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Neo-adjuvant Treatment With Temozolomide and Bevacizumab Previous to Temozolomide Plus Radiation Plus Bevacizumab Therapy in Unresectable Glioblastoma

Primary Purpose

Glioblastomas

Status

Completed

Phase

Phase 2

Locations

Spain

Study Type

Interventional

Intervention

Temozolomide

Bevacizumab

Standard radiation therapy

About this trial

This is an interventional treatment trial for Glioblastomas focused on measuring Unresectable/inoperable glioblastomas

Eligibility Criteria

18 Years - 75 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Patients with glioblastoma, non-resectable, biopsy only. Accepting a craniotomy with resection attempted if an RMN within a period of about 72 hours to confirm that the resection was less than 25% of the tumor and fulfill criterion
Measurable disease and contrast uptake ≥ 3 cm in one of its diameters.
Stable doses of dexamethasone during the week prior to inclusion.
Performance Status ≤ 2.
Age ≤ 75 years.
MiniMental Status> 25/30.
Bartel index > 50%.
The surgical incision should be healed prior to randomization. The treatment can be started at 3 weeks of a simple stereotactic biopsy or 4 weeks in case of open biopsy (craniotomy).
Maximum baseline MRI performed 4 weeks before starting treatment (acceptance of the MRI done for neuronavegation biopsy as baseline).
Adequate bone marrow reserve: neutrophils>2000x109/L, platelets>100x109/L, hemoglobin≥106g/dl.
Not received prior treatment with chemotherapy or radiation.
Adequate renal function: Creatinine <1.5 ULN of the laboratory performing the analysis.
Adequate liver function: Serum bilirubin <1.5/ULN SGOT, SGPT<2.5ULN. Serum alkaline phosphatase<3/ULN.
Absence of proteinuria.
Effective method of contraception for patients and their partners.
Written informed consent
Collecting material for a double histological confirmation of diagnosis.

Exclusion Criteria:

Prior radiotherapy or chemotherapy for the treatment of glioma.
Less than 5 years prior to any invasive neoplasia. Accepted carcinoma in situ of cervix carcinoma or cutaneous vasocelular.
Cerebral hemorrhage after biopsy.
Pregnancy or lactation.
Clinically significant cardiovascular disease: - Myocardial infarction or unstable angina (≤ 6 months before randomization) - Congestive heart failure (CHF) class ≥ II NYHA, New York Heart Association. - Cardiac Arrhythmia uncontrolled despite medication (may include patients with atrial fibrillation often controlled). - Peripheral vascular disease ≥ grade 3 (ie, symptomatic and interfering with everyday activities or specifying repairs or review).
Continued use of aspirin> 325 mg / day, currently or recently (within the 10 days prior to randomization).
Currently established treatment with therapeutic doses of anticoagulants Coumarin derivatives (courmarina, warfarin) or a week before starting treatment. It allows the administration of heparin for control of Deep Vein Thrombosis (DVT)
Patients with PTSD and patients with inflammatory bowel disease, with risk of perforation.
HT with values above 150 mmHg systolic pressure of 100 mmHg and diastolic tension is not controllable with standard antihypertensive drugs.
Not healed scars, ulcers or recent bone fracture.
Bleeding diathesis or coagulopathy.

Sites / Locations

Grupo Español de Investigacion en Neurooncologia

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Arm Label

1: Temozolomide plus Radiation

2: Temozolomide plus Radiation plus Bevacizumab

Arm Description

Group 1: Neoadjuvant phase: Temozolomide 85 mg/m2/d x 21 days every 28 days for 2 cycles. Adjuvant phase: Temozolomide 75 mg/m2/d x 42-49 days with standard radiation therapy (60 Gy). Maintenance phase: Temozolomide 150 - 200 mg/m2 d1-d5 q 28d for 6 cycles.

Neoadjuvant phase: Temozolomide 85 mg/m2/d x 21 days every 28 days for 2 cycles + bevacizumab 10 mg/kg every 15 days. Adjuvant phase: Temozolomide 75 mg/m2/d x 42-49 days with standard radiation therapy (60 Gy) + bevacizumab 10 mg/kg every 15 days. Maintenance phase: Temozolomide 150 - 200 mg/m2 d1-d5 q 28d for 6 cycles.

Outcomes

Primary Outcome Measures

Response Rate

To determine differences in clinical activity in terms of objective response after 2 cycles of 4 weeks in both treatment arms in inoperable patients with glioblastoma (RANO criteria)

Secondary Outcome Measures

Percentage of patients who finish treatment

Progression-free survival

Number of Participants with Adverse Events as a Measure of Safety and Tolerability

Assess the toxicity of the combination of the treatment. Temozolamide+bevacizumab+radiation Temozolamide+radiation After the inclusion of the first 10 patients treated with bevacizumab arm (arm 2)the inclusion will be temporarily interrupted until the last of these patients completed concomitant treatment (radiation, temozolomide, bevacizumab) to check the safety of treatment with analysis of adverse effects and toxicity. following the NCIC 3.0 criteria.

Percentage of patients without neurological deterioration before radiation therapy.

Overall survival

Full Information

NCT ID

NCT01102595

First Posted

April 1, 2010

Last Updated

August 25, 2015

Sponsor

Grupo Español de Investigación en Neurooncología

1. Study Identification

Unique Protocol Identification Number

NCT01102595

Brief Title

Neo-adjuvant Treatment With Temozolomide and Bevacizumab Previous to Temozolomide Plus Radiation Plus Bevacizumab Therapy in Unresectable Glioblastoma

Official Title

A Phase II Open Label Randomised Multicentric Study in Patients With Unresectable Glioblastoma Using Neo-adjuvant Treatment With Two Cycles of Temozolomide Previous Temozolomide Plus Radiation Therapy and Adjuvant Temozolomide vs. Neo-adjuvant Treatment With Two Cycles of Temozolomide Plus Bevacizumab Previous Temozolomide, Bevacizumab and Radiation Therapy and Adjuvant Temozolomide.

Study Type

Interventional

2. Study Status

Record Verification Date

August 2015

Overall Recruitment Status

Completed

Study Start Date

December 2009 (undefined)

Primary Completion Date

October 2013 (Actual)

Study Completion Date

December 2014 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Grupo Español de Investigación en Neurooncología

4. Oversight

Data Monitoring Committee

5. Study Description

Brief Summary

In the last 20 years, only temozolomide has obtained indication for the treatment of High-grade glioma (HGG). Temozolomide during and later radiation therapy has doubled one year survival and is the standard treatment for glioblastoma. But 30% of glioblastomas receive only a biopsy as they can't be resected and don't get benefit from this treatment. They and should be treated immediately after the biopsy to prevent neurological deterioration but in spite of this approach they often deteriorate neurologically during radiotherapy. . An effective pre-radiation treatment should improve their prognosis and allow them to complete concomitant radiotherapy and temozolomide treatment. Bevacizumab in recurrent HGG displays 63% of objective responses when combined with irinotecan. But irinotecan is not the most active treatment in this disease. We propose a phase II, two arms, open label, randomized, multicentric study with 2 cycles of temozolomide before radiation therapy and concomitant temozolomide, in patients with glioblastoma and 'biopsy-only'. Bevacizumab will be added to one arm.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Glioblastomas

Keywords

Unresectable/inoperable glioblastomas

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Parallel Assignment

Masking

None (Open Label)

Allocation

Randomized

Enrollment

102 (Actual)

8. Arms, Groups, and Interventions

Arm Title

1: Temozolomide plus Radiation

Arm Type

Experimental

Arm Description

Arm Title

2: Temozolomide plus Radiation plus Bevacizumab

Arm Type

Experimental

Arm Description

Intervention Type

Drug

Intervention Name(s)

Temozolomide

Intervention Description

Temozolomide 85 mg/m2/d x 21 days every 28 days for 2 cycles. Temozolomide 75 mg/m2/d x 42-49 days Temozolomide 150 - 200 mg/m2 d1-d5 q 28d for 6 cycles.

Intervention Type

Drug

Intervention Name(s)

Bevacizumab

Intervention Description

2 cycles + bevacizumab 10 mg/kg every 15 days each two cycles. Bevacizumab 10 mg/kg every 15 days, three dosis.

Intervention Type

Radiation

Intervention Name(s)

Standard radiation therapy

Intervention Description

42-49 days with standard radiation therapy (60 Gy): 2 Gy per day.

Primary Outcome Measure Information:

Title

Response Rate

Description

To determine differences in clinical activity in terms of objective response after 2 cycles of 4 weeks in both treatment arms in inoperable patients with glioblastoma (RANO criteria)

Time Frame

Until the first 9 weeks of treatment

Secondary Outcome Measure Information:

Title

Percentage of patients who finish treatment

Time Frame

41 weeks

Title

Progression-free survival

Time Frame

the participants will be followed until disease progression by RANO criteria

Title

Number of Participants with Adverse Events as a Measure of Safety and Tolerability

Description

Time Frame

21 weeks

Title

Percentage of patients without neurological deterioration before radiation therapy.

Time Frame

8 weeks

Title

Overall survival

Time Frame

Until death

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

75 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Patients with glioblastoma, non-resectable, biopsy only. Accepting a craniotomy with resection attempted if an RMN within a period of about 72 hours to confirm that the resection was less than 25% of the tumor and fulfill criterion Measurable disease and contrast uptake ≥ 3 cm in one of its diameters. Stable doses of dexamethasone during the week prior to inclusion. Performance Status ≤ 2. Age ≤ 75 years. MiniMental Status> 25/30. Bartel index > 50%. The surgical incision should be healed prior to randomization. The treatment can be started at 3 weeks of a simple stereotactic biopsy or 4 weeks in case of open biopsy (craniotomy). Maximum baseline MRI performed 4 weeks before starting treatment (acceptance of the MRI done for neuronavegation biopsy as baseline). Adequate bone marrow reserve: neutrophils>2000x109/L, platelets>100x109/L, hemoglobin≥106g/dl. Not received prior treatment with chemotherapy or radiation. Adequate renal function: Creatinine <1.5 ULN of the laboratory performing the analysis. Adequate liver function: Serum bilirubin <1.5/ULN SGOT, SGPT<2.5ULN. Serum alkaline phosphatase<3/ULN. Absence of proteinuria. Effective method of contraception for patients and their partners. Written informed consent Collecting material for a double histological confirmation of diagnosis. Exclusion Criteria: Prior radiotherapy or chemotherapy for the treatment of glioma. Less than 5 years prior to any invasive neoplasia. Accepted carcinoma in situ of cervix carcinoma or cutaneous vasocelular. Cerebral hemorrhage after biopsy. Pregnancy or lactation. Clinically significant cardiovascular disease: - Myocardial infarction or unstable angina (≤ 6 months before randomization) - Congestive heart failure (CHF) class ≥ II NYHA, New York Heart Association. - Cardiac Arrhythmia uncontrolled despite medication (may include patients with atrial fibrillation often controlled). - Peripheral vascular disease ≥ grade 3 (ie, symptomatic and interfering with everyday activities or specifying repairs or review). Continued use of aspirin> 325 mg / day, currently or recently (within the 10 days prior to randomization). Currently established treatment with therapeutic doses of anticoagulants Coumarin derivatives (courmarina, warfarin) or a week before starting treatment. It allows the administration of heparin for control of Deep Vein Thrombosis (DVT) Patients with PTSD and patients with inflammatory bowel disease, with risk of perforation. HT with values above 150 mmHg systolic pressure of 100 mmHg and diastolic tension is not controllable with standard antihypertensive drugs. Not healed scars, ulcers or recent bone fracture. Bleeding diathesis or coagulopathy.

Facility Information:

Facility Name

Grupo Español de Investigacion en Neurooncologia

City

Madrid

ZIP/Postal Code

28001

Country

Spain

12. IPD Sharing Statement

Learn more about this trial

Neo-adjuvant Treatment With Temozolomide and Bevacizumab Previous to Temozolomide Plus Radiation Plus Bevacizumab Therapy in Unresectable Glioblastoma

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