Avastin/Temozolomide/Irinotecan for Unresectable/Multifocal Glioblastoma Multiforme

• Sponsor: Katy Peters (Other)
• Overall Status: Completed
• CT.gov ID: NCT00979017
• Collaborator: Genentech, Inc. (Industry)
• Enrollment: 41
• Location: 1
• Arm: 1
• Duration (Months): 38
• Patients Per Site Per Month: 1.1

Study Details

Study Description

Brief Summary

The primary objective of the study is to determine the efficacy of Avastin in combination with temozolomide and irinotecan in terms of response rate. The secondary objectives are to describe the overall and progression-free survivals of unresectable patients treated with upfront Avastin, temozolomide and irinotecan and to assess the safety of Avastin, temozolomide and irinotecan in unresectable glioblastoma patients.

This is a phase II study with the combination of Avastin, temozolomide and irinotecan for unresectable or multifocal World Health Organization (WHO) grade IV malignant glioma patients. Patients will receive up to four cycles of Avastin, temozolomide and irinotecan. Approximately 41 subjects will take part in this study at Duke.

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

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: Avastin in Combination With Temozolomide and Irinotecan for Unresectable or Multifocal Glioblastoma Multiformes and Gliosarcomas
• Study Start Date: Nov 1, 2009
• Actual Primary Completion Date: Feb 1, 2011
• Actual Study Completion Date: Jan 1, 2013

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Avastin in combination with temozolomide and irinotecan Avastin 10 mg/kg every 14 days. Temozolomide 200 mg/m2 daily x 5 days in a 28-day cycle. Irinotecan dose depends on whether the patient is on an enzyme-inducing antiepileptic drug (EIAED). EIAED 340 mg/m2 every other week and no EIAED 125 mg/m2 every other week. Irinotecan dose also depends on if the patient has the UGT 1A1 polymorphism (7/7). If so, they do not metabolize the irinotecan normally, so these patients will start out at a two dose level reduction. EIAED starting dose will be 275 mg/m2 and no EIAED starting dose will be 75 mg/ m2.

Drug: Avastin; Avastin, by intravenous infusion, 10 mg/kg every 14 days; Other Names: Avastin (bevacizumab) ; Drug: Temozolomide; Oral temozolomide at 200 mg/m2 daily for 5 days; Other Names: Temodar ; Drug: Irinotecan; Irinotecan, by intravenous infusion, every other week (dose dependent upon if taking enzyme-inducing anti-epileptic drugs or if a blood test indicates the patient has the UGT 1A1 polymorphism); Other Names: CPT-11, Camptosar

Outcome Measures

Primary Outcome Measures

1. Response Rate [4 months]

   The percentage of participants with a complete or partial response as determined by a modification of the Response Assessment in Neuro-Oncology (RANO) criteria. Complete Response (CR) was defined as complete disappearance on MR/CT of all enhancing tumor and mass effect, off all corticosteroids (or receiving only adrenal replacement doses) and accompanied by a stable or improving neurologic examination. Partial Response (PR) was defined as greater than or equal to 50% reduction in tumor size on MR/CT by bi-dimensional measurement, on a stable or decreasing dose of corticosteroids and accompanied by a stable or improving neurologic examination. Per the criteria, confirmation of response was required. Response rate = CR+PR.

Secondary Outcome Measures

1. Incidence and Severity of Central Nervous System (CNS) Hemorrhage and Systemic Hemorrhage [4 months]

   Incidence and severity of CNS hemorrhage and systemic hemorrhage- The adverse events for this study were collected using Common Terminology Criteria for Adverse Events (CTCAE) version 3.0, and have been converted to CTCAE version 4.0 for entry into ClinicalTrials.gov.

2. Incidence of Grade ≥ 4 Hematologic and ≥ Grade 3 Non-hematologic Toxicities [4 months]

   Incidence of treatment-related, grade ≥ 4 hematologic and ≥ grade 3 non-hematologic toxicities- The adverse events for this study were collected using Common Terminology Criteria for Adverse Events (CTCAE) version 3.0, and have been converted to CTCAE version 4.0 for entry into ClinicalTrials.gov.

3. Median Progression-free Survival (PFS) [36 months]

   Time in months from the start of study treatment to the date of first progression according to RANO criteria, or to death due to any cause. Per RANO, progression is a ≥ 25% increase in the sum of the products of perpendicular diameters of enhancing lesions, worsening T2/FLAIR, any new lesion, or clinical deterioration. Patients alive who had not progressed as of the last follow-up had PFS censored at the last follow-up date. Median PFS was estimated using a Kaplan-Meier curve.

4. Median Overall Survival (OS) [36 months]

   Time in months from the start of study treatment to the date of death due to any cause. Patients alive as of the last follow-up had OS censored at the last follow-up date. Median OS was estimated using a Kaplan-Meier curve.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Patients must have histologically confirmed diagnosis of WHO grade IV primary malignant glioma (glioblastoma multiforme or gliosarcoma). Patients will be unresectable or have multifocal disease.

• Age > or = to 18 years and a life expectancy of >12 weeks.

• Evidence of measurable primary Central Nervous System (CNS) neoplasm on contrast enhanced MRI.

• An interval of at least one week between prior biopsy or four weeks from surgical resection and enrollment on this protocol.

• Karnofsky > or = to 60%.

• Hemoglobin > or = to 9g/dl, absolute neutrophil count (ANC) > or = to 1,500 cells/microliter, platelets > or = to 125,000 cells/microliter.

• Serum creatinine ≤ 1.5 mg/dl, serum serum glutamic oxaloacetic transaminase (SGOT) and direct bilirubin ≤ 1.5 times upper limit of normal (if the total bilirubin is greater than or equal to 1.5 x the upper limit of normal, then the direct bilirubin must be ≤ 1.5 x the upper limit of normal).

• Signed informed consent approved by the Institutional Review Board prior to patient entry.

• If sexually active, patients will take contraceptive measures for the duration of the treatments.

Exclusion Criteria:

• Pregnancy or breast feeding

• Co-medication that may interfere with study results; e.g. immuno-suppressive agents other than corticosteroids.

• Active infection requiring IV antibiotics.

• Treatment with radiotherapy or chemotherapy for a brain tumor, irrespective of the grade of the tumor.

• Evidence of > grade 1 CNS hemorrhage on baseline MRI or CT scan.

Avastin-specific Exclusion Criteria:

• Inadequately controlled hypertension (defined as systolic blood pressure > 150 and/or diastolic blood pressure > 100 mmHg on antihypertensive medications)

• Any prior history of hypertensive crisis or hypertensive encephalopathy

• New York Heart Association (NYHA) Grade II or greater congestive heart failure

• History of myocardial infarction or unstable angina within 6 months prior to study enrollment

• History of stroke or transient ischemic attack within 6 months prior to study enrollment

• Significant vascular disease (e.g., aortic aneurysm, aortic dissection)

• Symptomatic peripheral vascular disease

• Evidence of bleeding diathesis or coagulopathy

• Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to study enrollment or anticipation of need for major surgical procedure during the course of the study

• Core biopsy or other minor surgical procedure, excluding placement of a vascular access device, within 7 days prior to study enrollment

• History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 6 months prior to study enrollment

• Serious, non-healing wound, ulcer, or bone fracture

• Proteinuria at screening as demonstrated by either urine protein:creatinine (UPC) ratio > or = to 1.0 at screening OR urine dipstick for proteinuria ≥ 2+ (patients discovered to have ≥2+ proteinuria on dipstick urinalysis at baseline should undergo a 24-hour urine collection and must demonstrate ≤ 1g of protein in 24 hours to be eligible).

• Known hypersensitivity to any component of Avastin

• Pregnant (positive pregnancy test) or lactating. Use of effective means of contraception (men and women) in subjects of child-bearing potential

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	The Preston Robert Tisch Brain Tumor Center at Duke University Medical Center	Durham	North Carolina	United States	27710

Sponsors and Collaborators

• Katy Peters
• Genentech, Inc.

Investigators

• Principal Investigator: Katherine B Peters, MD, PhD, Duke University

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• The Preston Robert Tisch Brain Tumor Center

Publications

None provided.

• Responsible Party: Katy Peters, Assistant Professor, Duke University
• ClinicalTrials.gov Identifier: NCT00979017
• Other Study ID Numbers: Pro00019065
• First Posted: Sep 17, 2009
• Last Update Posted: Mar 19, 2014
• Last Verified: Feb 1, 2014

• Keywords provided by Katy Peters, Assistant Professor, Duke University: malignant glioma; glioblastoma multiforme; gliosarcoma; Avastin; bevacizumab; Temodar; temozolomide; Irinotecan; CPT-11; Pro00019065; Vredenburgh; Duke
• Additional relevant MeSH terms: Glioblastoma; Gliosarcoma; Bevacizumab; Irinotecan; Temozolomide

Study Results

Participant Flow

Arm/Group Title	Avastin in Combination With Temozolomide and Irinotecan
Arm/Group Description	Avastin 10 mg/kg every 14 days. Temozolomide 200 mg/m2 daily x 5 days in a 28-day cycle. Irinotecan dose depends on whether the patient is on an enzyme-inducing antiepileptic drug (EIAED). EIAED 340 mg/m2 every other week and no EIAED 125 mg/m2 every other week. Irinotecan dose also depends on if the patient has the UGT 1A1 polymorphism (7/7). If so, they do not metabolize the irinotecan normally, so these patients will start out at a two dose level reduction. EIAED starting dose will be 275 mg/m2 and no EIAED starting dose will be 75 mg/ m2. Avastin in combination with temozolomide and irinotecan : Avastin, by intravenous infusion, 10 mg/kg every 14 days in combination with oral temozolomide at 200 mg/m2 daily for 5 days and irinotecan, by intravenous infusion, every other week (dose dependent upon if taking enzyme-inducing anti-epileptic drugs or if a blood test indicates the patient has the UGT 1A1 polymorphism)
Period Title: Overall Study
STARTED	41
COMPLETED	41
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Avastin in Combination With Temozolomide and Irinotecan
Arm/Group Description	Avastin 10 mg/kg every 14 days. Temozolomide 200 mg/m2 daily x 5 days in a 28-day cycle. Irinotecan dose depends on whether the patient is on an enzyme-inducing antiepileptic drug (EIAED). EIAED 340 mg/m2 every other week and no EIAED 125 mg/m2 every other week. Irinotecan dose also depends on if the patient has the UGT 1A1 polymorphism (7/7). If so, they do not metabolize the irinotecan normally, so these patients will start out at a two dose level reduction. EIAED starting dose will be 275 mg/m2 and no EIAED starting dose will be 75 mg/ m2. Avastin in combination with temozolomide and irinotecan : Avastin, by intravenous infusion, 10 mg/kg every 14 days in combination with oral temozolomide at 200 mg/m2 daily for 5 days and irinotecan, by intravenous infusion, every other week (dose dependent upon if taking enzyme-inducing anti-epileptic drugs or if a blood test indicates the patient has the UGT 1A1 polymorphism)
Overall Participants	41
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	58 (10.2)
Sex: Female, Male (Count of Participants)
Female	23 56.1%
Male	18 43.9%

Outcome Measures

1. Primary Outcome

Title	Response Rate
Description	The percentage of participants with a complete or partial response as determined by a modification of the Response Assessment in Neuro-Oncology (RANO) criteria. Complete Response (CR) was defined as complete disappearance on MR/CT of all enhancing tumor and mass effect, off all corticosteroids (or receiving only adrenal replacement doses) and accompanied by a stable or improving neurologic examination. Partial Response (PR) was defined as greater than or equal to 50% reduction in tumor size on MR/CT by bi-dimensional measurement, on a stable or decreasing dose of corticosteroids and accompanied by a stable or improving neurologic examination. Per the criteria, confirmation of response was required. Response rate = CR+PR.
Time Frame	4 months

Outcome Measure Data

Analysis Population Description

Intent-to-treat

Arm/Group Title	Avastin in Combination With Temozolomide and Irinotecan
Arm/Group Description	Avastin 10 mg/kg every 14 days. Temozolomide 200 mg/m2 daily x 5 days in a 28-day cycle. Irinotecan dose depends on whether the patient is on an enzyme-inducing antiepileptic drug (EIAED). EIAED 340 mg/m2 every other week and no EIAED 125 mg/m2 every other week. Irinotecan dose also depends on if the patient has the UGT 1A1 polymorphism (7/7). If so, they do not metabolize the irinotecan normally, so these patients will start out at a two dose level reduction. EIAED starting dose will be 275 mg/m2 and no EIAED starting dose will be 75 mg/ m2. Avastin in combination with temozolomide and irinotecan : Avastin, by intravenous infusion, 10 mg/kg every 14 days in combination with oral temozolomide at 200 mg/m2 daily for 5 days and irinotecan, by intravenous infusion, every other week (dose dependent upon if taking enzyme-inducing anti-epileptic drugs or if a blood test indicates the patient has the UGT 1A1 polymorphism)
Measure Participants	41
Number (95% Confidence Interval) [percentage of participants]	22 53.7%

2. Secondary Outcome

Title	Incidence and Severity of Central Nervous System (CNS) Hemorrhage and Systemic Hemorrhage
Description	Incidence and severity of CNS hemorrhage and systemic hemorrhage- The adverse events for this study were collected using Common Terminology Criteria for Adverse Events (CTCAE) version 3.0, and have been converted to CTCAE version 4.0 for entry into ClinicalTrials.gov.
Time Frame	4 months

Outcome Measure Data

Analysis Population Description

Intent-to-treat

Arm/Group Title	Avastin in Combination With Temozolomide and Irinotecan
Arm/Group Description	Avastin 10 mg/kg every 14 days. Temozolomide 200 mg/m2 daily x 5 days in a 28-day cycle. Irinotecan dose depends on whether the patient is on an enzyme-inducing antiepileptic drug (EIAED). EIAED 340 mg/m2 every other week and no EIAED 125 mg/m2 every other week. Irinotecan dose also depends on if the patient has the UGT 1A1 polymorphism (7/7). If so, they do not metabolize the irinotecan normally, so these patients will start out at a two dose level reduction. EIAED starting dose will be 275 mg/m2 and no EIAED starting dose will be 75 mg/ m2. Avastin in combination with temozolomide and irinotecan : Avastin, by intravenous infusion, 10 mg/kg every 14 days in combination with oral temozolomide at 200 mg/m2 daily for 5 days and irinotecan, by intravenous infusion, every other week (dose dependent upon if taking enzyme-inducing anti-epileptic drugs or if a blood test indicates the patient has the UGT 1A1 polymorphism)
Measure Participants	41
CNS hemorrhage (grade 3)	1 2.4%
Systemic hemorrhage (all grade 3)	3 7.3%

3. Secondary Outcome

Title	Incidence of Grade ≥ 4 Hematologic and ≥ Grade 3 Non-hematologic Toxicities
Description	Incidence of treatment-related, grade ≥ 4 hematologic and ≥ grade 3 non-hematologic toxicities- The adverse events for this study were collected using Common Terminology Criteria for Adverse Events (CTCAE) version 3.0, and have been converted to CTCAE version 4.0 for entry into ClinicalTrials.gov.
Time Frame	4 months

Outcome Measure Data

Analysis Population Description

Intent-to-treat

Arm/Group Title	Avastin in Combination With Temozolomide and Irinotecan
Arm/Group Description	Avastin 10 mg/kg every 14 days. Temozolomide 200 mg/m2 daily x 5 days in a 28-day cycle. Irinotecan dose depends on whether the patient is on an enzyme-inducing antiepileptic drug (EIAED). EIAED 340 mg/m2 every other week and no EIAED 125 mg/m2 every other week. Irinotecan dose also depends on if the patient has the UGT 1A1 polymorphism (7/7). If so, they do not metabolize the irinotecan normally, so these patients will start out at a two dose level reduction. EIAED starting dose will be 275 mg/m2 and no EIAED starting dose will be 75 mg/ m2. Avastin in combination with temozolomide and irinotecan : Avastin, by intravenous infusion, 10 mg/kg every 14 days in combination with oral temozolomide at 200 mg/m2 daily for 5 days and irinotecan, by intravenous infusion, every other week (dose dependent upon if taking enzyme-inducing anti-epileptic drugs or if a blood test indicates the patient has the UGT 1A1 polymorphism)
Measure Participants	41
Grade > or = to 4 hematologic toxicity	7 17.1%
Grade > or = to 3 non-hematologic toxicity	17 41.5%

4. Secondary Outcome

Title	Median Progression-free Survival (PFS)
Description	Time in months from the start of study treatment to the date of first progression according to RANO criteria, or to death due to any cause. Per RANO, progression is a ≥ 25% increase in the sum of the products of perpendicular diameters of enhancing lesions, worsening T2/FLAIR, any new lesion, or clinical deterioration. Patients alive who had not progressed as of the last follow-up had PFS censored at the last follow-up date. Median PFS was estimated using a Kaplan-Meier curve.
Time Frame	36 months

Outcome Measure Data

Analysis Population Description

Intent-to-treat

Arm/Group Title	Avastin in Combination With Temozolomide and Irinotecan
Arm/Group Description	Avastin 10 mg/kg every 14 days. Temozolomide 200 mg/m2 daily x 5 days in a 28-day cycle. Irinotecan dose depends on whether the patient is on an enzyme-inducing antiepileptic drug (EIAED). EIAED 340 mg/m2 every other week and no EIAED 125 mg/m2 every other week. Irinotecan dose also depends on if the patient has the UGT 1A1 polymorphism (7/7). If so, they do not metabolize the irinotecan normally, so these patients will start out at a two dose level reduction. EIAED starting dose will be 275 mg/m2 and no EIAED starting dose will be 75 mg/ m2. Avastin in combination with temozolomide and irinotecan : Avastin, by intravenous infusion, 10 mg/kg every 14 days in combination with oral temozolomide at 200 mg/m2 daily for 5 days and irinotecan, by intravenous infusion, every other week (dose dependent upon if taking enzyme-inducing anti-epileptic drugs or if a blood test indicates the patient has the UGT 1A1 polymorphism)
Measure Participants	41
Median (95% Confidence Interval) [months]	8.6

5. Secondary Outcome

Title	Median Overall Survival (OS)
Description	Time in months from the start of study treatment to the date of death due to any cause. Patients alive as of the last follow-up had OS censored at the last follow-up date. Median OS was estimated using a Kaplan-Meier curve.
Time Frame	36 months

Outcome Measure Data

Analysis Population Description

Intent-to-treat

Arm/Group Title	Avastin in Combination With Temozolomide and Irinotecan
Arm/Group Description	Avastin 10 mg/kg every 14 days. Temozolomide 200 mg/m2 daily x 5 days in a 28-day cycle. Irinotecan dose depends on whether the patient is on an enzyme-inducing antiepileptic drug (EIAED). EIAED 340 mg/m2 every other week and no EIAED 125 mg/m2 every other week. Irinotecan dose also depends on if the patient has the UGT 1A1 polymorphism (7/7). If so, they do not metabolize the irinotecan normally, so these patients will start out at a two dose level reduction. EIAED starting dose will be 275 mg/m2 and no EIAED starting dose will be 75 mg/ m2. Avastin in combination with temozolomide and irinotecan : Avastin, by intravenous infusion, 10 mg/kg every 14 days in combination with oral temozolomide at 200 mg/m2 daily for 5 days and irinotecan, by intravenous infusion, every other week (dose dependent upon if taking enzyme-inducing anti-epileptic drugs or if a blood test indicates the patient has the UGT 1A1 polymorphism)
Measure Participants	41
Median (95% Confidence Interval) [months]	12

Adverse Events

Time Frame	4 months
Adverse Event Reporting Description	The adverse events for this study were collected using Common Terminology Criteria for Adverse Events (CTCAE) version 3.0, and have been converted to CTCAE version 4.0 for entry into ClinicalTrials.gov.
Arm/Group Title	Avastin in Combination With Temozolomide and Irinotecan
Arm/Group Description	Avastin 10 mg/kg every 14 days. Temozolomide 200 mg/m2 daily x 5 days in a 28-day cycle. Irinotecan dose depends on whether the patient is on an enzyme-inducing antiepileptic drug (EIAED). EIAED 340 mg/m2 every other week and no EIAED 125 mg/m2 every other week. Irinotecan dose also depends on if the patient has the UGT 1A1 polymorphism (7/7). If so, they do not metabolize the irinotecan normally, so these patients will start out at a two dose level reduction. EIAED starting dose will be 275 mg/m2 and no EIAED starting dose will be 75 mg/ m2. Avastin in combination with temozolomide and irinotecan : Avastin, by intravenous infusion, 10 mg/kg every 14 days in combination with oral temozolomide at 200 mg/m2 daily for 5 days and irinotecan, by intravenous infusion, every other week (dose dependent upon if taking enzyme-inducing anti-epileptic drugs or if a blood test indicates the patient has the UGT 1A1 polymorphism)
All Cause Mortality
	Avastin in Combination With Temozolomide and Irinotecan
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Avastin in Combination With Temozolomide and Irinotecan
	Affected / at Risk (%)	# Events
Total	18/41 (43.9%)
Blood and lymphatic system disorders
Anemia	1/41 (2.4%)
Blood and lymphatic system disorders - Other, specify	1/41 (2.4%)
Gastrointestinal disorders
Colitis	1/41 (2.4%)
Rectal hemorrhage	1/41 (2.4%)
General disorders
Death NOS	5/41 (12.2%)
Fatigue	1/41 (2.4%)
Infections and infestations
Infections and infestations - Other, specify	1/41 (2.4%)
Lung infection	3/41 (7.3%)
Investigations
Neutrophil count decreased	2/41 (4.9%)
Platelet count decreased	2/41 (4.9%)
White blood cell decreased	1/41 (2.4%)
Metabolism and nutrition disorders
Hypokalemia	1/41 (2.4%)
Hyponatremia	2/41 (4.9%)
Nervous system disorders
Intracranial hemorrhage	1/41 (2.4%)
Seizure	6/41 (14.6%)
Renal and urinary disorders
Hematuria	1/41 (2.4%)
Skin and subcutaneous tissue disorders
Erythema multiforme	1/41 (2.4%)
Rash maculo-papular	1/41 (2.4%)
Vascular disorders
Thromboembolic event	3/41 (7.3%)
Other (Not Including Serious) Adverse Events
	Avastin in Combination With Temozolomide and Irinotecan
	Affected / at Risk (%)	# Events
Total	20/41 (48.8%)
Gastrointestinal disorders
Upper gastrointestinal hemorrhage	1/41 (2.4%)
General disorders
Fatigue	2/41 (4.9%)
Infections and infestations
Infections and infestations - Other, specify	1/41 (2.4%)
Lung infection	1/41 (2.4%)
Investigations
Aspartate aminotransferase increased	1/41 (2.4%)
Neutrophil count decreased	3/41 (7.3%)
Platelet count decreased	10/41 (24.4%)
White blood cell decreased	4/41 (9.8%)
Metabolism and nutrition disorders
Hypokalemia	1/41 (2.4%)
Hyponatremia	1/41 (2.4%)
Psychiatric disorders
Confusion	1/41 (2.4%)
Renal and urinary disorders
Proteinuria	1/41 (2.4%)
Vascular disorders
Thromboembolic event	5/41 (12.2%)

Limitations/Caveats

[Not Specified]

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.