ATAG: Temozolomide Plus Bevacizumab in Supratentorial Glioblastoma in 70 Years and Older Patients With an Impaired Functional Status

Sponsor

Assistance Publique - Hôpitaux de Paris (Other)

Overall Status

Completed

CT.gov ID

NCT02898012

Collaborator

Roche Pharma AG (Industry)

Enrollment

Location

Arm

Duration (Months)

2.2

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The optimal treatment of glioblastoma multiforme (GBM) in patients aged ≥70 years with a Karnofsky performance status (KPS) <70 is unestablished. This clinical trial evaluated the efficacy and safety of upfront temozolomide (TMZ) and bevacizumab (Bev) in patients aged ≥70 years and a KPS <70.

Condition or Disease	Intervention/Treatment	Phase
Glioblastoma Multiforme Primary Brain Tumor	Drug: Temozolomide Drug: Bevacizumab	Phase 2

Detailed Description

Elderly patients aged 65 years and older account for approximately 45% of GBM patients, and this figure is expected to rise concurrently with the aging population of most countries. Unfortunately, few trials have been performed in this setting. In elderly patients with good functional status (KPS >70), radiotherapy (RT) prolongs overall survival (OS) without causing a detriment in quality of life compared with palliative care alone. Recently, it was shown that TMZ could be an alternative to RT. In elderly patients with poor functional status at symptom onset (KPS < 70), RT does not appear to be a satisfactory option in this frail population; however, investigators previously found that TMZ alone was associated with improvements in functional status in 1/3 of cases and appeared to increase survival compared with supportive care alone, especially in methylated MGMT promoter patients.

Bevacizumab (Bev) is an antiangiogenic monoclonal antibody targeting VEGF (vascular endothelial growth factor) that is currently used in recurrent GBM, particularly in combination with alkylating agents. Its effect as first line treatment in combination with TMZ and RT is controversial.

In this study, investigators evaluated the efficacy and safety of the upfront combination of TMZ + Bev as an initial treatment for elderly patients with GBM and impaired functional status (KPS <70).

Study Design

Study Type:

Interventional

Actual Enrollment :

70 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

Temozolomide Plus Bevacizumab Chemotherapy in Supratentorial Glioblastoma in 70 Years and Older Patients With an Impaired Functional Status (KPS<70)

Study Start Date :

Oct 1, 2010

Actual Primary Completion Date :

May 1, 2013

Actual Study Completion Date :

Jun 1, 2013

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Temozolomide and Bevacizumab Single experimental arm with two drugs : Temozolomide and Bevacizumab	Drug: Temozolomide Temozolomide (TMZ) Temozolomide (TMZ) administered at 130-150 mg/m2 for 5 consecutive days every 4 weeks up to 12 cycles. IV or oral administration was allowed according to the clinical status. TMZ starts at 130 mgs/m2 and increase to 150 mgs/m2 during the second cycle in the absence of hematologic toxicity. In the case of grade 3 or 4 toxicity, the dose for the next cycle is decreased to 110 mg/m2. If the grade 3 or 4 toxicity persists at a dose of 110 mg/m2, treatment is discontinued. Drug: Bevacizumab Bevacizumab (Bev) administered at a dose of 10 mgs/kg every 2 weeks. Bev was interrupted in cases of wound healing disturbances, gastrointestinal perforation, intestinal occlusion, fistula, uncontrolled hypertension, nephrotic syndrome, grade 4 or recurrent grade 3 thromboembolic events, arterial thrombosis, hemorrhage > grade 2, left ventricular failure, or posterior reversible leukoencephalopathy.

Arm

Intervention/Treatment

Experimental: Temozolomide and Bevacizumab

Single experimental arm with two drugs : Temozolomide and Bevacizumab

Drug: Temozolomide

Temozolomide (TMZ) Temozolomide (TMZ) administered at 130-150 mg/m2 for 5 consecutive days every 4 weeks up to 12 cycles. IV or oral administration was allowed according to the clinical status. TMZ starts at 130 mgs/m2 and increase to 150 mgs/m2 during the second cycle in the absence of hematologic toxicity. In the case of grade 3 or 4 toxicity, the dose for the next cycle is decreased to 110 mg/m2. If the grade 3 or 4 toxicity persists at a dose of 110 mg/m2, treatment is discontinued.

Drug: Bevacizumab

Bevacizumab (Bev) administered at a dose of 10 mgs/kg every 2 weeks. Bev was interrupted in cases of wound healing disturbances, gastrointestinal perforation, intestinal occlusion, fistula, uncontrolled hypertension, nephrotic syndrome, grade 4 or recurrent grade 3 thromboembolic events, arterial thrombosis, hemorrhage > grade 2, left ventricular failure, or posterior reversible leukoencephalopathy.

Outcome Measures

Primary Outcome Measures

Median Overall Survival (OS) [OS calculated from the date of surgery until death or up to 36 months.]
OS calculated from the date of surgery until death from any cause or up to 36 months.

Secondary Outcome Measures

Progression-free survival (PFS) [PFS calculated from the date of surgery until the date of first documented progression or up to 36 months.]
PFS calculated from the date of surgery to the date of progression or death or up to 36 months.
Toxicity grade according to the National Cancer Institute Common Toxicity Criteria (NCI CTCAE, version 3.0) [Assessment every 2 weeks until 12 months]
Assessment every 2 weeks until 12 months by physical and neurological examinations, complete blood counts and urine strip tests. Toxicity was graded according to the National Cancer Institute Common Toxicity Criteria (NCI CTCAE, version 3.0).
Health-related quality of life using QLQ-C30 questionnaire [at baseline and every month until 12 months]
The QLQ-C30 questionnaire includes 30 questions comprising five functioning scales (physical, role, emotional, cognitive and social), three symptom scales (fatigue, vomiting and pain) and six single item scales (dyspnea, insomnia, constipation, anorexia, diarrhea, and financial difficulties).
Health-related quality of life using QLQ-BN20 [at baseline and every month until 12 months]
The QLQ-BN20 questionnaire includes 20 items covering functional deficits, symptoms, toxic effects of treatment, and uncertainty about the future.
Cognitive assessment MMSEs [at baseline and they were repeated every month until 12 months]
The MMSE was used as a measure of general cognitive status. Higher scores on this exam, which uses a 30-point scale, indicate better cognitive function.
Radiological responses [Neuroimaging evaluation repeated every 2 months until 12 months]
Response assessment in neuro-oncology (RANO) criteria

Eligibility Criteria

Criteria

Ages Eligible for Study:

70 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Supratentorial Glioblastoma diagnosed by biopsy.
Patients aged ≥ 70 years
KPS >30 and < 70
Life expectancy > or = 8 weeks
Patients were enrolled at least 14 days after stereotactic biopsy and 28 days after surgical biopsy.
CT or brain MRI was performed within 4 weeks before treatment to rule out haemorrhage.
Included to health social security system
Medical assessment previous to inclusion
Informed consent form

Exclusion Criteria:

Previous treatment with Surgical resection, RT or chemotherapy to the tumor.
Hemoglobin level < 9 g%
Absolute neutrophil count < 1500
Platelet count < 100.000
ASAT or ALAT levels more than 3 times the upper limit of normal.
Bilirubin levels more than 2 times the upper limit of normal
Creatinin more than 1.5 times the upper limit of normal
Untreated high blood pressure >150/100 mmHg
Congestive cardiac failure
Proteinuria > 1 gr/24h
INR > 1.5 the upper limit of normal
Recent symptomatic haemorrhage
History of abnormal wound healing
Gastrointestinal fistula
Haemoptysis > grade 2 (NCI-CTC)
Intracranial abscess
Coagulation disorder
Active infection requiring intravenous antibiotics
Vascular disease (including myocardial infarction, unstable angina, cerebrovascular disease, peripheral arterial or aortic disease) in the previous 6 months
Malignancy diagnosed in the previous 5 years (except basocellular skin cancer and in situ cervix cancer)
Allergy to dacarbazine, Bevacizumab, Temozolomide or their excipients, recombinant human monoclonal antibodies, or ovarian cells of Chinese hamsters.