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

Primary Purpose

Central Nervous System Tumors

Status

Completed

Phase

Phase 1

Locations

United States

Study Type

Interventional

Intervention

Bevacizumab

Irinotecan

Temozolomide

About this trial

This is an interventional treatment trial for Central Nervous System Tumors

Eligibility Criteria

18 Months - 23 Years (Child, Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

Johns Hopkins All Children's Hospital

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm 5

Arm Type

Experimental

Arm Label

Dose Level 0

Dose Level 1

Dose Level 2

Dose Level 3

Dose Level 4

Arm Description

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

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

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

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

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

Outcomes

Primary Outcome Measures

Measurement of Number of Adverse Events

Collect and grade the all of the adverse events to evaluate for safety. This data was collected for the first 2 cycles for each participant.

Secondary Outcome Measures

Best Response of Children With Recurrent or Refractory Central Nervous System Tumors With This Combination of Chemotherapy Agents.

Best response by MRIs per definitions in the protocol (complete response, partial response, stable disease, progressive disease). MRI's were obtained every 2 cycles and the best response was reported.

2 Year Event Free Survival With Children Treated With This Regimen.

2 year actual event free survival.with children treated with this protocol

To Provide Safety and Efficacy Data for to Recommend Further Larger Studies.

Number participants with grade 3 and 4 hematologic and non-hematologic toxicities. All toxicities are for end of cycle 2.

Full Information

NCT ID

NCT00876993

First Posted

April 6, 2009

Last Updated

June 28, 2023

Sponsor

Johns Hopkins All Children's Hospital

Collaborators

The V Foundation, Brain Tumor Alliance

1. Study Identification

Unique Protocol Identification Number

NCT00876993

Brief Title

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

Official Title

A Phase I Study Of Irinotecan and Bevacizumab With Temozolomide in Children With Recurrent/Refractory Central Nervous System Tumors

Study Type

Interventional

2. Study Status

Record Verification Date

June 2023

Overall Recruitment Status

Completed

Study Start Date

September 2008 (undefined)

Primary Completion Date

September 2015 (Actual)

Study Completion Date

September 2015 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Johns Hopkins All Children's Hospital

Collaborators

The V Foundation, Brain Tumor Alliance

4. Oversight

Data Monitoring Committee

Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Central Nervous System Tumors

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1

Interventional Study Model

Sequential Assignment

Masking

None (Open Label)

Allocation

Non-Randomized

Enrollment

26 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Dose Level 0

Arm Type

Experimental

Arm Description

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

Arm Title

Dose Level 1

Arm Type

Experimental

Arm Description

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

Arm Title

Dose Level 2

Arm Type

Experimental

Arm Description

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

Arm Title

Dose Level 3

Arm Type

Experimental

Arm Description

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

Arm Title

Dose Level 4

Arm Type

Experimental

Arm Description

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

Intervention Type

Drug

Intervention Name(s)

Bevacizumab

Other Intervention Name(s)

Irinotecan and temozolomide

Intervention Description

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

Intervention Type

Drug

Intervention Name(s)

Irinotecan

Other Intervention Name(s)

Bevacizumab and temozolomide

Intervention Description

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

Intervention Name(s)

Temozolomide

Other Intervention Name(s)

Bevacizumab and irinotecan

Intervention Description

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)

Primary Outcome Measure Information:

Title

Measurement of Number of Adverse Events

Description

Collect and grade the all of the adverse events to evaluate for safety. This data was collected for the first 2 cycles for each participant.

Time Frame

Two 28-day cycles

Secondary Outcome Measure Information:

Title

Best Response of Children With Recurrent or Refractory Central Nervous System Tumors With This Combination of Chemotherapy Agents.

Description

Time Frame

Every 2 cycles up to 24 cycles

Title

2 Year Event Free Survival With Children Treated With This Regimen.

Description

2 year actual event free survival.with children treated with this protocol

Time Frame

2 year

Title

To Provide Safety and Efficacy Data for to Recommend Further Larger Studies.

Description

Number participants with grade 3 and 4 hematologic and non-hematologic toxicities. All toxicities are for end of cycle 2.

Time Frame

Two 28 day cycles

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Months

Maximum Age & Unit of Time

23 Years

Accepts Healthy Volunteers

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.

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Stacie Stapleton, MD

Organizational Affiliation

Johns Hopkins All Children's Hospital

Official's Role

Principal Investigator

Facility Information:

Facility Name

Johns Hopkins All Children's Hospital

City

Saint Petersburg

State/Province

Florida

ZIP/Postal Code

33701

Country

United States

12. IPD Sharing Statement

Plan to Share IPD

Undecided

IPD Sharing Plan Description

Will determine after further data analysis

Citations:

PubMed Identifier

35260913

Citation

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.

Results Reference

derived

Learn more about this trial

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

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