O6-Benzylguanine and Temozolomide in Treating Young Patients With Recurrent or Progressive Gliomas or Brain Stem Tumors

• Sponsor: National Cancer Institute (NCI) (NIH)
• Overall Status: Completed
• CT.gov ID: NCT00275002
• Collaborator: (none)
• Enrollment: 41
• Locations: 11
• Arm: 1
• Duration (Months): 58
• Patients Per Site: 3.7
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

This phase II trial is studying how well giving O6-benzylguanine together with temozolomide works in treating young patients with recurrent or progressive gliomas or brain stem tumors. Drugs used in chemotherapy, such as O6-benzylguanine and temozolomide , work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. O6-benzylguanine may help temozolomide work better by making tumor cells more sensitive to the drug. Giving more than one drug (combination chemotherapy) may kill more tumor cells.

Condition or Disease	Intervention/Treatment	Phase
Brain and Central Nervous System Tumors	Drug: O6-benzylguanine; Drug: temozolomide	Phase 2

Detailed Description

PRIMARY OBJECTIVES:

1. Determine the sustained objective response rate to the combination of O6-benzylguanine and temozolomide in pediatric patients with recurrent or progressive high-grade gliomas and brain stem tumors.

SECONDARY OBJECTIVES:

1. Determine the toxicity of this regimen in these patients.

OUTLINE: This is a multicenter study. Patients are stratified according to tumor type (high-grade gliomas vs brain stem tumors).

Patients receive O6-benzylguanine IV over 1 hour followed by oral temozolomide on days 1-5. Treatment repeats every 28 days for up to 12 courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed to the earliest of 30 days following discontinuation of therapy or the initiation of additional anti-cancer therapy or death.

PROJECTED ACCRUAL: A total of 50 patients will be accrued for this study.

Study Design

• Study Type: Interventional
• Actual Enrollment: 41 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase II Trial of O6-Benzylguanine and Temozolomide in Pediatric Patients With Recurrent or Progressive High-Grade Gliomas and Recurrent or Progressive Brainstem Tumors
• Study Start Date: Feb 1, 2006
• Actual Primary Completion Date: Dec 1, 2010
• Actual Study Completion Date: Dec 1, 2010

Arms and Interventions

Arm

Intervention/Treatment

Experimental: O6-BG and TMZ O6-benzylguanine (O6-BG) and temozolomide (TMZ)

Drug: O6-benzylguanine; Dosing is based on the body surface area (BSA) calculated at the beginning of each course of therapy. O6-Benzylguanine, 120 mg/m^2, will be administered as a one-hour intravenous (IV) infusion, daily for 5 days. Four consecutive weeks will constitute one course. Courses will be repeated every 4 weeks for up to 12 courses of therapy.; Drug: temozolomide; Dosing is based on the body surface area (BSA) calculated at the beginning of each course of therapy. Temozolomide, 75 mg/m^2 (rounded to the nearest 5 mg, the size of the smallest capsule) will be given orally, 30 minutes following the completion of each infusion of O6-Benzylguanine. Four consecutive weeks will constitute one course. Courses will be repeated every 4 weeks for up to 12 courses.; Other Names: Temodar

Outcome Measures

Primary Outcome Measures

1. Percentage of Participants With an Objective Response (Complete Response or Partial Response) [Week 8, 16, 24, 32, and 40 after starting therapy]

   The primary endpoint is to assess the percentage of participants with a sustained objective response (complete response (CR) or partial response (PR)). Response is assessed by magnetic resonance imaging (MRI) per the following criteria: CR - disappearance of tumor and PR - ≥50% reduction in tumor based on the maximal cross-sectional measurements. The response must be sustained for at least 8 weeks, and the date of the confirmed sustained response is the date at which the response was first noted by MRI.

Secondary Outcome Measures

1. Number of Patients With Grade 3 or 4 Adverse Events at Least Possibly Related to the Combination of O6-benzylguanine and Temozolomide [From day 1 of therapy up to 49 months]

   Clinical and laboratory studies to assess adverse events are obtained at least every four weeks (prior to each course) with some laboratory studies obtained every 2 weeks. Adverse events are graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 3.0 (CTCAE v3.0). Attribution of each adverse event to the treatment regimen is determined by the participant's attending physician at the enrolling institution and verified by the study chair.

Eligibility Criteria

Criteria

• Ages Eligible for Study: N/A to 21 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

INCLUSION CRITERIA

• Tumor: Participants must have a high-grade glioma (including e.g. histologically confirmed anaplastic astrocytoma, glioblastoma multiforme, anaplastic oligodendroglioma, anaplastic ganglioma, gliosarcoma) or a brainstem tumor (histologic confirmation waived) with documentation of disease recurrence or progression after treatment with standard therapy. Participants must have bi-dimensionally measurable disease, defined as at least 1 lesion that can be measured in ≥ 2 dimensions

• Age: 21 years of age or less

• Performance status: Karnofsky 60-100% (for patients > 16 years of age) or Lansky 60-100% (for patients ≤ 16 years of age)

• Life expectancy: Not specified

• Hematopoietic: Must have adequate bone marrow function defined as absolute neutrophil count > 1,500/mm^{3, platelet count > 100,000/mm}3 (unsupported), hemoglobin > 8 g/dL (may be supported), and absolute lymphocyte count ≥ 500/mm^3

• Hepatic: Must have SGOT and SGPT ≤ 2.5 times upper limit of normal (ULN), bilirubin ≤ 1.5 times ULN, and no overt hepatic disease

• Renal: Participants must have creatinine clearance ≥ 60 mL/min or creatinine based on age as follows: no greater than 0.8 mg/dL (for patients ≤ 5 years of age), no greater than 1.0 mg/dL (for patients 6 to 10 years of age), no greater than 1.2 mg/dL (for patients 11 to 15 years of age), or no greater than 1.5 mg/dL (for patients > 15 years of age). There must be no overt renal disease

• Cardiovascular: Must have no overt cardiac disease

• Pulmonary: Must have no overt pulmonary disease

• Other: Female participants of childbearing potential must have a negative pregnancy test prior to study registration, and must avoid breast-feeding. Female and male participants of childbearing or child-fathering potential must use effective contraception

• Bone Marrow Transplant: Must be at least 6 months since prior allogeneic bone marrow transplantation and at least 3 months since prior autologous bone marrow or stem cell transplantation

• Growth Factors: Must be at least 2 weeks since prior colony-stimulating factors (e.g., filgrastim [G-CSF], sargramostim [GM-CSF], or erythropoietin)

• Prior Chemotherapy: Must have received last dose of myelosuppressive anticancer chemotherapy ≥ 3 weeks prior to study registration and ≥ 6 weeks for nitrosoureas. Must have received last dose of nonmyelosuppressive investigational agents or anticancer drugs ≥ 7 days prior to study registration. Participants who have received prior temozolomide are eligible

• Concurrent Endocrine Therapy: Concurrent corticosteroid therapy is allowed

• Prior Radiotherapy: Must have received last fraction of craniospinal irradiation and local irradiation to the primary tumor ≥ 12 weeks prior to study registration

• Prior Therapy-Other: Must have recovered from all prior therapy

EXCLUSION CRITERIA

• Must not have history of severe toxicity (≥ grade 3) associated with temozolomide

• Must not be receiving other concurrent anticancer or investigational therapy

• Must not have history of hypersensitivity to dacarbazine, temozolomide, or polyethylene glycol (PEG)

• Must not have uncontrolled significant systemic illness including infection, or overt renal, hepatic, cardiac, or pulmonary disease

• Must not be HIV positive

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	UCSF Helen Diller Family Comprehensive Cancer Center	San Francisco	California	United States	94115
2	Children's National Medical Center	Washington	District of Columbia	United States	20010-2970
3	Children's Memorial Hospital - Chicago	Chicago	Illinois	United States	60614
4	Dana-Farber/Harvard Cancer Center at Dana Farber Cancer Institute	Boston	Massachusetts	United States	02115
5	Duke Comprehensive Cancer Center	Durham	North Carolina	United States	27710
6	Children's Hospital of Philadelphia	Philadelphia	Pennsylvania	United States	19104-4318
7	Children's Hospital of Pittsburgh	Pittsburgh	Pennsylvania	United States	15213
8	St. Jude Children's Research Hospital	Memphis	Tennessee	United States	38105
9	Texas Children's Cancer Center and Hematology Service at Texas Children's Hospital	Houston	Texas	United States	77030-2399
10	Dan L. Duncan Cancer Center at Baylor College of Medicine	Houston	Texas	United States	77030
11	Children's Hospital and Regional Medical Center - Seattle	Seattle	Washington	United States	98105

Sponsors and Collaborators

• National Cancer Institute (NCI)

Investigators

• Study Chair: Katherine Warren, MD, National Cancer Institute (NCI)

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: National Cancer Institute (NCI)
• ClinicalTrials.gov Identifier: NCT00275002
• Other Study ID Numbers: NCI-2012-03050; PBTC-015; NCI-06-C-0089; NCI-P6692; CDR0000455561; NCT00291291
• First Posted: Jan 11, 2006
• Last Update Posted: Feb 11, 2022
• Last Verified: Jan 1, 2022

• Keywords provided by National Cancer Institute (NCI): recurrent childhood brain stem glioma; recurrent childhood brain tumor
• Additional relevant MeSH terms: Glioma; Nervous System Neoplasms; Central Nervous System Neoplasms; Recurrence; Temozolomide; O(6)-benzylguanine

Study Results

Participant Flow

Recruitment Details	Participants from PBTC member institutions were enrolled between October 2005 and February 2008.

Arm/Group Title	Recurrent High-Grade Gliomas	Recurrent Brain Stem Tumors
Arm/Group Description	Participants with recurrent or progressive high-grade gliomas receive 120 mg/m^2 of O6-Benzylguanine administered as a one-hour intravenous infusion, daily for 5 days. Temozolomide, 75 mg/m^2 is administered orally, 30 minutes following the completion of each infusion of O6-Benzylguanine. Four consecutive weeks will constitute one course, and courses will be repeated every 4 weeks.	Participants with recurrent or progressive brain stem tumors receive 120 mg/m^2 of O6-Benzylguanine administered as a one-hour intravenous infusion, daily for 5 days. Temozolomide, 75 mg/m^2 is administered orally, 30 minutes following the completion of each infusion of O6-Benzylguanine. Four consecutive weeks will constitute one course, and courses will be repeated every 4 weeks.
Period Title: Overall Study
STARTED	25	16
COMPLETED	3	0
NOT COMPLETED	22	16

Baseline Characteristics

Arm/Group Title	Recurrent High-Grade Gliomas	Recurrent Brain Stem Tumors	Total
Arm/Group Description	Participants with recurrent or progressive high-grade gliomas receive 120 mg/m^2 of O6-Benzylguanine administered as a one-hour intravenous infusion, daily for 5 days. Temozolomide, 75 mg/m^2 is administered orally, 30 minutes following the completion of each infusion of O6-Benzylguanine. Four consecutive weeks will constitute one course, and courses will be repeated every 4 weeks.	Participants with recurrent or progressive brain stem tumors receive 120 mg/m^2 of O6-Benzylguanine administered as a one-hour intravenous infusion, daily for 5 days. Temozolomide, 75 mg/m^2 is administered orally, 30 minutes following the completion of each infusion of O6-Benzylguanine. Four consecutive weeks will constitute one course, and courses will be repeated every 4 weeks.	Total of all reporting groups
Overall Participants	25	16	41
Age (Count of Participants)
<=18 years	23 92%	16 100%	39 95.1%
Between 18 and 65 years	2 8%	0 0%	2 4.9%
>=65 years	0 0%	0 0%	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	13.4 (5.1)	7.8 (3.9)	11.2 (5.4)
Sex: Female, Male (Count of Participants)
Female	9 36%	12 75%	21 51.2%
Male	16 64%	4 25%	20 48.8%
Region of Enrollment (participants) [Number]
United States	25 100%	16 100%	41 100%

Outcome Measures

1. Primary Outcome

Title	Percentage of Participants With an Objective Response (Complete Response or Partial Response)
Description	The primary endpoint is to assess the percentage of participants with a sustained objective response (complete response (CR) or partial response (PR)). Response is assessed by magnetic resonance imaging (MRI) per the following criteria: CR - disappearance of tumor and PR - ≥50% reduction in tumor based on the maximal cross-sectional measurements. The response must be sustained for at least 8 weeks, and the date of the confirmed sustained response is the date at which the response was first noted by MRI.
Time Frame	Week 8, 16, 24, 32, and 40 after starting therapy

Outcome Measure Data

Analysis Population Description

Participants included in assessing objective response were those who completed two courses of therapy or those who died or experienced progressive disease prior to completing the second course.

Arm/Group Title	Recurrent High-Grade Gliomas	Recurrent Brain Stem Tumors
Arm/Group Description	Participants with recurrent or progressive high-grade gliomas receive 120 mg/m^2 of O6-Benzylguanine administered as a one-hour intravenous infusion, daily for 5 days. Temozolomide, 75 mg/m^2 is administered orally, 30 minutes following the completion of each infusion of O6-Benzylguanine. Four consecutive weeks will constitute one course, and courses will be repeated every 4 weeks.	Participants with recurrent or progressive brain stem tumors receive 120 mg/m^2 of O6-Benzylguanine administered as a one-hour intravenous infusion, daily for 5 days. Temozolomide, 75 mg/m^2 is administered orally, 30 minutes following the completion of each infusion of O6-Benzylguanine. Four consecutive weeks will constitute one course, and courses will be repeated every 4 weeks.
Measure Participants	25	16
Number (95% Confidence Interval) [Percent of Participants]	4 16%	0 0%

2. Secondary Outcome

Title	Number of Patients With Grade 3 or 4 Adverse Events at Least Possibly Related to the Combination of O6-benzylguanine and Temozolomide
Description	Clinical and laboratory studies to assess adverse events are obtained at least every four weeks (prior to each course) with some laboratory studies obtained every 2 weeks. Adverse events are graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 3.0 (CTCAE v3.0). Attribution of each adverse event to the treatment regimen is determined by the participant's attending physician at the enrolling institution and verified by the study chair.
Time Frame	From day 1 of therapy up to 49 months

Outcome Measure Data

Analysis Population Description

Participants who received at least one day of the treatment regimen were included in the analysis of this objective.

Arm/Group Title	Recurrent High-Grade Gliomas	Recurrent Brain Stem Tumors
Arm/Group Description	Participants with recurrent or progressive high-grade gliomas receive 120 mg/m^2 of O6-Benzylguanine administered as a one-hour intravenous infusion, daily for 5 days. Temozolomide, 75 mg/m^2 is administered orally, 30 minutes following the completion of each infusion of O6-Benzylguanine. Four consecutive weeks will constitute one course, and courses will be repeated every 4 weeks.	Participants with recurrent or progressive brain stem tumors receive 120 mg/m^2 of O6-Benzylguanine administered as a one-hour intravenous infusion, daily for 5 days. Temozolomide, 75 mg/m^2 is administered orally, 30 minutes following the completion of each infusion of O6-Benzylguanine. Four consecutive weeks will constitute one course, and courses will be repeated every 4 weeks.
Measure Participants	25	16
Number [Participants]	16 64%	10 62.5%

Adverse Events

Time Frame	Adverse events (AEs) were collected from day 1 of starting treatment until 30 days after ceasing treatment (off study). AEs possibly, probably, or definitely attributed to the study drug that occur after the patient is off the study are also collected.
Arm/Group Title	Recurrent High-Grade Gliomas		Recurrent Brain Stem Tumors
Arm/Group Description	Participants with recurrent or progressive high-grade gliomas receive 120 mg/m^2 of O6-Benzylguanine administered as a one-hour intravenous infusion, daily for 5 days. Temozolomide, 75 mg/m^2 is administered orally, 30 minutes following the completion of each infusion of O6-Benzylguanine. Four consecutive weeks will constitute one course, and courses will be repeated every 4 weeks.		Participants with recurrent or progressive brain stem tumors receive 120 mg/m^2 of O6-Benzylguanine administered as a one-hour intravenous infusion, daily for 5 days. Temozolomide, 75 mg/m^2 is administered orally, 30 minutes following the completion of each infusion of O6-Benzylguanine. Four consecutive weeks will constitute one course, and courses will be repeated every 4 weeks.
All Cause Mortality
	Recurrent High-Grade Gliomas		Recurrent Brain Stem Tumors
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Recurrent High-Grade Gliomas		Recurrent Brain Stem Tumors
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	15/25 (60%)		12/16 (75%)
Blood and lymphatic system disorders
Febrile neutropenia	1/25 (4%)		0/16 (0%)
Gastrointestinal disorders
Diarrhea	1/25 (4%)		0/16 (0%)
Nausea	1/25 (4%)		0/16 (0%)
Infections and infestations
Colitis, infectious	1/25 (4%)		1/16 (6.3%)
Investigations
Bilirubin	1/25 (4%)		0/16 (0%)
Leukocytes (total WBC)	2/25 (8%)		3/16 (18.8%)
Lipase	1/25 (4%)		0/16 (0%)
Lymphopenia	0/25 (0%)		3/16 (18.8%)
Neutrophils/granulocytes	6/25 (24%)		5/16 (31.3%)
Platelets	1/25 (4%)		0/16 (0%)
Metabolism and nutrition disorders
Hypomagnesemia	0/25 (0%)		1/16 (6.3%)
Hyponatremia	1/25 (4%)		0/16 (0%)
Nervous system disorders
Ataxia	1/25 (4%)		0/16 (0%)
Hydrocephalus	0/25 (0%)		1/16 (6.3%)
Mental Status	1/25 (4%)		0/16 (0%)
Seizure	1/25 (4%)		0/16 (0%)
Somnolence	2/25 (8%)		0/16 (0%)
Respiratory, thoracic and mediastinal disorders
Apnea	0/25 (0%)		1/16 (6.3%)
Aspiration	0/25 (0%)		1/16 (6.3%)
Hypoxia	0/25 (0%)		2/16 (12.5%)
Vascular disorders
Hypotension	0/25 (0%)		1/16 (6.3%)
Phlebitis	0/25 (0%)		1/16 (6.3%)
Other (Not Including Serious) Adverse Events
	Recurrent High-Grade Gliomas		Recurrent Brain Stem Tumors
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	25/25 (100%)		16/16 (100%)
Cardiac disorders
Palpitations	0/25 (0%)		2/16 (12.5%)
Endocrine disorders
Cushingoid appearance	0/25 (0%)		1/16 (6.3%)
Eye disorders
Dry eye syndrome	0/25 (0%)		1/16 (6.3%)
Gastrointestinal disorders
Constipation	4/25 (16%)		3/16 (18.8%)
Diarrhea	3/25 (12%)		5/16 (31.3%)
Dysphagia	0/25 (0%)		2/16 (12.5%)
Heartburn/dyspepsia	0/25 (0%)		1/16 (6.3%)
Nausea	10/25 (40%)		4/16 (25%)
Vomiting	11/25 (44%)		7/16 (43.8%)
General disorders
Edema:limb	0/25 (0%)		1/16 (6.3%)
Edema:trunk/genital	0/25 (0%)		1/16 (6.3%)
Fever	0/25 (0%)		1/16 (6.3%)
Injection site reaction/extravasation changes	0/25 (0%)		1/16 (6.3%)
Investigations
ALT,SGPT	6/25 (24%)		3/16 (18.8%)
ALT,SGOT	3/25 (12%)		1/16 (6.3%)
Alkaline phosphatase	2/25 (8%)		2/16 (12.5%)
Bilirubin	0/25 (0%)		1/16 (6.3%)
gamma-Glutamyl transpeptidase	0/25 (0%)		1/16 (6.3%)
Leukocytes (total WBC)	15/25 (60%)		9/16 (56.3%)
Lymphopenia	13/25 (52%)		8/16 (50%)
Neutrophils/granulocytes	13/25 (52%)		9/16 (56.3%)
Partial thromboplastin time	0/25 (0%)		1/16 (6.3%)
Platelets	16/25 (64%)		10/16 (62.5%)
Weight loss	0/25 (0%)		1/16 (6.3%)
Metabolism and nutrition disorders
Hypoalbuminemia	5/25 (20%)		2/16 (12.5%)
Anorexia	3/25 (12%)		0/16 (0%)
Bicarbonate, serum-low	3/25 (12%)		4/16 (25%)
Hypercalcemia	0/25 (0%)		1/16 (6.3%)
Hypocalcemia	7/25 (28%)		1/16 (6.3%)
Hyperglycemia	10/25 (40%)		4/16 (25%)
Hypoglycemia	5/25 (20%)		3/16 (18.8%)
Hypermagnesemia	5/25 (20%)		1/16 (6.3%)
Hypomagnesemia	4/25 (16%)		0/16 (0%)
Hypophosphatemia	6/25 (24%)		4/16 (25%)
Hyperkalemia	2/25 (8%)		2/16 (12.5%)
Hypokalemia	7/25 (28%)		4/16 (25%)
Hypernatremia	2/25 (8%)		1/16 (6.3%)
Hyponatremia	4/25 (16%)		2/16 (12.5%)
Hyperuricemia	0/25 (0%)		2/16 (12.5%)
Nervous system disorders
Ataxia	0/25 (0%)		3/16 (18.8%)
Dizziness	4/25 (16%)		2/16 (12.5%)
Extrapyramidal/involuntary movement/restlessness	0/25 (0%)		1/16 (6.3%)
Nystagmus	0/25 (0%)		1/16 (6.3%)
Pyramidal tract dysfunction	0/25 (0%)		1/16 (6.3%)
Tremor	0/25 (0%)		1/16 (6.3%)
Renal and urinary disorders
Hemoglobinuria	0/25 (0%)		1/16 (6.3%)
Proteinuria	0/25 (0%)		1/16 (6.3%)
Urinary retention	0/25 (0%)		2/16 (12.5%)
Respiratory, thoracic and mediastinal disorders
Cough	0/25 (0%)		3/16 (18.8%)
Dyspnea	0/25 (0%)		1/16 (6.3%)
Skin and subcutaneous tissue disorders
Dry skin	2/25 (8%)		0/16 (0%)
Hair loss/alopecia	2/25 (8%)		1/16 (6.3%)
Rash/desquamation	0/25 (0%)		1/16 (6.3%)
Vascular disorders
Flushing	0/25 (0%)		1/16 (6.3%)
Hypertension	0/25 (0%)		2/16 (12.5%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.