Dose-Intense Temozolomide in Recurrent Glioblastoma

• Sponsor: Patrick Y. Wen, MD (Other)
• Overall Status: Completed
• CT.gov ID: NCT00657267
• Collaborator: Brigham and Women's Hospital (Other), Massachusetts General Hospital (Other), University of Pennsylvania (Other), Wake Forest University Health Sciences (Other), Tufts Medical Center (Other), Dartmouth-Hitchcock Medical Center (Other), Schering-Plough (Industry)
• Enrollment: 58
• Locations: 6
• Arm: 1
• Duration (Months): 65
• Patients Per Site: 9.7
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

Temozolomide (Temodar) is an FDA approved medication for the treatment of newly diagnosed glioblastomas. In this study, we will be using temozolomide to treat recurrent glioblastomas. We will be using a different dose and schedule than the FDA approved dose and schedule. The purpose of this study is to determine if patients that have failed standard temozolomide treatment will respond to temozolomide when given at a different dose and schedule (21 days every 28 days).

Condition or Disease	Intervention/Treatment	Phase
Glioblastoma; Gliosarcoma	Drug: Temozolomide	Phase 2

Detailed Description

• Participants will be given a medication-dosing calendar for each treatment cycle. Each treatment cycle lasts 4 weeks (28 days) during which time they will be taking temozolomide orally once a day for the first three weeks.

• At the end of each cycle (day 28, +/- 2 days), the following procedures will be performed: Complete physical examination including a neurological exam; vital signs; a review of current medications and symptoms; blood samples; a pregnancy test for women of child-bearing potential; self-administered quality of life questionnaire; brain MRI or CT scan.

• Participants may continue taking temozolomide until their tumor grows or if they experience unacceptable side effects.

Study Design

• Study Type: Interventional
• Actual Enrollment: 58 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase 2 Study of Dose-Intense Temozolomide in Recurrent Glioblastoma
• Study Start Date: May 1, 2008
• Actual Primary Completion Date: Nov 1, 2011
• Actual Study Completion Date: Oct 1, 2013

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Single-Arm Study	Drug: Temozolomide; Taken orally daily for the first three weeks of a four-week cycle.; Other Names: Temodar

Outcome Measures

Primary Outcome Measures

1. 6 Month Progression Free Survival [6 months]

   Progression is defined using Modified Macdonald Criteria , using a >/= 25% increase in the sum of products of all measurable lesions over smallest sum observed (over baseline if no decrease) using the same techniques as baseline, OR clear worsening of any evaluable disease, OR appearance of any new lesion/site, OR clear clinical worsening or failure to return for evaluation due to death or deteriorating condition (unless clearly unrelated to this cancer).

Secondary Outcome Measures

1. Overall Survival [From patient registration until end of study, assessed up to 54 months]

2. Radiographic Response [From patient registration until end of study, assessed up to 54 months]

   Responders on study are those with a best response of either CR or PR. Per Modified Macdonald Criteria for lesions assessed by MRI/CT: Complete Response (CR) = Complete disappearance of all measurable and evaluable disease, no new lesions, no evidence of non-evaluable disease, with no steroids. Partial Response (PR) >/= 50% decrease under baseline in the sum of products of perpendicular diameters of all measurable lesions, no progression of evaluable disease, no new lesions, with steroid dose @ time of response </= max dose w/in the first 8 weeks of therapy.

3. Time to Progression. [From patient registration until end of study, assessed up to 54 months]

   Progression is defined using Modified Macdonald Criteria , using a >/= 25% increase in the sum of products of all measurable lesions over smallest sum observed (over baseline if no decrease) using the same techniques as baseline, OR clear worsening of any evaluable disease, OR appearance of any new lesion/site, OR clear clinical worsening or failure to return for evaluation due to death or deteriorating condition (unless clearly unrelated to this cancer).

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Must provide independent consent or must demonstrate willingness to participate in the study and to adhere to dose and visit schedules.

• 18 years of age or older (of either sex, and of any race)

• Histologic diagnosis of GBM or gliosarcoma with an unequivocal progression by MRI or CT scan

• Must have received standard combined modality therapy as first-line treatment consisting of RT plus concomitant temozolomide followed by adjuvant temozolomide (at least 2 cycles of adjuvant temozolomide)

• Gadolinium MRI or contrast CT scan must be obtained within 14 days prior to registration, and must be on a steroid dose that has been stable for at least 5 days.

• Karnofsky Performance status of 60 or greater

• Life expectancy of at least 8 weeks

• Recovered from the toxic effects of prior therapy, and 21 days must have elapsed since prior treatment with temozolomide

o If a patient has residual toxicity from any previous treatment, toxicity must be ≤ Grade 1

• Laboratory tests within parameters outlined in the protocol

• Female subjects of childbearing potential & male subjects with female partner of childbearing potential must agree to use a medically accepted method of contraception or be surgically sterilized prior to Screening, while receiving protocol-specified medication, and for 30 days after stopping the study medication

• Negative pregnancy test within 48 hours prior to dosing with the study drug (for female subjects of childbearing potential)

• Free of any clinically relevant disease that would, in the Principal Investigator's opinion, interfere with the conduct of the study or study evaluations

• Must be able to adhere to the dosing and visit schedules, and agree to record medication times, concomitant medications, and adverse events (AEs) accurately and consistently in a daily diary

• Unstained slides (at least 15 of 10 micron thickness, or 20 when < 10 micron thickness)or 1 tissue block must be available from the original diagnostic biopsy/surgery or from the biopsy/surgery recurrence

• Participants who have undergone recent resection of recurrent or progressive tumor will be eligible provided at least 2 weeks has elapsed since surgery, and subjects have recovered from surgical-related trauma

• Residual disease following resection of recurrent GBM or gliosarcoma is not mandated for eligibility into the study.

Exclusion Criteria:

• Participant has received a dosing schedule of temozolomide other than 75 mg/m2/day for 42 days during RT followed by adjuvant temozolomide at a dose of 150-200 mg/m2/day for 5 days of a 28-day schedule (standard dose adjustments for toxicity are allowed)

• Any other anti-tumor agent other than standard surgical resection, RT and temozolomide prior to enrollment or during the study period

• Received treatment with BCNU (Gliadel) wafers or GliaSite

• Progressed prior to receiving at least 2 cycles of adjuvant temozolomide

• Pregnant or intending to become pregnant during the study

• In a situation or condition that, in the opinion of the Investigator, may interfere with optimal participation in the study

• Participating in any other clinical study in which an investigational drug is prescribed

• Allergic to or has sensitivity to the study drug or its excipients

• History of any other cancer (except non-melanoma skin cancer or carcinoma in situ of the cervix), unless he/she is in complete remission and has not received treatment for that particular disease for the past 3 or more years

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Tufts Medical Center	Boston	Massachusetts	United States	02111
2	Massachusetts General Hospital	Boston	Massachusetts	United States	02114
3	Dana-Farber Cancer Institute	Boston	Massachusetts	United States	02115
4	Dartmouth-Hitchcock Medical Center	Lebanon	New Hampshire	United States	03756
5	Wake Forest Univsersity	Winston-Salem	North Carolina	United States	27157
6	University Of Pennsylvania	Philadelphia	Pennsylvania	United States	19104

Sponsors and Collaborators

• Patrick Y. Wen, MD
• Brigham and Women's Hospital
• Massachusetts General Hospital
• University of Pennsylvania
• Wake Forest University Health Sciences
• Tufts Medical Center
• Dartmouth-Hitchcock Medical Center
• Schering-Plough

Investigators

• Principal Investigator: Patrick Wen, MD, Dana-Farber Cancer Institute

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Patrick Y. Wen, MD, Director, Center for Neuro-Oncology, Dana-Farber Cancer Institute, Dana-Farber Cancer Institute
• ClinicalTrials.gov Identifier: NCT00657267
• Other Study ID Numbers: 08-013; P05516
• First Posted: Apr 14, 2008
• Last Update Posted: Mar 14, 2014
• Last Verified: Feb 1, 2014

• Keywords provided by Patrick Y. Wen, MD, Director, Center for Neuro-Oncology, Dana-Farber Cancer Institute, Dana-Farber Cancer Institute: recurrent glioblastoma; temodar; temozolomide
• Additional relevant MeSH terms: Glioblastoma; Gliosarcoma; Temozolomide

Study Results

Participant Flow

Recruitment Details	Study activated at DFCI in May 2008 and was eventually activated at MGH, UPENN, Wake Forest University Baptist Medical Center, Dartmouth-Hitchcock Medical Center, and Tufts NEMC.

Arm/Group Title	12 Cycles of Dose-Dense Temozolomide (Single Arm Study)
Arm/Group Description	Temozolomide dose = 100 mg/m2/day for 21 days of every 28-day cycle (75 mg/m2/day for 21 days of every 28-day cycle if pt experienced myelosuppression on prior regimen: gr 1 ANC &/or gr 2 platelets)
Period Title: Overall Study
STARTED	58
COMPLETED	4
NOT COMPLETED	54

Baseline Characteristics

Arm/Group Title	12 Cycles of Dose-Dense Temozolomide (Single Arm Study)
Arm/Group Description	Temozolomide dose = 100 mg/m2/day for 21 days of every 28-day cycle (75 mg/m2/day for 21 days of every 28-day cycle if pt experienced myelosuppression on prior regimen: gr 1 ANC &/or gr 2 platelets)
Overall Participants	58
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	48 82.8%
>=65 years	10 17.2%
Age (years) [Mean (Full Range) ]
Mean (Full Range) [years]	57
Sex: Female, Male (Count of Participants)
Female	23 39.7%
Male	35 60.3%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	54 93.1%
Not Hispanic or Latino	3 5.2%
Unknown or Not Reported	1 1.7%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	0 0%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	2 3.4%
White	51 87.9%
More than one race	2 3.4%
Unknown or Not Reported	3 5.2%
Karnofsky performance status (KPS) at registration (%) [Median (Full Range) ]
Median (Full Range) [%]	90

Outcome Measures

1. Primary Outcome

Title	6 Month Progression Free Survival
Description	Progression is defined using Modified Macdonald Criteria , using a >/= 25% increase in the sum of products of all measurable lesions over smallest sum observed (over baseline if no decrease) using the same techniques as baseline, OR clear worsening of any evaluable disease, OR appearance of any new lesion/site, OR clear clinical worsening or failure to return for evaluation due to death or deteriorating condition (unless clearly unrelated to this cancer).
Time Frame	6 months

Outcome Measure Data

Analysis Population Description

Patients evaluable for imaging analysis, as protocol-defined.

Arm/Group Title	12 Cycles of Dose-Dense Temozolomide (Single Arm Study)
Arm/Group Description	Temozolomide dose = 100 mg/m2/day for 21 days of every 28-day cycle (75 mg/m2/day for 21 days of every 28-day cycle if pt experienced myelosuppression on prior regimen: gr 1 ANC &/or gr 2 platelets)
Measure Participants	55
Number [percentage of evaluable participants]	11 19%

2. Secondary Outcome

Title	Overall Survival
Time Frame	From patient registration until end of study, assessed up to 54 months

Outcome Measure Data

Analysis Population Description

Entire study population

Arm/Group Title	12 Cycles of Dose-Dense Temozolomide (Single Arm Study)
Arm/Group Description	Temozolomide dose = 100 mg/m2/day for 21 days of every 28-day cycle (75 mg/m2/day for 21 days of every 28-day cycle if pt experienced myelosuppression on prior regimen: gr 1 ANC &/or gr 2 platelets)
Measure Participants	58
Median (95% Confidence Interval) [months]	11.7

3. Secondary Outcome

Title	Radiographic Response
Description	Responders on study are those with a best response of either CR or PR. Per Modified Macdonald Criteria for lesions assessed by MRI/CT: Complete Response (CR) = Complete disappearance of all measurable and evaluable disease, no new lesions, no evidence of non-evaluable disease, with no steroids. Partial Response (PR) >/= 50% decrease under baseline in the sum of products of perpendicular diameters of all measurable lesions, no progression of evaluable disease, no new lesions, with steroid dose @ time of response </= max dose w/in the first 8 weeks of therapy.
Time Frame	From patient registration until end of study, assessed up to 54 months

Outcome Measure Data

Analysis Population Description

Of the 58 patients registered, 3 of were ineligible for analysis based on path review, which is why only 55 patients were evaluated for this outcome.

Arm/Group Title	Partial Response	Complete Response
Arm/Group Description	Partial Responders on study; Temozolomide dose = 100 mg/m2/day for 21 days of every 28-day cycle (75 mg/m2/day for 21 days of every 28-day cycle if pt experienced myelosuppression on prior regimen: gr 1 ANC &/or gr 2 platelets)	Complete responders on study; Temozolomide dose = 100 mg/m2/day for 21 days of every 28-day cycle (75 mg/m2/day for 21 days of every 28-day cycle if pt experienced myelosuppression on prior regimen: gr 1 ANC &/or gr 2 platelets)
Measure Participants	55	55
Number [percentage of participants evaluated]	13 22.4%	0 NaN

4. Secondary Outcome

Title	Time to Progression.
Description	Progression is defined using Modified Macdonald Criteria , using a >/= 25% increase in the sum of products of all measurable lesions over smallest sum observed (over baseline if no decrease) using the same techniques as baseline, OR clear worsening of any evaluable disease, OR appearance of any new lesion/site, OR clear clinical worsening or failure to return for evaluation due to death or deteriorating condition (unless clearly unrelated to this cancer).
Time Frame	From patient registration until end of study, assessed up to 54 months

Outcome Measure Data

Analysis Population Description

Of the 58 patients registered, 3 of were ineligible for analysis based on path review, which is why only 55 patients were evaluated for this outcome.

Arm/Group Title	12 Cycles of Dose-Dense Temozolomide (Single Arm Study)
Arm/Group Description	Temozolomide dose = 100 mg/m2/day for 21 days of every 28-day cycle (75 mg/m2/day for 21 days of every 28-day cycle if pt experienced myelosuppression on prior regimen: gr 1 ANC &/or gr 2 platelets)
Measure Participants	55
Median (95% Confidence Interval) [days]	56

Adverse Events

Time Frame	SAEs are reported from the signing of the consent form until the 30-Days-After-Last Dose-of Study Drug Visit. (Any SAEs occurring within the 30 days after last dose of study drug need to be followed until resolved.)
Adverse Event Reporting Description	AEs collected via regular Investigator assessment and regular laboratory testing.
Arm/Group Title	12 Cycles of Dose-Dense Temozolomide (Single Arm Study)
Arm/Group Description	All 58 participants who started treatment: Temozolomide dose = 100 mg/m2/day for 21 days of every 28-day cycle (75 mg/m2/day for 21 days of every 28-day cycle if pt experienced myelosuppression on prior regimen: gr 1 ANC &/or gr 2 platelets
All Cause Mortality
	12 Cycles of Dose-Dense Temozolomide (Single Arm Study)
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	12 Cycles of Dose-Dense Temozolomide (Single Arm Study)
	Affected / at Risk (%)	# Events
Total	19/58 (32.8%)
Blood and lymphatic system disorders
Lymphopenia	1/58 (1.7%)	1
Blood/Bone Marrow - Other	1/58 (1.7%)	1
Neutrophils/granulocytes (ANC/AGC)	1/58 (1.7%)	1
Lymphopenia	7/58 (12.1%)	18
Leukocytes (total WBC)	1/58 (1.7%)	1
Platelets	1/58 (1.7%)	1
Cardiac disorders
Supraventricular and nodal arrhythmia: Sinus tachycardia	1/58 (1.7%)	1
Gastrointestinal disorders
Nausea	1/58 (1.7%)	4
Vomiting	1/58 (1.7%)	4
Diarrhea	1/58 (1.7%)	4
Distension/bloating,	1/58 (1.7%)	1
Pain - Abdomen NOS	1/58 (1.7%)	1
Colitis	1/58 (1.7%)	1
Enteritis	1/58 (1.7%)	2
General disorders
Disease Progression NOS	2/58 (3.4%)	2
Pain - Chest NOS	1/58 (1.7%)	1
Fatigue	1/58 (1.7%)	1
Metabolism and nutrition disorders
Glucose, serum-high (hyperglycemia)	1/58 (1.7%)	1
Potassium, serum-low (Hypokalemia)	1/58 (1.7%)	1
Albumin, serum-low (hypoalbuminemia)	1/58 (1.7%)	1
Musculoskeletal and connective tissue disorders
Extremity-lower (gait/walking)	1/58 (1.7%)	1
Muscle weakness - left-sided	1/58 (1.7%)	1
Fracture	1/58 (1.7%)	1
Musculoskeletal - Other	2/58 (3.4%)	3
Nervous system disorders
Seizure	6/58 (10.3%)	6
Neurology - Other	2/58 (3.4%)	2
Speech impairment	2/58 (3.4%)	2
Pain - headache	1/58 (1.7%)	2
Vascular disorders
Thrombosis/thrombus/embolism	2/58 (3.4%)	2
Other (Not Including Serious) Adverse Events
	12 Cycles of Dose-Dense Temozolomide (Single Arm Study)
	Affected / at Risk (%)	# Events
Total	58/58 (100%)
Blood and lymphatic system disorders
Hemoglobin	25/58 (43.1%)
Leukocytes	34/58 (58.6%)
Lymphopenia	49/58 (84.5%)
Neutrophils	17/58 (29.3%)
Platelets	30/58 (51.7%)
INR	3/58 (5.2%)
Edema limb	13/58 (22.4%)
Endocrine disorders
Cushingnoid appearance	5/58 (8.6%)
Eye disorders
Cataract	3/58 (5.2%)
Vision-blurred	8/58 (13.8%)
Gastrointestinal disorders
Anorexia	4/58 (6.9%)
Constipation	19/58 (32.8%)
Diarrhea w/o prior colostomy	9/58 (15.5%)
Dyspepsia	4/58 (6.9%)
Incontinence- anal	3/58 (5.2%)
Nausea	18/58 (31%)
Vomiting	7/58 (12.1%)
Abdomen- pain	3/58 (5.2%)
General disorders
Fatigue	41/58 (70.7%)
Insomnia	10/58 (17.2%)
Metabolism and nutrition disorders
Alkaline phosphatase	7/58 (12.1%)
ALT- SGPT	14/58 (24.1%)
AST- SGOT	13/58 (22.4%)
Bicarbonate	10/58 (17.2%)
Bilirubin	8/58 (13.8%)
Creatinine	4/58 (6.9%)
Hyperglycemia	39/58 (67.2%)
Hyperkalemia	12/58 (20.7%)
Hypernatremia	6/58 (10.3%)
Hypoalbuminemia	12/58 (20.7%)
Hypocalcemia	13/58 (22.4%)
Hypoglycemia	5/58 (8.6%)
Hypokalemia	8/58 (13.8%)
Hyponatremia	9/58 (15.5%)
Hypophosphatemia	8/58 (13.8%)
Proteinuria	3/58 (5.2%)
Musculoskeletal and connective tissue disorders
Extremity-lower (gait/walking)	14/58 (24.1%)
Nonneuropathic generalized weakness	7/58 (12.1%)
Nonneuropathic lower extr muscle weak	6/58 (10.3%)
Nonneuropathic right-side muscle weak	3/58 (5.2%)
Back- pain	5/58 (8.6%)
Extremity-limb- pain	4/58 (6.9%)
Joint- pain	5/58 (8.6%)
Nervous system disorders
Anxiety	6/58 (10.3%)
Ataxia	4/58 (6.9%)
Cognitive disturbance	5/58 (8.6%)
Confusion	15/58 (25.9%)
Depressed level of consciousness	3/58 (5.2%)
Depression	9/58 (15.5%)
Dizziness	9/58 (15.5%)
Memory impairment	22/58 (37.9%)
Neuropathy CN II vision	5/58 (8.6%)
Neuropathy CN VII face-motor / taste	6/58 (10.3%)
Neuropathy CN VIII hearing & balance	6/58 (10.3%)
Neuropathy-motor	22/58 (37.9%)
Neuropathy-sensory	14/58 (24.1%)
Seizure	11/58 (19%)
Speech impairment	17/58 (29.3%)
Tremor	4/58 (6.9%)
Head/headache	24/58 (41.4%)
Renal and urinary disorders
Incontinence urinary	10/58 (17.2%)
Urinary frequency/urgency	3/58 (5.2%)
Respiratory, thoracic and mediastinal disorders
Cough	6/58 (10.3%)
Dyspnea	5/58 (8.6%)
Voice changes/dysarthria	3/58 (5.2%)
Skin and subcutaneous tissue disorders
Rash/desquamation	3/58 (5.2%)

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 more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.