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NCT06368817PHASE2Recruiting

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

Children's Oncology Group

Start Date

10/22/2024

Completion Date

11/4/2033

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 (3D-CRT)/3-dimensional conformal proton radiation therapy (3D-CPRT) or intensity-modulated radiation therapy (IMRT)/intensity modulated proton therapy (IMPT) 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 3D-CRT/3D-CPRT or IMRT/IMPT 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 3D-CRT/3D-CPRT or IMRT/IMPT QD 5 days a week for 16 days. Patients with bifocal germinoma undergo 3D-CRT/3D-CPRT or IMRT/IMPT 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 3D-CRT/3D-CPRT or IMRT/IMPT 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 3D-CRT/3D-CPRT or IMRT/IMPT QD 5 days a week for 24 days. STRATUM IV: Patients with metastatic germinoma achieving CR undergo 3D-CRT/3D-CPRT or IMRT/IMPT 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 3D-CRT/3D-CPRT or IMRT/IMPT 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 3D-CRT/3D-CPRT or IMRT/IMPT QD 5 days a week for 24 days. STRATUM VI: Patients with basal ganglia and thalamic germinoma achieving CR undergo 3D-CRT/3D-CPRT or IMRT/IMPT 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 3D-CRT/3D-CPRT or IMRT/IMPT 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 3D-CRT/3D-CPRT or IMRT/IMPT 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.

Eligibility Criteria

Age Range: 3 years to 29 years

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/sex 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

Interventions

RADIATION

3-Dimensional Conformal Proton Radiation Therapy

RADIATION

3-Dimensional Conformal Radiation Therapy

PROCEDURE

Biospecimen Collection

DRUG

Carboplatin

DRUG

Etoposide

PROCEDURE

Intensity-Modulated Proton Therapy

RADIATION

Intensity-Modulated Radiation Therapy

PROCEDURE

Lumbar Puncture

PROCEDURE

Magnetic Resonance Imaging

OTHER

Questionnaire Administration

PROCEDURE

Surgical Procedure

Interested in This Trial?

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Conditions

Basal Ganglia GerminomaDiabetes InsipidusGerminomaPineal Region GerminomaSuprasellar GerminomaThalamic Germinoma

Locations

USA Health Strada Patient Care Center

Mobile, Alabama 36604

United States

Phoenix Childrens Hospital

Phoenix, Arizona 85016

United States

Arkansas Children's Hospital

Little Rock, Arkansas 72202-3591

United States

Loma Linda University Medical Center

Loma Linda, California 92354

United States

Children's Hospital Los Angeles

Los Angeles, California 90027

United States

UCSF Benioff Children's Hospital Oakland

Oakland, California 94609

United States

Children's Hospital of Orange County

Orange, California 92868

United States

Lucile Packard Children's Hospital Stanford University

Palo Alto, California 94304

United States

Rady Children's Hospital - San Diego

San Diego, California 92123

United States

UCSF Medical Center-Mission Bay

San Francisco, California 94158

United States

Children's Hospital Colorado

Aurora, Colorado 80045

United States

Connecticut Children's Medical Center

Hartford, Connecticut 06106

United States

Yale University

New Haven, Connecticut 06520

United States

Alfred I duPont Hospital for Children

Wilmington, Delaware 19803

United States

Children's National Medical Center

Washington D.C., District of Columbia 20010

United States

Memorial Regional Hospital/Joe DiMaggio Children's Hospital

Hollywood, Florida 33021

United States

Nemours Children's Clinic-Jacksonville

Jacksonville, Florida 32207

United States

University of Miami Miller School of Medicine-Sylvester Cancer Center

Miami, Florida 33136

United States

Nicklaus Children's Hospital

Miami, Florida 33155

United States

Arnold Palmer Hospital for Children

Orlando, Florida 32806

United States

Nemours Children's Hospital

Orlando, Florida 32827

United States

Nemours Children's Clinic - Pensacola

Pensacola, Florida 32504

United States

Sacred Heart Hospital

Pensacola, Florida 32504

United States

Johns Hopkins All Children's Hospital

St. Petersburg, Florida 33701

United States

Saint Joseph's Hospital/Children's Hospital-Tampa

Tampa, Florida 33607

United States

Children's Healthcare of Atlanta - Arthur M Blank Hospital

Atlanta, Georgia 30329

United States

Kapiolani Medical Center for Women and Children

Honolulu, Hawaii 96826

United States

Saint Luke's Cancer Institute - Boise

Boise, Idaho 83712

United States

Lurie Children's Hospital-Chicago

Chicago, Illinois 60611

United States

University of Illinois

Chicago, Illinois 60612

United States

University of Chicago Comprehensive Cancer Center

Chicago, Illinois 60637

United States

Loyola University Medical Center

Maywood, Illinois 60153

United States

Riley Hospital for Children

Indianapolis, Indiana 46202

United States

University of Iowa/Holden Comprehensive Cancer Center

Iowa City, Iowa 52242

United States

Norton Children's Hospital

Louisville, Kentucky 40202

United States

Maine Children's Cancer Program

Scarborough, Maine 04074

United States

Johns Hopkins University/Sidney Kimmel Cancer Center

Baltimore, Maryland 21287

United States

Massachusetts General Hospital Cancer Center

Boston, Massachusetts 02114

United States

Dana-Farber Cancer Institute

Boston, Massachusetts 02215

United States

C S Mott Children's Hospital

Ann Arbor, Michigan 48109

United States

Corewell Health Grand Rapids Hospitals - Helen DeVos Children's Hospital

Grand Rapids, Michigan 49503

United States

Children's Hospitals and Clinics of Minnesota - Minneapolis

Minneapolis, Minnesota 55404

United States

University of Minnesota/Masonic Cancer Center

Minneapolis, Minnesota 55455

United States

Mayo Clinic in Rochester

Rochester, Minnesota 55905

United States

University of Mississippi Medical Center

Jackson, Mississippi 39216

United States

Children's Mercy Hospitals and Clinics

Kansas City, Missouri 64108

United States

Cardinal Glennon Children's Medical Center

St Louis, Missouri 63104

United States

Washington University School of Medicine

St Louis, Missouri 63110

United States

Children's Hospital and Medical Center of Omaha

Omaha, Nebraska 68114

United States

University of Nebraska Medical Center

Omaha, Nebraska 68198

United States

Alliance for Childhood Diseases/Cure 4 the Kids Foundation

Las Vegas, Nevada 89135

United States

Summerlin Hospital Medical Center

Las Vegas, Nevada 89144

United States

Dartmouth Hitchcock Medical Center/Dartmouth Cancer Center

Lebanon, New Hampshire 03756

United States

Hackensack University Medical Center

Hackensack, New Jersey 07601

United States

Saint Peter's University Hospital

New Brunswick, New Jersey 08901

United States

Rutgers Cancer Institute of New Jersey-Robert Wood Johnson University Hospital

New Brunswick, New Jersey 08903

United States

Newark Beth Israel Medical Center

Newark, New Jersey 07112

United States

Saint Joseph's Regional Medical Center

Paterson, New Jersey 07503

United States

Albany Medical Center

Albany, New York 12208

United States

The Steven and Alexandra Cohen Children's Medical Center of New York

New Hyde Park, New York 11040

United States

Laura and Isaac Perlmutter Cancer Center at NYU Langone

New York, New York 10016

United States

Mount Sinai Hospital

New York, New York 10029

United States

NYP/Columbia University Medical Center/Herbert Irving Comprehensive Cancer Center

New York, New York 10032

United States

Memorial Sloan Kettering Cancer Center

New York, New York 10065

United States

State University of New York Upstate Medical University

Syracuse, New York 13210

United States

Montefiore Medical Center - Moses Campus

The Bronx, New York 10467

United States

UNC Lineberger Comprehensive Cancer Center

Chapel Hill, North Carolina 27599

United States

Wake Forest University Health Sciences

Winston-Salem, North Carolina 27157

United States

Sanford Broadway Medical Center

Fargo, North Dakota 58122

United States

Rainbow Babies and Childrens Hospital

Cleveland, Ohio 44106

United States

Nationwide Children's Hospital

Columbus, Ohio 43205

United States

University of Oklahoma Health Sciences Center

Oklahoma City, Oklahoma 73104

United States

Oregon Health and Science University

Portland, Oregon 97239

United States

Children's Hospital of Philadelphia

Philadelphia, Pennsylvania 19104

United States

Saint Christopher's Hospital for Children

Philadelphia, Pennsylvania 19134

United States

Children's Hospital of Pittsburgh of UPMC

Pittsburgh, Pennsylvania 15224

United States

Rhode Island Hospital

Providence, Rhode Island 02903

United States

Prisma Health Richland Hospital

Columbia, South Carolina 29203

United States

BI-LO Charities Children's Cancer Center

Greenville, South Carolina 29605

United States

Sanford USD Medical Center - Sioux Falls

Sioux Falls, South Dakota 57117-5134

United States

Saint Jude Children's Research Hospital

Memphis, Tennessee 38105

United States

Vanderbilt University/Ingram Cancer Center

Nashville, Tennessee 37232

United States

Dell Children's Medical Center of Central Texas

Austin, Texas 78723

United States

Driscoll Children's Hospital

Corpus Christi, Texas 78411

United States

Medical City Dallas Hospital

Dallas, Texas 75230

United States

UT Southwestern/Simmons Cancer Center-Dallas

Dallas, Texas 75390

United States

Baylor College of Medicine/Dan L Duncan Comprehensive Cancer Center

Houston, Texas 77030

United States

UT MD Anderson Cancer Center

Houston, Texas 77030

United States

Children's Hospital of San Antonio

San Antonio, Texas 78207

United States

University of Texas Health Science Center at San Antonio

San Antonio, Texas 78229

United States

Primary Children's Hospital

Salt Lake City, Utah 84113

United States

University of Virginia Cancer Center

Charlottesville, Virginia 22908

United States

Children's Hospital of The King's Daughters

Norfolk, Virginia 23507

United States

Seattle Children's Hospital

Seattle, Washington 98105

United States

Providence Sacred Heart Medical Center and Children's Hospital

Spokane, Washington 99204

United States

University of Wisconsin Carbone Cancer Center - University Hospital

Madison, Wisconsin 53792

United States

John Hunter Children's Hospital

Hunter Regional Mail Centre, New South Wales 2310

Australia

Sydney Children's Hospital

Randwick, New South Wales 2031

Australia

The Children's Hospital at Westmead

Westmead, New South Wales 2145

Australia

Queensland Children's Hospital

South Brisbane, Queensland 4101

Australia

Women's and Children's Hospital-Adelaide

North Adelaide, South Australia 5006

Australia

Royal Children's Hospital

Parkville, Victoria 3052

Australia

Perth Children's Hospital

Perth, Western Australia 6009

Australia

University of Alberta Hospital

Edmonton, Alberta T6G 2B7

Canada

British Columbia Children's Hospital

Vancouver, British Columbia V6H 3V4

Canada

CancerCare Manitoba

Winnipeg, Manitoba R3E 0V9

Canada

IWK Health Centre

Halifax, Nova Scotia B3K 6R8

Canada

McMaster Children's Hospital at Hamilton Health Sciences

Hamilton, Ontario L8N 3Z5

Canada

Children's Hospital

London, Ontario N6A 5W9

Canada

Hospital for Sick Children

Toronto, Ontario M5G 1X8

Canada

The Montreal Children's Hospital of the MUHC

Montreal, Quebec H3H 1P3

Canada

Centre Hospitalier Universitaire Sainte-Justine

Montreal, Quebec H3T 1C5

Canada

Centre Hospitalier Universitaire de Sherbrooke-Fleurimont

Sherbrooke, Quebec J1H 5N4

Canada

CHU de Quebec-Centre Hospitalier de l'Universite Laval (CHUL)

Québec, G1V 4G2

Canada