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

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ClinicalTrials.gov Identifier: NCT02898012
Recruitment Status : Completed
First Posted : September 13, 2016
Last Update Posted : September 13, 2016
Sponsor:
Collaborator:
Roche Pharma AG
Information provided by (Responsible Party):
Assistance Publique - Hôpitaux de Paris

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 Type : Interventional  (Clinical Trial)
Actual Enrollment : 70 participants
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 : October 2010
Actual Primary Completion Date : May 2013
Actual Study Completion Date : June 2013

Resource links provided by the National Library of Medicine


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.




Primary Outcome Measures :
  1. Median Overall Survival (OS) [ Time Frame: 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 :
  1. Progression-free survival (PFS) [ Time Frame: 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.

  2. Toxicity grade according to the National Cancer Institute Common Toxicity Criteria (NCI CTCAE, version 3.0) [ Time Frame: 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).

  3. Health-related quality of life using QLQ-C30 questionnaire [ Time Frame: 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).

  4. Health-related quality of life using QLQ-BN20 [ Time Frame: 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.

  5. Cognitive assessment MMSEs [ Time Frame: 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.

  6. Radiological responses [ Time Frame: Neuroimaging evaluation repeated every 2 months until 12 months ]
    Response assessment in neuro-oncology (RANO) criteria



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Ages Eligible for Study:   70 Years and older   (Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02898012


Locations
France
Groupe Hospitalier Pitié-Salpêtrière
Paris, France, 75013
Sponsors and Collaborators
Assistance Publique - Hôpitaux de Paris
Roche Pharma AG
Investigators
Principal Investigator: Jean-Yves Delattre, MD-PhD Pôle MSN, Groupe Hospitalier Pitié-Salpêtrière

Publications:

Responsible Party: Assistance Publique - Hôpitaux de Paris
ClinicalTrials.gov Identifier: NCT02898012     History of Changes
Other Study ID Numbers: P081213
First Posted: September 13, 2016    Key Record Dates
Last Update Posted: September 13, 2016
Last Verified: July 2016
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Keywords provided by Assistance Publique - Hôpitaux de Paris:
Glioblastoma Multiforme
temozolomide
bevacizumab

Additional relevant MeSH terms:
Glioblastoma
Brain Neoplasms
Astrocytoma
Glioma
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Central Nervous System Neoplasms
Nervous System Neoplasms
Neoplasms by Site
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Bevacizumab
Temozolomide
Dacarbazine
Angiogenesis Inhibitors
Angiogenesis Modulating Agents
Growth Substances
Physiological Effects of Drugs
Growth Inhibitors
Antineoplastic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action