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

Diabetes Insipidus Clinical Trial

Official title:

A Phase II Trial Evaluating Chemotherapy Followed by Response-Based Reduced Radiation Therapy for Patients With Central Nervous System Germinomas

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT06368817
• Other study ID #: ACNS2321
• Secondary ID: NCI-2024-03518AC
• Status: Not yet recruiting
• Phase: Phase 2
• Start date: July 12, 2024
• Est. completion date: November 4, 2033

Study information

• Verified date: May 2024
• Source: Children's Oncology Group
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This phase II trial studies how well lower dose radiotherapy after chemotherapy 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.

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 (hCGβ) ≤ 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.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 240
• Est. completion date: November 4, 2033
• Est. primary completion date: November 4, 2033
• Accepts healthy volunteers: No
• Gender: All
• Age group: 3 Years to 30 Years

Eligibility

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 hCGß 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 bifocal (pineal + suprasellar) involvement or pineal lesion with diabetes insipidus (DI) AND hCGß = 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 hCGß 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 HCGß-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

Related Conditions & MeSH terms

• Diabetes Insipidus
• Germinoma

Intervention

Radiation:
• 3-Dimensional Conformal Radiation Therapy
Undergo 3D-CRT

Procedure:
• Biospecimen Collection
Undergo blood and CSF sample collection

Drug:
• Carboplatin
Given IV
• Etoposide
Given IV

Radiation:
• Intensity-Modulated Radiation Therapy
Undergo IMRT

Procedure:
• Lumbar Puncture
Undergo LP
• Magnetic Resonance Imaging
Undergo MRI

Other:
• Questionnaire Administration
Ancillary studies

Procedure:
• Surgical Procedure
Undergo second-look surgery

Locations

Country	Name	City	State
n/a

Sponsors (1)

Lead Sponsor	Collaborator
Children's Oncology Group

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	EFS (Stratum IV and Stratum V)	Will use KM methods to visualize and summarize EFS and will use similar considerations for Cox models as the analysis of Stratum 1.	From initiation of radiation therapy as a standardized timepoint following determination of respective stratum assignment
Other	EFS (Stratum VI and Stratum VII)	Will use KM methods to visualize and summarize EFS and will use similar considerations for Cox models as the analysis of Stratum 1.	From initiation of radiation therapy as a standardized timepoint following determination of respective stratum assignment
Other	The number of patients consenting to collect blood, cerebrospinal fluid, and tumor tissue along with the number of submitted blood, cerebrospinal fluid, and tumor tissue samples	Will be recorded as a part of routine study monitoring. The analyses to be performed with the collected samples will be detailed in a future amendment or in a separate biology study protocol as appropriate.	Up to 9 years
Other	Incidence of cerebral vascular events (stroke or transient ischemic attacks)		Up to 9 years
Other	Working memory	Will be assessed by the COG Standardized assessment battery. Will be measured in these patients over time, and available data will be summarized by appropriate plots and descriptive statistics.	At 9 months (+/- 3 months), 30 months (+/- 3 months), and 60 months (+/- 3 months) after diagnosis
Other	Verbal learning	Will be assessed by the COG Standardized assessment battery. Will be measured in these patients over time, and available data will be summarized by appropriate plots and descriptive statistics.	At 9 months (+/- 3 months), 30 months (+/- 3 months), and 60 months (+/- 3 months) after diagnosis
Other	Patient-reported outcome measures of executive function	Will be assessed by the COG Standardized assessment battery. Will be measured in these patients over time, and available data will be summarized by appropriate plots and descriptive statistics.	At 9 months (+/- 3 months), 30 months (+/- 3 months), and 60 months (+/- 3 months) after diagnosis
Other	Health-reported quality of life	Will be assessed by the COG Standardized assessment battery. Will be measured in these patients over time, and available data will be summarized by appropriate plots and descriptive statistics.	At 9 months (+/- 3 months), 30 months (+/- 3 months), and 60 months (+/- 3 months) after diagnosis
Primary	Event-free survival (EFS) (Stratum I)	Will be compared to ACNS1123 stratum 2 as measured by EFS in eligible and evaluable patients assigned to Stratum 1. Will use the Kaplan-Meier (KM) method to visualize and summarize EFS, and will report the 2- and 3-year EFS estimates with respective 80% two-sided confidence intervals.	Time from initiation of radiation following confirmation of stratum assignment 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
Secondary	EFS (Stratum II)	Will use KM methods to visualize and summarize EFS and will use similar considerations for Cox models as the analysis of Stratum 1.	From initiation of radiation therapy as a standardized timepoint following determination of respective stratum assignment
Secondary	EFS (Stratum III)	Will use KM methods to visualize and summarize EFS and will use similar considerations for Cox models as the analysis of Stratum 1.	From initiation of radiation therapy as a standardized timepoint following determination of respective stratum assignment
Secondary	Radiographic response rate	Will report the response rates using the respective sample proportions and exact binomial two-sided 95% confidence intervals. Will descriptively report the locations of failures (local only, distant only or combination of local and distant).	Up to 9 years
Secondary	Marker tumor response rate	Will report the response rates using the respective sample proportions and exact binomial two-sided 95% confidence intervals. Will descriptively report the locations of failures (local only, distant only or combination of local and distant).	Up to 9 years
Secondary	Overall survival (OS)	Will use KM methods to visualize and summarize stratum-specific OS. For a given stratum, if an adequate sample size and number of events is observed, then Cox models will be used to study the association with OS of demographic, clinical and treatment-related variables including radiation therapy modality (proton versus photon), patient age, tumor location. Other definitions for OS may also be considered (e.g., using time from enrollment) to fully address this objective.	Time from initiation of radiation therapy following determination of stratum assignment until death by any cause
Secondary	Neuroendocrine dysfunction (including growth hormone deficiency)	Will be summarized by the Kalbfleisch-Prentice cumulative incidence function (CIF) approach, separately by stratum. 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. Will assess the association with tumor location as well as RT modality as feasible within the constraints of sample size and number of neuroendocrine events using Fine-Gray models. Other endocrine dysfunctions (e.g., thyroid hormone deficiency, adrenal hormone deficiency, hypogonadism, and central precocious puberty) will be respectively summarized in a similar manner.	Time from initiation of RT following determination of stratum assignment until date of diagnosis of growth hormone deficiency
Secondary	Processing speed impairments	Will be assessed by the Children's Oncology Group (COG) Standardized assessment battery. Will be measured in these patients over time, and available data will be summarized by appropriate plots and descriptive statistics.	Up to 9 years