Study of Systemic and Spinal Chemotherapy Followed by Radiation for Infants With Brain Tumors

NCT00042367 | Completed DMC

• 1 other identifier: H8619
• Study Type: interventional
• Target: 119
• Locations: 1 country
• Sites: 3

Brief Summary

The purposes of this study are to find the highest dose of mafosfamide that can be given without causing severe side effects, to see how well the combination of these chemotherapy drugs and lower doses of radiation work to delay or stop the growth of the tumor, and to evaluate the pharmacokinetics (how the body handles) of Mafosfamide.

Conditions

Brain Tumors

Outcome Measures

Primary Outcomes (2)

• To evaluate the feasibility, including expected disease progression, of delivering 20 weeks of systemic chemotherapy plus (IT) mafosfamide.

  controlling the disease for at least 20 weeks.

  20 weeks

• To evaluate the safety and feasibility of a limited dose escalation schedule of IT mafosfamide in children < 3 years of age.

  Toxicities observed during the last 18 weeks of IT therapy (prior to irradiation) together with the acute toxicities profiles observed during the initial 2 weeks of IT therapy will be used to derive the dose to be evaluated in the feasibility component of this study.

  5 years

Interventions

Induction therapy (Regimen 1, Course 1, Cycle A1 DRUG

2-8 hrs: Cisplatin 3.5 mg/kg + mannitol 0.4 g/kg in D5 NS (1000 ml/m2) over 6 hrs at approximately 167ml/m2/hr. 8-12 hrs: D5 NS (665 ml/m2) + KCl (2 mEq/100 ml) +MgSO4 (0.5 mEq/100 ml) at approximately 167ml/m2/hr. 12-24 hrs: D5 NS + KCl (2 mEq/100 ml) + MgSO4 (0.5mEq/100 ml) at approximately 65 ml/m2/hr. Days 2,3: 0 hrs: Mesna 6 mg/kg IV in 0.65 ml/kg of IVF over 15 min 15 min: Cyclophosphamide 30 mg/kg IV over 30 min 45 min: Post-chemotherapy hydration - D5 1/2 NS + KCl(1 mEq/100 ml) at approximately 130 ml/m2/hr for at least 24 hours. 3 hrs: Mesna 6 mg/kg IV in 0.65 ml/kg IVF over 15 min 6 hrs: Mesna 6 mg/kg IV in 0.65 ml/kg IVF over 15 min 9 hrs: Mesna 6 mg/kg IV in 0.65 ml/kg IVF over 15 min 12 hrs: Mesna 6 mg/kg IV in 0.65 ml/kg IVF over 15 min Day 4 G-CSF 5 µg/kg subcutaneously, daily until ANC ≥ 2000 on two consecutive days, post ANC nadir. Day 8: Vincristine 0.05 mg/kg IV push (max dose = 2 mg) Day 15: Vincristine 0.05 mg/kg IV push (max dose = 2 mg)

Regimen 1, Course 1, Cycle A2 (Days 22 - 42) DRUG

Drugs and doses are same as in Cycle A1. Cycle A2 begins following recovery from Cycle A1, but no sooner than day 21. Patients with delays in recovery beyond day 28 should have dose modifications

Cycle B DRUG

Days 43 - 63) Etoposide, 1.7 mg/kg p.o. qd x 21 days. The dose will be diluted immediately prior to administration in juice flavored syrup to a final concentration of 0.4 Each dose should be aken 1 hour before or 2 hours after a meal. Cycle B begins following recovery from Cycle A2; however, it begin no sooner than 21 days after the start of Cycle A2. Monitor weekly CBC/diff/plt. If ANC \< 500/mm3 or platelets (unsupported) \< 50,000/mm3 then discontinue etoposide. A 25% reduction should be made for the next cycle of oral etoposide. Interim Response Evaluation (Days 64 - 70) Interim Response Evaluation should be performed the week following the completion of Course 1.

Regimen 1, Course 2 DRUG

6.3.3 Regimen 1, Course 2 Repeat systemic therapy as per Course 1 (Cycle A1, Cycle A2, and Cycle B) in patients with SD or better at the interim response evaluation (see Figure 2 for IT mafosfamide guidelines). Course 2 should not begin any sooner than 7 days after the completion of Course 1.

Intrathecal Mafosfamide DRUG

Regimen 1, Course 1 Mafosfamide, 14 mg, is given two times/week during Cycle A1 and Cycle A2 of Course 1, for 12 total doses during days 1-41. The first dose of Cycles A1 and A2 should be given, if possible, on the same day as the first I.V. cyclophosphamide dose and the second dose 3 to 4 days later. The assigned dose is given one time/week during Cycle B, Course 1 for 3 total doses during days 43 - 63.

Regimen 1 Course 2, IT mafosfamide DRUG

Regimen 1, Course 2 The assigned dose is administered once with IV cyclophosphamide during each of Cycle A1 and Cycle A2, and day 1 of Cycle B for a total of 3 doses during Course 2. Patients with an initially abnormal flow study, who show no evidence of obstructive hydrocephalus or compartmentalization on the repeat study, may begin intrathecal mafosfamide administration with the initiation of Regimen 1, Course 2. The frequency of intrathecal mafosfamide administration, for such patients, will be as outlined in Regimen 1, Course 1\.

Regimen 2, Course 1 DRUG

Cycle C1 (Days 1 - 21) Day 1: Prehydrate with D5W 1/2 NS + KCl 2 mEq/100 ml) at 2 times the hourly maintenance rate until the urine specific gravity is \< 1.012. 0 hrs: Mesna 6 mg/kg IV over 15 min. Dilute in 0.65 ml/kg IVF. 15 min: Vincristine 0.05 mg/kg IV push (Day 1 only)(max dose = 2 mg) 20 min: Cyclophosphamide 30 mg/kg IV over 30 min. 50 min: Post-chemotherapy hydration - D5 1/2 NS + KCl (1 mEq/100 ml) at twice the hourly maintenance rate for at least 24 hours. 3 hrs: Mesna 6 mg/kg IV in 0.65 ml/kg IVF over 15 min 6 hrs: Mesna 6 mg/kg IV in 0.65 ml/kg IVF over 15 min 9 hrs: Mesna 6 mg/kg IV in 0.65 ml/kg IVF over 15 min 12 hrs: Mesna 6 mg/kg IV in 0.65 ml/kg IVF over 15 min Day 2: Repeat day 1, but omit vincristine. Day 3: G-CSF 5 µg/kg/day subcutaneously, daily, until ANC is \> 2000 on two consecutive days, post ANC nadir.

Regimen 2, Course, 1, Cycle C1 DRUG

Cycle C1, Weeks 2 and 3 Day 8: Vincristine 0.05 mg/kg IV push (max dose = 2 mg) Day 15: Vincristine 0.05 mg/kg IV push (max dose = 2 mg) Cycle C2 (Days 22-42) Drugs and doses are same as in Cycle C1. Cycle C2 begins following recovery from Cycle C1, but no sooner than day 21. Patients with delays in recovery beyond day 28 should have dose modificationsCycle D (Days 43 - 63) Etoposide 1.7 mg/kg, po qd x 21 days The dose will be diluted immediately prior to administration in juice or flavored syrup as per section 3.4.3. Each dose should be taken 1 hour before or 2 hours after a meal. Cycle D should begin following recovery from Cycle C2; however, it should begin no sooner than 21 days after the start of Cycle C2.

Regimen 2, Course 2 DRUG

Repeat Course 1 (Cycle C1, Cycle C2, and Cycle D) in patients with SD or better at the interim response evaluation. Chemotherapy should begin as soon as the patient has recovered from the toxicities of oral etoposide in cycle D, course 1. However, it should not begin any sooner than 7 days after the completion of Course 1.

radiation therapy RADIATION

Conformal Irradiation Patients who are initially M0 with a CR, PR, or SD to Regimen 1 induction chemotherapy (with or without second surgery) will receive local irradiation using conformal techniques. Treatment will commence within 2 weeks of completing Regimen 1 or second surgery. Treatment planning and technique may involve 3D conformal,IMRT, or proton planning and delivery, provided the guidelines regarding volume, dose,and normal tissue restrictions are honored. 8.3.1 Fraction Size 180 cGy fractions will be used for all target volumes. 8.3.2 Fractionation Conventional fractionation will be used. Treatments will be given once daily, 5 days/week except for necessary interruptions secondary to medical or administrative reasons.

Eligibility Criteria

• Age: Up to 36 Months
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may not qualify if:

• Age: \< 3 years.
• Histology: Patient must have a histologically confirmed primary intracranial CNS medulloblastoma/PNET or other embryonal tumor (medulloepithelioma, ependymoblastoma, neuroblastoma, pineoblastoma), atypical teratoid/rhabdoid tumor, intracranial germ cell tumor, or choroid plexus carcinoma. Patients with M+ ependymoma are also eligible.
• Performance Status: Karnofsky or Lansky \>= 30%
• Bone Marrow Function: All patients must have a Hgb \>= 10 g/dl, ANC \>= 1,500/mm3, and a platelet \>= 100,000/mm3. If the patient has a positive bone scan, then a pretreatment bone marrow aspirate and biopsy must be free of tumor.
• Hepatic/Renal Function: All patients must have adequate hepatic (total bilirubin \< 1.5 mg/dl, SGPT \< 5x normal), and renal (normal serum creatinine for age or technetium clearance \> 40/ml/min/m2) function.
• Prior Therapy: Patients may not have received prior radiotherapy or chemotherapy, with the exception of steroids. Patients must not be receiving any other investigational agents. (Patients may receive investigational agents for supportive care 30 days after completion of all mafosfamide therapy.)
• Surgery: Patients must begin protocol therapy within 35 days of definitive surgery.
• Central Line: Patients must be willing to have a central line.
• CSF flow: Patients must be willing to have a CSF flow study to determine whether or not they will receive intrathecal chemotherapy. Patients without a VP or VA shunt must be willing to have an Ommaya reservoir if their CSF flow study does not show any evidence of obstruction to or compartmentalization of flow. Patients with obstruction to or compartmentalization of CSF flow on their initial flow study must be willing to have a repeat flow performed within the initial 10 weeks of induction therapy, ideally during weeks 8-10. If a repeat flow study shows resolution of obstruction or compartmentalization, patients are expected to begin intrathecal mafosfamide during Regimen 1 course 2 of therapy. Patients without a VP or VA shunt who have resolution of normal flow should additionally have an Ommaya reservoir placed.

Sponsors & Collaborators

• Baylor College of Medicine: lead
• Duke University: collaborator
• St. Jude Children's Research Hospital: collaborator
• Children's National Research Institute: collaborator
• Seattle Children's Hospital: collaborator
• Children's Hospital of Philadelphia: collaborator
• University of Pittsburgh: collaborator
• Dana-Farber Cancer Institute: collaborator
• University of California, San Francisco: collaborator

Study Sites (3)

Brain Tumor Center at Duke University

Durham, North Carolina, 27710, United States

Location

St. Jude Children's Research Hospital

Memphis, Tennessee, 38105-0318, United States

Location

Texas Children's Hospital

Houston, Texas, 77030, United States

Location

Related Publications (1)

• McLendon RE, Adekunle A, Rajaram V, Kocak M, Blaney SM. Embryonal central nervous system neoplasms arising in infants and young children: a pediatric brain tumor consortium study. Arch Pathol Lab Med. 2011 Aug;135(8):984-93. doi: 10.5858/2010-0515-OAR1.

  PMID: 21809989 DERIVED

MeSH Terms

Conditions

Brain Neoplasms

Interventions

Neoadjuvant Therapy; Radiotherapy

Condition Hierarchy (Ancestors)

Central Nervous System Neoplasms; Nervous System Neoplasms; Neoplasms by Site; Neoplasms; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases

Intervention Hierarchy (Ancestors)

Combined Modality Therapy; Therapeutics

Study Officials

• Susan Blaney, MD

  Baylor College of Medicine

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor of Pediatrics

Study Record Dates

• First Submitted: July 26, 2002
• First Posted: August 1, 2002
• Study Start: April 4, 2000
• Primary Completion: December 1, 2005
• Study Completion: June 1, 2006
• Last Updated: March 4, 2020

Record last verified: 2020-03

Locations

US (3)