Chemotherapy Combined With Radiation Therapy for Newly Diagnosed CNS AT/RT

Central Nervous System Tumor, Pediatric Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00084838
• Other study ID #: 02-294 DFCI
• Secondary ID: P30CA006516
• Status: Completed
• Phase: Phase 2
• First received: June 10, 2004
• Last updated: December 18, 2015
• Start date: February 2003
• Est. completion date: March 2013

Study information

• Verified date: December 2015
• Source: Dana-Farber Cancer Institute
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Federal Government
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 25
• Est. completion date: March 2013
• Est. primary completion date: February 2008
• Accepts healthy volunteers: No
• Gender: Both
• Age group: N/A to 18 Years

Eligibility

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

Study Design

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Central Nervous System Neoplasms
• Central Nervous System Tumor, Pediatric
• Nervous System Neoplasms

Intervention

Biological:
• filgrastim

Drug:
• cisplatin

• cyclophosphamide

• cytarabine

• dexrazoxane hydrochloride

• doxorubicin hydrochloride

• etoposide

• leucovorin calcium

• methotrexate

• temozolomide

• therapeutic hydrocortisone

• vincristine sulfate

Radiation:
• radiation therapy

Drug:
• Dactinomycin

Locations

Country	Name	City	State
United States	AFLAC Cancer Center and Blood Disorders Service of Children's Healthcare of Atlanta - Scottish Rite Campus	Atlanta	Georgia
United States	Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins	Baltimore	Maryland
United States	Children's Hospital Boston	Boston	Massachusetts
United States	Dana-Farber/Harvard Cancer Center at Dana Farber Cancer Institute	Boston	Massachusetts
United States	Children's Memorial Hospital - Chicago	Chicago	Illinois
United States	Cleveland Clinic Taussig Cancer Center	Cleveland	Ohio
United States	Simmons Comprehensive Cancer Center at University of Texas Southwestern Medical Center - Dallas	Dallas	Texas
United States	Sunrise Hospital and Medical Center	Las Vegas	Nevada
United States	Children's Hospitals and Clinics of Minnesota - Minneapolis	Minneapolis	Minnesota
United States	Yale Cancer Center	New Haven	Connecticut
United States	Children's Hospital of Philadelphia	Philadelphia	Pennsylvania
United States	Stanford Cancer Center	Stanford	California

Sponsors (2)

Lead Sponsor	Collaborator
Dana-Farber Cancer Institute	National Cancer Institute (NCI)

Country where clinical trial is conducted

United States, 

References & Publications (1)

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 fo — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Grade 3/4 Events	All Grade 3-4 events based on CTCAEv2 as reported on case report forms.	Assessed during therapy up to 30 days post-therapy completion which is approximately 55 weeks for patients who completed therapy.	Yes
Other	Grade 3-4 Auditory/Hearing Events	All Grade 3-4 Auditory/Hearing events based on CTCAEv2 as reported on case report forms.	Assessed during therapy up to 30 days post-therapy completion which is approximately 55 weeks for patients who completed therapy.	Yes
Other	Grade 3-4 Blood/Bone Marrow Events	All Grade 3-4 Blood/Bone Marrow events based on CTCAEv2 as reported on case report forms.; Arm Name	Assessed during therapy up to 30 days post-therapy completion which is approximately 55 weeks for patients who completed therapy.	Yes
Other	Grade 3-4 Gastrointestinal Events	All Grade 3-4 Gastrointestinal events based on CTCAEv2 as reported on case report forms.	Assessed during therapy up to 30 days post-therapy completion which is approximately 55 weeks for patients who completed therapy.	Yes
Other	Grade 3-4 Metabolic/Laboratory Events	All Grade 3-4 Metabolic/Laboratory events based on CTCAEv2 as reported on case report forms.	Assessed during therapy up to 30 days post-therapy completion which is approximately 55 weeks for patients who completed therapy.	Yes
Other	Grade 3-4 Infection/Febrile Neutropenia Events	All Grade 3-4 Infection/Febrile Neutropenia events based on CTCAEv2 as reported on case report forms.	Assessed during therapy up to 30 days post-therapy completion which is approximately 55 weeks for patients who completed therapy.	Yes
Other	Grade 3-4 Neurology Events	All Grade 3-4 Neurology events based on CTCAEv2 as reported on case report forms.	Assessed during therapy up to 30 days post-therapy completion which is approximately 55 weeks for patients who completed therapy.	Yes
Other	Grade 3-4 Pain Events	All Grade 3-4 Pain events based on CTCAEv2 as reported on case report forms.	Assessed during therapy up to 30 days post-therapy completion which is approximately 55 weeks for patients who completed therapy.	Yes
Other	Grade 3-4 Constitutional Events	All Grade 3-4 Constitutional events based on CTCAEv2 as reported on case report forms.	Assessed during therapy up to 30 days post-therapy completion which is approximately 55 weeks for patients who completed therapy.	Yes
Other	Grade 3-4 Muscloskeletal Events	All Grade 3-4 Muscloskeletal events based on CTCAEv2 as reported on case report forms.	Assessed during therapy up to 30 days post-therapy completion which is approximately 55 weeks for patients who completed therapy.	Yes
Other	Grade 3-4 Hepatic Events	All Grade 3-4 Hepatic events based on CTCAEv2 as reported on case report forms.	Assessed during therapy up to 30 days post-therapy completion which is approximately 55 weeks for patients who completed therapy.	Yes
Other	Grade 3-4 Cardiovascular Events	All Grade 3-4 Cardiovascular events based on CTCAEv2 as reported on case report forms.	Assessed during therapy up to 30 days post-therapy completion which is approximately 55 weeks for patients who completed therapy.	Yes
Other	Grade 3-4 Pulmonary Events	All Grade 3-4 Pulmonary events based on CTCAEv2 as reported on case report forms.	Assessed during therapy up to 30 days post-therapy completion which is approximately 55 weeks for patients who completed therapy.	Yes
Other	Grade 3-4 Renal/Genitourinary Events	All Grade 3-4 Renal/Genitourinary events based on CTCAEv2 as reported on case report forms.	Assessed during therapy up to 30 days post-therapy completion which is approximately 55 weeks for patients who completed therapy.	Yes
Other	Grade 3-4 Dermatology Events	All Grade 3-4 Dermatology events based on CTCAEv2 as reported on case report forms.	Assessed during therapy up to 30 days post-therapy completion which is approximately 55 weeks for patients who completed therapy.	Yes
Other	Grade 3-4 Hemorrhage Events	All Grade 3-4 Hemorrhage events based on CTCAEv2 as reported on case report forms.	Assessed during therapy up to 30 days post-therapy completion which is approximately 55 weeks for patients who completed therapy.	Yes
Other	Grade 3-4 Allergy/Immunology	All Grade 3-4 Allergy/Immunology events based on CTCAEv2 as reported on case report forms.	Assessed during therapy up to 30 days post-therapy completion which is approximately 55 weeks for patients who completed therapy.	Yes
Primary	2-yr Overall Survival	Overall survival is defined as the time from date of diagnosis to death or date of last follow-up. 2-year overall survival is the probability of patients remaining alive at 2-years from study entry estimated using Kaplan-Meier (KM) methods which censors patients at date of last follow-up. Precision of this conditional probability estimate was measured in terms of standard error. Median OS, the original primary endpoint, was not estimable based on the Kaplan-Meier method because of insufficient follow-up.	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.	No
Secondary	Pre-Radiation Therapy Chemotherapeutic Response	Response pre-RT/post-CT was defined as follows with overall response defined as achieving PR or CR.; Complete Response (CR): Complete resolution of all initially demonstrable tumor on MRI or CT evaluation w/o appearance of any new areas of disease; negative CSF cytology. Partial Response (PR): >/= 50% decrease in the sum of the products of the maximum perpendicular diameters of the tumor (sum LD) relative to baseline w/o appearance of any new areas of disease; CSF cytology unchanged from that at diagnosis or clearing after being initially positive Stable Disease (SD): <50% decrease in the sum LD w/o appearance of any new areas of disease; CSF cytology unchanged from that at diagnosis or clearing after being initially positive Progressive Disease (PD): >/= 25% increase in the sum LD relative to baseline, or the appearance of any new areas of disease or appearance of positive cytology after two consecutive negative samples.	Assessed at study entry and pre-RT/post-CT at week 7.	No