Gliadel Wafer and Fluorescence-Guided Surgery With 5-ALA Followed by Radiation Therapy And Temozolomide in Treating Patients With Primary Glioblastoma

Study Overview
=================
Brief Summary
-----------------
RATIONALE: Drugs used in chemotherapy, such as Gliadel wafer and temozolomide, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Radiation therapy uses high-energy x-rays to kill tumor cells. Giving radiation therapy and temozolomide after surgery and Gliadel wafer may kill any tumor cells that remain after surgery. PURPOSE: This phase II trial is studying the side effects of fluorescence-guided surgery with 5-ALA given together with Gliadel wafer, followed by radiation therapy and temozolomide, in treating patients with primary glioblastoma.

Detailed Description
-----------------
OBJECTIVES: Primary To establish that the combined use of 5-ALA and Gliadel wafers during fluorescence-guided radical brain tumor resection is safe and does not compromise patients with primary glioblastoma from receiving or completing adjuvant standard radiotherapy plus temozolomide. Secondary To gather preliminary evidence that the combined use of 5-ALA and Gliadel wafers at surgery has the potential to improve clinical outcome, via measurement of time to clinical progression. To gather preliminary evidence that this regimen at surgery has the potential to improve clinical outcome via measurement of survival at 24 months. OUTLINE: This is a multicenter study. Gliadel wafers are applied to resection cavity immediately after 5-ALA fluorescence-guided radical brain tumor resection. After recovery from surgery (within 6 weeks of surgery when possible ), patients receive adjuvant chemoradiotherapy comprising standard radiotherapy and temozolomide. Tumor biopsy and blood sample may be collected at time of surgery for retrospective MGMT status analysis. After surgery, patients are followed up at post-surgical visits, during subsequent therapy at routine clinic visits, and at 12, 18, and 24 months. Peer reviewed and funded by Cancer Research UK.

Official Title
-----------------
An Evaluation of the Tolerability and Feasibility of Combining 5-Amino-Levulinic Acid (5-ALA) With Carmustine Wafers (Gliadel) in the Surgical Management of Primary Glioblastoma (GALA-5 Trial)

Conditions
-----------------
Glioblastoma

Intervention / Treatment
-----------------
* Drug: 5-ALA
* Drug: Gliadel wafers
* Radiation: Radiotherapy as normal based on standard clinical protocols determined by the neuro-oncologist
* Drug: Concomitant chemotherapy as normal based on standard clinical protocols determined by the neuro-oncologist
* Drug: Adjuvant chemotherapy as normal based on standard clinical protocols determined by the neuro-oncologist


Participation Criteria
=================
Eligibility Criteria
-----------------
INCLUSION CRITERIA i. The patient is reviewed at a specialist neuro-oncology multi-disciplinary team (MDT). ii. Stealth MRI (neuronavigation) will be performed prior to surgery. iii. Imaging is evaluated by a neuro-radiologist and judged to have typical appearances of a primary GBM iv. Radical resection is judged to be realistic by the neurosurgeons at the MDT (i.e. NICE criteria for the use of Carmustine wafers can be met) v. WHO performance status 0 or 1 vi. Age ≥18 vii. Patient judged by MDT to be fit for standard radical aggressive therapy for GBM (resection followed by RT with concomitant and adjuvant temozolomide) EXCLUSION CRITERIA i. GBM thought to be transformed low grade or secondary disease ii. The patient has not been seen by a specialist MDT. iii. There is uncertainty about the radiological diagnosis iv. 5-ALA or Carmustine wafers is contra-indicated (inc known or suspected allergies to 5-ALA or porphyrins, or acute or chronic types of porphyria) v. Pregnant or lactating women vi. Known or suspected HIV or other significant infection or comorbidity that would preclude radical aggressive therapy for GBM vii. Active liver disease (ALT or AST ≥5 x ULRR) viii. Concomitant anti-cancer therapy except steroids ix. History of other malignancies (except for adequately treated basal or squamous cell carcinoma or carcinoma in situ) within 5 years x. Previous brain surgery (including biopsy) or cranial radiotherapy xi. Platelets <100 x109/L xii. Mini mental status score <15

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 5-ALA and Gliadel wafers<br>This is a single arm feasibility study to evaluate the safety and tolerability of combining 2 technologies (5-ALA and Gliadel wafers) in the surgical management of patients with GBM. | Drug: 5-ALA<br>* 5-ALA is used to generate tumour specific fluorescence as an aid to surgical resection of GBM, prior to the insertion of Gliadel wafers<br>* Other names: Gliolan;Drug: Gliadel wafers<br>* The implantation of Carmustine Wafers (Gliadel) delivers carmustine- (3-bis 2-chloroethyl 1-1-nitrosourea (BCNU)) directly into the surgical cavity created after tumour resection.<br>* Other names: polifeprosan 20 with carmustine implant;Radiation: Radiotherapy as normal based on standard clinical protocols determined by the neuro-oncologist<br>* 60Gy in 30 fractions (2Gy per fraction given once daily, five days per week (Monday-Friday) over 6 weeks. Radiotherapy delivered to gross tumour volume with 2-3cm margin. Standard treatment following neurosurgery for glioblastoma<br>Drug: Concomitant chemotherapy as normal based on standard clinical protocols determined by the neuro-oncologist<br>* temozolomide given alongside the radiotherapy at 75mg/m2 daily from the first day of radiotherapy, until the last day of radiotherapy, but for no longer than 49 days. Standard treatment following neurosurgery for glioblastoma<br>Drug: Adjuvant chemotherapy as normal based on standard clinical protocols determined by the neuro-oncologist<br>* Following a 4 week break after contomitant chemo/RT, temozolomide given 150-200mg/m2 TMZ 5/28 days for 6 cycles (dosage increase to 200mg/m2 on second and subsequent cycles dependent on haematological toxicity. Sites should follow local guidelines if different.). TMZ to be given on 5 consecutive days followed by 23 days with no TMZ, per cycle. Standard treatment following neurosurgery and concomitant chemo/RT for glioblastoma<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety, Tolerability, and Feasibility of Combination Intra-operative 5-ALA and Gliadel Wafers Prior to Adjuvant Radiotherapy Plus Temozolomide | Procedure compliance: Proportion of 5-ALA resected patients who received Carmustine wafer implants (e.g to take into account rates of patients who did not receive Carmustine wafer implants due to 1) ventricular breach, 2) inaccurate peri-operative diagnosis, 3) intra-operative surgical decision) Post-operative complication rate: Proportion of patients with a new post-operative deficit or surgical complication (wound infection, CSF leakage, intracranial hypertension) No. of patients with chemoRT delay (i.e number who do not begin chemoRT 6 weeks after surgery) due to surgical complications* No. of patients failing to start chemoRT due to surgical complications rather than tumour progression No. of patients failing to complete chemoRT without interruption (RT with concomitant chemotherapy, and RT with concomitant plus adjuvant chemotherapy) Proportion of patients with a lower WHO performance status after surgery with Carmustine wafers (at first post-operative clinic visit) | Date of surgery to end of temozolomide and radiotherapy treatment (up to 34 weeks) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Clinical Progression |  | from the date of surgery to the date of the first MRI scan fitting the criteria for progression, or the date the clinical detrioration or death was first reported | 
| Survival at 24 Months |  | from the date of surgery to 24 months | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
adult giant cell glioblastoma, adult gliosarcoma, adult glioblastoma