Clinical trial NCT00084838: Chemotherapy Combined With Radiation Therapy for Newly Diagnosed CNS AT/RT
Official title: A Phase II Study of Intrathecal and Systemic Chemotherapy With Radiation Therapy for Children With Central Nervous System Atypical Teratoid/Rhabdoid Tumor (AT/RT) Tumor
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Central Nervous System Tumor, Pediatric
Keywords: childhood atypical teratoid/rhabdoid tumor
Lead sponsor: Dana-Farber Cancer Institute
Sponsor class: OTHER
Collaborators: name: National Cancer Institute (NCI)
First posted: 2004-06-11
Enrollment: 25
Sex: ALL
Maximum age (years): 18
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: RATIONALE: Drugs used in chemotherapy work in different ways to stop tumor cells from dividing so they stop growing or die. Radiation therapy uses high-energy x-rays to damage tumor cells. Giving more than one chemotherapy drug with radiation therapy may kill more tumor cells.

PURPOSE: This phase II trial is studying how well giving intrathecal and systemic combination chemotherapy together with radiation therapy works in treating young patients with newly diagnosed central nervous system (CNS) atypical teratoid/rhabdoid tumors.

Detailed description: 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 Magnetic Resonance Imaging (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.

STATISTICAL DESIGN: This was a single arm design evaluating median overall survival. The chosen historical control estimate of 7 months was based on 2 large multi-institutional studies in a similar setting and the alternative of 20.5 months based on a DFCI pilot study. There was 90% power to detect this improvement assuming 1-sided 0.10 alpha and 17 eligible patients. Sample size (n=20 patients) was inflated for expected 10-15% ineligible rate.

TREATMENT: Induction chemotherapy was required to be initiated within 50 days of the most definitive surgery.

* Central Nervous System (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 intravenous (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 granulocyte-colony stimulating factor (G-CSF) subcutaneous (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 cerebral spinal fluid (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.

Eligibility criteria: DISEASE CHARACTERISTICS:

* Histologically confirmed primary intracranial Central Nervous System (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 computer tomography (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

Primary outcomes:
measure: 2-yr Overall Survival
timeFrame: Patients are followed for survival up to 5 yrs post-therapy completion or death; As of this analysis, median follow-up among survivors was 31 months with the longest follow-up being 40 months.
Secondary outcomes:
measure: Pre-Radiation Therapy Chemotherapeutic Response
timeFrame: Assessed at study entry and pre-RT/post-CT at week 7.
Other outcomes:
measure: Grade 3/4 Events
timeFrame: Assessed during therapy up to 30 days post-therapy completion which is approximately 55 weeks for patients who completed therapy.
measure: Grade 3-4 Auditory/Hearing Events
timeFrame: Assessed during therapy up to 30 days post-therapy completion which is approximately 55 weeks for patients who completed therapy.
measure: Grade 3-4 Blood/Bone Marrow Events
timeFrame: Assessed during therapy up to 30 days post-therapy completion which is approximately 55 weeks for patients who completed therapy.
measure: Grade 3-4 Gastrointestinal Events
timeFrame: Assessed during therapy up to 30 days post-therapy completion which is approximately 55 weeks for patients who completed therapy.
measure: Grade 3-4 Metabolic/Laboratory Events
timeFrame: Assessed during therapy up to 30 days post-therapy completion which is approximately 55 weeks for patients who completed therapy.
measure: Grade 3-4 Infection/Febrile Neutropenia Events
timeFrame: Assessed during therapy up to 30 days post-therapy completion which is approximately 55 weeks for patients who completed therapy.
measure: Grade 3-4 Neurology Events
timeFrame: Assessed during therapy up to 30 days post-therapy completion which is approximately 55 weeks for patients who completed therapy.
measure: Grade 3-4 Pain Events
timeFrame: Assessed during therapy up to 30 days post-therapy completion which is approximately 55 weeks for patients who completed therapy.
measure: Grade 3-4 Constitutional Events
timeFrame: Assessed during therapy up to 30 days post-therapy completion which is approximately 55 weeks for patients who completed therapy.
measure: Grade 3-4 Muscloskeletal Events
timeFrame: Assessed during therapy up to 30 days post-therapy completion which is approximately 55 weeks for patients who completed therapy.
measure: Grade 3-4 Hepatic Events
timeFrame: Assessed during therapy up to 30 days post-therapy completion which is approximately 55 weeks for patients who completed therapy.
measure: Grade 3-4 Cardiovascular Events
timeFrame: Assessed during therapy up to 30 days post-therapy completion which is approximately 55 weeks for patients who completed therapy.
measure: Grade 3-4 Pulmonary Events
timeFrame: Assessed during therapy up to 30 days post-therapy completion which is approximately 55 weeks for patients who completed therapy.
measure: Grade 3-4 Renal/Genitourinary Events
timeFrame: Assessed during therapy up to 30 days post-therapy completion which is approximately 55 weeks for patients who completed therapy.
measure: Grade 3-4 Dermatology Events
timeFrame: Assessed during therapy up to 30 days post-therapy completion which is approximately 55 weeks for patients who completed therapy.
measure: Grade 3-4 Hemorrhage Events
timeFrame: Assessed during therapy up to 30 days post-therapy completion which is approximately 55 weeks for patients who completed therapy.
measure: Grade 3-4 Allergy/Immunology
timeFrame: Assessed during therapy up to 30 days post-therapy completion which is approximately 55 weeks for patients who completed therapy.
Locations:
city: Stanford
country: United States
facility: Stanford Cancer Center
state: California
city: New Haven
country: United States
facility: Yale Cancer Center
state: Connecticut
city: Atlanta
country: United States
facility: AFLAC Cancer Center and Blood Disorders Service of Children's Healthcare of Atlanta - Scottish Rite Campus
state: Georgia
city: Chicago
country: United States
facility: Children's Memorial Hospital - Chicago
state: Illinois
city: Baltimore
country: United States
facility: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
state: Maryland
city: Boston
country: United States
facility: Children's Hospital Boston
state: Massachusetts
city: Boston
country: United States
facility: Dana-Farber/Harvard Cancer Center at Dana Farber Cancer Institute
state: Massachusetts
city: Minneapolis
country: United States
facility: Children's Hospitals and Clinics of Minnesota - Minneapolis
state: Minnesota
city: Las Vegas
country: United States
facility: Sunrise Hospital and Medical Center
state: Nevada
city: Cleveland
country: United States
facility: Cleveland Clinic Taussig Cancer Center
state: Ohio
city: Philadelphia
country: United States
facility: Children's Hospital of Philadelphia
state: Pennsylvania
city: Dallas
country: United States
facility: Simmons Comprehensive Cancer Center at University of Texas Southwestern Medical Center - Dallas
state: Texas
Study officials:
affiliation: Dana-Farber Cancer Institute
name: Mark W. Kieran, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Chi SN, Zimmerman MA, Yao X, Cohen KJ, Burger P, Biegel JA, Rorke-Adams LB, Fisher MJ, Janss A, Mazewski C, Goldman S, Manley PE, Bowers DC, Bendel A, Rubin J, Turner CD, Marcus KJ, Goumnerova L, Ullrich NJ, Kieran MW. Intensive multimodality treatment for children with newly diagnosed CNS atypical teratoid rhabdoid tumor. J Clin Oncol. 2009 Jan 20;27(3):385-9. doi: 10.1200/JCO.2008.18.7724. Epub 2008 Dec 8.