Maintenance Chemotherapy or Observation Following Induction Chemotherapy and Radiation Therapy in Treating Younger Patients With Newly Diagnosed Ependymoma

Study Description

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Brief Summary:

This randomized phase III trial is studying maintenance chemotherapy to see how well it works compared to observation following induction chemotherapy and radiation therapy in treating young patients with newly diagnosed ependymoma. Drugs used in chemotherapy, such as vincristine sulfate, carboplatin, cyclophosphamide, etoposide, and cisplatin, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving more than one drug (combination chemotherapy) may kill more tumor cells. Radiation therapy uses high-energy x-rays to kill tumor cells. Specialized radiation therapy that delivers a high dose of radiation directly to the tumor may kill more tumor cells and cause less damage to normal tissue. Giving chemotherapy with radiation therapy may kill more tumor cells and allow doctors to save the part of the body where the cancer started.

Condition or disease	Intervention/treatment	Phase
Childhood Infratentorial Ependymoma; Childhood Supratentorial Ependymoma; Newly Diagnosed Childhood Ependymoma	Drug: liposomal vincristine sulfate; Other: clinical observation; Radiation: 3-dimensional conformal radiation therapy; Drug: carboplatin; Drug: cyclophosphamide; Drug: etoposide; Drug: cisplatin; Other: laboratory biomarker analysis	Phase 3

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Study Design

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Study Type :	Interventional (Clinical Trial)
Estimated Enrollment :	400 participants
Allocation:	Randomized
Intervention Model:	Parallel Assignment
Masking:	None (Open Label)
Primary Purpose:	Treatment
Official Title:	Phase III Randomized Trial of Post-Radiation Chemotherapy in Patients With Newly Diagnosed Ependymoma Ages 1 to 21 Years
Study Start Date :	March 2010
Estimated Primary Completion Date :	March 2020
Estimated Study Completion Date :	March 2020

Arms and Interventions

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Arm	Intervention/treatment
Experimental: Arm I (radiotherapy, chemotherapy); Patients undergo 3-dimensional conformal radiation therapy over 6-7 weeks. Patients then receive liposomal vincristine sulfate IV on days 1, 8, and 15 (courses 1-3 only); etoposide IV over 1-2 hours on days 1-3; carboplatin on day 1, cisplatin IV over 1-8 hours on day 1; cyclophosphamide IV over 30-60 minutes on days 1-2 and filgrastim. Treatment repeats every 21 days for 4 courses in the absence of disease progression or unacceptable toxicity.	Drug: liposomal vincristine sulfate; Given IV; Other Names: liposomal vincristine; Marqibo; vincristine liposomal; vincristine sulfate liposome injection; Radiation: 3-dimensional conformal radiation therapy; Patients undergo conformal radiotherapy; Other Names: 3D conformal radiation therapy; 3D-CRT; Drug: carboplatin; Given IV; Other Names: Carboplat; CBDCA; JM-8; Paraplat; Paraplatin; Drug: cyclophosphamide; Given IV; Other Names: CPM; CTX; Cytoxan; Endoxan; Endoxana; Drug: etoposide; Given IV; Other Names: EPEG; VP-16; VP-16-213; Drug: cisplatin; Given IV; Other Names: CACP; CDDP; CPDD; DDP; Other: laboratory biomarker analysis; Optional correlative studies
Active Comparator: Arm II (radiotherapy); Patients undergo 3-dimensional conformal radiation therapy over 6-7 weeks.	Other: clinical observation; Patients undergo observation; Other Name: observation; Radiation: 3-dimensional conformal radiation therapy; Patients undergo conformal radiotherapy; Other Names: 3D conformal radiation therapy; 3D-CRT; Other: laboratory biomarker analysis; Optional correlative studies

Outcome Measures

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Primary Outcome Measures :

1. Event-free survival (EFS) defined as time to the first occurrence of disease progression, disease recurrence, second malignant neoplasm, or death from any cause [ Time Frame: Up to 5 years ]
   Using Kaplan-Meier curves to estimate the observed EFS for the two randomization arms (post-radiation Maintenance arm and post-radiation Observation only arm). Log rank tests will be used to compare the observed EFS between the two randomization arms. Stratified log rank test will also be performed to examine the treatment difference with consideration and adjustment for the randomization groups.
2. Overall survival (OS) [ Time Frame: From the time of randomization to death, assessed up to 5 years ]
   Using Kaplan-Meier curves to estimate the observed OS for the two randomization arms (post-radiation Maintenance arm and post-radiation Observation only arm). Log rank tests will be used to compare the observed OS between the two randomization arms. Stratified log rank test will also be performed to examine the treatment difference with consideration and adjustment for the randomization groups.

Secondary Outcome Measures :

1. EFS and OS of children with incompletely resected ependymoma who are unable to achieve a complete response (CR) by post-operative induction chemotherapy or by second surgery [ Time Frame: Up to 5 years ]
   Kaplan-Meier curves will be used to estimate the EFS and OS for patients who were non-randomly assigned to receive maintenance chemotherapy after incomplete resection
2. EFS and OS of children with supratentorial classic ependymoma who achieve a complete resection at first or second surgery or children who achieve a CR after induction chemotherapy assigned to observation [ Time Frame: Up to 5 years ]
   Estimated using Kaplan-Meier curves for patients with supratentorial classic disease that achieve complete resection or CR to induction chemotherapy and are assigned to observation only.
3. Neurologic, neuropsychological, and endocrine long-term sequelae of surgery, conformal radiotherapy, and maintenance chemotherapy [ Time Frame: At 9, 30, and 60 months post diagnosis ]
4. Gene expression signatures and genomic alterations in pediatric ependymoma [ Time Frame: At the time of first or second surgery ]

Eligibility Criteria

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Ages Eligible for Study:	1 Year to 21 Years (Child, Adult)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

• Histologically confirmed intracranial ependymoma meeting the following criteria:

  • Newly diagnosed disease

  • Classic ependymoma (WHO II) or anaplastic ependymoma (WHO III), including the following subtypes:

    • Clear cell
    • Papillary
    • Cellular
    • Combination of the above
• No diagnosis of spinal cord ependymoma, myxopapillary ependymoma, subependymoma, ependymoblastoma, or mixed glioma

• Has undergone surgical resection of the primary tumor

  • More than 1 attempted resection allowed

• No metastatic disease by MRI or cerebrospinal fluid (CSF) cytology

  • CSR cytology from a ventriculostomy or permanent VP shunt that reveals the presence of tumor cells is indicative of metastatic disease

• No evidence of non-contiguous spread beyond the primary site as determined by pre- or post-operative MRI of brain, pre- or post-operative MRI of the spine, and post-operative CSF cytology obtained from the lumbar CSF space

  • Lumbar CSF examination may be waived if deemed to be medically contraindicated

• ECOG performance status (PS) 0-2

  • Karnofsky PS for patients > 16 years of age
  • Lansky PS for patients ≤ 16 years of age
• ANC ≥ 1,000/μL
• Platelet count ≥ 100,000/μL (transfusion independent)

• Creatinine clearance or radioisotope GFR ≥ 70 mL/min OR serum creatinine based on age/gender as follows:

  • 0.4 mg/dL (1 month to < 6 months of age)
  • 0.5 mg/dL (6 months to < 1 year of age)
  • 0.6 mg/dL (1 to 2 years of age)
  • 0.8 mg/dL (2 to < 6 years of age)
  • 1.0 mg/dL (6 to 10 years of age)
  • 1.2 mg/dL (10 to 13 years of age)
  • 1.5 mg/dL (male) or 1.4 mg/dL (female) (13 to < 16 years of age)
  • 1.7 mg/dL (male) or 1.4 mg/dL (female) (≥ 16 years of age)
• Total bilirubin ≤ 1.5 times upper limit of normal (ULN) (≤ 3 times ULN for patients with Gilbert syndrome or hemolytic anemia)
• AST or ALT < 3 times ULN

• Adequate cardiac function defined as 1 of the following:

  • Shortening fraction ≥ 27% by ECHO
  • Ejection fraction ≥ 50% by gated radionuclide study.

• Not pregnant or nursing

  • Patients who agree to stop nursing while on this study are allowed
• Negative pregnancy test
• Fertile patients must use effective contraception
• No prior treatment for ependymoma other than surgical intervention and corticosteroids

Contacts and Locations

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Contacts

Contact: Amy A. Smith, MD	321-841-8560	amy.smith@orlandohealth.com

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Sponsors and Collaborators

Children's Oncology Group

National Cancer Institute (NCI)

Investigators

Principal Investigator:	Amy A. Smith, MD	Children's Oncology Group

More Information

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Responsible Party:	Children's Oncology Group
ClinicalTrials.gov Identifier:	NCT01096368 History of Changes
Other Study ID Numbers:	ACNS0831; NCI-2011-02029 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) ); COG-ACNS0831 ( Other Identifier: Children's Oncology Group ); CDR0000668560 ( Other Identifier: Clinical Trials.gov ); U10CA098543 ( U.S. NIH Grant/Contract )
First Posted:	March 31, 2010
Last Update Posted:	September 12, 2017
Last Verified:	September 2017

Additional relevant MeSH terms:

Ependymoma; Glioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue; Etoposide phosphate; Cisplatin; Cyclophosphamide; Carboplatin; Etoposide; Vincristine	Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Physiological Effects of Drugs; Antirheumatic Agents; Antineoplastic Agents, Alkylating; Alkylating Agents; Molecular Mechanisms of Pharmacological Action; Myeloablative Agonists; Antineoplastic Agents, Phytogenic; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Enzyme Inhibitors; Tubulin Modulators; Antimitotic Agents