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

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

Status

Completed

Phases

Phase 2

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT00084838

Enrollment

Registered

2004-06-11

Start date

2003-02-28

Completion date

2013-03-31

Last updated

2015-12-24

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Central Nervous System Tumor, Pediatric

Keywords

childhood atypical teratoid/rhabdoid tumor

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.

Interventions

BIOLOGICALfilgrastim

DRUGcisplatin

DRUGcyclophosphamide

DRUGcytarabine

DRUGdexrazoxane hydrochloride

DRUGdoxorubicin hydrochloride

DRUGetoposide

DRUGleucovorin calcium

DRUGmethotrexate

DRUGtemozolomide

DRUGtherapeutic hydrocortisone

DRUGvincristine sulfate

RADIATIONradiation therapy

DRUGDactinomycin

Study design

Allocation

Intervention model

SINGLE_GROUP

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

No minimum to 18 Years

Healthy volunteers

Inclusion 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

Design outcomes

Primary

Measure	Time frame	Description
2-yr Overall Survival	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.	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.

Secondary

Measure	Time frame	Description
Pre-Radiation Therapy Chemotherapeutic Response	Assessed at study entry and pre-RT/post-CT at week 7.	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.

Other

Measure	Time frame	Description
Grade 3-4 Auditory/Hearing Events	Assessed during therapy up to 30 days post-therapy completion which is approximately 55 weeks for patients who completed therapy.	All Grade 3-4 Auditory/Hearing events based on CTCAEv2 as reported on case report forms.
Grade 3-4 Blood/Bone Marrow Events	Assessed during therapy up to 30 days post-therapy completion which is approximately 55 weeks for patients who completed therapy.	All Grade 3-4 Blood/Bone Marrow events based on CTCAEv2 as reported on case report forms. Arm Name
Grade 3-4 Gastrointestinal Events	Assessed during therapy up to 30 days post-therapy completion which is approximately 55 weeks for patients who completed therapy.	All Grade 3-4 Gastrointestinal events based on CTCAEv2 as reported on case report forms.
Grade 3-4 Metabolic/Laboratory Events	Assessed during therapy up to 30 days post-therapy completion which is approximately 55 weeks for patients who completed therapy.	All Grade 3-4 Metabolic/Laboratory events based on CTCAEv2 as reported on case report forms.
Grade 3-4 Infection/Febrile Neutropenia Events	Assessed during therapy up to 30 days post-therapy completion which is approximately 55 weeks for patients who completed therapy.	All Grade 3-4 Infection/Febrile Neutropenia events based on CTCAEv2 as reported on case report forms.
Grade 3-4 Neurology Events	Assessed during therapy up to 30 days post-therapy completion which is approximately 55 weeks for patients who completed therapy.	All Grade 3-4 Neurology events based on CTCAEv2 as reported on case report forms.
Grade 3-4 Pain Events	Assessed during therapy up to 30 days post-therapy completion which is approximately 55 weeks for patients who completed therapy.	All Grade 3-4 Pain events based on CTCAEv2 as reported on case report forms.
Grade 3-4 Hemorrhage Events	Assessed during therapy up to 30 days post-therapy completion which is approximately 55 weeks for patients who completed therapy.	All Grade 3-4 Hemorrhage events based on CTCAEv2 as reported on case report forms.
Grade 3-4 Muscloskeletal Events	Assessed during therapy up to 30 days post-therapy completion which is approximately 55 weeks for patients who completed therapy.	All Grade 3-4 Muscloskeletal events based on CTCAEv2 as reported on case report forms.
Grade 3-4 Hepatic Events	Assessed during therapy up to 30 days post-therapy completion which is approximately 55 weeks for patients who completed therapy.	All Grade 3-4 Hepatic events based on CTCAEv2 as reported on case report forms.
Grade 3-4 Cardiovascular Events	Assessed during therapy up to 30 days post-therapy completion which is approximately 55 weeks for patients who completed therapy.	All Grade 3-4 Cardiovascular events based on CTCAEv2 as reported on case report forms.
Grade 3-4 Pulmonary Events	Assessed during therapy up to 30 days post-therapy completion which is approximately 55 weeks for patients who completed therapy.	All Grade 3-4 Pulmonary events based on CTCAEv2 as reported on case report forms.
Grade 3-4 Renal/Genitourinary Events	Assessed during therapy up to 30 days post-therapy completion which is approximately 55 weeks for patients who completed therapy.	All Grade 3-4 Renal/Genitourinary events based on CTCAEv2 as reported on case report forms.
Grade 3-4 Dermatology Events	Assessed during therapy up to 30 days post-therapy completion which is approximately 55 weeks for patients who completed therapy.	All Grade 3-4 Dermatology events based on CTCAEv2 as reported on case report forms.
Grade 3-4 Allergy/Immunology	Assessed during therapy up to 30 days post-therapy completion which is approximately 55 weeks for patients who completed therapy.	All Grade 3-4 Allergy/Immunology events based on CTCAEv2 as reported on case report forms.
Grade 3-4 Constitutional Events	Assessed during therapy up to 30 days post-therapy completion which is approximately 55 weeks for patients who completed therapy.	All Grade 3-4 Constitutional events based on CTCAEv2 as reported on case report forms.
Grade 3/4 Events	Assessed during therapy up to 30 days post-therapy completion which is approximately 55 weeks for patients who completed therapy.	All Grade 3-4 events based on CTCAEv2 as reported on case report forms.

Countries

United States

Participant flow

Recruitment details

Enrollment Sep 2004 to Sep 2006 at 9 institutions.

Participants by arm

Arm	Count
Multi-agent Intrathecal & Systemic CT w/ RT (Modified IRS III) Pre-irradiation induction therapy (wks 1-6); Chemoradiation induction therapy (wks 7-12); Post-radiation induction therapy (wks 13-18); Maintenance therapy (wks 19-44); Continuation therapy (wks 45-51) Induction Chemotherapy: CT backbone of the IRS-III regimen \[vincristine, dactinomycin, cyclophosphamide (specifically, in combination), cisplatin, doxorubicin, and imidazole carboximide (DTIC)\] was modified to incl temozolomide in lieu of DTIC. Pts w/ M0 dz (and initially positive CSF cytology) rcvd intrathecal (IT) CT (alt btwn intralumbar and intraventricular routes) w/ methotrexate, cytarabine,and hydrocortisone, coinciding with a cycle of CT. Radiation Therapy: Pts w/ M0 dz OR M+ dz aged \<3y received focal RT (3D conformal or intensity-modulated delivery). Pts \>3y w/ M+ dz rcvd craniospinal irradiation. Continuation Therapy: Pts treated with either non-doxorubicin or doxorubicin dose therapy if receiving CSI or mediastinal radiotherapy or not, respectively.	20
Total	20

Arm

Count

Multi-agent Intrathecal & Systemic CT w/ RT (Modified IRS III)

Pre-irradiation induction therapy (wks 1-6); Chemoradiation induction therapy (wks 7-12); Post-radiation induction therapy (wks 13-18); Maintenance therapy (wks 19-44); Continuation therapy (wks 45-51) Induction Chemotherapy: CT backbone of the IRS-III regimen \[vincristine, dactinomycin, cyclophosphamide (specifically, in combination), cisplatin, doxorubicin, and imidazole carboximide (DTIC)\] was modified to incl temozolomide in lieu of DTIC. Pts w/ M0 dz (and initially positive CSF cytology) rcvd intrathecal (IT) CT (alt btwn intralumbar and intraventricular routes) w/ methotrexate, cytarabine,and hydrocortisone, coinciding with a cycle of CT. Radiation Therapy: Pts w/ M0 dz OR M+ dz aged \<3y received focal RT (3D conformal or intensity-modulated delivery). Pts \>3y w/ M+ dz rcvd craniospinal irradiation. Continuation Therapy: Pts treated with either non-doxorubicin or doxorubicin dose therapy if receiving CSI or mediastinal radiotherapy or not, respectively.

Total

Withdrawals & dropouts

Period	Reason	FG000
Overall Study	Adverse Event	2
Overall Study	Death	1
Overall Study	Ineligible	4
Overall Study	Progressive Disease	4
Overall Study	Pt Non-Compliance	1
Overall Study	Withdrawal by Subject	1

Baseline characteristics

Characteristic	Multi-agent Intrathecal & Systemic CT w/ RT (Modified IRS III)
Age, Continuous	2.2 years
Chang Stage M0	14 participants
Chang Stage M2	1 participants
Chang Stage M3	5 participants
Region of Enrollment United States	20 participants
Sex: Female, Male Female	11 Participants
Sex: Female, Male Male	9 Participants

Adverse events

Event type	EG000 affected / at risk
deaths Total, all-cause mortality	— / —
other Total, other adverse events	0 / 0
serious Total, serious adverse events	4 / 20

Outcome results

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.

Time frame: 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.

Population: The analysis dataset is comprised of all eligible and treated patients.

Arm	Measure	Value (NUMBER)
Multi-agent Intrathecal and Systemic CT With RT (Modified IRS	2-yr Overall Survival	0.70 probability

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.

Time frame: Assessed at study entry and pre-RT/post-CT at week 7.

Population: The pre-RT CT response evaluable population is defined as patients who completed chemotherapy per protocol.

Arm	Measure	Value (NUMBER)
Multi-agent Intrathecal and Systemic CT With RT (Modified IRS	Pre-Radiation Therapy Chemotherapeutic Response	0.58 proportion of evaluable patients

Other Pre-specified

Grade 3-4 Allergy/Immunology

All Grade 3-4 Allergy/Immunology events based on CTCAEv2 as reported on case report forms.

Time frame: Assessed during therapy up to 30 days post-therapy completion which is approximately 55 weeks for patients who completed therapy.