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A Single-Arm, Open Label Limited-Institutional Phase II Study of Multi-Agent Intrathecal and Systemic Chemotherapy With Radiation Therapy for Children < or = 18 Years With Newly Diagnosed Central Nervous System Atypical Teratoid/Rhabdoid Tumor


Phase 2
N/A
18 Years
Open (Enrolling)
Both
Brain and Central Nervous System Tumors

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Trial Information

A Single-Arm, Open Label Limited-Institutional Phase II Study of Multi-Agent Intrathecal and Systemic Chemotherapy With Radiation Therapy for Children < or = 18 Years With Newly Diagnosed Central Nervous System Atypical Teratoid/Rhabdoid Tumor


OBJECTIVES:

Primary

- Determine the efficacy of intensive systemic and intrathecal chemotherapy and
radiotherapy, in terms of medial survival, in children with newly diagnosed central
nervous system atypical teratoid/rhabdoid tumors in comparison with historical outcomes
from prior trials.

Secondary

- Determine the toxicity profile and tolerability of this regimen in these patients.

- Determine the chemosensitivity of these patients' tumors by MRI after an attempt at
maximum surgical resection after 2 courses of this regimen.

- Determine the predictive value of the INI 1 gene mutation in determining prognosis by
comparing tumor samples from patients with vs without this mutation treated with this
regimen.

OUTLINE: This is a multicenter study.

- CNS/intrathecal therapy: All patients with M0 disease receive triple intrathecal (IT)
chemotherapy comprising methotrexate (MTX), cytarabine, and hydrocortisone on day 1 of
weeks 1, 2, 4, 7, 13, 19, 27, 33, 39, 45, and 51 followed by oral or IV leucovorin
calcium given 24 hours after each MTX dose. Patients with initially positive
cerebrospinal fluid (CSF) cytology (M+) receive triple IT chemotherapy weekly until 2
consecutive CSF samples are negative for malignant cells.

- Pre-irradiation induction therapy (weeks 1-6): Patients receive vincristine IV on day 1
of weeks 1-6; cisplatin IV over 8 hours on day 1 and doxorubicin IV continuously over
48 hours beginning on day 2 of weeks 1 and 4; cyclophosphamide IV continuously over 72
hours beginning on day 2 of week 1; etoposide IV over 1 hour on days 1-3 of week 4; and
filgrastim (G-CSF) subcutaneously (SC) beginning on day 6 of week 1 and day 4 of week 4
and continuing until blood counts recover.

- Induction chemoradiotherapy (weeks 7-12): Patients receive vincristine IV on day 1 of
weeks 7-12; cisplatin IV over 8 hours on day 1, cyclophosphamide IV over 1 hour on day
2, etoposide IV over 1 hour on days 1-3 of weeks 7 and 10; and G-CSF SC daily beginning
on day 4 of weeks 7 and 10 and continuing until blood counts recover. Patients with M0
disease and patients under 3 years of age with M+ disease undergo radiotherapy to the
primary tumor daily on weeks 7-12. Patients 3 years of age and over with M+ disease
undergo craniospinal irradiation (CSI) daily on weeks 7-12 until negative CSF cytology
is achieved.

- Post-radiation induction therapy (weeks 13-18): Patients receive vincristine IV on day
1 of weeks 13 and 16; doxorubicin and cyclophosphamide as in pre-irradiation induction
therapy beginning on day 1 of week 13; cyclophosphamide IV over 1 hour on days 1-3 of
week 16; dactinomycin IV on days 1-5 of week 16; and G-CSF SC daily beginning on day 6
of weeks 13 and 16 and continuing until blood counts recover.

- Maintenance chemotherapy (weeks 19-42): Patients receive vincristine IV on day 1 of
weeks 27, 33, and 39 and days 1 and 5 of weeks 30, 36, and 42; doxorubicin and
cyclophosphamide as in pre-irradiation induction beginning on day 1 of weeks 27 and 33;
doxorubicin IV over 15 minutes and dexrazoxane (DX) IV over 15 minutes on days 1 and 2
of week 39; cyclophosphamide IV over 1 hour on days 1-3 of weeks 30, 36, 39, and 42;
dactinomycin IV on days 1-5 of weeks 30, 36, and 42 and on day 1 of weeks 19 and 23;
oral temozolomide on days 1-5 of weeks 19 and 23; and G-CSF SC daily beginning on day 6
of weeks 19, 23, 30, 36, and 42, day 5 of weeks 27 and 33, and day 4 of week 39 and
continuing until blood counts recover.

- Doxorubicin continuation therapy (for patients not receiving CSI and mediastinal
radiotherapy)(weeks 45-51): Patients receive vincristine IV on day 1 of weeks 45, 48,
and 51 and day 5 of week 48; doxorubicin IV over 15 minutes and DX IV over 15 minutes
on days 1 and 2 of weeks 45 and 51; cyclophosphamide IV over 1 hour on days 1-3 of
weeks 45, 48, and 51; dactinomycin IV on days 1-5 of week 48; and G-CSF SC daily
beginning on day 4 of weeks 45 and 51 and day 6 of week 48 and continuing until blood
counts recover.

- Non-doxorubicin continuation therapy (for patients receiving CSI or mediastinal
radiotherapy)(weeks 45-51): Patients receive cyclophosphamide and G-CSF as in
doxorubicin continuation therapy; vincristine IV on days 1 and 5 of weeks 45, 48, and
51; and dactinomycin IV on days 1-5 of weeks 45, 48, and 51.

Treatment continues in the absence of disease progression or unacceptable toxicity.

Patients are followed every 3 months for 1 year, every 6 months for 2 years, and then
annually for 2 years.

PROJECTED ACCRUAL: A total of 26 patients will be accrued for this study.

Inclusion Criteria


DISEASE CHARACTERISTICS:

- Histologically confirmed primary intracranial CNS atypical teratoid/rhabdoid tumor OR

- Tumor tissue that possesses the INI 1 gene mutation

- No metastases that disseminate outside the CNS by abdominal and chest CT scans,
kidney imaging, and bone marrow biopsy

- No obstruction of cerebrospinal fluid (CSF) flow by CSF flow study

- Definitive surgical resection of tumor within the past 35 days

PATIENT CHARACTERISTICS:

Age

- 18 and under

Performance status

- Karnofsky 50-100% OR

- Lansky 50-100%

Life expectancy

- Not specified

Hematopoietic

- Hemoglobin > 10 g/dL

- Absolute neutrophil count > 1,000/mm^3

- Platelet count > 100,000/mm^3

Hepatic

- Bilirubin ≤ 1.5 mg/dL

- SGPT < 10 times normal

Renal

- Creatinine ≤ 1.5 times normal

Other

- Willing to have placement of central venous access line

PRIOR CONCURRENT THERAPY:

Biologic therapy

- Not specified

Chemotherapy

- No prior chemotherapy

Endocrine therapy

- Prior steroids allowed

Radiotherapy

- No prior radiotherapy

Surgery

- See Disease Characteristics

Other

- No other prior or concurrent investigational agents

- Concurrent anticonvulsant agents allowed

Type of Study:

Interventional

Study Design:

Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Efficacy as assessed by improvement in median survival from 50-79% in comparison to historical outcomes from prior trials at 7 months

Safety Issue:

No

Principal Investigator

Mark W. Kieran, MD, PhD

Investigator Role:

Principal Investigator

Investigator Affiliation:

Dana-Farber Cancer Institute

Authority:

United States: Federal Government

Study ID:

CDR0000365641

NCT ID:

NCT00084838

Start Date:

February 2003

Completion Date:

Related Keywords:

  • Brain and Central Nervous System Tumors
  • childhood atypical teratoid/rhabdoid tumor
  • Nervous System Neoplasms
  • Central Nervous System Neoplasms
  • Rhabdoid Tumor

Name

Location

Children's Hospital of PhiladelphiaPhiladelphia, Pennsylvania  19104
Sidney Kimmel Comprehensive Cancer Center at Johns HopkinsBaltimore, Maryland  21231-2410
Cleveland Clinic Taussig Cancer CenterCleveland, Ohio  44195
Children's Memorial Hospital - ChicagoChicago, Illinois  60614
Dana-Farber/Harvard Cancer Center at Dana Farber Cancer InstituteBoston, Massachusetts  02115
Sunrise Hospital and Medical CenterLas Vegas, Nevada  89109-2306
Yale Cancer CenterNew Haven, Connecticut  06520-8028
Simmons Comprehensive Cancer Center at University of Texas Southwestern Medical Center - DallasDallas, Texas  75390
AFLAC Cancer Center and Blood Disorders Service of Children's Healthcare of Atlanta - Scottish Rite CampusAtlanta, Georgia  30342
Children's Hospitals and Clinics of Minnesota - MinneapolisMinneapolis, Minnesota  55404
Stanford Cancer CenterStanford, California  94305-5824
Children's Hospital BostonBoston, Massachusetts  02115