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

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)

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.

Study Overview

• Status: Completed
• 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

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.

• Study Type: Interventional
• Enrollment (Actual): 59
• Phase: Phase 2

Contacts and Locations

Study Locations

• United Kingdom
  • Dundee, United Kingdom
    • Ninewells Hospital
  • Glasgow, United Kingdom
    • Southern General Hospital
  • Hull, United Kingdom
    • Hull Royal Infirmary
  • Leeds, United Kingdom
    • Leeds General Infirmary
  • Liverpool, United Kingdom
    • The Walton Centre
  • London, United Kingdom
    • King's College Hospital
  • London, United Kingdom
    • University College London Hospital/ National Hospital for Neurology and Neurosurgery
  • Sheffield, United Kingdom
    • Royal Hallamshire Hospital
  • England
    • Cambridge, England, United Kingdom, CB2 2QQ
      • Addenbrooke's Hospital
  • Lancashire
    • Preston, Lancashire, United Kingdom
      • Royal Preston Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: 5-ALA and Gliadel wafers; 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; 5-ALA is used to generate tumour specific fluorescence as an aid to surgical resection of GBM, prior to the insertion of Gliadel wafers; Other Names: Gliolan; Amino-levulinic Acid; Drug: Gliadel wafers; 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.; Other Names: Carmustine wafers; polifeprosan 20 with carmustine implant; Radiation: Radiotherapy as normal based on standard clinical protocols determined by the neuro-oncologist; 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; Drug: Concomitant chemotherapy as normal based on standard clinical protocols determined by the neuro-oncologist; 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; Drug: Adjuvant chemotherapy as normal based on standard clinical protocols determined by the neuro-oncologist; 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

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	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

Collaborators and Investigators

• Sponsor: University College, London
• Investigators: Principal Investigator: Colin Watts, Cambridge University Hospitals NHS Foundation Trust

Study record dates

Study Major Dates

• Study Start: May 1, 2011
• Primary Completion (Actual): March 1, 2015
• Study Completion (Actual): March 1, 2015

Study Registration Dates

• First Submitted: March 5, 2011
• First Submitted That Met QC Criteria: March 5, 2011
• First Posted (Estimate): March 9, 2011

Study Record Updates

• Last Update Posted (Actual): October 5, 2017
• Last Update Submitted That Met QC Criteria: September 6, 2017
• Last Verified: September 1, 2017

More Information

Terms related to this study

• Keywords: adult glioblastoma; adult giant cell glioblastoma; adult gliosarcoma
• 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; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Antineoplastic Agents, Alkylating; Alkylating Agents; Photosensitizing Agents; Dermatologic Agents; Aminolevulinic Acid; Carmustine; Levulinic acid
• Other Study ID Numbers: CDR0000696316; CRUK-UCL-09-0398 (Other Grant/Funding Number: Cancer Research UK and Samantha Dixon Brain Tumour Trust); 2010-022496-66 (EudraCT Number); 09/0398 (Other Identifier: University College London); 10/H0304/100 (Other Identifier: NRES Committee East of England - Cambridge East)