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A Study of a New Way to Treat Children and Young Adults With a Brain Tumor Called NGGCT

PHASE2RECRUITING

This phase II trial studies the best approach to combine chemotherapy and radiation therapy (RT) based on the patient's response to induction chemotherapy in patients with non-germinomatous germ cell tumors (NGGCT) that have not spread to other parts of the brain or body (localized). This study has 2 goals: 1) optimizing radiation for patients who respond well to induction chemotherapy to diminish spinal cord relapses, 2) utilizing higher dose chemotherapy followed by conventional RT in patients who did not respond to induction chemotherapy. Chemotherapy drugs, such as carboplatin, etoposide, ifosfamide, and thiotepa, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading.

Radiation therapy uses high energy x-rays or high-energy protons to kill tumor cells and shrink tumors. Studies have shown that patients with newly-diagnosed localized NGGCT, whose disease responds well to chemotherapy before receiving radiation therapy, are more likely to be free of the disease for a longer time than are patients for whom the chemotherapy does not efficiently eliminate or reduce the size of the tumor. The purpose of this study is to see how well the tumors respond to induction chemotherapy to decide what treatment to give next.

Some patients will be given RT to the spine and a portion of the brain. Others will be given high dose chemotherapy and a stem cell transplant before RT to the whole brain and spine. Giving treatment based on the response to induction chemotherapy may lower the side effects of radiation in some patients and adjust the therapy to a more efficient one for other patients with localized NGGCT.

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Study details:

PRIMARY OBJECTIVES:. I. To monitor outcome to ensure that children and young adults with localized central nervous system (CNS) non-germinomatous germ cell tumors (NGGCT) treated with induction chemotherapy followed by response evaluation and whole ventricular + spinal canal irradiation (WVSCI) will maintain the excellent 2-year progression free survival (PFS) rate as compared to ACNS0122 (NCT00047320).

II. To improve disease control by decreasing the number of spinal relapses for patients who achieve a complete response (CR) or partial response (PR) and receive WVSCI as compared to whole ventricular radiation on ACNS1123 (NCT01602666). SECONDARY OBJECTIVES:.

I. To estimate the response rates to induction chemotherapy and WVSCI for localized NGGCT patients who achieve a CR/PR. II.

To estimate the PFS and overall survival (OS) for localized NGGCT patients who achieve a CR/PR and receive WVSCI. III. To estimate the PFS and OS for patients with less than a CR/PR following Induction who subsequently receive high-dose chemotherapy with peripheral stem cell rescue (HDCSCR).

IV. To estimate the response rate for patients with less than a CR/PR following Induction who subsequently receive HDCSCR. EXPLORATORY OBJECTIVES:.

I. To prospectively compare outcomes based on radiation modality, photon versus proton, including cognitive, social and behavioral functioning, auditory, and neuro-endocrine function. II.

To compare spinal column growth and cell counts following radiation as measured by height and weight, and complete blood count (CBC) values during and after radiation therapy, based on treatment modality (photon versus \[vs. \] proton therapy) and planned inclusion/exclusion of the vertebral body in patients \< 13 years of age. III.

To compare local vs. central review recommendations for second-look surgery and document barriers for performing such surgeries as well as their clinical benefit in pediatric NGGCT. IV.

To prospectively evaluate and longitudinally model the cognitive, social, and behavioral functioning of children and young adults with localized CNS NGGCT with testing as per the Children's Oncology Group (COG) Standardized Neuropsychological and Behavioral Battery. V. To evaluate patterns of disease recurrence/failure with respect to radiation dose distribution.

OUTLINE:. INDUCTION CHEMOTHERAPY: Patients receive carboplatin intravenously (IV) over 15-60 minutes on day 1 and etoposide IV over 90-120 minutes on days 1-3 of cycles 1, 3, and 5. Patients also receive ifosfamide IV over 60 minutes and etoposide IV over 60-120 minutes on days 1-5 of cycles 2, 4, and 6.

Treatment repeats every 21 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Patients are assigned to 1 of 2 plans (ventricular + spinal canal irradiation \[WVSCI\] or high-dose chemotherapy with peripheral stem cell rescue \[HDCSCR\]) based on response to induction chemotherapy:. * Patients who achieve radiographic CR/PR with marker normalization proceed to WVSCI.

Patients who achieve radiographic CR without marker normalization proceed to HDCSCR. * Patients who achieve less than radiographic CR/PR with marker normalization proceed to second-look surgery (unless contraindicated). If second-look surgery reveals mature teratoma or non-viable tumor, proceed to WVSCI.

If second-look surgery reveals viable tumor, proceed to HDCSCR. Patients who are unable to undergo second-look surgery are removed from protocol therapy but remain on study for follow-up. * Patients who achieve less than radiographic CR/PR without marker normalization proceed to second-look surgery (unless contraindicated).

Patients then proceed to HDCSCR regardless of whether or not a second-look surgery is performed. * Patients who achieve radiographic PR without marker normalization proceed to second-look surgery (unless contraindicated). Patients then proceed to HDCSCR regardless of whether or not a second-look surgery is performed.

PLAN A (WVSCI THERAPY): Within 6 weeks of the end of induction chemotherapy or second-look surgery, patients undergo WVSCI once daily (QD) for 5 days weekly (17 fractions followed by a boost dose for 13 fractions) for 6 weeks in the absence of disease progression or unacceptable toxicity. PLAN B (CONSOLIDATION THERAPY \[HDCSCR\]): Within 6-8 weeks of the end of induction chemotherapy or second-look surgery, patients receive etoposide IV and thiotepa IV over 3 hours on days -5 to -3 and undergo peripheral blood stem cell (PBSC) transplant on day 0. Patients then undergo radiation therapy QD for 5 days weekly (20 fractions followed by a boost dose for 10 fractions) for 6 weeks in the absence of disease progression or unacceptable toxicity.

Patients also undergo magnetic resonance imaging (MRI), as well as collection of cerebral spinal fluid (CSF) and blood sample throughout the trial. After completion of study treatment, patients are followed for up to 10 years.

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Eligibility criteria

Researchers look for people who fit a certain description, called eligibility criteria. See if you qualify.

Inclusion criteria

Patients must be >= 3 years and < 30 years at the time of study enrollment

Patients must be newly diagnosed with localized primary CNS NGGCT of the suprasellar and/or pineal region by pathology and/or serum or cerebrospinal fluid (CSF) elevation of AFP above institutional normal or > 10 ng/mL or human chorionic gonadotropin (hCG) beta > 100 mIU/mL as confirmed by Rapid Central Marker Screening Review on APEC14B1-CNS. Suprasellar, pineal and bifocal tumors are included. (CSF tumor markers and cytology must be within 31 days prior to enrollment and start of protocol therapy [repeat if necessary]. Serum tumor markers, AFP and hCGbeta must be within 7 days prior to enrollment and start of protocol therapy [repeat if necessary]). Basal ganglia or other primary sites are excluded

Patients with any of the following pathological elements are eligible: endodermal sinus (yolk sac), embryonal carcinoma, choriocarcinoma, malignant/immature teratoma and mixed germ cell tumor (GCT) (i.e., may include some pure germinoma) if malignant elements listed above are present. Patients with only mature teratoma are excluded. Patients with pure germinoma admixed with mature teratoma are excluded (would be eligible for pure germinoma protocols)

Patients must have a cranial 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 (within 31 days prior to study enrollment and start of protocol therapy)

Patients must have a spine MRI with gadolinium obtained at diagnosis/prior to enrollment. Spine MRI with and without gadolinium is recommended (within 31 days prior to study enrollment and start of protocol therapy)

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

Patients must have RAPID CENTRAL TUMOR MARKER REVIEW CSF tumor markers obtained prior to 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

Peripheral absolute neutrophil count (ANC) >= 1000/uL (within 7 days prior to enrollment)

Platelet count >= 100,000/uL (transfusion independent) (within 7 days prior to enrollment)

Hemoglobin >= 8.0 g/dL (may receive red blood cell [RBC] transfusions) (within 7 days prior to enrollment)

Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70 mL/min/1.73 m^2 or a serum creatinine based on age/gender as follows (within 7 days prior to enrollment): Age: Maximum serum creatinine (mg/dL): 3 to < 6 years: 0.8 (male), 0.8 (female), 6 to < 10 years: 1 (male), 1 (female), 10 to < 13 years: 1.2 (male), 1.2 (female), 13 to < 16 years: 1.5 (male), 1.4 (female), >= 16 years: male (1.7), 1.4 (female)

Total bilirubin <= 1.5 x upper limit of normal (ULN) for age (within 7 days prior to enrollment)

Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) <= 135 U/L (within 7 days prior to enrollment): Note: For the purpose of this study, the ULN for SGPT (ALT) has been set to the value of 45 U/L

Central nervous system function defined as: Patients with seizure disorder may be enrolled if on anticonvulsants and well controlled. Patients must not be in status epilepticus, coma or assisted ventilation prior to study enrollment

Protocol therapy must begin within 31 calendar days of definitive surgery or clinical diagnosis, whichever is later. If a biopsy only was performed, the biopsy date will be considered the date of definitive surgery. For patients who have a biopsy or incomplete resection at diagnosis followed by additional surgery, the date of the last resection will be considered the date of definitive surgery.

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

NEUROCOGNITIVE FUNCTION AND QUALITY OF LIFE ASSESSMENT: English-, Spanish-, or French- speaking: Note: Patients who speak a language other than English, Spanish, or French will be allowed to participate in ACNS2021 but will not complete the neurocognitive and quality of life assessments

No known history of neurodevelopmental disorder prior to diagnosis of NGGCT (e.g., Down syndrome, fragile X, William syndrome, intellectual disability). Patients with NF1 will be allowed to participate

Additional eligibility criteria for the COG Standardized Neuropsychological Battery only: must be at a site that has a psychologist to administer the battery: Note: If not eligible for the COG Standardized Battery, patients should still complete the Behavior Rating Inventory of Executive Function, Second Edition (BRIEF-2), Pediatric Quality of Life Inventory (PedsQL), Adaptive Behavior Assessment System Third Edition (ABAS-3), and Behavior Assessment System for Children, Third Edition (BASC-3) questionnaires

Exclusion criteria

Patients with tumors located outside the ventricles (i.e., basal ganglia, thalamus)

Patients with only mature teratoma and non-elevated markers upon tumor sampling at diagnosis

Patients who have received any prior tumor-directed therapy for their diagnosis of NGGCT other than surgical intervention and corticosteroids

Patients with metastatic disease (i.e., MRI evaluation, lumbar CSF cytology or intraoperative evidence of dissemination)

Female patients who are pregnant, since fetal toxicities and teratogenic effects have been noted for several of the study drugs: 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

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Eligibility

Age eligible for study : 3 and older

Healthy volunteers accepted : No

Gender eligible for study: All

Things to know

Study dates

Study start: 2021-07-13

Primary completion: 2029-12-21

Study completion finish: 2029-12-21

Study type

TREATMENT

Phase

PHASE2

Trial ID

NCT04684368

Intervention or treatment

PROCEDURE: Biospecimen Collection

DRUG: Carboplatin

DRUG: Etoposide

BIOLOGICAL: Filgrastim

DRUG: Ifosfamide

PROCEDURE: Magnetic Resonance Imaging

DRUG: Mesna

BIOLOGICAL: Pegfilgrastim

PROCEDURE: Peripheral Blood Stem Cell Transplantation

OTHER: Questionnaire Administration

RADIATION: Radiation Therapy

PROCEDURE: Second-Look Surgery

DRUG: Thiotepa

Conditions

• Central Nervous System Nongerminomatous Germ Cell Tumor
• Choriocarcinoma
• Embryonal Carcinoma
• Immature Teratoma
• Malignant Teratoma
• Mixed Germ Cell Tumor
• Pineal Region Germ Cell Tumor
• Pineal Region Immature Teratoma
• Pineal Region Yolk Sac Tumor
• Suprasellar Germ Cell Tumor

Image related to Central Nervous System Nongerminomatous Germ Cell Tumor

Condition: Central Nervous System Nongerminomatous Germ Cell Tumor, Choriocarcinoma and more
PROCEDURE: Biospecimen Collection and other drugs
Westmead, New South Wales, Australia and more
Sponsor: Children's Oncology Group

You may be eligible to participate in this trial based on your search. Check eligibility by answering some questions.

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Find a site

Closest Location:

The Children's Hospital at Westmead

Research sites nearby

Select from list below to view details:

The Children's Hospital at Westmead
Westmead, New South Wales, Australia
Queensland Children's Hospital
South Brisbane, Queensland, Australia
Royal Children's Hospital
Parkville, Victoria, Australia
Perth Children's Hospital
Perth, Western Australia, Australia

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Participant Group/Arm	Intervention/Treatment
EXPERIMENTAL: Plan A (chemotherapy, WVSCI, second-look surgery if needed) See Outline in Detailed Description.	PROCEDURE: Biospecimen Collection Undergo collection of CSF and blood samples
EXPERIMENTAL: Plan B (chemotherapy, HDCSCR, second-look surgery if needed) See Outline in Detailed Description.	PROCEDURE: Biospecimen Collection Undergo collection of CSF and blood samples

What is the study measuring?

Primary outcome

Primary Outcome Measure	Primary Outcome Description	Primary Outcome Time Frame
Failure rate	Will be measured by the number of progressions or deaths within 2 years of enrollment for the cohort treated with whole ventricular + spinal canal irradiation (WVSCI). The final analysis will include an exact binomial confidence interval of the failure rate for each of the failure types (local, distant/spinal or both) without adjustment for multiplicity.	Within 2 years of enrollment
Spinal failure rate	Will be measured by the number of spinal relapses (spine alone or distant relapses including the spine) within 2 years of enrollment in patients treated with WVSCI. The final analysis will include an exact binomial confidence interval of spinal failure rate.	Within 2 years of enrollment

Secondary outcome

Secondary Outcome Measure	Secondary Outcome Description	Secondary Outcome Time Frame
Radiographic complete response (CR)/partial response (PR) with marker normalization rate post induction/second-look surgery	Will be assessed in patients treated with induction chemotherapy. Will be estimated using an exact binomial approach and its confidence interval.	Approximately 6 to 9 months post-treatment initiation
Radiographic complete response (CR)/partial response (PR) with marker normalization rate post high-dose chemotherapy with peripheral stem cell rescue (HDCSCR)	Will be assessed in patients treated with HDCSCR. Will be estimated using an exact binomial approach and its confidence interval.	Up to 2 years post-treatment initiation
Progression-free survival (PFS)	Will be estimated separately for those treated with WVSCI and with HDCSCR + radiation therapy. Kaplan-Maier based PFS curve estimates will be included, where patients who are lost to follow up will be treated as censored observations as part of the primary analyses.	From enrollment until disease progression or death from any cause for patients with events, and until final follow up for those who are event free at the time of analysis, assessed up to 10 years
Overall survival (OS)	Will be estimated separately for those treated with WVSCI and with HDCSCR + radiation therapy. Kaplan-Maier based OS curve estimates will be included, where patients who are lost to follow up will be treated as censored observations as part of the secondary analyses.	From enrollment until death from any cause for patients with events and until final follow up for those who are alive at the time of analysis, assessed up to 10 years
Patterns of disease recurrence/failure	Will be analyzed in an exploratory manner with respect to radiation dose distribution.	Up to 10 years

Frequently Asked Questions

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References

Clinical Trials Gov: A Study of a New Way to Treat Children and Young Adults With a Brain Tumor Called NGGCT