HeadStart4: Newly Diagnosed Children (<10 y/o) With Medulloblastoma and Other CNS Embryonal Tumors

Sponsor

Nationwide Children's Hospital (Other)

Overall Status

Recruiting

CT.gov ID

NCT02875314

Collaborator

Children's of Alabama (Other)

250

Enrollment

Locations

Arms

120

Anticipated Duration (Months)

Patients Per Site

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This is a prospective randomized clinical trial, to determine whether dose-intensive tandem Consolidation, in a randomized comparison with single cycle Consolidation, provides an event-free survival (EFS) and overall survival (OS). The study population will be high-risk patients (non-Wnt and non-Shh sub-groups) with medulloblastoma, and for all patients with central nervous system (CNS) embryonal tumors completing "Head Start 4" Induction. This study will further determine whether the additional labor intensity (duration of hospitalizations and short-term and long-term morbidities) associated with the tandem treatment is justified by the improvement in outcome. It is expected that the tandem (3 cycles) Consolidation regimen will produce a superior outcome compared to the single cycle Consolidation, given the substantially higher dose intensity of the tandem regimen, without significant addition of either short-term or long-term morbidities.

Condition or Disease	Intervention/Treatment	Phase
Medulloblastoma Central Nervous System Embryonal Tumors	Drug: Induction Drug: Single Cycle Intensive Chemotherapy Drug: Tandem 3 Cycle Intensive Chemotherapy	Phase 4

Detailed Description

Due to the inferior response and event-free survival data of Regimens D and D2 on "Head Start III" for all children with supratentorial embryonal tumors, in comparison with the published data from "Head Start II" with Regimen A2 for metastatic patients, all such patients will receive the "Head Start II" Induction Regimen A2, on "Head Start 4", for either three or five cycles, depending upon whether or not they achieve complete remission by the end of Induction cycle #3. They will then undergo randomization to either single cycle or three tandem cycles of Consolidation marrow-ablative chemotherapy with AuHPCR.

Because of the unsatisfactory event-free survival for young children with non-desmoplastic/extensive nodular medulloblastoma (predominantly non-Shh and non-Wnt medulloblastoma subgroups) on Regimens D and D2 of "Head Start III", all these patients will receive the "Head Start II" Induction Regimen A2 on Head Start 4, for either three or five cycles, depending upon whether or not they achieve complete remission by the end of Induction cycle #3. They will then undergo randomization to either single cycle or three tandem cycles of Consolidation marrow-ablative chemotherapy with AuHPCR.

Because of the excellent event-free and overall survival for young children with good risk medullo-blastoma (Shh or Wnt subgroups) treated with up-front "Head Start" chemotherapy strategies, such patients will undergo risk-tailored reduction of duration of Induction therapy from five cycles to three cycles of the "Head Start II" Induction Regimen A2 on "Head Start 4" for patients achieving a complete response to 3 cycles, followed, provided they are also without evidence of residual tumor following recovery from Induction cycle #3. They will NOT then undergo randomization, but will follow with a single cycle of Consolidation marrow-ablative chemotherapy as in "Head Start" studies.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

250 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

HeadStart4: Newly Diagnosed Children (<10 y/o) With Medulloblastoma and Other CNS Embryonal Tumors Clinical and Molecular Risk-Tailored Intensive and Compressed Induction Chemotherapy Followed by Consolidation With Randomization to Either Single Cycle or to Three Tandem Cycles of Marrow-Ablative Chemotherapy With Autologous Hematopoietic Progenitor Cell Rescue

Actual Study Start Date :

Sep 1, 2015

Anticipated Primary Completion Date :

Sep 1, 2025

Anticipated Study Completion Date :

Sep 1, 2025

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Induction The 5 chemotherapy drugs used in the Induction part of treatment are vincristine, cisplatin, cyclophosphamide, etoposide and high-dose methotrexate. Three medications are also given to help reduce the side effects of the chemotherapy drugs. Filgrastim will be given through a vein or through a tiny needle into the tissue just under the skin to help blood counts recover after the chemotherapy. Mesna will be given through a vein with cyclophosphamide to help prevent bleeding in the bladder. Leucovorin will be given through a vein after the methotrexate to protect the body from the side effects of the methotrexate.	Drug: Induction vincristine, cisplatin, cyclophosphamide, etoposide, high-dose methotrexate Other Names: vincristine, cisplatin, cyclophosphamide, etoposide, high-dose methotrexate
Experimental: Single Cycle Intensive Chemotherapy The three drugs to be used in this research study are thiotepa, etoposide and carboplatin. These drugs will be given over 6 days to help kill the cancer cells. After 72 hours from getting these drugs, previously collected and frozen blood cells will be thawed and returned through the venous catheter. Carboplatin is given by vein over 4 hours. Thiotepa is given by vein over 3 hours. Etoposide is given by vein over 3 hours. The schedule for these drugs is as follows: Day -8: Carboplatin Day -7: Carboplatin Day -6: Carboplatin Day -5: Thiotepa, Etoposide Day -4: Thiotepa, Etoposide Day -3: Thiotepa, Etoposide Day -2: Rest Day -1: Rest Day 0: Re-infusion of blood cells	Drug: Single Cycle Intensive Chemotherapy Carboplatin, thiotepa, etoposide Other Names: Carboplatin, thiotepa, etoposide
Experimental: Tandem 3 Cycle Intensive Chemotherapy The 2 drugs to be used in this treatment are thiotepa and carboplatin. These drugs will be given over 2 days to help kill the cancer cells. After 72 hours from getting these drugs, previously collected and frozen blood cells will be thawed and returned through the venous catheter. Day -4: Thiotepa, Carboplatin Day -3: Thiotepa, Carboplatin Day -2: Rest Day -1: Rest Day 0: Re-infusion of blood cells. Following recovery from the first cycle of this chemotherapy, about 28 days following the Day 0 reinfusion of blood cells, the same cycle will be repeated again. A total of 3 cycles of this therapy will be administered, over the course of 12 weeks.	Drug: Tandem 3 Cycle Intensive Chemotherapy Carboplatin, thiotepa Other Names: Carboplatin, thiotepa

Arm

Intervention/Treatment

Experimental: Induction

The 5 chemotherapy drugs used in the Induction part of treatment are vincristine, cisplatin, cyclophosphamide, etoposide and high-dose methotrexate. Three medications are also given to help reduce the side effects of the chemotherapy drugs. Filgrastim will be given through a vein or through a tiny needle into the tissue just under the skin to help blood counts recover after the chemotherapy. Mesna will be given through a vein with cyclophosphamide to help prevent bleeding in the bladder. Leucovorin will be given through a vein after the methotrexate to protect the body from the side effects of the methotrexate.

Drug: Induction

vincristine, cisplatin, cyclophosphamide, etoposide, high-dose methotrexate

Other Names:

vincristine, cisplatin, cyclophosphamide, etoposide, high-dose methotrexate

Experimental: Single Cycle Intensive Chemotherapy

The three drugs to be used in this research study are thiotepa, etoposide and carboplatin. These drugs will be given over 6 days to help kill the cancer cells. After 72 hours from getting these drugs, previously collected and frozen blood cells will be thawed and returned through the venous catheter. Carboplatin is given by vein over 4 hours. Thiotepa is given by vein over 3 hours. Etoposide is given by vein over 3 hours. The schedule for these drugs is as follows: Day -8: Carboplatin Day -7: Carboplatin Day -6: Carboplatin Day -5: Thiotepa, Etoposide Day -4: Thiotepa, Etoposide Day -3: Thiotepa, Etoposide Day -2: Rest Day -1: Rest Day 0: Re-infusion of blood cells

Drug: Single Cycle Intensive Chemotherapy

Carboplatin, thiotepa, etoposide

Other Names:

Carboplatin, thiotepa, etoposide

Experimental: Tandem 3 Cycle Intensive Chemotherapy

The 2 drugs to be used in this treatment are thiotepa and carboplatin. These drugs will be given over 2 days to help kill the cancer cells. After 72 hours from getting these drugs, previously collected and frozen blood cells will be thawed and returned through the venous catheter. Day -4: Thiotepa, Carboplatin Day -3: Thiotepa, Carboplatin Day -2: Rest Day -1: Rest Day 0: Re-infusion of blood cells. Following recovery from the first cycle of this chemotherapy, about 28 days following the Day 0 reinfusion of blood cells, the same cycle will be repeated again. A total of 3 cycles of this therapy will be administered, over the course of 12 weeks.

Drug: Tandem 3 Cycle Intensive Chemotherapy

Carboplatin, thiotepa

Other Names:

Carboplatin, thiotepa

Outcome Measures

Primary Outcome Measures

Compare tandem consolidation vs. single cycle consolidation A [5 years]
Dose-intensive tandem Consolidation will be compared with single cycle consolidation via randomization. The randomized consolidations will provide an event-free survival (EFS) analysis after completing "Head Start 4" Induction.
Compare tandem consolidation vs. single cycle consolidation B [5 years]
Dose-intensive tandem Consolidation will be compared with single cycle consolidation via randomization. The randomized consolidations will provide an overall survival (OS) analysis after completing "Head Start 4" Induction.

Secondary Outcome Measures

Induction Cycle Reduction [5 years]
Induction chemotherapy cycles will be reduced in number from five to three for molecularly high-risk medulloblastoma (non-Shh/non-Wnt) and CNS embryonal tumors who achieve a complete response (CR) after three cycles of Induction therapy results in equivalent 3-year EFS. Outcome will be analyzed irrespective of Consolidation assignment (Primary Aim) and compared to historical controls.
Uniform Treatment Regimen [5 years]
Assess the rate of response of sequential dose-intensive and dose-compressed Induction chemotherapy followed by marrow-ablative chemotherapy and autologous hematopoietic progenitor cell rescue (AuHPCR) for children with medulloblastoma and other CNS embryonal tumors enrolled on the "Head Start 4" study utilizing a uniform treatment regimen.
Therapy-Related Hearing Loss Evaluation A [5 years]
The prevalence and severity of therapy-related hearing loss as a function of cumulative dosing of cisplatin (three versus five cycles during Induction) will be evaluated. Distortion-Product Oto-acoustic Emissions (DPOAE) will be used as an early predictor of hearing loss to identify at-risk patients.
Therapy-Related Hearing Loss Evaluation B [5 years]
The prevalence and severity of therapy-related hearing loss as a function of AuHPCR (one versus three tandem transplants in Consolidation) will be evaluated. Distortion-Product Oto-acoustic Emissions (DPOAE) will be used as an early predictor of hearing loss to identify at-risk patients.
Neuropsychological effects will be evaluated using age based tests and questionnaires. [5 years]
The long-term neuropsychological effects will be evaluated.
Endocrine studies will be conducted using Serum-free T4, TSH, Cortisol, IGF and IGFBP3 laboratory tests. [5 years]
The long-term endocrine functions effect will be evaluated.
Physical growth will be evaluated by collecting patient's height, weight and BSA. [5 years]
The long-term physical growth effect will be evaluated.
The development of second neoplasms will be monitored. [5 years]
The long-term development of second neoplasms will be evaluated.
Neuropathology Biorepository and Clinical Database [5 years]
The study will establish a "Head Start 4" repository of clinical, radiographic and biologic specimens, including nucleic acids derived from these specimens, for future genomic, biologic and pharmacologic research.

Eligibility Criteria

Criteria

Ages Eligible for Study:

N/A to 10 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Patients 10 years of age at the time of definitive confirmatory eligible histologic or cytologic diagnosis of eligible CNS tumor (brain or spinal cord)
Patients may not have received irradiation or chemotherapy (except corticosteroids)
Have histologically proven diagnosis of medulloblastoma or CNS embryonal tumors of the brain or spinal cord
Medulloblastoma
Posterior fossa classic, desmoplastic or extensive nodular or anaplastic/large cell medulloblastoma with appropriate and sufficient tumor material (FFPE or snap frozen) for proposed assays: all stages, age less than 6 years at diagnosis
Posterior fossa classic or anaplastic/large cell medulloblastoma with sufficient tumor material (FFPE or snap frozen) for proposed assays: clinically high-stage (neuraxis or extra-neural dissemination, M1-4), age greater than 6 years to less than 10 years at diagnosis
Posterior fossa medulloblastoma, those 6 years of age and above at diagnosis, will only be eligible if they have evidence of neuraxis or extraneural dissemination. Patients 6 years of age and above with low-stage (standard-risk, M0) medulloblastoma will NOT be eligible for this study, irrespective of molecular subgroup and extend of local resection
CNS Embryonal Tumors:
Pineoblastoma, CNS neuroblastoma, CNS ganglioneuroblastoma, embryonal tumor with multi-layered rosettes (ETMR, including embryonal tumor with abundant neuropil and true rosettes (ETANTR), ependymoblastoma and ETMR not otherwise specified), medulloepithelioma, CNS embryonal tumor with rhabdoid features (INI1 intact) and CNS embryonal tumor, not otherwise specified.
Must commence Induction chemotherapy within 28 days of the most recent definitive surgical procedure and within 21 days of the most recent neuro-imaging studies (MRI of brain, performed with and without gadolinium contrast, and MRI of total spine, performed with gadolinium contrast) and lumbar CSF cytological examination
Patients must have adequate organ functions at the time of registration:
Liver: bilirubin less than 1.5 mg/dL (except for patients with Gilbert's Syndrome of indirect hyperbilirubinemia) and transaminases [SGPT or ALT, and SGOT or AST] less than 2.5 (two and a half) times the upper limits of institutional normal.
Renal: Creatinine clearance and/or glomerular filtration rate (GFR) greater than or equal to 60 mL/min/1.73m² within 21 days of protocol therapy.
Bone Marrow Function:

Peripheral absolute phagocyte count (APC) > 1000/ µL. APC = numbers of banded neutrophils + segmented neutrophils + metamyelocytes + monocytes + eosinophils Please note, if institution reports differential as a percentage, then APC = [percentage of banded neutrophils + segmented neutrophils+ metamyelocytes+monocytes+eosinophils] x total white cell count.
Platelet Count > 100,000/µL (transfusion independent)
Hemoglobin > 8 gm/dL (may have received RBC transfusions).

Exclusion Criteria:

Patients older than 10 years of age at time of diagnosis
Following diagnoses are not eligible for study enrollment: CNS atypical teratoid/rhabdoid tumor (AT/RT); all ependymomas including anaplastic ependymomas of the brain or spinal cord; all choroid plexus carcinomas; all high-grade glial and glio-neuronal tumors; all primary CNS germ cell tumors; all primary CNS sarcomas; all primary or metastatic CNS lymphomas and solid leukemic lesions (i.e., chloromas, granulocytic sarcomas).
Patients with unbiopsied diffuse intrinsic pontine tumors will NOT be eligible for this study.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Children's of Alabama	Birmingham	Alabama	United States	35233
2	Phoenix Children's Hospital	Phoenix	Arizona	United States	85016
3	Arkansas Children's Hospital	Little Rock	Arkansas	United States	72202
4	Memorial Care Health Services	Fountain Valley	California	United States	92708
5	Loma Linda University Medical Center	Loma Linda	California	United States	92350
6	Children's Hospital Los Angeles	Los Angeles	California	United States	90027
7	Mattel Children's Hospital (UCLA)	Los Angeles	California	United States	90095
8	UCSF Oakland Benioff	Oakland	California	United States	94609
9	Children's Hospital Orange County	Orange	California	United States	91868
10	Children's Hospital Colorado	Aurora	Colorado	United States	80045
11	Nemours Center for Cancer and Blood Disorders	Wilmington	Delaware	United States	19803
12	Children's National Medical Center	Washington	District of Columbia	United States	20010
13	Shands Children's Hospital/ University of FL	Gainesville	Florida	United States	32610
14	Nemours Center for Cancer and Blood Disorders	Jacksonville	Florida	United States	19803
15	Nicklaus Children's Hospital	Miami	Florida	United States	33155
16	Orlando Health	Orlando	Florida	United States	32806
17	John's Hopkins All Children's Hospital	Saint Petersburg	Florida	United States	33701
18	Children's Healthcare of Atlanta	Atlanta	Georgia	United States	30342
19	Riley Children's Hospital/University of Indiana	Indianapolis	Indiana	United States	46202
20	University of Iowa Hospital and Clinics	Iowa City	Iowa	United States	52242
21	University of Louisville School of Medicine	Louisville	Kentucky	United States	40202
22	John's Hopkins University School of Medicine	Baltimore	Maryland	United States	21287
23	Dana Farber Cancer Institute	Boston	Massachusetts	United States	02215
24	University of Michigan	Ann Arbor	Michigan	United States	48109
25	Wayne State University	Detroit	Michigan	United States	48201
26	Helen DeVos Children's Hospital	Grand Rapids	Michigan	United States	49503
27	Children's Hospital of Minnesota	Minneapolis	Minnesota	United States	55404
28	Masonic Children's Hospital/University of Minnesota	Minneapolis	Minnesota	United States	55454
29	Mayo Clinic	Rochester	Minnesota	United States	55905
30	Washington University School of Medicine	Saint Louis	Missouri	United States	63110
31	Children's Specialty Care of Nevada	Las Vegas	Nevada	United States	89135
32	Joseph Sanzari Children's Hospital/ Hackensack University	Hackensack	New Jersey	United States	07601
33	Morristown Medical Center, Atlantic Health System	Morristown	New Jersey	United States	07960
34	Northwell Health	Hempstead	New York	United States	11549
35	NYU Langone Medical Center	New York	New York	United States	10016
36	Columbia Presbyterian Children's Hospital	New York	New York	United States	10032
37	Memorial Sloan Kettering Cancer Center	New York	New York	United States	10065
38	Upstate Golisano Children's Hospital/ SUNY Upstate Medical University	Syracuse	New York	United States	13210
39	New York Medical College	Valhalla	New York	United States	10595
40	Carolina's HealthCare System/Levine Cancer Institute	Charlotte	North Carolina	United States	28204
41	Duke University Medical Center	Durham	North Carolina	United States	27710
42	Akron Children's Hospital	Akron	Ohio	United States	44308
43	Rainbow Babies & Children's Hospital	Cleveland	Ohio	United States	44106
44	Cleveland Clinic	Cleveland	Ohio	United States	44195
45	Nationwide Children's Hospital	Columbus	Ohio	United States	43205
46	Dayton Children's Hospital	Dayton	Ohio	United States	45404
47	Penn State Hershey Children's Hospital	Hershey	Pennsylvania	United States	17033
48	Children's Hospital of Philadelphia	Philadelphia	Pennsylvania	United States	19104
49	Medical University of South Carolina	Charleston	South Carolina	United States	29425
50	Vanderbilt-Ingram Cancer Center	Nashville	Tennessee	United States	37232
51	MD Anderson Cancer Center	Houston	Texas	United States	77030
52	Primary Children's Hospital	Salt Lake City	Utah	United States	84113
53	Virginia Commonwealth University	Richmond	Virginia	United States	23298
54	American Family Children's Hospital/University of Wisconsin	Madison	Wisconsin	United States	53792
55	Medical College of Wisconsin	Milwaukee	Wisconsin	United States	58226
56	B.C. Children's Hospital	Vancouver	British Columbia	Canada	V6H 3V4
57	Alberta Children's Hospital	Calgary		Canada
58	Stollery Children's Hospital	Edmonton		Canada
59	Hamilton Health/McMasters Children's Hospital, Hamilton, Canada	Hamilton		Canada
60	The Hospital of Sick Children	Toronto		Canada
61	Starship Children's Hospital	Auckland		New Zealand
62	Christchurch Children's Hospital	Christchurch		New Zealand