Clinical and Molecular Risk-Directed Craniospinal Irradiation and Combination Chemotherapy in Treating Younger Patients with Newly Diagnosed Medulloblastoma

Status: Active

Description

This partially randomized phase II trial studies clinical and molecular risk-directed craniospinal irradiation and combination chemotherapy in treating younger patients with newly diagnosed medulloblastoma. Radiation therapy uses high energy x-rays to kill tumor cells and shrink tumors. Drugs used in chemotherapy, such as cisplatin, carboplatin, cyclophosphamide, vincristine sulfate, vismodegib, gemcitabine hydrochloride, and pemetrexed disodium, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving clinical and molecular risk-directed radiation therapy and combination chemotherapy may kill more tumor cells.

Eligibility Criteria

Inclusion Criteria

  • Medulloblastoma or medulloblastoma variants including posterior fossa primitive neuroectodermal tumor (PNET) as documented by an institutional pathologist
  • No previous radiotherapy, chemotherapy or other brain tumor directed therapy other than corticosteroid therapy and surgery
  • Patients must begin treatment as outlined in the protocol within 36 days of definitive surgery (day of surgery is day 0; definitive surgery includes second surgeries to resect residual tumor)
  • Adequate performance status: children < 10-Lansky score >= 30; children >= 10-Karnofsky >= 30 (except for posterior fossa syndrome)
  • Females of child-bearing potential cannot be pregnant or breast-feeding; female participants > 10 years of age or post-menarche must have a negative serum or urine pregnancy test prior to enrollment
  • Biological parent(s) of participant (child) enrolling on SJMB12; these parents will be assigned to cohort P; the exclusion criteria below do not apply to this cohort
  • EXERCISE INTERVENTION:
  • Must be at least 5 years old and enrolling on SJMB12
  • Must have no congenital heart disease
  • Must be capable of performing the exercise intervention at the time of baseline assessment as determined by the treating physician
  • Eligible participants will be asked to sign a separate consent form for this optional study at the time they are enrolling on SJMB12; participants will then be randomly assigned to either the standard-of-care control group or the exercise intervention group
  • NEUROCOGNITIVE REMEDIATION INTERVENTION
  • Enrolled on SJMB12 and completed protocol directed radiation therapy
  • At least 5 years old and < 22 years at time of consent to remediation intervention OR age is greater than or equal to 22 years and less than 40 years AND patient has SHH medulloblastoma
  • Patient must have English as their primary language and a training aide who speaks English available to participate in required sessions
  • No significant cognitive impairment operationalized as either an intelligence quotient (IQ) < 70 for children with SJMB12 baseline testing or based on clinician judgment in the case of missing baseline IQ
  • No major sensory or motor impairment that would preclude valid cognitive testing (e.g., unresolved posterior fossa syndrome, blindness, poorly controlled seizures/photosensitive epilepsy, psychosis) or a major psychological condition that would preclude completion of the intervention (e.g., significant oppositionality, autism spectrum disorder, severe anxiety or depressive symptoms)
  • Eligible participants will be asked to sign a separate consent form for this optional study; participants will then be randomly assigned to either the standard-of-care control group or the Cogmed computerized intervention group
  • ELIGIBILITY FOR STRATUM S PATIENTS TO START MAINTENANCE CHEMOTHERAPY
  • Participants must be Stratum S (SHH)
  • Participants must be skeletally mature defined as females with a bone age >= 15 years and males with a bone age >= 17 years
  • Must be able to swallow pills
  • Body surface area (BSA) must be > 0.67 and < 2.5 m^2
  • Male and female participants of reproductive potential must agree to effective contraception during and after study treatment
  • Absolute neutrophil count (ANC) >= 1000/mm^3 (after granulocyte colony-stimulating factor [G-CSF] discontinued)
  • Platelets >= 50,000/mm^3 (without support)
  • Hemoglobin (Hgb) >= 8 g/dL (with or without transfusion support)
  • Serum creatinine =< 1.5 x mg/dL
  • Total bilirubin =< 1.5 x the institutional upper limit of normal (ULN)
  • Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 2.5 x the institutional ULN
  • Serum glutamic oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST]) =< 2.5 x the institutional ULN
  • Alkaline phosphatase =< 1.5 x the institutional ULN
  • Serum albumin >= 2.5 g/dL

Exclusion Criteria

  • Central nervous system (CNS) embryonal tumor other than medulloblastoma or PNET in the posterior fossa, for example, patients with diagnosis of atypical teratoid/rhabdoid tumor (ATRT), supratentorial PNET, pineoblastoma, ependymoblastoma, embryonal tumor with abundant neuropil and true Rosettes (ETANTR) are excluded
  • Research participants with other clinically significant medical disorders that could compromise their ability to tolerate protocol therapy or would interfere with the study procedures or results history
  • ELIGIBILITY FOR STRATUM S PATIENTS TO START MAINTENANCE CHEMOTHERAPY:
  • Participants who are less than 10 years of age at start of maintenance chemotherapy
  • Malabsorption syndrome or other condition that would interfere with enteral absorption
  • History of congestive heart failure
  • History of ventricular arrhythmia requiring medication
  • Uncontrolled hypocalcemia, hypomagnesemia, hyponatremia or hypokalemia defined as less than the lower limit of normal for the institution despite adequate electrolyte supplementation
  • Clinically important history of liver disease, including viral or other hepatitis or cirrhosis

Locations & Contacts

California

Palo Alto
Lucile Packard Children's Hospital Stanford University
Status: Active
Contact: Sonia Partap
Phone: 650-723-0993
Email: spartap@stanford.edu
San Diego
Rady Children's Hospital - San Diego
Status: Active
Contact: John Ross Crawford
Phone: 858-576-1700

Connecticut

New Haven
Yale University
Status: Active
Contact: Nina Singh Kadan-Lottick
Phone: 203-785-5702
Email: nina.kadan-lottick@yale.edu

District of Columbia

Washington
Children's National Medical Center
Status: Active
Contact: Eugene Ickjin Hwang
Phone: 202-476-4481
Email: ehwang@cnmc.org

Florida

Orlando
UF Cancer Center at Orlando Health
Status: Active
Contact: Amy Amundson Smith
Phone: 321-841-8588
Email: amy.smith@orlandohealth.com

Minnesota

Minneapolis
Children's Hospitals and Clinics of Minnesota - Minneapolis
Status: Active
Contact: Anne Elizabeth Bendel
Phone: 651-220-6732
Email: anne.bendel@childrensmn.org

Pennsylvania

Philadelphia
Children's Hospital of Philadelphia
Status: Active
Contact: Jane E. Minturn
Phone: 267-426-5026
Email: minturn@email.cohop.edu

Tennessee

Memphis
St. Jude Children's Research Hospital
Status: Active
Contact: Amar Gajjar
Phone: 901-595-4599
Email: amar.gajjar@stjude.org

Texas

Dallas
UT Southwestern / Simmons Cancer Center-Dallas
Status: Active
Contact: Daniel Charles Bowers
Phone: 214-648-3150
Email: Daniel.Bowers@utsouthwestern.edu
Fort Worth
Cook Children's Medical Center
Status: Active
Contact: Jeffrey Carlton Murray
Phone: 682-885-4007
Email: jeffrey.murray@cookchildrens.org
Houston
Texas Children's Hospital
Status: Active
Contact: Murali Mohan Chintagumpala
Phone: 713-798-1354
Email: mxchinta@texaschildrenshospital.org

Ontario

Toronto
Hospital for Sick Children
Status: Active
Contact: Ute Katharina Bartels
Phone: 416-813-5249
Email: ute.bartels@sickkids.ca

Quebec

Montreal
Centre Hospitalier Universitaire Sainte-Justine
Status: Active
Contact: Sebastien Perreault
Phone: 514-345-4931
Email: s.perreault@umontreal.ca

Australia

Parkville
Royal Children's Hospital
Status: Active
Contact: Michael James Sullivan
Phone: 61 3 9345 5522
Email: michael.sullivan@rch.org.au
Perth
Princess Margaret Hospital for Children
Status: Active
Contact: Nicholas Joseph Gottardo
Phone: 08-9340-8330
Email: admin@childcancerresearch.com.au
South Brisbane
Queensland Children's Hospital
Status: Active
Contact: Timothy Edward George Hassall
Phone: 61-7-3636-9115
Email: tim_hassall@health.qld.gov.au
Westmead
The Children's Hospital at Westmead
Status: Active
Contact: Geoffrey Brian McCowage
Phone: 61-2-9845-1400
Email: geoffm@chw.edu.au

New Zealand

Grafton
Starship Children's Hospital
Status: Active
Contact: Sarah Elizabeth Hunter
Phone: 649-307-4949-X-22416
Email: shunter@adhb.govt.nz

Trial Objectives and Outline

PRIMARY OBJECTIVES:

I. To estimate the progression free survival distribution of wingless + int-1 (WNT)-medulloblastoma patients treated on Stratum W1 with reduced-dose craniospinal irradiation and reduced-dose cyclophosphamide.

II. To estimate progression-free survival distribution of non-WNT non-sonic Hedgehog (SHH) medulloblastoma patients treated on Stratum N1 with reduced dose cyclophosphamide.

III. To estimate the progression free survival distribution of skeletally mature SHH medulloblastoma patients assigned to Stratum S1 and treated with oral maintenance therapy using a targeted SHH pathway inhibitor (vismodegib) after the adjuvant chemotherapy regimen is complete and to compare the outcome to molecularly and clinically matched historical controls from SJMB03 as well as outcome from other published cohorts.

IV. To evaluate the effect of an aerobic training intervention, delivered during the radiation therapy period and at home, prior to the start of chemotherapy, on cardiopulmonary fitness, as measured by change in volume of oxygen (VO2) peak at 12 weeks post randomization.

V. To assess the impact of a computer-based working memory intervention (administered prophylactically at the end of chemotherapy), relative to standard of care, on a performance-based measure of working memory.

SECONDARY OBJECTIVES:

I. To estimate overall survival distribution of WNT-medulloblastoma patients treated on Stratum W1 with reduced-dose craniospinal irradiation and reduced-dose cyclophosphamide and compare progression free and overall survival distributions to molecularly and clinically matched historical controls from SJMB03.

II. To estimate the progression free (in S1 skeletally immature and S2 both sub-strata) and overall survival distributions of SHH medulloblastoma patients enrolled on Strata S1 and S2 some of whom will be treated with oral maintenance therapy using a targeted SHH pathway inhibitor (vismodegib) after adjuvant chemotherapy regimen is complete and compare these outcomes to molecularly and clinically matched historical controls from SJMB03 as well as outcome from other published cohorts.

III. To estimate the progression free and overall survival distributions of non-WNT non-SHH medulloblastoma patients treated on Strata N2 and N3 with 3 cycles of pemetrexed (pemetrexed disodium) and gemcitabine (gemcitabine hydrochloride) in addition to 4 cycles of conventional adjuvant chemotherapy and compare the progression-free and overall survival distributions to molecularly and clinically matched historical controls from SJMB03 separately for each stratum.

IV. To estimate the overall survival distribution of non-WNT non-SHH medulloblastoma patients treated on Stratum N1 with reduced dose cyclophosphamide and compare progression free and overall survival distributions to molecularly and clinically matched historical controls from SJMB03.

V. To evaluate the feasibility and toxicity of adding pemetrexed and gemcitabine to adjuvant chemotherapy regimen of intermediate and high risk non-WNT non-SHH medulloblastoma patients (Strata N2 and N3).

VI. To evaluate the feasibility and toxicity of oral maintenance therapy with the targeted SHH inhibitor (vismodegib) after conventional adjuvant chemotherapy regimen is complete.

VII. To estimate the cumulative incidence of local disease failure at 2 and 5 years based on treatment regimen, strata, and clinical and treatment factors.

VIII. To evaluate the effects of an aerobic training intervention, delivered during the radiation therapy period and at home, prior to the start of chemotherapy, on physical performance at the end of the intervention, at the end of adjuvant chemotherapy, and one, two and five years off adjuvant chemotherapy, among children treated for medulloblastoma.

IX. To evaluate the effects of an aerobic training intervention, delivered during the radiation therapy period and at home, prior to the start of chemotherapy, on fatigue and health related quality of life at the end of the intervention, at the end of adjuvant chemotherapy, and one, two and five years off adjuvant chemotherapy, among children treated for medulloblastoma.

X. To evaluate the effects of an aerobic training intervention, delivered during the radiation therapy period and at home prior to start of chemotherapy, on memory, attention and executive function at the end of the intervention and at the end of adjuvant chemotherapy, among children treated for medulloblastoma.

XI. To evaluate the impact of an aerobic training intervention on sleep quality and quantity in children with medulloblastoma.

XII. To evaluate the relation between baseline cognitive performance and the variables of sleep quality and quantity, and fatigue in children with medulloblastoma.

XIII. To estimate change in neurocognitive performance using a comprehensive assessment battery (e.g., measures of intellectual function, academic abilities, attention, memory, processing speed and executive functions) and investigate the relationship of change to relevant demographic factors (e.g., gender, age at treatment, time since treatment and socioeconomic status) and clinical factors (e.g., treatment intensity/risk group, posterior fossa syndrome).

XIV. To assess the impact of a computer-based working memory intervention, relative to standard of care, on additional performance- and rater-based measures of attention, processing speed and executive functions.

XV. To compare the impact of a computer-based working memory intervention in conjunction with an aerobic training intervention, relative to either intervention in isolation, on measures of attention, processing speed and executive functions.

XVI. To evaluate the maintenance of improvements on measures of attention, working memory, processing speed and executive functions six months following participation in the computer-based working memory intervention program.

EXPLORATORY OBJECTIVES:

I. To evaluate the feasibility of attaining high resolution genomic information from formalin fixed paraffin embedded (FFPE) material using high resolution molecular tools (targeted or complete mutational analysis, targeted or complete transcriptomic analyses, deoxyribonucleic acid [DNA] copy number variation analyses, protein, and methylome analyses).

II. To estimate the relationship of specific tumor molecular abnormalities (mutation, amplification, deletion, methylation) acquired from either high resolution genome wide analysis on fresh frozen tissue or from FFPE analysis on outcome and therapeutic response.

III. To compare medulloblastoma subgroup assignment from standard pathology techniques on FFPE (immunohistochemistry [IHC], fluorescent in situ hybridization [FISH]) to other high resolution molecular tools (i.e. Affymetrix Quantigene) and evaluate the relationship of alternate/additional subgroup assignments to prognosis, clinical characteristics, or response.

IV. To validate the subgroup assignment from standard pathology techniques as well as from other molecular tools (i.e. Quantigene, Nanostring, Illumina 450K methylation microarray) against subgroup assignment from high resolution genome wide expression analysis.

V. To identify new prognostic factors by applying new techniques to study patient and parent material (i.e. stored plasma, serum, cerebrospinal fluid, white blood cell [WBC]).

VI. To evaluate intracellular gemcitabine triphosphate in peripheral blood mononuclear cells in patients.

VII. To quantify the effect of spinal radiation therapy method and dose on pulmonary function evaluated prior to and six months following radiation therapy and annually thereafter. (Data collection complete as of October 19, 2018)

VIII. To estimate the cumulative incidence and the tolerance dose (TD) 5/5 and TD50/5 for radiation necrosis, subnormal cognitive function (standardized test score), endocrine deficiency (growth, thyroid, adrenal, or gonadotropin replacement) and clinically significant hearing loss based on normal tissue dose, treatment regimen and clinical and treatment factors.

IX. To quantify the effect of therapy on cardiac function evaluated prior to therapy and annually after completion of therapy.

X. To quantify the effect of therapy on gonadal function evaluated prior to therapy and annually after completion of therapy. (Data collection complete as of October 19, 2018)

XI. To quantify the effect of radiation method and dose on sitting height evaluated prior to therapy and annually after completion of therapy. (Data collection complete as of October 19, 2018)

XII. To determine if sleep duration, sleep efficiency, and fatigue are related to outcomes of a cognitive intervention. (Data collection complete as of October 19, 2018)

XIII. To determine if sleep duration and sleep efficiency are related to corticocortical connections. (Data collection complete as of October 19, 2018)

XIV. To assess changes in sleep patterns that occur longitudinally over the first year following diagnosis of an embryonal tumor including day-to-day variability, changes over the course of treatment, and the stability of sleep patterns in relation to cognitive functioning. (Data collection complete as of October 19, 2018)

XV. To investigate cerebellar topography by evaluating whether cognitive and affective deficits vary according to the site of cerebellar lesion/resection cavity/radiation dosimetry.

XVI. To use functional magnetic resonance imaging (fMRI) to examine the neural correlates of working memory performance before and after computer-based working memory intervention.

XVII. To evaluate the sensitivity of magnetization transfer (MT)-sensitized balanced steady-state free precession (bSSFP) for detection of early therapy-related white matter and gray matter damage. (Data collection complete as of October 19, 2018)

XVIII. To correlate the number, distribution and time course of development of small vascular lesions as measured by susceptibility weighted imaging (SWI) with measures of neurocognitive and motor performance.(Data collection complete as of October 19, 2018)

XIX. To describe anatomical and pathophysiological imaging features of medulloblastoma subtypes (based on histopathologic, molecular, and cytogenetic data) using qualitative and quantitative MRI metrics.

XX. To evaluate surgical damage patterns in the posterior fossa and their functional correlates in the supratentorial brain in medulloblastoma subtypes by MRI (structural and functional), with an emphasis on damage to the efferent cerebellar pathways (“proximal efferent cerebellar pathway [pECP] damage”). (Data collection complete as of October 19, 2018)

XXI. To model differences between photon and proton treatment planning for each patient to estimate difference in normal tissue irradiation and tumor control. (Data collection complete as of October 19, 2018)

XXII. To model the longitudinal pattern of brainstem imaging parameters based on treatment regimen and clinical and treatment factors. (Data collection complete as of October 19, 2018)

XXIII. To characterize the structural and functional brain connectomes, and compare longitudinal changes in connection strength and topology of brain networks after radiation therapy between low, standard, and high risk patients during the first two years of therapy.

XIV. To investigate associations between structural and functional brain connectomes and neurocognitive performance, sleep quality, and cancer control interventions.

OUTLINE:

RADIATION THERAPY: Patients undergo risk stratified high-, standard-, or low-dose craniospinal irradiation (CSI) 5 days a week in weeks 1-6.

ADJUVANT CHEMOTHERAPY: Beginning 6 weeks after completion of radiation therapy patients in strata W1, W2, W3, S1, S2, and N1 receive 4 consecutive courses of "A Cycle" chemotherapy and patients in strata N2 and N3 receive sequential chemotherapy comprising AABAABB.

A CYCLE (ALL PATIENTS): Patients receive vincristine sulfate intravenously (IV) on day 1 and 8, amifostine trihydrate (omitted in high risk patients; strata W3, S2, N3) IV over 1-5 minutes on day 1, cisplatin IV over 6 hours or carboplatin IV over 1 hour on day 1, and cyclophosphamide IV over 1 hour on days 2-3. Treatment repeats every 28 days for up to 4 cycle in the absence of disease progression or unacceptable toxicity.

B CYCLE (INTERMEDIATE AND HIGH RISK ONLY): Patients receive pemetrexed disodium IV over 10 minutes followed by gemcitabine hydrochloride IV over 30 minutes on days 1 and 15.

MAINTENANCE CHEMOTHERAPY (STRATUM S ONLY): Within 6 weeks of the start of the last course of adjuvant chemotherapy, patients receive vismodegib orally (PO) once daily (QD) on days 1-28. Treatment repeats every 28 days for 12 months in the absence of disease progression or unacceptable toxicity.

OPTIONAL EXERCISE INTERVENTION: Patients are randomized to 1 of 2 arms.

ARM I: Patients undergo physical therapy over 60 minutes, 3 days a week for 6 weeks during radiation therapy. After completion of radiation therapy and prior to chemotherapy, patients undergo an individualized 50-60 minutes home exercise program with an emphasis on completing 30 minutes of aerobic exercise and activity 3 days a week for 4-6 weeks. At the end of radiation therapy and at the beginning of chemotherapy, patients wear a wrist mounted activity monitor at 3 different times to record physical activity levels and sleep patterns.

ARM II: Patients receive traditional physical therapy 3 days a week for 6 weeks during radiation therapy. After completion of radiation and before initiation of chemotherapy, patients may also undergo an individualized, traditional (standard of care) home exercise program as needed.

COGNITIVE REMEDIATION INTERVENTION: Patients are randomized to 1 of 2 arms.

ARM I: Patients receive standard medical, rehabilitative and educational services. Patients and caregivers also receive weekly phone calls from a research team member inquiring about the patient’s well-being and offering generic social support.

ARM II: Patients receive a computer-based training program comprising 25 sessions lasting 15-45 minutes over 5-9 weeks. Research team member also monitors patients' weekly progress online and offers support through weekly phone calls to patients and caregivers.

After completion of study intervention, patients are followed up periodically for 10 years.

Trial Phase & Type

Trial Phase

Phase II

Trial Type

Treatment

Lead Organization

Lead Organization
St. Jude Children's Research Hospital

Principal Investigator
Amar Gajjar

Trial IDs

Primary ID SJMB12
Secondary IDs NCI-2013-01125
Clinicaltrials.gov ID NCT01878617