A Study of Avastin (Bevacizumab) And Fotemustine in Patients With Recurrent Glioblastoma

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Hoffmann-La Roche
ClinicalTrials.gov Identifier:
NCT01474239
First received: November 8, 2011
Last updated: August 11, 2015
Last verified: August 2015
  Purpose

This randomized, non-comparative study will evaluate the efficacy and safety of Avastin (bevacizumab) in patients with recurrent glioblastoma. Patients will be randomized to receive Avastin 10 mg/kg intravenously every 2 weeks or fotemustine 75 mg/m2 on days 1, 8 and 15, followed by, after a 5 weeks interval, 100 mg/m2 intravenously every 3 weeks. Treatment with fotemustine serves as a calibration arm and no formal efficacy comparison will be made between the two treatment arms. The anticipated time of study treatment is until disease progression or unacceptable toxicity.


Condition Intervention Phase
Glioblastoma Multiforme
Drug: bevacizumab [Avastin]
Drug: fotemustine
Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Randomized Non Comparative Phase II Trial With Bevacizumab and Fotemustine in the Treatment of Recurrent Glioblastoma

Resource links provided by NLM:


Further study details as provided by Hoffmann-La Roche:

Primary Outcome Measures:
  • Percentage of Participants Alive 6 Months After Start of Treatment [ Time Frame: 6 months ] [ Designated as safety issue: No ]
    Overall survival (OS) was defined as the time in months from the start of treatment to death due to any cause. If a participant was not known to have died, time was censored at the last date the participant was known to be alive, which was defined as the latest among date of last visit, date of last sample collected for laboratory exam, date of magnetic resonance imaging (MRI) assessment, date of last treatment, date of discontinuation and date of last available follow-up visit. Participants with no information after baseline were censored at Day 1. OS was estimated by Kaplan-Meier method.

  • Overall Survival (OS) [ Time Frame: Baseline until death (up to 691 days) ] [ Designated as safety issue: No ]
    OS was defined as the time in months from the start of treatment to death due to any cause. If a participant was not known to have died, time was censored at the last date the participant was known to be alive, which was defined as the latest among date of last visit, date of last sample collected for laboratory exam, date of MRI assessment, date of last treatment, date of discontinuation and date of last available follow-up visit. Participants with no information after baseline were censored at Day 1. OS was estimated by Kaplan-Meier method.


Secondary Outcome Measures:
  • Percentage of Participants Who Were Alive and Progression Free 6 Months After Start of Treatment [ Time Frame: 6 months ] [ Designated as safety issue: No ]
    Progression-free survival (PFS) was defined as the time in months from the start of treatment to the date of the first occurrence of disease progression or death from any cause, whichever occurred first. PFS was estimated by Kaplan-Meier method. Progression was assessed using Response Assessment in Neuro-Oncology (RANO) or Macdonald Response Criteria, whichever occurred first. As per RANO criteria, progression was defined as 25% or more increase in enhancing lesions despite stable or increasing steroid dose; increase (significant) in non-enhancing T2/FLAIR lesions, not attributable to other non-tumor causes; any new lesions; and clinical deterioration (not attributable to other non-tumor causes and not due to steroid decrease). As per Macdonald criteria, progression was defined as 25% or more increase in enhancing lesions; any new lesions; and clinical deterioration.

  • Progression-Free Survival (PFS) [ Time Frame: Baseline until disease progression or death (baseline, 46 days after first administration of study drug, and thereafter every 56 days up to 691 days) ] [ Designated as safety issue: No ]
    PFS was defined as the time in months from the start of treatment to the date of the first occurrence of disease progression or death from any cause, whichever occurred first. PFS was estimated by Kaplan-Meier method. Progression was assessed using RANO or Macdonald Response Criteria, whichever occurred first. As per RANO criteria, progression was defined as 25% or more increase in enhancing lesions despite stable or increasing steroid dose; increase (significant) in non-enhancing T2/FLAIR lesions, not attributable to other non-tumor causes; any new lesions; and clinical deterioration (not attributable to other non-tumor causes and not due to steroid decrease). As per Macdonald criteria, progression was defined as 25% or more increase in enhancing lesions; any new lesions; and clinical deterioration.

  • Percentage of Participants Alive 9 Months After Start of Treatment [ Time Frame: 9 months ] [ Designated as safety issue: No ]
    OS was defined as the time in months from the start of treatment to death due to any cause. If a participant was not known to have died, time was censored at the last date the participant was known to be alive, which was defined as the latest among date of last visit, date of last sample collected for laboratory exam, date of MRI assessment, date of last treatment, date of discontinuation and date of last available follow-up visit. Participants with no information after baseline were censored at Day 1. OS was estimated by Kaplan-Meier method.

  • Percentage of Participants Alive 12 Months After Start of Treatment [ Time Frame: 12 months ] [ Designated as safety issue: No ]
    OS was defined as the time in months from the start of treatment to death due to any cause. If a participant was not known to have died, time was censored at the last date the participant was known to be alive, which was defined as the latest among date of last visit, date of last sample collected for laboratory exam, date of MRI assessment, date of last treatment, date of discontinuation and date of last available follow-up visit. Participants with no information after baseline were censored at Day 1. OS was estimated by Kaplan-Meier method.

  • Percentage of Participants Alive 30 Days After Last Dose of Study Drug [ Time Frame: 30 days after last dose of study drug (up to Day 600) ] [ Designated as safety issue: No ]
    OS was defined as the time in months from the start of treatment to death due to any cause. If a participant was not known to have died, time was censored at the last date the participant was known to be alive, which was defined as the latest among date of last visit, date of last sample collected for laboratory exam, date of MRI assessment, date of last treatment, date of discontinuation and date of last available follow-up visit. Participants with no information after baseline were censored at Day 1. OS was estimated by Kaplan-Meier method.

  • Percentage of Participants With a Best Overall Response of Complete Response (CR) or Partial Response (PR) [ Time Frame: Baseline until disease progression or death (baseline, 46 days after first administration of study drug, and thereafter every 56 days up to 691 days) ] [ Designated as safety issue: No ]
    Percentage of participants achieving CR or PR as overall response between first drug administration and documented disease progression were calculated. Tumor response was evaluated according to both RANO and Macdonald response criteria. As per Macdonald criteria, CR was defined as disappearance of all enhancing disease, sustained for at least 4 weeks, and no new lesions along with clinical features of clinically stable or improved, with no corticosteroid; PR was defined as 50% or more decrease of all measurable enhancing lesions, sustained for at least 4 weeks, and no new lesion along with clinical features of clinically stable or improved, with stable or reduced corticosteroids. RANO criteria defined CR and PR the same as Macdonald criteria with the following additions: CR - improved non enhancing T2/FLAIR lesions; PR - no progression of non-measurable disease, stable or improved non enhancing FLAIR/T2 lesions.

  • Change From Screening in European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) Scores at Weeks 8, 16, 24, 32, 40, 48, 56, 64, and 72 [ Time Frame: Screening, Weeks 8, 16, 24, 32, 40, 48, 56, 64, and 72 ] [ Designated as safety issue: No ]
    EORTC QLQ-C30: included global health status/quality of life (QOL), functional scales (physical, role, cognitive, emotional, and social), symptom scales (fatigue, pain, nausea/vomiting), and single items (dyspnea, appetite loss, insomnia, constipation, diarrhea, and financial difficulties). Most questions used a 4- point scale (1 'Not at All' to 4 'Very Much'); 2 questions used a 7-point scale (1 'Very Poor' to 7 'Excellent'). Scores were averaged and transformed to 0-100 scale; a higher score for Global Qol/functional scales=better level of QoL/functioning, or a higher score for symptom scale=greater degree of symptoms.

  • Percentage of Participants With Corticosteroid Initiation During the Study Period [ Time Frame: Baseline until recurrence (up to 691 days) ] [ Designated as safety issue: No ]
    Corticosteroid initiation was assessed in participants not receiving corticosteroids at screening. The participant had the event if he/she started on corticosteroids with a dosage ≥2 mg dexamethasone equivalent.

  • Time to Corticosteroid Initiation [ Time Frame: Baseline until recurrence (up to 691 days) ] [ Designated as safety issue: No ]
    Time to corticosteroid initiation was defined as the time from screening to the start date of the first corticosteroid administration in participants not receiving corticosteroids at screening. The participant had the event if he/she started on corticosteroids with a dosage ≥2 mg dexamethasone equivalent. Instead, if the participant was not known to have the event, time was censored at the last available visit date. Time to corticosteroid initiation was estimated using Kaplan Meier method.

  • Percentage of Participants in Each Class of Corticosteroid Use [ Time Frame: Weeks 8, 16, 24, 32, 40, 48, 56, 64, 72, 80, 88, post-treatment follow-up (up to Day 691) ] [ Designated as safety issue: No ]
    Corticosteroid use was classified as: 1. No Change (if corticosteroid dose at each assessment was equal to baseline); 2. Decreased (if corticosteroid dose at each assessment was lower than baseline); 3. Increased (corticosteroid dose at each assessment was greater than baseline).

  • Percentage of Participants With Karnofsky Performance Status (KPS) Deterioration [ Time Frame: Baseline until KPS deterioration (up to 691 days) ] [ Designated as safety issue: No ]
    Deterioration of KPS was defined as a decrease of at least 20 percentage points with respect to the screening. KPS is an 11-level score which ranges between 0 (death) to 100 (complete healthy status); a higher score represents a higher ability to perform daily tasks.

  • Time to Karnofsky Performance Status (KPS) Deterioration [ Time Frame: Baseline until KPS deterioration (up to 691 days) ] [ Designated as safety issue: No ]
    Time to KPS deterioration was defined as the time from screening to the first date of deterioration of the KPS score. Deterioration of KPS was defined as a decrease of at least 20 percentage points with respect to the screening. KPS is an 11-level score which ranges between 0 (death) to 100 (complete healthy status); a higher score represents a higher ability to perform daily tasks. Time to KPS deterioration was estimated using Kaplan Meier method. If the participant was not known to have the event, time was censored at the last available visit date.


Enrollment: 91
Study Start Date: November 2011
Study Completion Date: December 2013
Primary Completion Date: December 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Calibration Arm Drug: fotemustine
75 mg/m2 intravenously on days 1, 8 and 15 followed by, after a 5 weeks interval, 100 mg/m2 on day 1 of a 3-weeks cycle. Until disease progression or unacceptable toxicity
Experimental: Investigational Arm Drug: bevacizumab [Avastin]
10 mg/kg every 2 weeks intravenously until disease progression or unacceptable toxicity

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Adult patients, >/=18 years of age
  • Diagnosis of recurrent glioblastoma multiforme (Grade IV)
  • Previous treatment with temozolomide and radiotherapy
  • First recurrence after standard adjuvant treatment (surgery, followed by radiotherapy and chemotherapy)
  • Adequate hematological, biochemical and organ functions

Exclusion Criteria:

  • Previous treatment with Avastin or other anti-angiogenic drugs
  • Residual relevant toxicity resulting from previous therapy
  • Radiotherapy within the 3 months prior to the diagnosis of disease progression
  • Chemotherapy in the previous 4 weeks
  • Other active or inactive malignancies (except for carcinoma in situ of the cervix, of the prostate or basal cell carcinoma)
  • Clinically significant cardiovascular diseases
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01474239

Locations
Italy
Napoli, Campania, Italy, 80131
Bologna, Emilia-Romagna, Italy, 40133
Roma, Lazio, Italy, 00168
Genova, Liguria, Italy, 16128
Milano, Lombardia, Italy, 20132
Milano, Lombardia, Italy, 20133
San Giovanni Rotondo, Puglia, Italy, 71013
Terni, Umbria, Italy, 05100
Padova, Veneto, Italy, 35128
Treviso, Veneto, Italy, 31100
Sponsors and Collaborators
Hoffmann-La Roche
Investigators
Study Director: Clinical Trials Hoffmann-La Roche
  More Information

No publications provided

Responsible Party: Hoffmann-La Roche
ClinicalTrials.gov Identifier: NCT01474239     History of Changes
Other Study ID Numbers: ML25739
Study First Received: November 8, 2011
Results First Received: July 9, 2015
Last Updated: August 11, 2015
Health Authority: Italy: Ministry of Health

Additional relevant MeSH terms:
Glioblastoma
Astrocytoma
Glioma
Neoplasms
Neoplasms by Histologic Type
Neoplasms, Germ Cell and Embryonal
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Bevacizumab
Fotemustine
Angiogenesis Inhibitors
Angiogenesis Modulating Agents
Antineoplastic Agents
Growth Inhibitors
Growth Substances
Pharmacologic Actions
Physiological Effects of Drugs
Therapeutic Uses

ClinicalTrials.gov processed this record on September 03, 2015