Study of Irinotecan and Bevacizumab With Temozolomide in Refractory/Relapsed Central Nervous System (CNS) Tumors

NCT ID: NCT00876993

Last Updated: 2023-07-03

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1
• Total Enrollment: 26 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2008-09-30
• Study Completion Date: 2015-09-30

Brief Summary

Bevacizumab, irinotecan, and temozolomide are three agents shown to have promising activity in a variety of central nervous system tumors. No prospective studies have been published or are currently in progress within the major consortiums with this combination of drugs. Brain tumors are the second most common cause of cancer in pediatrics and the leading cause of cancer death in children. For children with High Grade Gliomas or with relapsed/refractory brain tumors, new agents in new combinations are needed. Historical data shows that newly diagnosed high grade gliomas 5 year progression free survival is 28-42%. Recurrent malignant gliomas median survival is 3-9 months. Recurrent medulloblastoma's 2 years survival is 9%. This study is a phase I study designed to provide an objective observation of toxicity and establish a maximum tolerated dose of this combination. In addition, this study will observe the response of children with relapsed or refractory central nervous system tumors.

Detailed Description

Bevacizumab dosing is 10 mg/kg on day 1 and day 15 of a 28 days course given IV.

Irinotecan dosing is 125 mg/m2 on day 1 and day 15 of a 28 day course given IV for the first 3 dose levels. If the MTD of temozolomide is not reached at dose level 3, then dose level 4 will be an escalation of irinotecan to 150 mg/m2.

For dose level 0 Temozolomide, dosing is 75 mg/m2/day day 1-5 of a 28 day course given PO. Doses will be escalated according to standard phase I dose escalation criteria.

Conditions

Central Nervous System Tumors

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: SEQUENTIAL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Dose Level 0

Bevacizmuab 10 mg/kg IV Irinotecan 125 mg/m\^2 IV Temozolomide 75 mg/m\^2 PO

Group Type: EXPERIMENTAL

Bevacizumab

Intervention Type: DRUG

Bevacizumab 10 mg/kg IV on day 1 and day 15 of a 28 day cycle

Irinotecan

Intervention Type: DRUG

Irinotecan 125 mg/m2 on day 1 and day 15 of a 28 day course given IV for the first 3 dose levels. If the Maximum Tolerated Dose of temozolomide is not reached at dose level 3, then dose level 4 will be an escalation of irinotecan to 150mg/m2.

Temozolomide

Intervention Type: DRUG

For the first cohort (dose level 0) of patients, dosing is 75 mg/m2/day day 1-5 of a 28 day course given PO for the first course. Doses will be escalated according to standard phase I dose escalation criteria. Dose levels are as follows (Dose level 1 = 125mg/m2, Dose level 2 = 175mg/m2, Dose levels 3 and 4 = 200 mg/m2)

Dose Level 1

Bevacizmuab 10 mg/kg IV Irinotecan 125 mg/m\^2 IV Temozolomide 125 mg/m\^2 PO

Group Type: EXPERIMENTAL

Bevacizumab

Intervention Type: DRUG

Bevacizumab 10 mg/kg IV on day 1 and day 15 of a 28 day cycle

Irinotecan

Intervention Type: DRUG

Irinotecan 125 mg/m2 on day 1 and day 15 of a 28 day course given IV for the first 3 dose levels. If the Maximum Tolerated Dose of temozolomide is not reached at dose level 3, then dose level 4 will be an escalation of irinotecan to 150mg/m2.

Temozolomide

Intervention Type: DRUG

For the first cohort (dose level 0) of patients, dosing is 75 mg/m2/day day 1-5 of a 28 day course given PO for the first course. Doses will be escalated according to standard phase I dose escalation criteria. Dose levels are as follows (Dose level 1 = 125mg/m2, Dose level 2 = 175mg/m2, Dose levels 3 and 4 = 200 mg/m2)

Dose Level 2

Bevacizmuab 10 mg/kg IV Irinotecan 125 mg/m\^2 IV Temozolomide 175 mg/m\^2 PO

Group Type: EXPERIMENTAL

Bevacizumab

Intervention Type: DRUG

Bevacizumab 10 mg/kg IV on day 1 and day 15 of a 28 day cycle

Irinotecan

Intervention Type: DRUG

Irinotecan 125 mg/m2 on day 1 and day 15 of a 28 day course given IV for the first 3 dose levels. If the Maximum Tolerated Dose of temozolomide is not reached at dose level 3, then dose level 4 will be an escalation of irinotecan to 150mg/m2.

Temozolomide

Intervention Type: DRUG

For the first cohort (dose level 0) of patients, dosing is 75 mg/m2/day day 1-5 of a 28 day course given PO for the first course. Doses will be escalated according to standard phase I dose escalation criteria. Dose levels are as follows (Dose level 1 = 125mg/m2, Dose level 2 = 175mg/m2, Dose levels 3 and 4 = 200 mg/m2)

Dose Level 3

Bevacizmuab 10 mg/kg IV Irinotecan 125 mg/m\^2 IV Temozolomide 200 mg/m\^2 PO

Group Type: EXPERIMENTAL

Bevacizumab

Intervention Type: DRUG

Bevacizumab 10 mg/kg IV on day 1 and day 15 of a 28 day cycle

Irinotecan

Intervention Type: DRUG

Irinotecan 125 mg/m2 on day 1 and day 15 of a 28 day course given IV for the first 3 dose levels. If the Maximum Tolerated Dose of temozolomide is not reached at dose level 3, then dose level 4 will be an escalation of irinotecan to 150mg/m2.

Temozolomide

Intervention Type: DRUG

For the first cohort (dose level 0) of patients, dosing is 75 mg/m2/day day 1-5 of a 28 day course given PO for the first course. Doses will be escalated according to standard phase I dose escalation criteria. Dose levels are as follows (Dose level 1 = 125mg/m2, Dose level 2 = 175mg/m2, Dose levels 3 and 4 = 200 mg/m2)

Dose Level 4

Bevacizmuab 10 mg/kg IV Irinotecan 150 mg/m\^2 IV Temozolomide 200 mg/m\^2 PO

Group Type: EXPERIMENTAL

Bevacizumab

Intervention Type: DRUG

Bevacizumab 10 mg/kg IV on day 1 and day 15 of a 28 day cycle

Irinotecan

Intervention Type: DRUG

Irinotecan 125 mg/m2 on day 1 and day 15 of a 28 day course given IV for the first 3 dose levels. If the Maximum Tolerated Dose of temozolomide is not reached at dose level 3, then dose level 4 will be an escalation of irinotecan to 150mg/m2.

Temozolomide

Intervention Type: DRUG

For the first cohort (dose level 0) of patients, dosing is 75 mg/m2/day day 1-5 of a 28 day course given PO for the first course. Doses will be escalated according to standard phase I dose escalation criteria. Dose levels are as follows (Dose level 1 = 125mg/m2, Dose level 2 = 175mg/m2, Dose levels 3 and 4 = 200 mg/m2)

Interventions

Bevacizumab

Bevacizumab 10 mg/kg IV on day 1 and day 15 of a 28 day cycle

Intervention Type: DRUG

Irinotecan

Irinotecan 125 mg/m2 on day 1 and day 15 of a 28 day course given IV for the first 3 dose levels. If the Maximum Tolerated Dose of temozolomide is not reached at dose level 3, then dose level 4 will be an escalation of irinotecan to 150mg/m2.

Intervention Type: DRUG

Temozolomide

For the first cohort (dose level 0) of patients, dosing is 75 mg/m2/day day 1-5 of a 28 day course given PO for the first course. Doses will be escalated according to standard phase I dose escalation criteria. Dose levels are as follows (Dose level 1 = 125mg/m2, Dose level 2 = 175mg/m2, Dose levels 3 and 4 = 200 mg/m2)

Intervention Type: DRUG

Other Intervention Names

Irinotecan and temozolomide; Bevacizumab and temozolomide; Bevacizumab and irinotecan

Eligibility Criteria

Inclusion Criteria

• Medulloblastomas, high-grade glioma, low-grade glioma, and ependymoma are eligible. Other central nervous system tumors may be considered for treatment at discretion of investigator. Pathology is required unless diffuse intrinsic pontine glioma or optic pathway tumor.
• The patient should have failed first line therapy and be considered refractory, relapsed, or recurrent. Exceptions are high grade gliomas including brain stem gliomas.
• Age 18 months though age 23 years are eligible for this protocol.
• The patient may have received any of the agents, but not in this combination. Patients will not be eligible if they have received the combination of bevacizumab and IV irinotecan as prior therapy. They will not be eligible if they had progressive disease on any of these agents. Investigator discretion may also be used.
• Bone marrow should be recovered from prior therapy with ANC >1500 and platelets >100,000.
• Serum creatinine should be less than institutional upper limit of norm.
• ALT/AST <3 times normal and bilirubin <1.5 times normal.
• Neurologic symptoms should be stable for 1 week with stable or decreasing doses of steroids.
• Patients should not be pregnant or breast feeding.

Exclusion Criteria

• Patients with bleeding disorders or on anticoagulants.
• Uncontrolled hypertension.
• Other risks of bleeding determined on individual basis.
• Patients receiving enzyme inducing anticonvulsants.
• Patients with significant cardiac or pulmonary dysfunction that would compromise the patient's ability to tolerate protocol therapy or would likely interfere with the study procedures or results.
• For patients receiving bevacizumab, those who have had surgical procedures should not receive bevacizumab within 28 days of a major procedure, 14 days of an intermediate procedure and 7 days of a minor procedure. Lumbar punctures or placement of PICC lines are not considered minor procedures and may occur at any time prior to or during therapy.

• Minimum Eligible Age: 18 Months
• Maximum Eligible Age: 23 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

The V Foundation

OTHER

Sponsor Role: collaborator

Brain Tumor Alliance

UNKNOWN

Sponsor Role: collaborator

Johns Hopkins All Children's Hospital

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Stacie Stapleton, MD

Role: PRINCIPAL_INVESTIGATOR

Johns Hopkins All Children's Hospital

Locations

Johns Hopkins All Children's Hospital

St. Petersburg, Florida, United States

Countries

United States

References

Metts J, Harrington B, Salman E, Bradfield SM, Flanary J, Mosha M, Amankwah E, Stapleton S. A phase I study of irinotecan and temozolomide with bevacizumab in children with recurrent/refractory central nervous system tumors. Childs Nerv Syst. 2022 May;38(5):919-928. doi: 10.1007/s00381-022-05479-7. Epub 2022 Mar 8.

Reference Type: DERIVED

PMID: 35260913 (View on PubMed)

Other Identifiers

ACH-CNS-001

Identifier Type: -

Identifier Source: org_study_id