Brief Summary
This phase II trial studies how well lower dose radiotherapy after chemotherapy (Carboplatin \& Etoposide) works in treating children with central nervous system (CNS) germinomas. Radiation therapy uses high energy x-rays, particles, or radioactive seeds to kill cancer cells and shrink tumors. Carboplatin is in a class of medications known as platinum-containing compounds. It works in a way similar to the anticancer drug cisplatin, but may be better tolerated than cisplatin. Carboplatin works by killing, stopping or slowing the growth of tumor cells. Etoposide is in a class of medications known as podophyllotoxin derivatives. It blocks a certain enzyme needed for cell division and DNA repair and may kill cancer cells. Researchers want to see if lowering the dose of standard radiotherapy (RT) after chemotherapy can help get rid of CNS germinomas with fewer long-term side effects.
Brief Title
A Study of Lower Radiotherapy Dose to Treat Children With CNS Germinoma
Detailed Description
PRIMARY OBJECTIVE:
I. To determine whether 12 Gy whole ventricular irradiation (WVI) and 12 Gy tumor boost would maintain similar efficacy compared to ACNS1123 stratum 2 as measured by event-free survival (EFS) in eligible patients with localized primary central nervous system (CNS) germinoma who present with serum and/or cerebrospinal fluid (CSF) human chorionic gonadotropin-beta (hCGbeta) ≤ 100 IU/L and normal alpha-fetoprotein (AFP), and meet complete response (CR) or continued complete response (CCR) criteria following chemotherapy/second-look surgery (Stratum 1).
SECONDARY OBJECTIVES:
I. To estimate the EFS distribution for patients with localized midline - including bifocal - CNS germinoma with partial response (PR) after chemotherapy, followed by 18 Gy WVI and 12 Gy tumor boost (Stratum 2).
II. To estimate the EFS distribution for patients with localized midline - including bifocal - CNS germinoma with less than a PR after chemotherapy, followed by 24 Gy WVI and 12 Gy tumor boost (Stratum 3).
III. To estimate the overall survival (OS), response rates to chemotherapy and radiotherapy (RT), as well as the patterns of failure of the various cohorts based on tumor characteristics, treatment regimen, and treatment modality.
IV. To determine the impact of tumor characteristics, treatment regimen and treatment modalities on the long-term neuroendocrine function for patients with CNS germinomas.
V. To prospectively evaluate processing speed of children and young adults with CNS germinoma through the Children's Oncology Group (COG) Standardized assessment battery.
EXPLORATORY OBJECTIVES:
I. To estimate the EFS distribution for patients with metastatic germinomas treated with chemotherapy followed by craniospinal irradiation (CSI) \[18 Gy for CR/CCR (Stratum 4)\] or \[24 Gy for less than CR (Stratum 5)\] with a 12 Gy tumor boost to the pre-treatment volume, including metastatic sites.
II. To estimate the EFS distribution for patients with basal ganglia and thalamic germinomas (BGTG) treated with chemotherapy followed by whole brain irradiation (WBI) \[18 Gy for CR/CCR (Stratum 6)\] or \[24 Gy for less than CR (Stratum 7)\] with a 12 Gy tumor boost to the pre-treatment volume.
III. To prospectively collect blood, cerebrospinal fluid, and tumor tissue at diagnosis and second-look surgery (if feasible) for future biology studies.
IV. To prospectively measure the incidence of cerebral vascular events (stroke or transient ischemic attacks) in the follow-up period and longitudinally evaluate and model the cognitive, social and behavioral functioning of children and young adults with CNS germinoma through the COG Standardized assessment battery, and compare these outcomes based on tumor characteristics, treatment regimen, and treatment modality.
OUTLINE:
INDUCTION PHASE: All patients receive carboplatin intravenously (IV) over 15-60 minutes on day 1 and etoposide IV over 90-120 minutes on days 1-3 of each cycle. Treatment repeats every 21 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity.
Patients are then assigned to 1 of 7 strata.
STRATUM I: Patients with localized germinoma achieving CR with normalization of markers undergo 3-dimensional conformal radiation therapy (3DCRT) or intensity-modulated radiation therapy (IMRT) once daily (QD) 5 days a week for 16 days. Patients achieving PR with normalization of markers may undergo second-look surgery. Patients found to have mature teratoma or non-viable tumor undergo 3DRT or IMRT QD 5 days a week for 16 days. Patients with normalization of markers who fail to achieve CR or PR may undergo second-look surgery. Patients found to have mature teratoma or non-viable tumor undergo 3DRT or IMRT QD 5 days a week for 16 days. Patients with bifocal germinoma undergo 3DRT or IMRT QD 5 days a week for 16 days.
STRATUM II: Patients with localized germinoma achieving PR with normalization of markers who do not undergo second-look surgery undergo 3DRT or IMRT QD 5 days a week for 20 days.
STRATUM III: Patients with localized germinoma with normalization of markers who fail to achieve CR or PR who do not undergo second-look surgery undergo 3DRT or IMRT QD 5 days a week for 24 days.
STRATUM IV: Patients with metastatic germinoma achieving CR undergo 3DRT or IMRT QD 5 days a week for 20 days. Patients with metastatic germinoma and normalization of markers who fail to achieve CR may undergo second-look surgery. Patients found to have mature teratoma or non-viable tumor undergo 3DRT or IMRT QD 5 days a week for 20 days.
STRATUM V: Patients with metastatic germinoma with normalization of markers who fail to achieve CR who do not undergo second-look surgery undergo 3DRT or IMRT QD 5 days a week for 24 days.
STRATUM VI: Patients with basal ganglia and thalamic germinoma achieving CR undergo 3DRT or IMRT QD 5 days a week for 20 days. Patients with basal ganglia and thalamic germinoma and normalization of markers who fail to achieve CR may undergo second-look surgery. Patients found to have mature teratoma or non-viable tumor undergo 3DRT or IMRT QD 5 days a week for 20 days.
STRATUM VII: Patients with basal ganglia and thalamic germinoma with normalization of markers who fail to achieve CR who do not undergo second-look surgery undergo 3DRT or IMRT QD 5 days a week for 24 days.
Patients with non-normalized tumor markers or PD and no second-look surgery or viable tumor during second-look surgery discontinue protocol therapy.
All patients undergo magnetic resonance imaging (MRI) and optional blood and tissue sample collection throughout the study. Patients may undergo lumbar puncture (LP) for CSF sample collection during screening and follow up.
After completion of study treatment, patients are followed up every 3 months for 12 months, every 4 months for 24 months, and then annually for up to 120 months.
I. To determine whether 12 Gy whole ventricular irradiation (WVI) and 12 Gy tumor boost would maintain similar efficacy compared to ACNS1123 stratum 2 as measured by event-free survival (EFS) in eligible patients with localized primary central nervous system (CNS) germinoma who present with serum and/or cerebrospinal fluid (CSF) human chorionic gonadotropin-beta (hCGbeta) ≤ 100 IU/L and normal alpha-fetoprotein (AFP), and meet complete response (CR) or continued complete response (CCR) criteria following chemotherapy/second-look surgery (Stratum 1).
SECONDARY OBJECTIVES:
I. To estimate the EFS distribution for patients with localized midline - including bifocal - CNS germinoma with partial response (PR) after chemotherapy, followed by 18 Gy WVI and 12 Gy tumor boost (Stratum 2).
II. To estimate the EFS distribution for patients with localized midline - including bifocal - CNS germinoma with less than a PR after chemotherapy, followed by 24 Gy WVI and 12 Gy tumor boost (Stratum 3).
III. To estimate the overall survival (OS), response rates to chemotherapy and radiotherapy (RT), as well as the patterns of failure of the various cohorts based on tumor characteristics, treatment regimen, and treatment modality.
IV. To determine the impact of tumor characteristics, treatment regimen and treatment modalities on the long-term neuroendocrine function for patients with CNS germinomas.
V. To prospectively evaluate processing speed of children and young adults with CNS germinoma through the Children's Oncology Group (COG) Standardized assessment battery.
EXPLORATORY OBJECTIVES:
I. To estimate the EFS distribution for patients with metastatic germinomas treated with chemotherapy followed by craniospinal irradiation (CSI) \[18 Gy for CR/CCR (Stratum 4)\] or \[24 Gy for less than CR (Stratum 5)\] with a 12 Gy tumor boost to the pre-treatment volume, including metastatic sites.
II. To estimate the EFS distribution for patients with basal ganglia and thalamic germinomas (BGTG) treated with chemotherapy followed by whole brain irradiation (WBI) \[18 Gy for CR/CCR (Stratum 6)\] or \[24 Gy for less than CR (Stratum 7)\] with a 12 Gy tumor boost to the pre-treatment volume.
III. To prospectively collect blood, cerebrospinal fluid, and tumor tissue at diagnosis and second-look surgery (if feasible) for future biology studies.
IV. To prospectively measure the incidence of cerebral vascular events (stroke or transient ischemic attacks) in the follow-up period and longitudinally evaluate and model the cognitive, social and behavioral functioning of children and young adults with CNS germinoma through the COG Standardized assessment battery, and compare these outcomes based on tumor characteristics, treatment regimen, and treatment modality.
OUTLINE:
INDUCTION PHASE: All patients receive carboplatin intravenously (IV) over 15-60 minutes on day 1 and etoposide IV over 90-120 minutes on days 1-3 of each cycle. Treatment repeats every 21 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity.
Patients are then assigned to 1 of 7 strata.
STRATUM I: Patients with localized germinoma achieving CR with normalization of markers undergo 3-dimensional conformal radiation therapy (3DCRT) or intensity-modulated radiation therapy (IMRT) once daily (QD) 5 days a week for 16 days. Patients achieving PR with normalization of markers may undergo second-look surgery. Patients found to have mature teratoma or non-viable tumor undergo 3DRT or IMRT QD 5 days a week for 16 days. Patients with normalization of markers who fail to achieve CR or PR may undergo second-look surgery. Patients found to have mature teratoma or non-viable tumor undergo 3DRT or IMRT QD 5 days a week for 16 days. Patients with bifocal germinoma undergo 3DRT or IMRT QD 5 days a week for 16 days.
STRATUM II: Patients with localized germinoma achieving PR with normalization of markers who do not undergo second-look surgery undergo 3DRT or IMRT QD 5 days a week for 20 days.
STRATUM III: Patients with localized germinoma with normalization of markers who fail to achieve CR or PR who do not undergo second-look surgery undergo 3DRT or IMRT QD 5 days a week for 24 days.
STRATUM IV: Patients with metastatic germinoma achieving CR undergo 3DRT or IMRT QD 5 days a week for 20 days. Patients with metastatic germinoma and normalization of markers who fail to achieve CR may undergo second-look surgery. Patients found to have mature teratoma or non-viable tumor undergo 3DRT or IMRT QD 5 days a week for 20 days.
STRATUM V: Patients with metastatic germinoma with normalization of markers who fail to achieve CR who do not undergo second-look surgery undergo 3DRT or IMRT QD 5 days a week for 24 days.
STRATUM VI: Patients with basal ganglia and thalamic germinoma achieving CR undergo 3DRT or IMRT QD 5 days a week for 20 days. Patients with basal ganglia and thalamic germinoma and normalization of markers who fail to achieve CR may undergo second-look surgery. Patients found to have mature teratoma or non-viable tumor undergo 3DRT or IMRT QD 5 days a week for 20 days.
STRATUM VII: Patients with basal ganglia and thalamic germinoma with normalization of markers who fail to achieve CR who do not undergo second-look surgery undergo 3DRT or IMRT QD 5 days a week for 24 days.
Patients with non-normalized tumor markers or PD and no second-look surgery or viable tumor during second-look surgery discontinue protocol therapy.
All patients undergo magnetic resonance imaging (MRI) and optional blood and tissue sample collection throughout the study. Patients may undergo lumbar puncture (LP) for CSF sample collection during screening and follow up.
After completion of study treatment, patients are followed up every 3 months for 12 months, every 4 months for 24 months, and then annually for up to 120 months.
Categories
Completion Date
Completion Date Type
Estimated
Conditions
Basal Ganglia Germinoma
Central Nervous System Germinoma
Diabetes Insipidus
Pineal Region Germinoma
Suprasellar Germinoma
Thalamic Germinoma
Eligibility Criteria
Inclusion Criteria:
* Patients must be ≥ 3 years and \< 30 years at the time of study enrollment
* Patients must be newly-diagnosed primary localized germinoma of the suprasellar and/or pineal region by pathology and/or serum and/or CSF hCGbeta 5-50 mIU/mL AND institutional normal AFP (or ≤ 10 ng/mL if no institutional normal exists), including tumors with contiguous ventricular or unifocal parenchymal extension. No histologic confirmation required
* Patients with EITHER (A) bifocal (pineal + suprasellar) involvement OR (B) pineal lesion with diabetes insipidus (DI) AND hCGbeta ≤ 100 mIU/mL in serum and/or CSF AND institutional normal AFP (or ≤ 10 ng/mL if no institutional normal exists) in both serum and CSF. No histologic confirmation required
* Patients with hCGbeta 51-100 mIU/mL in serum and/or CSF and institutional normal AFP (or ≤ 10 ng/mL if no institutional normal exists) in both serum and CSF. Histologic confirmation of germinoma IS required
* Patients with germinoma of the basal ganglia and or/thalamic primary sites are eligible
* Patients with metastatic germinoma including non-contiguous disease or distant disease in the brain, ventricles, or spine are eligible
* Patients with germinoma admixed with mature teratoma are eligible
* Patients must have a performance status corresponding to Eastern Cooperative Oncology Group (ECOG) scores of 0, 1 or 2. Use Karnofsky for patients \> 16 years of age and Lansky for patients ≤ 16 years of age
* Patients must have eligibility confirmed by Rapid Central Imaging Review performed on APEC14B1-CNS
* Imaging studies must be obtained within 31 days prior to study enrollment and start of protocol therapy. (Note: for patients that have had surgery and post-operative imaging performed, it is the post-operative MRI that must be obtained within 31 days prior to enrollment.)
* Patients must have a cranial magnetic resonance imaging (MRI) with and without gadolinium at diagnosis/prior to enrollment. If surgical resection is performed, patients must have pre-operative and post-operative brain MRI with and without gadolinium. The post-operative brain MRI should be obtained within 72 hours of surgery. If patient has a biopsy only, post-operative brain MRI is recommended but not required
* Patients must have a spine MRI with gadolinium obtained at diagnosis/prior to enrollment
* Patients must be enrolled, and protocol therapy must begin, no later than 31 days after definitive surgery or clinical diagnosis, whichever is later
* Patients must have eligibility confirmed by Rapid Central Tumor Marker Review performed on APEC14B1-CNS
* Lumbar CSF must be obtained prior to study enrollment unless medically contraindicated. If a patient undergoes surgery and lumbar CSF cytology cannot be obtained at the time of surgery, then it should be performed at least 10 days following surgery and prior to study enrollment. False positive cytology can occur within 10 days of surgery. Of note, lumbar CSF should not be performed prior to obtaining spine MRI, as this can make interpretation of the spine MRI less clear
* Patients must have CSF tumor markers obtained prior to study enrollment unless medically contraindicated. Ventricular CSF obtained at the time of CSF diversion procedure (if performed) is acceptable for tumor markers but lumbar CSF is preferred. In case CSF diversion and biopsy/surgery are combined, CSF tumor markers should be collected first. Ideally serum and CSF tumor markers should be collected at the same time and processed without delay
* For patients with solid tumors: Peripheral absolute neutrophil count (ANC) \>= 1000/uL (Must be performed within 7 days prior to enrollment unless otherwise indicated)
* For patients with solid tumors: Platelet count \>= 100,000/uL (transfusion independent) (Must be performed within 7 days prior to enrollment unless otherwise indicated)
* For patients with solid tumors: Hemoglobin \>= 8.0 g/dL (may receive red blood cell \[RBC\] transfusions) (Must be performed within 7 days prior to enrollment unless otherwise indicated)
* For pediatric patients (age 3-17 years): A serum creatinine based on age/gender as follows (Must be performed within 7 days prior to enrollment unless otherwise indicated):
* Age: 3 to \< 6 years; maximum serum creatinine (mg/dL): 0.8 (male); 0.8 (female)
* Age: 6 to \< 10 years; maximum serum creatinine (mg/dL): 1 (male); 1 (female)
* Age: 10 to \< 13 years; maximum serum creatinine (mg/dL): 1.2 (male); 1.2 (female)
* Age: 13 to \< 16 years; maximum serum creatinine (mg/dL): 1.5 (male); 1.4 (female)
* Age: ≥ 17 years; maximum serum creatinine (mg/dL): 1.7 (male); 1.4 (female) OR a 24-hour urine creatinine clearance ≥ 70 mL/min/1.73 m\^2 OR a glomerular filtration rate (GFR) ≥ 50 mL/min/1.73 m\^2. GFR must be performed using direct measurement with a nuclear blood sampling method OR direct small molecule clearance method (iothalamate or other molecule per institutional standard).
* Note: Estimated GFR (eGFR) from serum or plasma creatinine, cystatin C or other estimates are not acceptable for determining eligibility.
* For adult patients (age 18 years or older) (Must be performed within 7 days prior to enrollment unless otherwise indicated):
* Creatinine clearance ≥ 70 mL/min, as estimated by the Cockcroft and Gault formula or a 24-hour urine collection. The creatinine value used in the calculation must have been obtained within 28 days prior to registration. Estimated creatinine clearance is based on actual body weight
* Total bilirubin ≤ 1.5 x upper limit of normal (ULN) for age (Must be performed within 7 days prior to enrollment unless otherwise indicated)
* Serum glutamic-pyruvic transaminase (SGPT) (alanine transaminase \[ALT\]) ≤ 135 U/L (Must be performed within 7 days prior to enrollment unless otherwise indicated)
* Note: For the purpose of this study, the ULN for SGPT (ALT) has been set to the value of 45 U/L
* No evidence of dyspnea at rest, no exercise intolerance, and a pulse oximetry \> 94% if there is clinical indication for determination
* Patients with seizure disorder may be enrolled if on anticonvulsants and well controlled
* CNS toxicity =\< grade 2
* Patients must not be in status epilepticus, coma or assisted ventilation prior to study enrollment
* HIV-infected patients on effective anti-retroviral therapy with undetectable viral load are eligible for this study
Exclusion Criteria:
* Patients with any of the following malignant pathological elements are not eligible:
* Endodermal sinus (yolk sac)
* Embryonal carcinoma, choriocarcinoma
* Malignant/immature teratoma and mixed germ cell tumor (GCT) (i.e., may include some germinoma)
* Patients with only mature teratoma upon tumor sampling at diagnosis and negative tumor markers are not eligible
* Patients who have received any prior tumor-directed therapy for their diagnosis of germinoma other than surgical intervention and corticosteroids are not eligible
* Female patients who are pregnant since fetal toxicities and teratogenic effects have been noted for several of the study drugs. A pregnancy test is required for female patients of childbearing potential.
* Note: Serum and urine pregnancy tests may be falsely positive due to HCGbeta-secreting germ cell tumors. Ensure the patient is not pregnant by institutional standards
* Lactating females who plan to breastfeed their infants
* Sexually active patients of reproductive potential who have not agreed to use an effective contraceptive method for the duration of their study participation
* All patients and/or their parents or legal guardians must sign a written informed consent
* All institutional, Food and Drug Administration (FDA), and National Cancer Institute (NCI) requirements for human studies must be met
* Patients must be ≥ 3 years and \< 30 years at the time of study enrollment
* Patients must be newly-diagnosed primary localized germinoma of the suprasellar and/or pineal region by pathology and/or serum and/or CSF hCGbeta 5-50 mIU/mL AND institutional normal AFP (or ≤ 10 ng/mL if no institutional normal exists), including tumors with contiguous ventricular or unifocal parenchymal extension. No histologic confirmation required
* Patients with EITHER (A) bifocal (pineal + suprasellar) involvement OR (B) pineal lesion with diabetes insipidus (DI) AND hCGbeta ≤ 100 mIU/mL in serum and/or CSF AND institutional normal AFP (or ≤ 10 ng/mL if no institutional normal exists) in both serum and CSF. No histologic confirmation required
* Patients with hCGbeta 51-100 mIU/mL in serum and/or CSF and institutional normal AFP (or ≤ 10 ng/mL if no institutional normal exists) in both serum and CSF. Histologic confirmation of germinoma IS required
* Patients with germinoma of the basal ganglia and or/thalamic primary sites are eligible
* Patients with metastatic germinoma including non-contiguous disease or distant disease in the brain, ventricles, or spine are eligible
* Patients with germinoma admixed with mature teratoma are eligible
* Patients must have a performance status corresponding to Eastern Cooperative Oncology Group (ECOG) scores of 0, 1 or 2. Use Karnofsky for patients \> 16 years of age and Lansky for patients ≤ 16 years of age
* Patients must have eligibility confirmed by Rapid Central Imaging Review performed on APEC14B1-CNS
* Imaging studies must be obtained within 31 days prior to study enrollment and start of protocol therapy. (Note: for patients that have had surgery and post-operative imaging performed, it is the post-operative MRI that must be obtained within 31 days prior to enrollment.)
* Patients must have a cranial magnetic resonance imaging (MRI) with and without gadolinium at diagnosis/prior to enrollment. If surgical resection is performed, patients must have pre-operative and post-operative brain MRI with and without gadolinium. The post-operative brain MRI should be obtained within 72 hours of surgery. If patient has a biopsy only, post-operative brain MRI is recommended but not required
* Patients must have a spine MRI with gadolinium obtained at diagnosis/prior to enrollment
* Patients must be enrolled, and protocol therapy must begin, no later than 31 days after definitive surgery or clinical diagnosis, whichever is later
* Patients must have eligibility confirmed by Rapid Central Tumor Marker Review performed on APEC14B1-CNS
* Lumbar CSF must be obtained prior to study enrollment unless medically contraindicated. If a patient undergoes surgery and lumbar CSF cytology cannot be obtained at the time of surgery, then it should be performed at least 10 days following surgery and prior to study enrollment. False positive cytology can occur within 10 days of surgery. Of note, lumbar CSF should not be performed prior to obtaining spine MRI, as this can make interpretation of the spine MRI less clear
* Patients must have CSF tumor markers obtained prior to study enrollment unless medically contraindicated. Ventricular CSF obtained at the time of CSF diversion procedure (if performed) is acceptable for tumor markers but lumbar CSF is preferred. In case CSF diversion and biopsy/surgery are combined, CSF tumor markers should be collected first. Ideally serum and CSF tumor markers should be collected at the same time and processed without delay
* For patients with solid tumors: Peripheral absolute neutrophil count (ANC) \>= 1000/uL (Must be performed within 7 days prior to enrollment unless otherwise indicated)
* For patients with solid tumors: Platelet count \>= 100,000/uL (transfusion independent) (Must be performed within 7 days prior to enrollment unless otherwise indicated)
* For patients with solid tumors: Hemoglobin \>= 8.0 g/dL (may receive red blood cell \[RBC\] transfusions) (Must be performed within 7 days prior to enrollment unless otherwise indicated)
* For pediatric patients (age 3-17 years): A serum creatinine based on age/gender as follows (Must be performed within 7 days prior to enrollment unless otherwise indicated):
* Age: 3 to \< 6 years; maximum serum creatinine (mg/dL): 0.8 (male); 0.8 (female)
* Age: 6 to \< 10 years; maximum serum creatinine (mg/dL): 1 (male); 1 (female)
* Age: 10 to \< 13 years; maximum serum creatinine (mg/dL): 1.2 (male); 1.2 (female)
* Age: 13 to \< 16 years; maximum serum creatinine (mg/dL): 1.5 (male); 1.4 (female)
* Age: ≥ 17 years; maximum serum creatinine (mg/dL): 1.7 (male); 1.4 (female) OR a 24-hour urine creatinine clearance ≥ 70 mL/min/1.73 m\^2 OR a glomerular filtration rate (GFR) ≥ 50 mL/min/1.73 m\^2. GFR must be performed using direct measurement with a nuclear blood sampling method OR direct small molecule clearance method (iothalamate or other molecule per institutional standard).
* Note: Estimated GFR (eGFR) from serum or plasma creatinine, cystatin C or other estimates are not acceptable for determining eligibility.
* For adult patients (age 18 years or older) (Must be performed within 7 days prior to enrollment unless otherwise indicated):
* Creatinine clearance ≥ 70 mL/min, as estimated by the Cockcroft and Gault formula or a 24-hour urine collection. The creatinine value used in the calculation must have been obtained within 28 days prior to registration. Estimated creatinine clearance is based on actual body weight
* Total bilirubin ≤ 1.5 x upper limit of normal (ULN) for age (Must be performed within 7 days prior to enrollment unless otherwise indicated)
* Serum glutamic-pyruvic transaminase (SGPT) (alanine transaminase \[ALT\]) ≤ 135 U/L (Must be performed within 7 days prior to enrollment unless otherwise indicated)
* Note: For the purpose of this study, the ULN for SGPT (ALT) has been set to the value of 45 U/L
* No evidence of dyspnea at rest, no exercise intolerance, and a pulse oximetry \> 94% if there is clinical indication for determination
* Patients with seizure disorder may be enrolled if on anticonvulsants and well controlled
* CNS toxicity =\< grade 2
* Patients must not be in status epilepticus, coma or assisted ventilation prior to study enrollment
* HIV-infected patients on effective anti-retroviral therapy with undetectable viral load are eligible for this study
Exclusion Criteria:
* Patients with any of the following malignant pathological elements are not eligible:
* Endodermal sinus (yolk sac)
* Embryonal carcinoma, choriocarcinoma
* Malignant/immature teratoma and mixed germ cell tumor (GCT) (i.e., may include some germinoma)
* Patients with only mature teratoma upon tumor sampling at diagnosis and negative tumor markers are not eligible
* Patients who have received any prior tumor-directed therapy for their diagnosis of germinoma other than surgical intervention and corticosteroids are not eligible
* Female patients who are pregnant since fetal toxicities and teratogenic effects have been noted for several of the study drugs. A pregnancy test is required for female patients of childbearing potential.
* Note: Serum and urine pregnancy tests may be falsely positive due to HCGbeta-secreting germ cell tumors. Ensure the patient is not pregnant by institutional standards
* Lactating females who plan to breastfeed their infants
* Sexually active patients of reproductive potential who have not agreed to use an effective contraceptive method for the duration of their study participation
* All patients and/or their parents or legal guardians must sign a written informed consent
* All institutional, Food and Drug Administration (FDA), and National Cancer Institute (NCI) requirements for human studies must be met
Inclusion Criteria
Inclusion Criteria:
* Patients must be ≥ 3 years and \< 30 years at the time of study enrollment
* Patients must be newly-diagnosed primary localized germinoma of the suprasellar and/or pineal region by pathology and/or serum and/or CSF hCGbeta 5-50 mIU/mL AND institutional normal AFP (or ≤ 10 ng/mL if no institutional normal exists), including tumors with contiguous ventricular or unifocal parenchymal extension. No histologic confirmation required
* Patients with EITHER (A) bifocal (pineal + suprasellar) involvement OR (B) pineal lesion with diabetes insipidus (DI) AND hCGbeta ≤ 100 mIU/mL in serum and/or CSF AND institutional normal AFP (or ≤ 10 ng/mL if no institutional normal exists) in both serum and CSF. No histologic confirmation required
* Patients with hCGbeta 51-100 mIU/mL in serum and/or CSF and institutional normal AFP (or ≤ 10 ng/mL if no institutional normal exists) in both serum and CSF. Histologic confirmation of germinoma IS required
* Patients with germinoma of the basal ganglia and or/thalamic primary sites are eligible
* Patients with metastatic germinoma including non-contiguous disease or distant disease in the brain, ventricles, or spine are eligible
* Patients with germinoma admixed with mature teratoma are eligible
* Patients must have a performance status corresponding to Eastern Cooperative Oncology Group (ECOG) scores of 0, 1 or 2. Use Karnofsky for patients \> 16 years of age and Lansky for patients ≤ 16 years of age
* Patients must have eligibility confirmed by Rapid Central Imaging Review performed on APEC14B1-CNS
* Imaging studies must be obtained within 31 days prior to study enrollment and start of protocol therapy. (Note: for patients that have had surgery and post-operative imaging performed, it is the post-operative MRI that must be obtained within 31 days prior to enrollment.)
* Patients must have a cranial magnetic resonance imaging (MRI) with and without gadolinium at diagnosis/prior to enrollment. If surgical resection is performed, patients must have pre-operative and post-operative brain MRI with and without gadolinium. The post-operative brain MRI should be obtained within 72 hours of surgery. If patient has a biopsy only, post-operative brain MRI is recommended but not required
* Patients must have a spine MRI with gadolinium obtained at diagnosis/prior to enrollment
* Patients must be enrolled, and protocol therapy must begin, no later than 31 days after definitive surgery or clinical diagnosis, whichever is later
* Patients must have eligibility confirmed by Rapid Central Tumor Marker Review performed on APEC14B1-CNS
* Lumbar CSF must be obtained prior to study enrollment unless medically contraindicated. If a patient undergoes surgery and lumbar CSF cytology cannot be obtained at the time of surgery, then it should be performed at least 10 days following surgery and prior to study enrollment. False positive cytology can occur within 10 days of surgery. Of note, lumbar CSF should not be performed prior to obtaining spine MRI, as this can make interpretation of the spine MRI less clear
* Patients must have CSF tumor markers obtained prior to study enrollment unless medically contraindicated. Ventricular CSF obtained at the time of CSF diversion procedure (if performed) is acceptable for tumor markers but lumbar CSF is preferred. In case CSF diversion and biopsy/surgery are combined, CSF tumor markers should be collected first. Ideally serum and CSF tumor markers should be collected at the same time and processed without delay
* For patients with solid tumors: Peripheral absolute neutrophil count (ANC) \>= 1000/uL (Must be performed within 7 days prior to enrollment unless otherwise indicated)
* For patients with solid tumors: Platelet count \>= 100,000/uL (transfusion independent) (Must be performed within 7 days prior to enrollment unless otherwise indicated)
* For patients with solid tumors: Hemoglobin \>= 8.0 g/dL (may receive red blood cell \[RBC\] transfusions) (Must be performed within 7 days prior to enrollment unless otherwise indicated)
* For pediatric patients (age 3-17 years): A serum creatinine based on age/gender as follows (Must be performed within 7 days prior to enrollment unless otherwise indicated):
* Age: 3 to \< 6 years; maximum serum creatinine (mg/dL): 0.8 (male); 0.8 (female)
* Age: 6 to \< 10 years; maximum serum creatinine (mg/dL): 1 (male); 1 (female)
* Age: 10 to \< 13 years; maximum serum creatinine (mg/dL): 1.2 (male); 1.2 (female)
* Age: 13 to \< 16 years; maximum serum creatinine (mg/dL): 1.5 (male); 1.4 (female)
* Age: ≥ 17 years; maximum serum creatinine (mg/dL): 1.7 (male); 1.4 (female) OR a 24-hour urine creatinine clearance ≥ 70 mL/min/1.73 m\^2 OR a glomerular filtration rate (GFR) ≥ 50 mL/min/1.73 m\^2. GFR must be performed using direct measurement with a nuclear blood sampling method OR direct small molecule clearance method (iothalamate or other molecule per institutional standard).
* Note: Estimated GFR (eGFR) from serum or plasma creatinine, cystatin C or other estimates are not acceptable for determining eligibility.
* For adult patients (age 18 years or older) (Must be performed within 7 days prior to enrollment unless otherwise indicated):
* Creatinine clearance ≥ 70 mL/min, as estimated by the Cockcroft and Gault formula or a 24-hour urine collection. The creatinine value used in the calculation must have been obtained within 28 days prior to registration. Estimated creatinine clearance is based on actual body weight
* Total bilirubin ≤ 1.5 x upper limit of normal (ULN) for age (Must be performed within 7 days prior to enrollment unless otherwise indicated)
* Serum glutamic-pyruvic transaminase (SGPT) (alanine transaminase \[ALT\]) ≤ 135 U/L (Must be performed within 7 days prior to enrollment unless otherwise indicated)
* Note: For the purpose of this study, the ULN for SGPT (ALT) has been set to the value of 45 U/L
* No evidence of dyspnea at rest, no exercise intolerance, and a pulse oximetry \> 94% if there is clinical indication for determination
* Patients with seizure disorder may be enrolled if on anticonvulsants and well controlled
* CNS toxicity =\< grade 2
* Patients must not be in status epilepticus, coma or assisted ventilation prior to study enrollment
* HIV-infected patients on effective anti-retroviral therapy with undetectable viral load are eligible for this study
* Patients must be ≥ 3 years and \< 30 years at the time of study enrollment
* Patients must be newly-diagnosed primary localized germinoma of the suprasellar and/or pineal region by pathology and/or serum and/or CSF hCGbeta 5-50 mIU/mL AND institutional normal AFP (or ≤ 10 ng/mL if no institutional normal exists), including tumors with contiguous ventricular or unifocal parenchymal extension. No histologic confirmation required
* Patients with EITHER (A) bifocal (pineal + suprasellar) involvement OR (B) pineal lesion with diabetes insipidus (DI) AND hCGbeta ≤ 100 mIU/mL in serum and/or CSF AND institutional normal AFP (or ≤ 10 ng/mL if no institutional normal exists) in both serum and CSF. No histologic confirmation required
* Patients with hCGbeta 51-100 mIU/mL in serum and/or CSF and institutional normal AFP (or ≤ 10 ng/mL if no institutional normal exists) in both serum and CSF. Histologic confirmation of germinoma IS required
* Patients with germinoma of the basal ganglia and or/thalamic primary sites are eligible
* Patients with metastatic germinoma including non-contiguous disease or distant disease in the brain, ventricles, or spine are eligible
* Patients with germinoma admixed with mature teratoma are eligible
* Patients must have a performance status corresponding to Eastern Cooperative Oncology Group (ECOG) scores of 0, 1 or 2. Use Karnofsky for patients \> 16 years of age and Lansky for patients ≤ 16 years of age
* Patients must have eligibility confirmed by Rapid Central Imaging Review performed on APEC14B1-CNS
* Imaging studies must be obtained within 31 days prior to study enrollment and start of protocol therapy. (Note: for patients that have had surgery and post-operative imaging performed, it is the post-operative MRI that must be obtained within 31 days prior to enrollment.)
* Patients must have a cranial magnetic resonance imaging (MRI) with and without gadolinium at diagnosis/prior to enrollment. If surgical resection is performed, patients must have pre-operative and post-operative brain MRI with and without gadolinium. The post-operative brain MRI should be obtained within 72 hours of surgery. If patient has a biopsy only, post-operative brain MRI is recommended but not required
* Patients must have a spine MRI with gadolinium obtained at diagnosis/prior to enrollment
* Patients must be enrolled, and protocol therapy must begin, no later than 31 days after definitive surgery or clinical diagnosis, whichever is later
* Patients must have eligibility confirmed by Rapid Central Tumor Marker Review performed on APEC14B1-CNS
* Lumbar CSF must be obtained prior to study enrollment unless medically contraindicated. If a patient undergoes surgery and lumbar CSF cytology cannot be obtained at the time of surgery, then it should be performed at least 10 days following surgery and prior to study enrollment. False positive cytology can occur within 10 days of surgery. Of note, lumbar CSF should not be performed prior to obtaining spine MRI, as this can make interpretation of the spine MRI less clear
* Patients must have CSF tumor markers obtained prior to study enrollment unless medically contraindicated. Ventricular CSF obtained at the time of CSF diversion procedure (if performed) is acceptable for tumor markers but lumbar CSF is preferred. In case CSF diversion and biopsy/surgery are combined, CSF tumor markers should be collected first. Ideally serum and CSF tumor markers should be collected at the same time and processed without delay
* For patients with solid tumors: Peripheral absolute neutrophil count (ANC) \>= 1000/uL (Must be performed within 7 days prior to enrollment unless otherwise indicated)
* For patients with solid tumors: Platelet count \>= 100,000/uL (transfusion independent) (Must be performed within 7 days prior to enrollment unless otherwise indicated)
* For patients with solid tumors: Hemoglobin \>= 8.0 g/dL (may receive red blood cell \[RBC\] transfusions) (Must be performed within 7 days prior to enrollment unless otherwise indicated)
* For pediatric patients (age 3-17 years): A serum creatinine based on age/gender as follows (Must be performed within 7 days prior to enrollment unless otherwise indicated):
* Age: 3 to \< 6 years; maximum serum creatinine (mg/dL): 0.8 (male); 0.8 (female)
* Age: 6 to \< 10 years; maximum serum creatinine (mg/dL): 1 (male); 1 (female)
* Age: 10 to \< 13 years; maximum serum creatinine (mg/dL): 1.2 (male); 1.2 (female)
* Age: 13 to \< 16 years; maximum serum creatinine (mg/dL): 1.5 (male); 1.4 (female)
* Age: ≥ 17 years; maximum serum creatinine (mg/dL): 1.7 (male); 1.4 (female) OR a 24-hour urine creatinine clearance ≥ 70 mL/min/1.73 m\^2 OR a glomerular filtration rate (GFR) ≥ 50 mL/min/1.73 m\^2. GFR must be performed using direct measurement with a nuclear blood sampling method OR direct small molecule clearance method (iothalamate or other molecule per institutional standard).
* Note: Estimated GFR (eGFR) from serum or plasma creatinine, cystatin C or other estimates are not acceptable for determining eligibility.
* For adult patients (age 18 years or older) (Must be performed within 7 days prior to enrollment unless otherwise indicated):
* Creatinine clearance ≥ 70 mL/min, as estimated by the Cockcroft and Gault formula or a 24-hour urine collection. The creatinine value used in the calculation must have been obtained within 28 days prior to registration. Estimated creatinine clearance is based on actual body weight
* Total bilirubin ≤ 1.5 x upper limit of normal (ULN) for age (Must be performed within 7 days prior to enrollment unless otherwise indicated)
* Serum glutamic-pyruvic transaminase (SGPT) (alanine transaminase \[ALT\]) ≤ 135 U/L (Must be performed within 7 days prior to enrollment unless otherwise indicated)
* Note: For the purpose of this study, the ULN for SGPT (ALT) has been set to the value of 45 U/L
* No evidence of dyspnea at rest, no exercise intolerance, and a pulse oximetry \> 94% if there is clinical indication for determination
* Patients with seizure disorder may be enrolled if on anticonvulsants and well controlled
* CNS toxicity =\< grade 2
* Patients must not be in status epilepticus, coma or assisted ventilation prior to study enrollment
* HIV-infected patients on effective anti-retroviral therapy with undetectable viral load are eligible for this study
Gender
All
Gender Based
false
Healthy Volunteers
No
Last Update Post Date
Last Update Post Date Type
Actual
Last Update Submit Date
Maximum Age
29 Years
Minimum Age
3 Years
NCT Id
NCT06368817
Org Class
Network
Org Full Name
Children's Oncology Group
Org Study Id
ACNS2321
Overall Status
Recruiting
Phases
Phase 2
Primary Completion Date
Primary Completion Date Type
Estimated
Official Title
A Phase II Trial Evaluating Chemotherapy Followed by Response-Based Reduced Radiation Therapy for Patients With Central Nervous System Germinomas
Primary Outcomes
Outcome Description
Will be estimated for eligible and evaluable patients assigned to Stratum 1 using Kaplan-Meier (KM) EFS estimates at 2 and 3 years with respective 80% two-sided confidence intervals. Time from initiation of radiation to the first occurrence of any of the following events: biochemical or radiographic disease progression, disease recurrence, second malignant neoplasm, or death from any cause.
Outcome Measure
Event-free survival (EFS) (Stratum I)
Outcome Time Frame
Evaluated at 2- and 3-years post-radiation initiation
Secondary Ids
Secondary Id
NCI-2024-03518
Secondary Id
ACNS2321
Secondary Id
ACNS2321
Secondary Id
U10CA180886
Secondary Outcomes
Outcome Description
Will be estimated for eligible and evaluable patients assigned to Stratum 2 using KM methods at 2 and 3 years with respective 80% two-sided confidence intervals. Time from initiation of radiation to the first occurrence of any of the following events: biochemical or radiographic disease progression, disease recurrence, second malignant neoplasm, or death from any cause.
Outcome Time Frame
Evaluated at 2- and 3-years post-radiation initiation
Outcome Measure
EFS (Stratum II)
Outcome Description
Will be estimated for eligible and evaluable patients assigned to Stratum 3 using KM methods at 2 and 3 years with respective 80% two-sided confidence intervals. Time from initiation of radiation to the first occurrence of any of the following events: biochemical or radiographic disease progression, disease recurrence, second malignant neoplasm, or death from any cause.
Outcome Time Frame
Evaluated at 2- and 3-years post-radiation initiation
Outcome Measure
EFS (Stratum III)
Outcome Description
Will report the response rates using the respective sample proportions and exact binomial two-sided 95% confidence intervals.
Outcome Time Frame
Following the completion of Induction therapy, approximately 12 weeks post-chemotherapy initiation
Outcome Measure
Radiographic response rate
Outcome Description
Will report the response rates using the respective sample proportions and exact binomial two-sided 95% confidence intervals.
Outcome Time Frame
Following the completion of Induction therapy, approximately 12 weeks post-chemotherapy initiation
Outcome Measure
Marker tumor response rate
Outcome Description
Will use KM methods to estimate stratum-specific OS.
Outcome Time Frame
Time from initiation of radiation therapy until death by any cause, up to 10 years post-enrollment
Outcome Measure
Overall survival (OS)
Outcome Description
Will be summarized by the Kalbfleisch-Prentice cumulative incidence function (CIF) approach, separately by stratum and by neuroendocrine dysfunction event. Competing risks will include disease progression and death, and patients without events or competing risks will be censored at the time of their last follow-up.
Outcome Time Frame
Time from initiation of RT until date of diagnosis of neuroendocrine dysfunction event, up to 10 years post-enrollment
Outcome Measure
Neuroendocrine dysfunction (including growth hormone deficiency)
Outcome Description
Will be assessed by processing speed index tasks for the Wechsler Preschool and Primary Scale of Intelligence - Fourth Edition (WPPSI-IV), Wechsler Intelligence Scale for Children - Fifth Edition (WISC-V) or Wechsler Adult Intelligence Scale - Fourth Edition (WAIS-IV) depending on age. The mean processing speed at 30-months post-diagnosis in ACNS2321 Stratum 1 patients will be compared to the respective mean in ACNS1123 Stratum 2 patients who had a CR/CCR and received 18 Gy WVI + 12 Gy boost to primary site.
Outcome Time Frame
At 9 months (+/- 3 months), 30 months (+/- 3 months), and 60 months (+/- 3 months) after diagnosis
Outcome Measure
Processing speed
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
Child
Adult
Maximum Age Number (converted to Years and rounded down)
29
Minimum Age Number (converted to Years and rounded down)
3
Investigators
Investigator Type
Principal Investigator
Investigator Name
Alice Lee
Investigator Email
alee5@montefiore.org