Celecoxib in Patients With Newly Diagnosed GBM Who Are Receiving Anticonvulsant Drugs and Undergoing RT

• Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins (Other)
• Overall Status: Terminated
• CT.gov ID: NCT00068770
• Collaborator: National Cancer Institute (NCI) (NIH)
• Enrollment: 35
• Locations: 7
• Arms: 2
• Duration (Months): 31
• Patients Per Site: 5
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

RATIONALE: Celecoxib may stop the growth of tumor cells by blocking the enzymes necessary for their growth. It is not yet known whether the effectiveness of celecoxib in treating glioblastoma multiforme is decreased in patients who are receiving anticonvulsant drugs and undergoing radiation therapy.

PURPOSE: Phase II trial to study the effectiveness of celecoxib in treating patients who are receiving anticonvulsant drugs and undergoing radiation therapy for newly diagnosed glioblastoma multiforme.

Condition or Disease	Intervention/Treatment	Phase
Brain and Central Nervous System Tumors	Radiation: radiation therapy; Drug: Celecoxib	Phase 2

Detailed Description

OBJECTIVES:

Primary

• Determine the effects of hepatic enzyme-inducing drugs, such as anticonvulsants, on the pharmacokinetics of celecoxib in patients with newly diagnosed glioblastoma multiforme undergoing radiotherapy.

• Determine the effects of steroids on the pharmacokinetics of celecoxib in these patients.

Secondary

• Determine the safety of celecoxib in these patients.

• Determine the duration of survival of patients treated with this regimen.

OUTLINE: This is a multicenter study.

Patients are assigned to 1 of 2 groups based on anticonvulsant therapy.

• Group A: Patients treated with any of the following anticonvulsant drugs that induce hepatic metabolic enzymes:

• Phenytoin

• Carbamazepine

• Phenobarbital

• Primidone

• Oxcarbazepine

• Group B: Patients treated with any of the following anticonvulsant drugs that cause modest or no induction of hepatic metabolic enzymes OR no anticonvulsant drug:

• Gabapentin

• Lamotrigine

• Valproic acid

• Levetiracetam

• Tiagabine

• Topiramate

• Zonisamide

• Felbamate

• Induction therapy: Patients in both groups receive oral celecoxib twice* daily on weeks 1-11 and undergo radiotherapy 5 days a week on weeks 2-7.

• Maintenance therapy: Patients receive oral celecoxib twice daily. Courses repeat every 4 weeks in the absence of disease progression or unacceptable toxicity.

NOTE: *Patients receive only 1 dose on the first day of celecoxib administration.

Patients are followed every 2 months.

PROJECTED ACCRUAL: A total of 44 patients (22 per group) will be accrued for this study within approximately 8 months.

Study Design

• Study Type: Interventional
• Actual Enrollment: 35 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Pharmacokinetic Study of the Interaction Between Celecoxib and Anticonvulsant Drugs in Patients With Newly Diagnosed Glioblastoma Multiforme Undergoing Radiation Therapy
• Study Start Date: Oct 1, 2003
• Actual Primary Completion Date: May 1, 2005
• Actual Study Completion Date: May 1, 2006

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: p450 ( +EIASD) on p450 inhibitor (Patients taking anttiseizure drugs that are known to induce the hepatic drug-metabolizing enzymes - including phenytoin, carbamazepine, phenobarbital, primidone and oxcarbazepine) celecoxib and radiation therapy will be adminstered with this arm	Radiation: radiation therapy; Radiation is standard treatment 6000cGy in 30 fractions. Patients will receive celecoxib 400 mg bid during RT treatment; Other Names: RT ; Drug: Celecoxib; Celecoxib will begin 1 week prior to RT at 400mg bid orally. One day 1 only 1 dose will be administered. Starting on day 2 and throughout treatment until progression, 2 doses will be administered at least 12 hours apart. Celecoxib will continue throughout the 6 week course of RT.; Other Names: Cox2
Active Comparator: nonp450 (-EIASD) not on p450 inhibitor (Patients either NOT taking anti-seizure drugs or ones that are known to not significantly influence the hepatic drug-metabolizing enzymes - including gabapentin, lamotrigine, valproic acid, levetiracetam, tiagabine,topiramate, zonisamide and filbamate. celecoxib and radiation therapy will be adminstered with this arm	Radiation: radiation therapy; Radiation is standard treatment 6000cGy in 30 fractions. Patients will receive celecoxib 400 mg bid during RT treatment; Other Names: RT ; Drug: Celecoxib; Celecoxib will begin 1 week prior to RT at 400mg bid orally. One day 1 only 1 dose will be administered. Starting on day 2 and throughout treatment until progression, 2 doses will be administered at least 12 hours apart. Celecoxib will continue throughout the 6 week course of RT.; Other Names: Cox2

Outcome Measures

Primary Outcome Measures

1. Effects of Hepatic Enzyme Inducing Drugs Such as Anticonvulsants, on the PK of Celecoxib [First dose of celecoxib through completion of radiation, 6 weeks.]

   subjects will take one dose of celecoxib and will then have 6 hours of blood draws, day 2 subject will take 2 doses of celecoxib 8 hours apart with 2 additional blood samples, one hour apart. Subject, will continue to take 2 doses of celecoxib for 6 weeks, with a sample (PK) drawn every week prior to the first dose of the week. Comparison of Cmax of Celecoxib is reported

Secondary Outcome Measures

1. Overall Survival [date pt started treatment to date pt last known alive]

   duration of survival when celecoxib is administered concurrently with radiation in pts with newly diagnosed glioblastoma multiforme

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

DISEASE CHARACTERISTICS:

• Histologically confirmed glioblastoma multiforme

• Supratentorial

• Grade IV astrocytoma

PATIENT CHARACTERISTICS:

Age

• 18 and over

Performance status

• Karnofsky 60-100%

Life expectancy

• Not specified

Hematopoietic

• Absolute neutrophil count at least 1,500/mm^3

• Platelet count at least 100,000/mm^3

• Hemoglobin at least 9.0 g/dL

Hepatic

• Bilirubin no greater than 1.5 mg/dL

• Transaminases no greater than 4 times upper limit of normal

Renal

• Creatinine no greater than 1.7 mg/dL

• Creatinine clearance at least 60 mL/min

• No prior renal toxicity with nonsteroidal anti-inflammatory drugs

Other

• Not pregnant or nursing

• Negative pregnancy test

• Fertile patients must use effective contraception

• Mini mental score at least 15

• No history of peptic disease

• No serious concurrent infection

• No other medical illness that would preclude study participation

• No other malignancy within the past 5 years except curatively treated carcinoma in situ or basal cell skin cancer

• No allergy to sulfonamides

• Able to tolerate cyclo-oxygenase-2 (COX-2) inhibitors

PRIOR CONCURRENT THERAPY:

Biologic therapy

• No prior immunotherapy or biologic agents for the malignancy, including any of the following:

• Immunotoxins

• Immunoconjugates

• Antisense agents

• Peptide receptor antagonists

• Interferons

• Interleukins

• Tumor-infiltrating lymphocytes

• Lymphokine-activated killer cells

• Gene therapy

• No concurrent prophylactic growth factors (e.g., filgrastim [G-CSF] or sargramostim [GM-CSF])

Chemotherapy

• No prior chemotherapy for the malignancy

Endocrine therapy

• No prior hormonal therapy for the malignancy

• Prior glucocorticoid therapy allowed

• Concurrent corticosteroids allowed provided there has been no dose increase within the past 5 days

Radiotherapy

• No prior radiotherapy for the malignancy

Surgery

• Recovered from prior surgery

Other

• At least 1 week since prior fluconazole

• More than 10 days since prior anticonvulsant drugs that induce hepatic metabolic enzymes (Group A)

• No other prior therapy for the malignancy

• No concurrent enrollment in another therapeutic clinical trial

• No concurrent fluconazole

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	H. Lee Moffitt Cancer Center and Research Institute	Tampa	Florida	United States	33612-9497
2	Winship Cancer Institute of Emory University	Atlanta	Georgia	United States	30322
3	Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins	Baltimore	Maryland	United States	21231-2410
4	Massachusetts General Hospital Cancer Center	Boston	Massachusetts	United States	02114-2617
5	Comprehensive Cancer Center at Wake Forest University	Winston-Salem	North Carolina	United States	27157-1030
6	Cleveland Clinic Taussig Cancer Center	Cleveland	Ohio	United States	44195
7	Abramson Cancer Center of the University of Pennsylvania	Philadelphia	Pennsylvania	United States	19104-4283

Sponsors and Collaborators

• Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
• National Cancer Institute (NCI)

Investigators

• Study Chair: Stuart A. Grossman, MD, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Study Documents (Full-Text)

None provided.

More Information

Publications

• Grossman SA, Olson J, Batchelor T, Peereboom D, Lesser G, Desideri S, Ye X, Hammour T, Supko JG; New Approaches to Brain Tumor Therapy CNS Consortium. Effect of phenytoin on celecoxib pharmacokinetics in patients with glioblastoma. Neuro Oncol. 2008 Apr;10(2):190-8. doi: 10.1215/15228517-2007-055. Epub 2008 Feb 20.

• Responsible Party: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
• ClinicalTrials.gov Identifier: NCT00068770
• Other Study ID Numbers: NABTT-2100 CDR0000328117; U01CA062475; NABTT-2100; JHOC-NABTT-2100
• First Posted: Sep 11, 2003
• Last Update Posted: Mar 18, 2015
• Last Verified: Mar 1, 2015

• Keywords provided by Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins: adult glioblastoma; adult giant cell glioblastoma; adult gliosarcoma
• Additional relevant MeSH terms: Nervous System Neoplasms; Central Nervous System Neoplasms; Celecoxib

Study Results

Participant Flow

Recruitment Details	pts were enrolled on this study from October 2003 to September 2004. Pts were enrolled in an outpatient clinical setting
Pre-assignment Detail	pts were assigned to an arm at the time of enrollment

Arm/Group Title	nonp450	p450
Arm/Group Description	not on p450 inhibitor celecoxib : radiation therapy :	on p450 inhibitor celecoxib : radiation therapy :
Period Title: Overall Study
STARTED	13	22
COMPLETED	13	22
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	p450 ( +EIASD)	nonp450 (-EIASD)	Total
Arm/Group Description	on p450 inhibitor (Patients taking anttiseizure drugs that are known to induce the hepatic drug-metabolizing enzymes - including phenytoin, carbamazepine, phenobarbital, primidone and oxcarbazepine)	not on p450 inhibitor (Patients either NOT taking anti-seizure drugs or ones that are known to not significantly influence the hepatic drug-metabolizing enzymes - including gabapentin, lamotrigine, valproic acid, levetiracetam, tiagabine,topiramate, zonisamide and filbamate.	Total of all reporting groups
Overall Participants	22	13	35
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	58 (12)	56 (17)	57 (26)
Sex: Female, Male (Count of Participants)
Female	8 36.4%	7 53.8%	15 42.9%
Male	14 63.6%	6 46.2%	20 57.1%
Karnofsky Perfomance Status (KPS) (scores on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [scores on a scale]	88 (11)	83 (9)	86 (10)
Mini Mental State Exam Score (scores on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [scores on a scale]	28 (4)	28 (3)	28 (3)
Corticosteroid therapy (Number) [Number]
Yes	18 81.8%	11 84.6%	29 82.9%
No	4 18.2%	2 15.4%	6 17.1%
Prior Surgery (Participant) [Number]
Craniotomy	21	10	31
Biopsy	1	3	4

Outcome Measures

1. Primary Outcome

Title	Effects of Hepatic Enzyme Inducing Drugs Such as Anticonvulsants, on the PK of Celecoxib
Description	subjects will take one dose of celecoxib and will then have 6 hours of blood draws, day 2 subject will take 2 doses of celecoxib 8 hours apart with 2 additional blood samples, one hour apart. Subject, will continue to take 2 doses of celecoxib for 6 weeks, with a sample (PK) drawn every week prior to the first dose of the week. Comparison of Cmax of Celecoxib is reported
Time Frame	First dose of celecoxib through completion of radiation, 6 weeks.

Outcome Measure Data

Analysis Population Description

pts who had PK data for the first dose of celecoxib. observations were excluded if sample was not collected within 12 +/- 2h after taking prior dose, was drawn after dosing on same day or determine to be outlier by dixon's test. PK data was available for 15 pts in the +EIASD group and 12 pts in the -EIASD group

Arm/Group Title	nonp450	p450
Arm/Group Description	not on p450 inhibitor celecoxib : radiation therapy :	on p450 inhibitor celecoxib : radiation therapy :
Measure Participants	12	15
Geometric Mean (Standard Deviation) [(ng/ml)]	1752 (550)	1813 (813)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	nonp450, p450
	Comments	two independent group comparisons
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.82
	Comments	not adjusted
	Method	t-test, 2 sided
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	3.5
	Confidence Interval	(2-Sided) 95%; 1.5 to 5.5
	Parameter Dispersion	Type: Standard Deviation; Value: 1
	Estimation Comments

2. Secondary Outcome

Title	Overall Survival
Description	duration of survival when celecoxib is administered concurrently with radiation in pts with newly diagnosed glioblastoma multiforme
Time Frame	date pt started treatment to date pt last known alive

Outcome Measure Data

Analysis Population Description

latest survial data was obtained on May 30, 2006. 31/35 pts had died (89%) 21 in the +EIASD group and 10 in -EIASD group

Arm/Group Title	p450 ( +EIASD)	nonp450 (-EIASD)
Arm/Group Description	on p450 inhibitor (Patients taking anttiseizure drugs that are known to induce the hepatic drug-metabolizing enzymes - including phenytoin, carbamazepine, phenobarbital, primidone and oxcarbazepine) latest survial data was obtained on May 30, 2006. 31/35 pts had died (89%) 21 in the +EIASD group and 10 in -EIASD group	not on p450 inhibitor (Patients either NOT taking anti-seizure drugs or ones that are known to not significantly influence the hepatic drug-metabolizing enzymes - including gabapentin, lamotrigine, valproic acid, levetiracetam, tiagabine,topiramate, zonisamide and filbamate. latest survial data was obtained on May 30, 2006. 31/35 pts had died (89%) 21 in the +EIASD group and 10 in -EIASD group
Measure Participants	21	10
Mean (95% Confidence Interval) [months]	11.5	16

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	nonp450, p450
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	equivalence analysis
Statistical Test of Hypothesis	p-Value	0.11
	Comments
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	2.7
	Confidence Interval	(2-Sided) 95%; 1.1 to 6.3
	Parameter Dispersion	Type: Standard Deviation; Value: 1.8
	Estimation Comments

Adverse Events

Time Frame	until pts progressed off treatment - in this study approximately avg 117 days.
Arm/Group Title	P450 ARM		Non P450 ARM
Arm/Group Description	on p450 inhibitor (Patients taking anttiseizure drugs that are known to induce the hepatic drug-metabolizing enzymes - including phenytoin, carbamazepine, phenobarbital, primidone and oxcarbazepine)		NOT on p450 inhibitor *non P450 ARM (Patients either NOT taking anti-seizure drugs or ones that are known to not significantly influence the hepatic drug-metabolizing enzymes - including gabapentin, lamotrigine, valproic acid, levetiracetam, tiagabine,topiramate, zonisamide and filbamate, Keppra.
All Cause Mortality
	P450 ARM		Non P450 ARM
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	P450 ARM		Non P450 ARM
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/22 (0%)		0/13 (0%)
Other (Not Including Serious) Adverse Events
	P450 ARM		Non P450 ARM
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	22/22 (100%)		13/13 (100%)
Blood and lymphatic system disorders
Hemoglobin / anemia	6/22 (27.3%)	8	2/13 (15.4%)	3
Ear and labyrinth disorders
Auditory/Hearing	1/22 (4.5%)	2	0/13 (0%)	0
vision - blurred vision	1/22 (4.5%)	1	0/13 (0%)	0
Endocrine disorders
cushingoid appearance	5/22 (22.7%)	6	5/13 (38.5%)	7
Salivary Gland Changes	0/22 (0%)	0	1/13 (7.7%)	1
Eye disorders
tearing	1/22 (4.5%)	1	1/13 (7.7%)	1
Gastrointestinal disorders
abdominal pain or cramping	1/22 (4.5%)	2	1/13 (7.7%)	1
constipation	4/22 (18.2%)	5	1/13 (7.7%)	1
dyspepsia/heartburn	4/22 (18.2%)	5	5/13 (38.5%)	5
gastritis	1/22 (4.5%)	1	0/13 (0%)	0
dry mouth	1/22 (4.5%)	1	0/13 (0%)	0
nausea	5/22 (22.7%)	5	4/13 (30.8%)	4
vomiting	1/22 (4.5%)	1	1/13 (7.7%)	1
General disorders
edema	5/22 (22.7%)	6	1/13 (7.7%)	1
fatigue	7/22 (31.8%)	8	6/13 (46.2%)	7
Infections and infestations
infection without neutropenia	0/22 (0%)	0	1/13 (7.7%)	1
Injury, poisoning and procedural complications
radiation dermatitis	1/22 (4.5%)	1	0/13 (0%)	0
Investigations
weight gain	1/22 (4.5%)	1	0/13 (0%)	0
alkaline phosphatase	5/22 (22.7%)	11	1/13 (7.7%)	1
Platelets	3/22 (13.6%)	4	4/13 (30.8%)	5
Activated partial thromboplastin time prolonged	1/22 (4.5%)	1	0/13 (0%)	0
Asoartate aminotransferase (SGOT)	2/22 (9.1%)	2	1/13 (7.7%)	1
alanine aminotransferase (SGPT)	3/22 (13.6%)	6	2/13 (15.4%)	5
bilirubin	2/22 (9.1%)	2	1/13 (7.7%)	1
white blood count	4/22 (18.2%)	6	0/13 (0%)	0
Metabolism and nutrition disorders
anorexia	5/22 (22.7%)	5	4/13 (30.8%)	4
dehydration	0/22 (0%)	0	1/13 (7.7%)	1
Hyperglycemia	7/22 (31.8%)	15	2/13 (15.4%)	4
Hyperkalemia	1/22 (4.5%)	2	3/13 (23.1%)	3
hypernatremia	1/22 (4.5%)	1	0/13 (0%)	0
Hypocalcemia	3/22 (13.6%)	5	1/13 (7.7%)	1
hypoglycemia	2/22 (9.1%)	4	1/13 (7.7%)	1
hypokalemia	2/22 (9.1%)	2	0/13 (0%)	0
hypomagnesemia	2/22 (9.1%)	4	0/13 (0%)	0
hyponatremia	2/22 (9.1%)	2	0/13 (0%)	0
Musculoskeletal and connective tissue disorders
muscle weakness (not due to neuropathy)	4/22 (18.2%)	4	2/13 (15.4%)	2
Nervous system disorders
ataxia	3/22 (13.6%)	3	1/13 (7.7%)	1
Dizziness/lightheadedness	5/22 (22.7%)	6	0/13 (0%)	0
headache	6/22 (27.3%)	7	4/13 (30.8%)	5
memory loss	0/22 (0%)	0	1/13 (7.7%)	1
neurology -cranial	2/22 (9.1%)	2	1/13 (7.7%)	1
neuropathy-motor	5/22 (22.7%)	6	0/13 (0%)	0
neuropathy - sensory	1/22 (4.5%)	1	0/13 (0%)	0
Seizure	2/22 (9.1%)	2	1/13 (7.7%)	1
speech impairment	2/22 (9.1%)	2	1/13 (7.7%)	1
taste disturbance	0/22 (0%)	0	1/13 (7.7%)	1
tremor	2/22 (9.1%)	2	0/13 (0%)	0
Photophobia	2/22 (9.1%)	2	0/13 (0%)	0
Psychiatric disorders
confusion	5/22 (22.7%)	5	1/13 (7.7%)	1
Insomnia	0/22 (0%)	0	1/13 (7.7%)	1
depression	1/22 (4.5%)	1	1/13 (7.7%)	1
anxiety	2/22 (9.1%)	3	2/13 (15.4%)	2
Renal and urinary disorders
incontinence	1/22 (4.5%)	1	0/13 (0%)	0
urinary frequency/urgency	2/22 (9.1%)	2	0/13 (0%)	0
Respiratory, thoracic and mediastinal disorders
dyspnea	1/22 (4.5%)	1	1/13 (7.7%)	1
Skin and subcutaneous tissue disorders
alopecia	2/22 (9.1%)	2	3/13 (23.1%)	3
rash/desquamation	3/22 (13.6%)	3	3/13 (23.1%)	4
dry skin	0/22 (0%)	0	1/13 (7.7%)	1
Vascular disorders
Hypotension	0/22 (0%)	0	1/13 (7.7%)	1

Limitations/Caveats

Study ended early when results from another study became available documenting Temozolomide (TMZ) and radiation improved survival, we felt it was unethical to continue this study, our study did not include TMZ.

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.