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Trial Title: A Study of Lower Radiotherapy Dose to Treat Children With CNS Germinoma

NCT ID: NCT06368817

Condition: Basal Ganglia Germinoma
Central Nervous System Germinoma
Diabetes Insipidus
Pineal Region Germinoma
Suprasellar Germinoma
Thalamic Germinoma

Conditions: Official terms:
Germinoma
Diabetes Insipidus
Carboplatin
Etoposide
Etoposide phosphate
Podophyllotoxin

Study type: Interventional

Study phase: Phase 2

Overall status: Recruiting

Study design:

Allocation: Non-Randomized

Intervention model: Parallel Assignment

Primary purpose: Treatment

Masking: None (Open Label)

Intervention:

Intervention type: Radiation
Intervention name: 3-Dimensional Conformal Radiation Therapy
Description: Undergo 3D-CRT
Arm group label: Stratum I (carboplatin, etoposide, 3D-CRT, IMRT, surgery)
Arm group label: Stratum II (carboplatin, etoposide, 3D-CRT, IMRT)
Arm group label: Stratum III (carboplatin, etoposide, 3D-CRT, IMRT)
Arm group label: Stratum IV (carboplatin, etoposide, 3D-CRT, IMRT, surgery)
Arm group label: Stratum V (carboplatin, etoposide, 3D-CRT, IMRT)
Arm group label: Stratum VI (carboplatin, etoposide, 3D-CRT, IMRT, surgery)
Arm group label: Stratum VII (carboplatin, etoposide, 3D-CRT, IMRT)

Other name: 3-dimensional radiation therapy

Other name: 3D Conformal

Other name: 3D CONFORMAL RADIATION THERAPY

Other name: 3D CRT

Other name: 3D radiotherapy

Other name: 3D-CRT

Other name: Conformal Therapy

Other name: Radiation Conformal Therapy

Other name: Radiation, 3D Conformal

Other name: Three dimensional external beam radiation therapy (procedure)

Intervention type: Procedure
Intervention name: Biospecimen Collection
Description: Undergo blood and CSF sample collection
Arm group label: Stratum I (carboplatin, etoposide, 3D-CRT, IMRT, surgery)
Arm group label: Stratum II (carboplatin, etoposide, 3D-CRT, IMRT)
Arm group label: Stratum III (carboplatin, etoposide, 3D-CRT, IMRT)
Arm group label: Stratum IV (carboplatin, etoposide, 3D-CRT, IMRT, surgery)
Arm group label: Stratum V (carboplatin, etoposide, 3D-CRT, IMRT)
Arm group label: Stratum VI (carboplatin, etoposide, 3D-CRT, IMRT, surgery)
Arm group label: Stratum VII (carboplatin, etoposide, 3D-CRT, IMRT)

Other name: Biological Sample Collection

Other name: Biospecimen Collected

Other name: Specimen Collection

Intervention type: Drug
Intervention name: Carboplatin
Description: Given IV
Arm group label: Stratum I (carboplatin, etoposide, 3D-CRT, IMRT, surgery)
Arm group label: Stratum II (carboplatin, etoposide, 3D-CRT, IMRT)
Arm group label: Stratum III (carboplatin, etoposide, 3D-CRT, IMRT)
Arm group label: Stratum IV (carboplatin, etoposide, 3D-CRT, IMRT, surgery)
Arm group label: Stratum V (carboplatin, etoposide, 3D-CRT, IMRT)
Arm group label: Stratum VI (carboplatin, etoposide, 3D-CRT, IMRT, surgery)
Arm group label: Stratum VII (carboplatin, etoposide, 3D-CRT, IMRT)

Other name: Blastocarb

Other name: Carboplat

Other name: Carboplatin Hexal

Other name: Carboplatino

Other name: Carboplatinum

Other name: Carbosin

Other name: Carbosol

Other name: Carbotec

Other name: CBDCA

Other name: Displata

Other name: Ercar

Other name: JM-8

Other name: JM8

Other name: Nealorin

Other name: Novoplatinum

Other name: Paraplatin

Other name: Paraplatin AQ

Other name: Paraplatine

Other name: Platinwas

Other name: Ribocarbo

Intervention type: Drug
Intervention name: Etoposide
Description: Given IV
Arm group label: Stratum I (carboplatin, etoposide, 3D-CRT, IMRT, surgery)
Arm group label: Stratum II (carboplatin, etoposide, 3D-CRT, IMRT)
Arm group label: Stratum III (carboplatin, etoposide, 3D-CRT, IMRT)
Arm group label: Stratum IV (carboplatin, etoposide, 3D-CRT, IMRT, surgery)
Arm group label: Stratum V (carboplatin, etoposide, 3D-CRT, IMRT)
Arm group label: Stratum VI (carboplatin, etoposide, 3D-CRT, IMRT, surgery)
Arm group label: Stratum VII (carboplatin, etoposide, 3D-CRT, IMRT)

Other name: Demethyl Epipodophyllotoxin Ethylidine Glucoside

Other name: EPEG

Other name: Lastet

Other name: Toposar

Other name: Vepesid

Other name: VP 16

Other name: VP 16-213

Other name: VP 16213

Other name: VP-16

Other name: VP-16-213

Other name: VP-16213

Other name: VP16

Other name: VP16213

Intervention type: Radiation
Intervention name: Intensity-Modulated Radiation Therapy
Description: Undergo IMRT
Arm group label: Stratum I (carboplatin, etoposide, 3D-CRT, IMRT, surgery)
Arm group label: Stratum II (carboplatin, etoposide, 3D-CRT, IMRT)
Arm group label: Stratum III (carboplatin, etoposide, 3D-CRT, IMRT)
Arm group label: Stratum IV (carboplatin, etoposide, 3D-CRT, IMRT, surgery)
Arm group label: Stratum V (carboplatin, etoposide, 3D-CRT, IMRT)
Arm group label: Stratum VI (carboplatin, etoposide, 3D-CRT, IMRT, surgery)
Arm group label: Stratum VII (carboplatin, etoposide, 3D-CRT, IMRT)

Other name: IMRT

Other name: Intensity modulated radiation therapy (procedure)

Other name: Intensity Modulated RT

Other name: Intensity-Modulated Radiotherapy

Other name: Radiation, Intensity-Modulated Radiotherapy

Intervention type: Procedure
Intervention name: Lumbar Puncture
Description: Undergo LP
Arm group label: Stratum I (carboplatin, etoposide, 3D-CRT, IMRT, surgery)
Arm group label: Stratum II (carboplatin, etoposide, 3D-CRT, IMRT)
Arm group label: Stratum III (carboplatin, etoposide, 3D-CRT, IMRT)
Arm group label: Stratum IV (carboplatin, etoposide, 3D-CRT, IMRT, surgery)
Arm group label: Stratum V (carboplatin, etoposide, 3D-CRT, IMRT)
Arm group label: Stratum VI (carboplatin, etoposide, 3D-CRT, IMRT, surgery)
Arm group label: Stratum VII (carboplatin, etoposide, 3D-CRT, IMRT)

Other name: LP

Other name: Spinal Tap

Intervention type: Procedure
Intervention name: Magnetic Resonance Imaging
Description: Undergo MRI
Arm group label: Stratum I (carboplatin, etoposide, 3D-CRT, IMRT, surgery)
Arm group label: Stratum II (carboplatin, etoposide, 3D-CRT, IMRT)
Arm group label: Stratum III (carboplatin, etoposide, 3D-CRT, IMRT)
Arm group label: Stratum IV (carboplatin, etoposide, 3D-CRT, IMRT, surgery)
Arm group label: Stratum V (carboplatin, etoposide, 3D-CRT, IMRT)
Arm group label: Stratum VI (carboplatin, etoposide, 3D-CRT, IMRT, surgery)
Arm group label: Stratum VII (carboplatin, etoposide, 3D-CRT, IMRT)

Other name: Magnetic Resonance

Other name: Magnetic Resonance Imaging (MRI)

Other name: Magnetic resonance imaging (procedure)

Other name: Magnetic Resonance Imaging Scan

Other name: Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance

Other name: MR

Other name: MR Imaging

Other name: MRI

Other name: MRI Scan

Other name: MRIs

Other name: NMR Imaging

Other name: NMRI

Other name: Nuclear Magnetic Resonance Imaging

Other name: sMRI

Other name: Structural MRI

Intervention type: Other
Intervention name: Questionnaire Administration
Description: Ancillary studies
Arm group label: Stratum I (carboplatin, etoposide, 3D-CRT, IMRT, surgery)
Arm group label: Stratum II (carboplatin, etoposide, 3D-CRT, IMRT)
Arm group label: Stratum III (carboplatin, etoposide, 3D-CRT, IMRT)
Arm group label: Stratum IV (carboplatin, etoposide, 3D-CRT, IMRT, surgery)
Arm group label: Stratum V (carboplatin, etoposide, 3D-CRT, IMRT)
Arm group label: Stratum VI (carboplatin, etoposide, 3D-CRT, IMRT, surgery)
Arm group label: Stratum VII (carboplatin, etoposide, 3D-CRT, IMRT)

Intervention type: Procedure
Intervention name: Surgical Procedure
Description: Undergo second-look surgery
Arm group label: Stratum I (carboplatin, etoposide, 3D-CRT, IMRT, surgery)
Arm group label: Stratum IV (carboplatin, etoposide, 3D-CRT, IMRT, surgery)
Arm group label: Stratum VI (carboplatin, etoposide, 3D-CRT, IMRT, surgery)

Other name: Operation

Other name: Surgery

Other name: Surgery Type

Other name: Surgery, NOS

Other name: Surgical

Other name: Surgical Intervention

Other name: Surgical Interventions

Other name: Surgical Procedures

Other name: Type of Surgery

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.

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.

Criteria for 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

Gender: All

Minimum age: 3 Years

Maximum age: 29 Years

Healthy volunteers: No

Locations:

Facility:
Name: Arkansas Children's Hospital

Address:
City: Little Rock
Zip: 72202-3591
Country: United States

Status: Recruiting