Radiation Therapy and Temozolomide Followed by Temozolomide and Poly ICLC in Treating Patients With Newly Diagnosed GBM

• Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins (Other)
• Overall Status: Completed
• CT.gov ID: NCT00262730
• Collaborator: National Cancer Institute (NCI) (NIH)
• Enrollment: 97
• Locations: 9
• Arm: 1
• Duration (Months): 51
• Patients Per Site: 10.8
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

RATIONALE: Radiation therapy uses high-energy x-rays to kill tumor cells. Drugs used in chemotherapy, such as temozolomide, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Biological therapies, such as poly ICLC, may stimulate the immune system in different ways and stop tumor cells from growing. Giving poly ICLC after radiation therapy and temozolomide may stop any remaining tumor cells from growing.

PURPOSE: This phase II trial is studying how well giving radiation therapy together with temozolomide followed by temozolomide and poly ICLC works in treating patients with newly diagnosed glioblastoma multiforme.

Condition or Disease	Intervention/Treatment	Phase
Glioblastoma Multiforme	Drug: poly ICLC; Drug: temozolomide; Radiation: radiation therapy	Phase 2

Detailed Description

OBJECTIVES:

Primary

• Evaluate the safety and efficacy of radiation plus low-dose temozolomide followed by adjuvant temozolomide and intramuscular poly ICLC for adult patients with newly diagnosed glioblastoma multiforme.

Secondary

• Estimate the frequency of toxicity associated with this treatment regimen.

OUTLINE: This is an open-label, multicenter study.

• Induction chemoradiotherapy: Patients undergo radiotherapy once daily, 5 days a week, for 6 weeks. During the same 6 weeks, patients also receive oral temozolomide once daily. Four weeks later, patients are evaluated for disease progression. Patients with progressive disease are removed from the study. Patients with no progressive disease proceed to maintenance therapy.

• Maintenance therapy: Patients receive oral temozolomide once daily on days 1-5 (week 1). Patients also receive poly ICLC intramuscularly three times a week in weeks 2-8. Courses repeat every 9 weeks in the absence of disease progression or unacceptable toxicity.

After completion of study therapy, patients are followed every 2 months for survival.

PROJECTED ACCRUAL: A total of 96 patients will be accrued for this study.

Study Design

• Study Type: Interventional
• Actual Enrollment: 97 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase II Trial of Radiation Plus Temozolomide Followed by Adjuvant Temozolomide and Poly-ICLC in Patients With Newly Diagnosed Glioblastoma Multiforme
• Study Start Date: Jan 1, 2006
• Actual Primary Completion Date: Aug 1, 2009
• Actual Study Completion Date: Apr 1, 2010

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Treatment Arm RT + TMZ 6wks, followed by poly ICLC, temozolomide, radiation: radiation therapy	Drug: poly ICLC; 20 mcg/kg 3x each week (Maintenance cycles); Other Names: Holtonol ; Drug: temozolomide; daily 75mg/m2 6wks concomitant therapy Wk 1 - days 1-5 150-200 mg/m2 maintenance cycles (adjuvant); Other Names: Temodar ; Radiation: radiation therapy; RT: 60 Gy (6 weeks) concomitant therapy; Other Names: RT

Outcome Measures

Primary Outcome Measures

1. Survival [30 months]

   survival time is defined from time of histological diagnosis to death occurrence.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 120 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

DISEASE CHARACTERISTICS:

• Histologically confirmed supratentorial grade IV astrocytoma (glioblastoma multiforme) by biopsy or resection within the past 3 months

PATIENT CHARACTERISTICS:

• Karnofsky performance status ≥ 60%

• Absolute neutrophil count ≥ 1500/mm^3

• Platelet count ≥ 100,000/mm^3

• Bilirubin ≤ 1.5 mg/dL

• Transaminases ≤ 4 times above the upper limits of the institutional normal

• Creatinine ≤ 1.7 mg/dL

• Not pregnant or breast-feeding

• Patients must agree to follow acceptable birth control methods to avoid conception

• Negative pregnancy test

• Patients must have a Mini Mental State Exam score of ≥ 15

• No serious concurrent infection or medical illness which would jeopardize the ability of the patient to receive the treatment outlined in this protocol with reasonable safety

• Patients with a concurrent or prior malignancy are ineligible unless they are patients with curatively treated carcinoma-in-situ or basal cell carcinoma of the skin

• Patients who have been free of disease (any prior malignancy) for ≥ five years are eligible for this study

• Patients requiring ongoing therapy for psychoses with antipsychotic medications at the time of enrollment will be ineligible

PRIOR CONCURRENT THERAPY:

• Patients must not have received prior radiation therapy, chemotherapy, immunotherapy or therapy with biologic agent (including immunotoxins, immunoconjugates, antisense, peptide receptor antagonists, interferons, interleukins, TIL, LAK or gene therapy), or hormonal therapy for their brain tumor

• Prior glucocorticoid therapy is allowed

• Patients must be willing to forego other cytotoxic and non-cytotoxic drug therapy against the tumor while being treated with poly ICLC plus temozolomide on this protocol

• No other concurrent therapy for their tumor (i.e., chemotherapeutics or investigational agents)

• Patients who have received prior Gliadel wafers are not eligible for this study

• No concurrent prophylactic filgrastim (G-CSF)

• No concurrent electron, particle, implant, or stereotactic radiosurgery boost

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Lurleen Wallace Comprehensive Cancer at University of Alabama-Birmingham	Birmingham	Alabama	United States	35294
2	H. Lee Moffitt Cancer Center and Research Institute at University of South Florida	Tampa	Florida	United States	33612-9497
3	Winship Cancer Institute of Emory University	Atlanta	Georgia	United States	30322
4	Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins	Baltimore	Maryland	United States	21231-2410
5	Massachusetts General Hospital Cancer Center	Boston	Massachusetts	United States	02114
6	Josephine Ford Cancer Center at Henry Ford Hospital	Detroit	Michigan	United States	48202
7	Wake Forest University Comprehensive Cancer Center	Winston-Salem	North Carolina	United States	27157-1096
8	Cleveland Clinic Taussig Cancer Center	Cleveland	Ohio	United States	44195
9	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: Myrna Rosenfeld, MD, PhD, Abramson Cancer Center of the University of Pennsylvania

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
• ClinicalTrials.gov Identifier: NCT00262730
• Other Study ID Numbers: NABTT-0501; U01CA062475; NABTT-0501 CDR0000454915; NA_00001963
• First Posted: Dec 7, 2005
• Last Update Posted: Jun 12, 2019
• Last Verified: May 1, 2019

• Keywords provided by Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins: adult glioblastoma; adult giant cell glioblastoma; adult gliosarcoma
• Additional relevant MeSH terms: Glioblastoma; Temozolomide; Poly ICLC

Study Results

Participant Flow

Recruitment Details	outpatient clinic

Arm/Group Title	Treatment Arm - All Subjects
Arm/Group Description	poly ICLC, temozolomide, radiation: radiation therapy poly ICLC : 20 mcg/kg 3x each week (Maintenance cycles) temozolomide : daily 75mg/m2 6wks concomitant therapy Wk 1 - days 1-5 150-200 mg/m2 maintenance cycles (adjuvant) radiation therapy : RT: 60 Gy (6 weeks) concomitant therapy
Period Title: Overall Study
STARTED	97
COMPLETED	97
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Treatment Arm - All Subjects
Arm/Group Description	poly ICLC, temozolomide, radiation: radiation therapy poly ICLC : 20 mcg/kg 3x each week (Maintenance cycles) temozolomide : daily 75mg/m2 6wks concomitant therapy Wk 1 - days 1-5 150-200 mg/m2 maintenance cycles (adjuvant) radiation therapy : RT: 60 Gy (6 weeks) concomitant therapy
Overall Participants	97
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	56.6
Sex: Female, Male (Count of Participants)
Female	37 38.1%
Male	60 61.9%
Karnofsky Performance Status (Units on a scale) [Number]
100	34
90	45
80	12
70	3
60	3
Extent of surgery (Patient) [Number]
Biopsy	18
Craniotomy	79
time from diagnosis to radiotherapy (weeks) [Median (Full Range) ]
Median (Full Range) [weeks]	4.4
Baseline Mini-Mental State Examiniation (MMSE) Score (Scores on a Scale) [Number]
30	56
27-29	30
Less than or equal 26	11
Corticosteroid Therapy (Participant) [Number]
Yes	70
No	26
Missing Data	1
Histologic Diagnosis (Patient) [Number]
Glioblastoma	94
Anaplastic Astrocytoma	1
Other	2

Outcome Measures

1. Primary Outcome

Title	Survival
Description	survival time is defined from time of histological diagnosis to death occurrence.
Time Frame	30 months

Outcome Measure Data

Analysis Population Description

all patients who were treated were analyzed (intent to treat)

Arm/Group Title	Treatment Arm - All Subjects
Arm/Group Description	poly ICLC, temozolomide, radiation: radiation therapy poly ICLC : 20 mcg/kg 3x each week (Maintenance cycles) temozolomide : daily 75mg/m2 6wks concomitant therapy Wk 1 - days 1-5 150-200 mg/m2 maintenance cycles (adjuvant) radiation therapy : RT: 60 Gy (6 weeks) concomitant therapy
Measure Participants	97
Mean (95% Confidence Interval) [months]	17.2

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Treatment Arm - All Subjects
	Comments
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	study design has 85% power to detect 25% deduction in hazard rate compared to EORTC Phase 3 results.
Statistical Test of Hypothesis	p-Value	>.1
	Comments
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.8
	Confidence Interval	(2-Sided) 95%; 0.8 to 0.85
	Parameter Dispersion	Type: Standard Deviation; Value: .025
	Estimation Comments

Adverse Events

Time Frame	While on Treatment
Arm/Group Title	Treatment Arm All Subjects
Arm/Group Description	poly ICLC, TMZ, RT: poly ICLC : 20 mcg/kg 3x each week (Maintenance cycles) TMX : daily 75mg/m2 6wks concomitant therapy Wk 1 - days 1-5 150-200 mg/m2 maintenance cycles (adjuvant) RT : RT: 60 Gy (6 weeks) concomitant therapy AEs Grades 4 with Attributions of Possible, probably or definitely related to TMZ AND poly-ICLI
All Cause Mortality
	Treatment Arm All Subjects
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Treatment Arm All Subjects
	Affected / at Risk (%)	# Events
Total	20/97 (20.6%)
Blood and lymphatic system disorders
febrile neutropenia	2/97 (2.1%)	2
hemoglobin increased	2/97 (2.1%)	2
leukopenia	16/97 (16.5%)	16
Gastrointestinal disorders
Diarrhea	1/97 (1%)	1
vomiting	1/97 (1%)	1
General disorders
fatigue	3/97 (3.1%)	3
Infections and infestations
Lung infection	1/97 (1%)	1
Investigations
aspartate aminotransferase increased	1/97 (1%)	1
Neutrophils/granulocytes (ANC/AGC)	20/97 (20.6%)	20
platelet count decreased	9/97 (9.3%)	9
Musculoskeletal and connective tissue disorders
muscle weakness, generalized	1/97 (1%)	1
Nervous system disorders
nausea	1/97 (1%)	1
Skin and subcutaneous tissue disorders
rash	2/97 (2.1%)	2
Other (Not Including Serious) Adverse Events
	Treatment Arm All Subjects
	Affected / at Risk (%)	# Events
Total	97/97 (100%)
Blood and lymphatic system disorders
febrile neutropenia	3/97 (3.1%)	3
anemia	71/97 (73.2%)	760
hemoglobin increase	2/97 (2.1%)	2
leukocytes	2/97 (2.1%)	2
lymphopenia	1/97 (1%)	1
PLTS	59/97 (60.8%)	468
PO4	19/97 (19.6%)	31
platelets	2/97 (2.1%)	3
Cardiac disorders
pain - cardiac/heart/chest	3/97 (3.1%)	3
palpitations	4/97 (4.1%)	4
supraventricular and nodal arrhythmia	1/97 (1%)	1
supraventricular and nodal arrhythmia	1/97 (1%)	1
supraventricular and nodal arrhythmia	1/97 (1%)	1
Ear and labyrinth disorders
ear and labyrinth disorder	4/97 (4.1%)	4
hearing	4/97 (4.1%)	4
otitis	2/97 (2.1%)	2
pain - external ear	1/97 (1%)	1
pain - middle ear	3/97 (3.1%)	3
tinnitus	7/97 (7.2%)	9
Endocrine disorders
cushingoid	8/97 (8.2%)	8
endocrine	1/97 (1%)	1
Eye disorders
cataract	1/97 (1%)	1
dry eye	3/97 (3.1%)	3
ocular/vision disorder	2/97 (2.1%)	2
diplopia (double vision)	3/97 (3.1%)	4
pain - eye	2/97 (2.1%)	2
photosensitivity	1/97 (1%)	1
vision - blurred	16/97 (16.5%)	20
vision - flashing lights/floaters	4/97 (4.1%)	4
watery eye	1/97 (1%)	1
Gastrointestinal disorders
ascites	1/97 (1%)	1
colitis	3/97 (3.1%)	3
constipation	38/97 (39.2%)	52
periodontal disease	1/97 (1%)	1
diarrhea	13/97 (13.4%)	19
distension/bloating	1/97 (1%)	1
dry mouth	2/97 (2.1%)	2
dysphagia	3/97 (3.1%)	3
gastritis	3/97 (3.1%)	3
gastrointestinal	4/97 (4.1%)	8
dyspepsia	12/97 (12.4%)	12
rectal hemorrhage	1/97 (1%)	1
mucositis oral	11/97 (11.3%)	12
nausea	41/97 (42.3%)	64
pain - abdomen	2/97 (2.1%)	2
pain - dental/teeth/peridontal	1/97 (1%)	1
pain - oral	1/97 (1%)	1
pain - stomach	2/97 (2.1%)	2
taste alteration	11/97 (11.3%)	12
ulceration	1/97 (1%)	2
General disorders
cough	18/97 (18.6%)	22
edema	5/97 (5.2%)	5
edema	19/97 (19.6%)	28
fatigue	70/97 (72.2%)	112
fever	9/97 (9.3%)	13
flu like symptoms	3/97 (3.1%)	4
pain - chest/thorax	4/97 (4.1%)	6
pain - other	4/97 (4.1%)	4
rigors/chills	5/97 (5.2%)	7
syndromes - other	1/97 (1%)	1
Hepatobiliary disorders
International Normalized Ratio of prothrombin time	2/97 (2.1%)	2
Immune system disorders
allergic reaction	2/97 (2.1%)	2
Infections and infestations
esophageal hemorrhage	1/97 (1%)	1
infection	42/97 (43.3%)	45
Injury, poisoning and procedural complications
bruising	12/97 (12.4%)	17
fracture	1/97 (1%)	1
injury	1/97 (1%)	1
rash	20/97 (20.6%)	20
Investigations
Alkaline phosphatase increased	19/97 (19.6%)	66
blood bicarbonate decreased	10/97 (10.3%)	13
creatinine increased	3/97 (3.1%)	3
Neutrophils/granulocytes (ANC/AGC)	3/97 (3.1%)	3
PTT	4/97 (4.1%)	10
SGOT/AST	18/97 (18.6%)	37
SGPT/ALT	34/97 (35.1%)	131
total bilirubin	3/97 (3.1%)	5
white blood cells	64/97 (66%)	793
Metabolism and nutrition disorders
anorexia	28/97 (28.9%)	35
dehydration	3/97 (3.1%)	3
hyperglycemia	1/97 (1%)	3
hypercalcemia	6/97 (6.2%)	9
hyperglycemia	65/97 (67%)	246
hyperkalemia	15/97 (15.5%)	32
hypermagnesemia	18/97 (18.6%)	27
hypernatremia	12/97 (12.4%)	20
hypocalcemia	18/97 (18.6%)	33
hypoglycemia	20/97 (20.6%)	41
hypokalemia	18/97 (18.6%)	32
hypomagnesemia	6/97 (6.2%)	9
hyponatremia	20/97 (20.6%)	53
hyperkalemia	1/97 (1%)	1
hypokalemia	3/97 (3.1%)	4
hyponatremia	2/97 (2.1%)	2
uric acid	6/97 (6.2%)	13
weight gain	2/97 (2.1%)	2
weight loss	10/97 (10.3%)	10
Musculoskeletal and connective tissue disorders
arthritis	1/97 (1%)	1
extremity - lower (gait/walking)	1/97 (1%)	1
joint function	2/97 (2.1%)	2
lumbar spine range of motion decreased	1/97 (1%)	1
muscle weakness, generalized or specific area	33/97 (34%)	43
soft tissue	5/97 (5.2%)	7
pain - back	8/97 (8.2%)	10
pain - bone	1/97 (1%)	1
pain - extremity	14/97 (14.4%)	16
pain - joint	16/97 (16.5%)	21
pain - muscle	17/97 (17.5%)	23
pain - neck	6/97 (6.2%)	6
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
hyperpigmentation	1/97 (1%)	1
Nervous system disorders
ataxia	10/97 (10.3%)	12
ischemia cerebrovascular	3/97 (3.1%)	3
cognitive disturbance	2/97 (2.1%)	2
confusion	18/97 (18.6%)	26
dizziness	24/97 (24.7%)	28
encephalopathy	1/97 (1%)	1
hemorrhage	1/97 (1%)	1
hydrocephalus	4/97 (4.1%)	4
memory impairment	27/97 (27.8%)	32
neurological disorder	8/97 (8.2%)	8
neuropathy	58/97 (59.8%)	80
headache	51/97 (52.6%)	80
pyramidal tract dysfunction	1/97 (1%)	1
seizure	34/97 (35.1%)	68
somnolence	4/97 (4.1%)	4
speech impairment	22/97 (22.7%)	34
syncope	3/97 (3.1%)	3
thrombosis/thrombus/embolism	12/97 (12.4%)	14
tremor	6/97 (6.2%)	6
Psychiatric disorders
insomnia	20/97 (20.6%)	26
libido decreased	2/97 (2.1%)	2
mood alteration	36/97 (37.1%)	39
personality/behavioral disorder	1/97 (1%)	1
psychosis	3/97 (3.1%)	3
Renal and urinary disorders
cystitis	1/97 (1%)	1
hemorrhage	1/97 (1%)	1
urinary incontinence	4/97 (4.1%)	5
obstruction	2/97 (2.1%)	2
urinary frequency	3/97 (3.1%)	3
urinary retention	3/97 (3.1%)	3
Reproductive system and breast disorders
pain - breast	1/97 (1%)	1
vaginal discharge	1/97 (1%)	1
Respiratory, thoracic and mediastinal disorders
allergic rhinitis	4/97 (4.1%)	4
dyspnea	15/97 (15.5%)	18
hemorrhage	2/97 (2.1%)	2
hiccups	1/97 (1%)	1
hypoxia	1/97 (1%)	1
paranasal sinus reaction	2/97 (2.1%)	2
pneumothorax	1/97 (1%)	1
pulmonary/upper respiratory	2/97 (2.1%)	2
voice changes	2/97 (2.1%)	2
Skin and subcutaneous tissue disorders
dermatology/skin	5/97 (5.2%)	5
dry skin	4/97 (4.1%)	5
alopecia	39/97 (40.2%)	39
nail changes	1/97 (1%)	1
pain - scalp	3/97 (3.1%)	3
pain - skin	3/97 (3.1%)	3
pruritus/itching	9/97 (9.3%)	11
purpura	2/97 (2.1%)	3
rash - acneiform	4/97 (4.1%)	4
rash - desquamation	20/97 (20.6%)	27
skin breakdown/decubitus ulcer	1/97 (1%)	1
sweating (diaphoresis)	3/97 (3.1%)	3
urticaria	1/97 (1%)	1
Vascular disorders
flushing	1/97 (1%)	1
hot flashes	2/97 (2.1%)	2
hypertension	2/97 (2.1%)	2
hypotension	7/97 (7.2%)	9
vascular - other	2/97 (2.1%)	3

Limitations/Caveats

"Other Adverse Events" not reported for this study. Only serious(grade 3/4)related to either TMZ and/or Poly were reported. Subjects may have experienced grade 1 and grade 2 other adverse event but they have no bearing on clinical outcome of agent

More Information

Certain Agreements

Principal Investigators are NOT 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.