKC
NTRK1
NTRK2
NTRK3
NTRK fusion positive
NTRK1 fusion
NTRK2 fusion
NTRK3 fusion
NTRK1 gene rearrangement
NTRK2 gene rearrangement
NTRK3 gene fusion
ETV6-NTRK3
fusion
tumors
solid tumors
CNS tumors
central nervous system tumors
TRK fusion
ETV6
ETV6 fusion
solid CNS tumor
advanced CNS tumor
primary CNS tumor
Healthy Volunteers
No
Last Update Post Date
Last Update Post Date Type
Actual
Last Update Submit Date
Minimum Age
18 Years
NCT Id
NCT03182257
Org Class
Industry
Org Full Name
Ono Pharmaceutical Co. Ltd
Org Study Id
ONO-7579-01
Overall Status
Terminated
Phases
Phase 1
Primary Completion Date
Primary Completion Date Type
Actual
Official Title
An Open-label, Multi-center, Dose-escalation and Expansion Study to Evaluate the Safety and Efficacy of ONO-7579 in Patients With Advanced Solid Tumors/ NTRK Gene Fusion Positive Advanced Solid Tumors
Primary Outcomes
Outcome Description
To investigate the safety and tolerability of ONO-7579 to determine MTD/RCD
Outcome Measure
Part A: Incidence, nature and severity of Adverse Events
Outcome Time Frame
up to 28 days
Outcome Description
To investigate the safety and tolerability of ONO-7579 to determine MTD/RCD
Outcome Measure
Part A: Clinically significant changes in physical examinations
Outcome Time Frame
up to 28 days
Outcome Description
To investigate the safety and tolerability of ONO-7579 to determine MTD/RCD
Outcome Measure
Part A: Clinically significant changes in neurological examinations
Outcome Time Frame
up to 28 days
Outcome Description
To investigate the safety and tolerability of ONO-7579 to determine MTD/RCD
Outcome Measure
Part A: Clinically significant changes in vital signs and electrocardiogram - including the evaluation of the QT interval
Outcome Time Frame
up to 28 days
Outcome Description
Assessed by Independent Central Review using RECIST 1.1 or RANO criteria
Outcome Measure
Part B: Overall Response Rate (ORR)
Outcome Time Frame
up to 24 months
Secondary Outcomes
Outcome Description
Assessment of the maximum plasma concentration of ONO-7579
Outcome Time Frame
Day 1, 2, 7, 14 and 28
Outcome Measure
Part A and B Pharmacokinetics (Cmax)
Outcome Description
Assessment of the time to reach maximum observed plasma concentration of ONO-7579
Outcome Time Frame
Day 1, 2, 7, 14 and 28
Outcome Measure
Part A and B Pharmacokinetics (Tmax)
Outcome Description
Assessment of the plasma area under the curve from time zero to 24 hours after dosing
Outcome Time Frame
Day 1, 2, 7, 14 and 28
Outcome Measure
Part A and B Pharmacokinetics (AUC)
Outcome Description
Assessment of the plasma decay half life of ONO-7579
Outcome Time Frame
Day 1, 2, 7, 14 and 28
Outcome Measure
Part A and B Pharmacokinetics (T1/2)
Outcome Description
Assessment of the trough concentration of ONO-7579 in plasma
Outcome Time Frame
Day 1, 2, 7, 14 and 28
Outcome Measure
Part A and B Pharmacokinetics (Ctrough)
Outcome Description
Assessed by investigator using RECIST 1.1 or RANO criteria
Outcome Time Frame
up to 28 days
Outcome Measure
Part A Overall Response Rate (ORR)
Outcome Description
Assessed by investigator using RECIST 1.1 or RANO criteria
Outcome Time Frame
up to 28 days
Outcome Measure
Part A Duration of Response (DoR)
Outcome Description
Assessed by investigator using RECIST 1.1 or RANO criteria
Outcome Time Frame
up to 28 days
Outcome Measure
Part A Progression Free Survival (PFS)
Outcome Description
Assessed by Independent Central Review using RECIST 1.1 or RANO criteria
Outcome Time Frame
up to 24 months
Outcome Measure
Part B Progression Free Survival (PFS)
Outcome Description
Assessed by Independent Central Review using RECIST 1.1 or RANO criteria
Outcome Time Frame
up to 24 months
Outcome Measure
Part B Overall Survival (OS)
Outcome Description
Assessed by Independent Central Review using RECIST 1.1 or RANO criteria
Outcome Time Frame
up to 24 months
Outcome Measure
Part B Time to Response (TTR)
Outcome Description
Assessed by Independent Central Review using RECIST 1.1 or RANO criteria
Outcome Time Frame
up to 24 months
Outcome Measure
Part B Time to Progression (TTP)
Outcome Description
To determine the safety and tolerability of ONO-7579
Outcome Time Frame
up to 24 months
Outcome Measure
Part B Incidence, nature and severity of Adverse Events
Outcome Description
To determine the safety and tolerability of ONO-7579
Outcome Time Frame
up to 24 months
Outcome Measure
Part B: Clinically significant changes in physical examinations
Outcome Description
To determine the safety and tolerability of ONO-7579
Outcome Time Frame
up to 24 months
Outcome Measure
Part B: Clinically significant changes in neurological examinations
Outcome Description
To determine the safety and tolerability of ONO-7579
Outcome Time Frame
up to 24 months
Outcome Measure
Part B: Clinically significant changes in vital signs and electrocardiogram - including the evaluation of the QT interval
Start Date
Start Date Type
Actual
Status Verified Date
First Post Date
First Post Date Type
Actual
First Submit Date
First Submit QC Date
Std Ages
Adult
Older Adult
Maximum Age Number (converted to Years and rounded down)
999
Minimum Age Number (converted to Years and rounded down)
18
Investigators
Investigator Type
Principal Investigator
Investigator Name
Sanjay Goel
Investigator Email
sgoel@montefiore.org
Investigator Phone
718-405-8404
Categories Mesh Debug
Cancer --- NEOPLASMS
Brain, Spine & Nerve Cancers --- CENTRAL NERVOUS SYSTEM NEOPLASMS
Brain, Spine & Nerve Cancers --- NERVOUS SYSTEM NEOPLASMS
Cancer --- NEOPLASMS BY SITE
Brain, Spinal Cord & Nervous System --- NERVOUS SYSTEM DISEASES
Brain, Spine & Nerve Cancers --- NERVOUS SYSTEM DISEASES
MeSH Terms
NEOPLASMS
CENTRAL NERVOUS SYSTEM NEOPLASMS
NERVOUS SYSTEM NEOPLASMS
NEOPLASMS BY SITE
NERVOUS SYSTEM DISEASES
ONO-7579