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

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Brief Title

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

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

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.
    

Detailed Description

      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.

      After completion of study treatment, patients are followed for up to 10 years.
    

Study Phase

Phase 2

Study Type

Interventional


Primary Outcome

Failure rate

Secondary Outcome

 Radiographic complete response (CR)/partial response (PR) with marker normalization rate post induction/second-look surgery

Condition

Central Nervous System Nongerminomatous Germ Cell Tumor

Intervention

Carboplatin

Study Arms / Comparison Groups

 Plan A (chemotherapy, WVSCI, second-look surgery if needed)
Description:  See Outline in Detailed Description.

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Drug

Estimated Enrollment

160

Start Date

June 5, 2021

Completion Date

December 21, 2029

Primary Completion Date

December 21, 2029

Eligibility 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)

          -  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. 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
      

Gender

All

Ages

3 Years - 30 Years

Accepts Healthy Volunteers

No

Contacts

Shannon M MacDonald, , 



Administrative Informations


NCT ID

NCT04684368

Organization ID

ACNS2021

Secondary IDs

NCI-2020-13175

Responsible Party

Sponsor

Study Sponsor

Children's Oncology Group


Study Sponsor

Shannon M MacDonald, Principal Investigator, Children's Oncology Group


Verification Date

May 2021