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

• Sponsor: University College, London (Other)
• Overall Status: Completed
• CT.gov ID: NCT01310868
• Collaborator: (none)
• Enrollment: 59
• Locations: 10
• Arm: 1
• Duration (Months): 46
• Patients Per Site: 5.9
• Patients Per Site Per Month: 0.1

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Glioblastoma	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	Phase 2

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 Design

• Study Type: Interventional
• Actual Enrollment: 59 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• 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)
• Study Start Date: May 1, 2011
• Actual Primary Completion Date: Mar 1, 2015
• Actual Study Completion Date: Mar 1, 2015

Arms and Interventions

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: Amino-levulinic Acid Gliolan ; 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

Outcome Measures

Primary Outcome Measures

1. Safety, Tolerability, and Feasibility of Combination Intra-operative 5-ALA and Gliadel Wafers Prior to Adjuvant Radiotherapy Plus Temozolomide [Date of surgery to end of temozolomide and radiotherapy treatment (up to 34 weeks)]

   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)

Secondary Outcome Measures

1. 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]

2. Survival at 24 Months [from the date of surgery to 24 months]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

INCLUSION CRITERIA

1. The patient is reviewed at a specialist neuro-oncology multi-disciplinary team (MDT).

2. Stealth MRI (neuronavigation) will be performed prior to surgery.

3. Imaging is evaluated by a neuro-radiologist and judged to have typical appearances of a primary GBM

4. 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)

5. WHO performance status 0 or 1

6. Age ≥18

7. 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

1. GBM thought to be transformed low grade or secondary disease

2. The patient has not been seen by a specialist MDT.

3. There is uncertainty about the radiological diagnosis

4. 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)

5. Pregnant or lactating women

6. Known or suspected HIV or other significant infection or comorbidity that would preclude radical aggressive therapy for GBM

7. Active liver disease (ALT or AST ≥5 x ULRR)

8. Concomitant anti-cancer therapy except steroids

9. History of other malignancies (except for adequately treated basal or squamous cell carcinoma or carcinoma in situ) within 5 years

10. Previous brain surgery (including biopsy) or cranial radiotherapy

11. Platelets <100 x109/L

12. Mini mental status score <15

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Addenbrooke's Hospital	Cambridge	England	United Kingdom	CB2 2QQ
2	Royal Preston Hospital	Preston	Lancashire	United Kingdom
3	Ninewells Hospital	Dundee		United Kingdom
4	Southern General Hospital	Glasgow		United Kingdom
5	Hull Royal Infirmary	Hull		United Kingdom
6	Leeds General Infirmary	Leeds		United Kingdom
7	The Walton Centre	Liverpool		United Kingdom
8	King's College Hospital	London		United Kingdom
9	University College London Hospital/ National Hospital for Neurology and Neurosurgery	London		United Kingdom
10	Royal Hallamshire Hospital	Sheffield		United Kingdom

Sponsors and Collaborators

• University College, London

Investigators

• Principal Investigator: Colin Watts, Cambridge University Hospitals NHS Foundation Trust

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: University College, London
• ClinicalTrials.gov Identifier: NCT01310868
• Other Study ID Numbers: CDR0000696316; CRUK-UCL-09-0398; 2010-022496-66; 09/0398; 10/H0304/100
• First Posted: Mar 9, 2011
• Last Update Posted: Oct 5, 2017
• Last Verified: Sep 1, 2017

• Keywords provided by University College, London: adult giant cell glioblastoma; adult gliosarcoma; adult glioblastoma
• Additional relevant MeSH terms: Glioblastoma; Carmustine; Aminolevulinic Acid; Levulinic acid

Study Results

Participant Flow

Pre-assignment Detail	Study entry was based on imaging that has been judged to have typical appearances of a primary glioblastoma multiforme (GBM). Patients would have neurosurgery and GBM would be confirmed peri/post-operatively. If not GBM patients OR wafers+ 5-ala not administered then remain in the trial for follow up but were not included in the final analysis.

Arm/Group Title	5-ALA and Gliadel Wafers
Arm/Group Description	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. 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 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.
Period Title: Overall Study
STARTED	72
COMPLETED	59
NOT COMPLETED	13

Baseline Characteristics

Arm/Group Title	5-ALA and Gliadel Wafers
Arm/Group Description	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. 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 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.
Overall Participants	72
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	54 75%
>=65 years	18 25%
Sex: Female, Male (Count of Participants)
Female	23 31.9%
Male	49 68.1%
Region of Enrollment (participants) [Number]
United Kingdom	72 100%

Outcome Measures

1. Primary Outcome

Title	Safety, Tolerability, and Feasibility of Combination Intra-operative 5-ALA and Gliadel Wafers Prior to Adjuvant Radiotherapy Plus Temozolomide
Description	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)
Time Frame	Date of surgery to end of temozolomide and radiotherapy treatment (up to 34 weeks)

Outcome Measure Data

Analysis Population Description

of 72 patients recruited, 62 received 5-ALA and carmustine wafers. Of these 62 patients, 59 were found to be eligible and included in the final analysis

Arm/Group Title	5-ALA and Gliadel Wafers
Arm/Group Description	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. 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 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.
Measure Participants	72
5-ALA resected patients receiving carmustine wafer	62 86.1%
No. patients with post-op complications	9 12.5%
No. Patients with chemoRT delay	6 8.3%
No. pts failing to complete uninterrupted chemoRT	45 62.5%
no. pts w decr perform status after 5ala/carmustin	27 37.5%
no. pts not starting chemoRT due to surgical comp	2 2.8%

2. Secondary Outcome

Title	Time to Clinical Progression
Time Frame	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

Outcome Measure Data

Analysis Population Description

Patients receiving 5-ala and carmustine wafers during surgical resection for glioblastoma multiforme that was confirmed peri/post-operatively

Arm/Group Title	5-ALA and Gliadel Wafers
Arm/Group Description	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. 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 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.
Measure Participants	59
Median (95% Confidence Interval) [months]	9.5

3. Secondary Outcome

Title	Survival at 24 Months
Time Frame	from the date of surgery to 24 months

Outcome Measure Data

Analysis Population Description

Patients receiving 5-ala and carmustine wafers during surgical resection for glioblastoma multiforme that was confirmed peri/post-operatively

Arm/Group Title	5-ALA and Gliadel Wafers
Arm/Group Description	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. 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 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.
Measure Participants	59
Median (95% Confidence Interval) [months]	15

Adverse Events

Arm/Group Title	5-ALA and Gliadel Wafers
Arm/Group Description	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. 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 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.
All Cause Mortality
	5-ALA and Gliadel Wafers
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	5-ALA and Gliadel Wafers
	Affected / at Risk (%)	# Events
Total	26/59 (44.1%)
Eye disorders
retinal detachment	1/59 (1.7%)
Gastrointestinal disorders
colonic perforation	1/59 (1.7%)
other - bowel perforation	1/59 (1.7%)
intra-abdomial hemorrhage	1/59 (1.7%)
nausea	1/59 (1.7%)
vomiting	1/59 (1.7%)
General disorders
fever	1/59 (1.7%)
Infections and infestations
infection - cerebral abscess	1/59 (1.7%)
infections other (not specified)	2/59 (3.4%)
sepsis	2/59 (3.4%)
urinary tract infection	1/59 (1.7%)
wound infection	2/59 (3.4%)
Injury, poisoning and procedural complications
Wound dehiscence	1/59 (1.7%)
Musculoskeletal and connective tissue disorders
muscle weakness left sided	1/59 (1.7%)
Nervous system disorders
cerebral spinal fluid leak	2/59 (3.4%)
headache	1/59 (1.7%)
stroke	1/59 (1.7%)
vasovagal reaction	1/59 (1.7%)
seizure	8/59 (13.6%)
Psychiatric disorders
psychiatric disorders - other (steroid induced aggression)	1/59 (1.7%)
Respiratory, thoracic and mediastinal disorders
pulmonary edema	1/59 (1.7%)
Vascular disorders
hematoma	1/59 (1.7%)
thromboembolic event	3/59 (5.1%)
Other (Not Including Serious) Adverse Events
	5-ALA and Gliadel Wafers
	Affected / at Risk (%)	# Events
Total	23/59 (39%)
Gastrointestinal disorders
nausea	4/59 (6.8%)
vomiting	3/59 (5.1%)
Injury, poisoning and procedural complications
wound infection	3/59 (5.1%)
Investigations
neutrophil count decreased	4/59 (6.8%)
platelet count decreased	4/59 (6.8%)
white blood cell decreased	3/59 (5.1%)
Musculoskeletal and connective tissue disorders
muscle weakness	5/59 (8.5%)
Nervous system disorders
seizure	5/59 (8.5%)
lethargy	3/59 (5.1%)
Vascular disorders
thrombolytic event	4/59 (6.8%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results.