A Study of a New Way to Treat Children and Young Adults With a Brain Tumor Called NGGCT
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| ClinicalTrials.gov Identifier: NCT04684368 |
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Recruitment Status :
Recruiting
First Posted : December 24, 2020
Last Update Posted : September 15, 2023
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Sponsor:
Children's Oncology Group
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Children's Oncology Group
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Brief Summary:
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.
| Condition or disease | Intervention/treatment | Phase |
|---|---|---|
| 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 | Drug: Carboplatin Drug: Etoposide Biological: Filgrastim Drug: Ifosfamide Drug: Mesna Biological: Pegfilgrastim Procedure: Peripheral Blood Stem Cell Transplantation Other: Questionnaire Administration Radiation: Radiation Therapy Procedure: Second-Look Surgery Drug: Thiotepa | Phase 2 |
Show detailed description
| Study Type : | Interventional (Clinical Trial) |
| Estimated Enrollment : | 160 participants |
| Allocation: | Non-Randomized |
| Intervention Model: | Parallel Assignment |
| Masking: | None (Open Label) |
| Primary Purpose: | Treatment |
| Official Title: | A Phase 2 Trial of Chemotherapy Followed by Response-Based Whole Ventricular &Amp; Spinal Canal Irradiation (WVSCI) for Patients With Localized Non-Germinomatous Central Nervous System Germ Cell Tumor |
| Actual Study Start Date : | June 4, 2021 |
| Estimated Primary Completion Date : | December 21, 2029 |
| Estimated Study Completion Date : | December 21, 2029 |
Resource links provided by the National Library of Medicine
| Arm | Intervention/treatment |
|---|---|
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Experimental: Plan A (chemotherapy, WVSCI, second-look surgery if needed)
See Outline in Detailed Description.
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Drug: Carboplatin
Given IV
Other Names:
Drug: Etoposide Given IV
Other Names:
Biological: Filgrastim Given subcutaneously (SC) or IV
Other Names:
Drug: Ifosfamide Given IV
Other Names:
Drug: Mesna Given IV or orally
Other Names:
Biological: Pegfilgrastim Given SC
Other Names:
Other: Questionnaire Administration Ancillary studies Radiation: Radiation Therapy Undergo WVSCI radiation therapy
Other Names:
Procedure: Second-Look Surgery Undergo second-look surgery if needed
Other Names:
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Experimental: Plan B (chemotherapy, HDCSCR, second-look surgery if needed)
See Outline in Detailed Description.
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Drug: Carboplatin
Given IV
Other Names:
Drug: Etoposide Given IV
Other Names:
Biological: Filgrastim Given subcutaneously (SC) or IV
Other Names:
Drug: Ifosfamide Given IV
Other Names:
Drug: Mesna Given IV or orally
Other Names:
Biological: Pegfilgrastim Given SC
Other Names:
Procedure: Peripheral Blood Stem Cell Transplantation Undergo PBSC transplant
Other Names:
Other: Questionnaire Administration Ancillary studies Radiation: Radiation Therapy Undergo radiation therapy
Other Names:
Procedure: Second-Look Surgery Undergo second-look surgery if needed
Other Names:
Drug: Thiotepa Given IV
Other Names:
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Primary Outcome Measures :
- Failure rate [ Time Frame: Within 2 years of enrollment ]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.
- Spinal failure rate [ Time Frame: Within 2 years of enrollment ]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.
Secondary Outcome Measures :
- Radiographic complete response (CR)/partial response (PR) with marker normalization rate post induction/second-look surgery [ Time Frame: Up to 60 months post-treatment initiation ]Will be assessed in patients treated with induction chemotherapy. Will be estimated using an exact binomial approach and its confidence interval.
- Radiographic complete response (CR)/partial response (PR) with marker normalization rate post high-dose chemotherapy with peripheral stem cell rescue (HDCSCR) [ Time Frame: Up to 60 months post-treatment initiation ]Will be assessed in patients treated with HDCSCR. Will be estimated using an exact binomial approach and its confidence interval.
- Progression-free survival (PFS) [ Time Frame: 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 ]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.
- Overall survival (OS) [ Time Frame: 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 ]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.
- Patterns of disease recurrence/failure [ Time Frame: Up to 10 years ]Will be analyzed in an exploratory manner with respect to radiation dose distribution.
Other Outcome Measures:
- Change in intelligence scores within each treatment arm [ Time Frame: Baseline up to 60 months post-treatment initiation ]Will be assessed by the Wechsler Preschool and Primary Scale of Intelligence 4th Edition (WPPSI-IV), Wechsler Intelligence Scale for Children 5th Edition (WISC-V), and the Wechsler Adult Intelligence Scale 4th Edition (WAIS-IV), depending on patient's age. One-sample confidence intervals will be used to estimate mean pairwise changes in intelligence scores between 2 time points within each treatment arm.
- Change in intelligence scores between treatment arms [ Time Frame: Baseline up to 60 months post-treatment initiation ]Will be assessed by the Wechsler Preschool and Primary Scale of Intelligence 4th Edition (WPPSI- IV), Wechsler Intelligence Scale for Children 5th Edition (WISC V), and the Wechsler Adult Intelligence Scale 4th Edition (WAIS-IV), depending on patient's age. A 2-sample confidence interval approach will be used to estimate the difference in score changes between the two cohorts (WVSCI versus HDCSCR) in order to describe differential effects of the 2 treatment strategies.
- Change in processing speed/attention within each treatment arm [ Time Frame: Baseline up to 60 months post-treatment initiation ]Will be assessed by the WISC-V or WAIS-IV processing speed index tasks. One-sample confidence intervals will be used to estimate mean pairwise changes in scores between 2 time points within each treatment arm.
- Change in processing speed/attention between the two treatment arms [ Time Frame: Baseline up to 60 months post-treatment initiation ]Will be assessed by the WISC-V or WAIS-IV processing speed index tasks. A 2-sample confidence interval approach will be used to estimate the difference in score changes between the two cohorts (WVSCI versus HDCSCR) in order to describe differential effects of the 2 treatment strategies.
- Change in immediate visual memory within each arm [ Time Frame: Baseline up to 60 months post-treatment initiation ]Will be assessed by the Children's Memory Scale and California Verbal Learning Test. One-sample confidence intervals will be used to estimate mean pairwise changes in scores between 2 time points within treatment arms, as appropriate.
- Change in social-emotional functioning within each arm [ Time Frame: Baseline up to 60 months post-treatment initiation ]Will be assessed by the Behavior Assessment System for Children - 3rd Edition. One-sample confidence intervals will be used to estimate mean pairwise changes in scores between 2 time points within treatment arms, as appropriate.
- Change in adaptive functioning within each arm [ Time Frame: Baseline up to 60 months post-treatment initiation ]Will be assessed by the Adaptive Behavior Assessment System - 3rd Edition. One-sample confidence intervals will be used to estimate mean pairwise changes in scores between 2 time points within treatment arms, as appropriate.
- Change in health-related quality of life within each arm [ Time Frame: Baseline up to 60 months post-treatment initiation ]Will be assessed by the Pediatric Quality of Life Inventory version 4.0. One-sample confidence intervals will be used to estimate mean pairwise changes in scores between 2 time points within treatment arms, as appropriate.
- Change in health-related quality of life between the two treatment arms [ Time Frame: Baseline up to 60 months post-treatment initiation ]Will be assessed by the Pediatric Quality of Life Inventory version 4.0. 2-sample confidence interval approach will be used to estimate the difference in score changes between the two cohorts (WVSCI versus HDCSCR) in order to describe differential effects of the 2 treatment strategies.
- Radiation modality (proton versus photon) [ Time Frame: Up to 10 years ]Will summarize and compare functional outcomes, including cognitive, social and behavioral functioning, and auditory and neuro-endocrine function, in the context of the radiation therapy modality used. Two sample t-tests for specified timepoints within each of the two treatment cohorts (WVSCI versus HDCSCR) will be used for comparisons.
- Growth comparisons following radiation by radiation modality [ Time Frame: Up to 10 years ]Will compare early and late outcomes for proton and photon therapy with and without vertebral body sparing. Height and weight of subjects who are < 13 years at the time of radiation therapy will be collected until subjects go off study or reach the age of 21, whichever is earlier. Percentile values standardizing height and weight based on appropriate growth curves will be used to compare cohorts treated with proton- versus photon-based radiation therapy.
- Complete blood count values following radiation by radiation modality [ Time Frame: Up to 1 year post treatment initiation ]Complete blood count values during radiation therapy will be used to compare these outcomes in the context of proton- versus photon-based radiation therapy.
- Local versus central review recommendations for second-look surgery [ Time Frame: Up to 1 year post treatment initiation ]Will summarize the local versus central review recommendations for second-look surgery and document any discrepancies.
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| Ages Eligible for Study: | 3 Years to 30 Years (Child, Adult) |
| Sexes Eligible for Study: | All |
| Accepts Healthy Volunteers: | No |
Criteria
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. Suprasellar, pineal and bifocal tumors are included. (CSF tumor markers and cytology must be within 21 days prior to enrollment and within 35 days prior to 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 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 (within 14 days prior to study enrollment)
- Patients must have a spine MRI with gadolinium obtained at diagnosis/prior to enrollment. Spine MRI with and without gadolinium is recommended (within 14 days prior to study enrollment)
- 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 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)
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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):
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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)
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- Total bilirubin =< 1.5 x upper limit of normal (ULN) for age (within 7 days prior to enrollment)
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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
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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. 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:
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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
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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)
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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
Information from the National Library of Medicine
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04684368
Locations
Show 140 study locations
Sponsors and Collaborators
Children's Oncology Group
National Cancer Institute (NCI)
Investigators
| Principal Investigator: | Shannon M MacDonald | Children's Oncology Group |
| Responsible Party: | Children's Oncology Group |
| ClinicalTrials.gov Identifier: | NCT04684368 |
| Other Study ID Numbers: |
ACNS2021 NCI-2020-13175 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) ) ACNS2021 ( Other Identifier: Children's Oncology Group ) ACNS2021 ( Other Identifier: CTEP ) U10CA180886 ( U.S. NIH Grant/Contract ) |
| First Posted: | December 24, 2020 Key Record Dates |
| Last Update Posted: | September 15, 2023 |
| Last Verified: | September 2023 |
| Studies a U.S. FDA-regulated Drug Product: | Yes |
| Studies a U.S. FDA-regulated Device Product: | No |
Additional relevant MeSH terms:
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Neoplasms Neoplasms, Germ Cell and Embryonal Teratoma Carcinoma, Embryonal Endodermal Sinus Tumor Choriocarcinoma Neoplasms by Histologic Type Mesonephroma Trophoblastic Neoplasms Adenocarcinoma Carcinoma Neoplasms, Glandular and Epithelial Pregnancy Complications, Neoplastic Pregnancy Complications Female Urogenital Diseases and Pregnancy Complications |
Urogenital Diseases Carboplatin Etoposide Etoposide phosphate Ifosfamide Isophosphamide mustard Thiotepa Podophyllotoxin Lenograstim Mesna Antineoplastic Agents Antineoplastic Agents, Phytogenic Topoisomerase II Inhibitors Topoisomerase Inhibitors Enzyme Inhibitors |