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

• ClinicalTrials.gov Identifier: NCT01102595
• Recruitment Status: Completed
• First Posted: April 13, 2010
• Last Update Posted: August 26, 2015
• Sponsor: Grupo Español de Investigación en Neurooncología
• Information provided by (Responsible Party): Grupo Español de Investigación en Neurooncología

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.

Condition or disease	Intervention/treatment	Phase
Glioblastomas	Drug: Temozolomide; Drug: Bevacizumab; Radiation: Standard radiation therapy	Phase 2

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 102 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• 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 Start Date: December 2009
• Actual Primary Completion Date: October 2013
• Actual Study Completion Date: December 2014

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures :

1. Response Rate [ Time Frame: Until the first 9 weeks of treatment ]
   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 :

1. Percentage of patients who finish treatment [ Time Frame: 41 weeks ]
2. Progression-free survival [ Time Frame: the participants will be followed until disease progression by RANO criteria ]
3. Number of Participants with Adverse Events as a Measure of Safety and Tolerability [ Time Frame: 21 weeks ]

   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.

4. Percentage of patients without neurological deterioration before radiation therapy. [ Time Frame: 8 weeks ]
5. Overall survival [ Time Frame: Until death ]

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 75 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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.

Contacts and Locations

Locations

Spain

Grupo Español de Investigacion en Neurooncologia

Madrid, Spain, 28001

Sponsors and Collaborators

Grupo Español de Investigación en Neurooncología

More Information

• Responsible Party: Grupo Español de Investigación en Neurooncología
• ClinicalTrials.gov Identifier: NCT01102595
• Other Study ID Numbers: GENOM-009
• First Posted: April 13, 2010
• Last Update Posted: August 26, 2015
• Last Verified: August 2015

Keywords provided by Grupo Español de Investigación en Neurooncología:

Unresectable/inoperable glioblastomas

Additional relevant MeSH terms:

Glioblastoma; Astrocytoma; Glioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue; Bevacizumab; Temozolomide; Antineoplastic Agents, Immunological; Antineoplastic Agents; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Physiological Effects of Drugs; Growth Inhibitors; Antineoplastic Agents, Alkylating; Alkylating Agents; Molecular Mechanisms of Pharmacological Action