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

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.

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.

Study Overview

• Status: Completed
• Conditions: Glioblastomas
• Intervention / Treatment: Drug: Temozolomide; Radiation: Standard radiation therapy; Drug: Bevacizumab

• Study Type: Interventional
• Enrollment (Actual): 102
• Phase: Phase 2

Contacts and Locations

Study Locations

• Spain
  • Madrid, Spain, 28001
    • Grupo Español de Investigacion en Neurooncologia

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. 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
2. Measurable disease and contrast uptake ≥ 3 cm in one of its diameters.
3. Stable doses of dexamethasone during the week prior to inclusion.
4. Performance Status ≤ 2.
5. Age ≤ 75 years.
6. MiniMental Status> 25/30.
7. Bartel index > 50%.
8. 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).
9. Maximum baseline MRI performed 4 weeks before starting treatment (acceptance of the MRI done for neuronavegation biopsy as baseline).
10. Adequate bone marrow reserve: neutrophils>2000x109/L, platelets>100x109/L, hemoglobin≥106g/dl.
11. Not received prior treatment with chemotherapy or radiation.
12. Adequate renal function: Creatinine <1.5 ULN of the laboratory performing the analysis.
13. Adequate liver function: Serum bilirubin <1.5/ULN SGOT, SGPT<2.5ULN. Serum alkaline phosphatase<3/ULN.
14. Absence of proteinuria.
15. Effective method of contraception for patients and their partners.
16. Written informed consent
17. Collecting material for a double histological confirmation of diagnosis.

Exclusion Criteria:

1. Prior radiotherapy or chemotherapy for the treatment of glioma.
2. Less than 5 years prior to any invasive neoplasia. Accepted carcinoma in situ of cervix carcinoma or cutaneous vasocelular.
3. Cerebral hemorrhage after biopsy.
4. Pregnancy or lactation.
5. 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).
6. Continued use of aspirin> 325 mg / day, currently or recently (within the 10 days prior to randomization).
7. 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)
8. Patients with PTSD and patients with inflammatory bowel disease, with risk of perforation.
9. HT with values above 150 mmHg systolic pressure of 100 mmHg and diastolic tension is not controllable with standard antihypertensive drugs.
10. Not healed scars, ulcers or recent bone fracture.
11. Bleeding diathesis or coagulopathy.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: 1: Temozolomide plus Radiation; 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.	Drug: Temozolomide; 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.; Radiation: Standard radiation therapy; 42-49 days with standard radiation therapy (60 Gy): 2 Gy per day.
EXPERIMENTAL: 2: Temozolomide plus Radiation plus Bevacizumab; 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.	Drug: Temozolomide; 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.; Radiation: Standard radiation therapy; 42-49 days with standard radiation therapy (60 Gy): 2 Gy per day.; Drug: Bevacizumab; 2 cycles + bevacizumab 10 mg/kg every 15 days each two cycles.; Bevacizumab 10 mg/kg every 15 days, three dosis.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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)	Until the first 9 weeks of treatment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall survival		Until death
Percentage of patients who finish treatment		41 weeks
Progression-free survival		the participants will be followed until disease progression by RANO criteria
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.	21 weeks
Percentage of patients without neurological deterioration before radiation therapy.		8 weeks

Collaborators and Investigators

• Sponsor: Grupo Español de Investigación en Neurooncología

Study record dates

Study Major Dates

• Study Start: December 1, 2009
• Primary Completion (ACTUAL): October 1, 2013
• Study Completion (ACTUAL): December 1, 2014

Study Registration Dates

• First Submitted: April 1, 2010
• First Submitted That Met QC Criteria: April 12, 2010
• First Posted (ESTIMATE): April 13, 2010

Study Record Updates

• Last Update Posted (ESTIMATE): August 26, 2015
• Last Update Submitted That Met QC Criteria: August 25, 2015
• Last Verified: August 1, 2015

More Information

Terms related to this study

• Keywords: Unresectable/inoperable glioblastomas
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Astrocytoma; Glioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Glioblastoma; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Antineoplastic Agents, Alkylating; Alkylating Agents; Antineoplastic Agents, Immunological; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Temozolomide; Bevacizumab
• Other Study ID Numbers: GENOM-009