Phase II Study of Laser Interstitial Thermal Therapy (LITT) in Recurrent Glioblastoma
Phase: PHASE2
Conditions: IDH Family Wildtype, Recurrent Anaplastic Astrocytoma, Recurrent Glioblastoma
Sponsor: M.D. Anderson Cancer Center

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Phase II Study of Laser Interstitial Thermal Therapy (LITT) in Recurrent 
 Glioblastoma 
 
 
 
Principal Investigators: Barbara O’Brien and John de Groot 
Co-Principal Investigators: Sujit Prabhu and Ganesh Rao  
 
Department of Neuro-Oncology and Neurosurgery 
University of Texas – M. D. Anderson Cancer Center 
 
 

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Table of Contents 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PAGE 
1.0 
OBJECTIVES 
3 
2.0 
BACKGROUND 
4 
3.0 
DRUG & DEVICE INFORMATION 
8 
4.0 
ELIGIBILITY CRITERIA 
14 
5.0 
STRATIFICATION/DESCRIPTIVE FACTORS 
18 
6.0 
TREATMENT PLAN 
18 
7.0 
PRETREATMENT EVALUATION 
25 
8.0 
EVALUATION DURING STUDY 
25 
9.0 
CRITERIA FOR EVALUATION AND ENDPOINT DEFINITIONS 
27 
10.0 CRITERIA FOR REMOVAL FROM STUDY 
30 
11.0 STATISTICAL CONSIDERATIONS 
30 
12.0 DISCIPLINE REVIEW 
33 
13.0 SAFETY ASSESSMENTS AND TOXICITY MONITORING 
33 
14.0 REFERENCES 
37 
15.0 APPENDIX 
40 
 

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1.0  
OBJECTIVES 
 
1.1  
Primary Objective 
 
Determine the disease control rate at 6 months in patients with recurrent glioblastoma or 
isocitrate dehydrogenase (IDH)-wildype anaplastic astrocytoma treated with LITT at 
recurrence, followed by salvage chemotherapy. 
 
1.2  
Secondary Objectives 
 
1.2.1  Estimate overall survival (OS) of patients with recurrent glioblastoma, or IDH-wildtype 
anaplastic astrocytoma treated with LITT at tumor recurrence, followed by salvage 
chemotherapy. 
 
1.2.2  Estimate time to progression (TTP) of patients with recurrent glioblastoma, or IDH-
wildtype anaplastic astrocytoma that are treated with LITT at tumor recurrence, followed 
by salvage chemotherapy. 
 
1.2.3  Analyze volumetric data consisting of thermal damage threshold lines and overall tumor 
volume to determine any role of ‘extent of ablation’ in outcomes (OS and/or TTP). 
 
1.2.4  Characterize the safety profile of LITT followed by treatment with lomustine 
chemotherapy in the recurrent disease setting, using the CTCAE version 4.0. 
 
1.2.5  Assess the long-term steroid requirements following LITT. 
 
1.2.6  Determine the radiographic evolution of LITT-treated glioblastoma over time, using 
conventional MRI (T1 pre and post-contrast images, T2-weighted images (T2WI), Fluid 
attenuating inversion recovery (FLAIR) images) and advanced brain tumor imaging 
(ABTI) [MR perfusion [dynamic susceptibility contrast (DSC), dynamic contrast 
enhancement (DCE) and arterial spin labeling (ASL)], MR- diffusion, and MR 
spectroscopy), to include quantitative tumor metrics (volumetric extent of ablation and 
RANO criteria).  
 
1.2.7  Analyze health care utilization as measured by length of hospital stay following LITT 
(including inpatient rehabilitation care). 
 
1.2.8  Evaluate patients’ functional status (using the Karnofsky Performance Score (KPS) and the 
occurrence of symptoms (using the MD Anderson Symptom Inventory-Brain Tumor 
Module (MDASI-BT(English)) self-reporting tool), and correlate to disease progression 
and tolerance to treatment. 
 
1.3  
Exploratory Objectives 
 

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1.3.1  Identify correlative tumor and peripheral blood molecular markers that impact outcomes, 
etc, and identify inflammatory/immunologic markers to assess neoantigen expression, etc, 
if sufficient tissue is available.  
 
1.3.2  Identify and characterize changes in tumor tissue following LITT, by analyzing and 
comparing pre- and post-procedure tissue samples, if sufficient tissue is available. 
 
2.0  
BACKGROUND 
 
2.1  
Glioblastoma 
 
Glioblastoma (GBM) is the most common and the most aggressive primary adult brain 
tumor. Prognosis for patients with glioblastoma is quite dismal despite aggressive 
treatment. The current standard of care consists of maximal safe surgical resection, 
followed by 6 weeks of concurrent chemoradiation with daily temozolomide, followed by 
6 4-week cycles of adjuvant temozolomide, with many patients remaining on treatment for 
12 cycles. The overall median survival for patients with glioblastoma is less than 15 months 
[21]. Following disease progression, therapy most commonly consists of second-line 
chemotherapy, although radiation therapy, and/or surgery are also considerations. The 
response to single or multiple-agent chemotherapy is poor, with a response rate of 6%, 6-
month progression-free survival rates for patients with recurrent GBM of 15% and median 
survival of 6 months [26]. Interestingly, although histologically grade 3 gliomas, patients 
with IDH wildtype anaplastic astrocytomas seem to have similar prognosis to patients with 
glioblastoma, and likely benefit from similar treatments. 
 
Studies have shown a correlation between initial resection of glioblastoma and survival, 
with gross-total resection of tumor independently associated with longer survival [11]. 
Subtotal resection of tumor may still provide symptomatic benefits [11]. Tumors in deep 
or eloquent regions of brain are often not amenable to resection due to high risk of 
neurologic morbidity, and patients with these tumors most often only undergo biopsy. Over 
70% of patients are not candidates for a complete resection due to a variety of factors [7]. 
Unfortunately, without initial cytoreductive surgery, radiation and chemotherapy appear to 
have more limited benefit [11, 12, 18]. Due to volume of tumor and associated edema, 
patients who have undergone biopsy only may be more likely to require long-term, high-
dose corticosteroid treatment, and may experience  shorter survival, compared to patients 
undergoing gross-total resection. At MD Anderson Cancer Center, for patients with good 
performance status and unresectable (biopsy-only) glioblastoma, the median survival is 
about 10 months. These findings suggest a need for an alternate cytoreductive treatment 
modality. 
 
2.2  
Laser Interstitial Thermal Therapy 
 
LITT is a minimally invasive procedure for destroying tissue using heat generated through 
light absorption [3, 4]. Laser induced hyperthermia as a cytoreductive treatment option has 
been present since the 1980s [1]. Laser-induced thermal therapy was used as a treatment 

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for a range of different brain pathologies [10, 16, 22]. However, limitations in monitoring 
and controlling the extent of thermal damage delivered during treatment prevented this 
modality from being widely used until recently [13].  MR-thermography based on the 
temperature dependence of the proton resonance frequency (PRF) now allows for real-time 
image guidance of the extent of thermal damage from lasing [8]. Technologic advances 
such as this, as well as laser probe design, surgical navigation, and computer algorithms 
predictive of tissue kill, have allowed for a resurgence in the use of LITT for brain tumor 
cytoreduction [15]. The NeuroBlate System® (Monteris Medical Corporation, Plymouth, 
MN) is one such LITT device. NeuroBlate received FDA 510k clearance (K081509) in 
May 2009 without any specific limitations for intracranial use [13]. This was followed by 
a successful first in human study [19]. 
 
The LITT equipment manufactured as the NeuroBlate System uses a diode laser which 
transfers energy to the target tissue via a CO2 gas-cooled, side-firing probe [13].  The 
NeuroBlate system also includes a tool for obtaining biopsy of tumor tissue. The lasing is 
planned and controlled via the NeuroBlate System computer workstation using proprietary 
software under real-time MR-thermography guidance.  The real-time extent of thermal 
ablation is calculated based on an algorithm of heat kill of cells (a relationship between 
time and temperature) demonstrated as thermal damage threshold (TDT) lines. A yellow 
TDT line encircles the area of tissue heated to an equivalent of 43 degrees Celsius for at 
least 2 minutes and a blue TDT line encircles the tissue heated to an equivalent of 43 
degrees Celsius for at least 10 minutes, or to a higher temperature for a shorter interval 
[19].   
 
Interactions between the laser and tissue are mostly thermal and rely on the power applied 
by the laser.  The optical fiber emits photons that are absorbed by tumor chromophores 
causing excitation and release of thermal energy [20]. Maintaining the temperature above 
a critical threshold causes protein denaturation and irreversible tissue coagulation. Damage 
is produced in the tissue due to extrinsic properties of the laser and intrinsic properties of 
the target tissue [5].  The lesions produced by LITT are due to the combined effects of 
internal thermal generation and heat conduction [15]. 
 
LITT was first popularized as a percutaneous means of killing malignant hepatic and renal 
lesions [15]. Several animal studies using LITT to treat tumors in vivo, followed by clinical 
trials, have established the feasibility of LITT in treating intracranial tumors [15]. LITT 
has been used previously in the ablation of cerebral metastasis, with safety and efficacy 
demonstrated in small studies [3]. There are limited published studies describing clinical 
outcomes in patients with glioblastoma treated with LITT. Schwarzmaier et al studied 16 
patients with recurrent GBM treated with LITT. They reported a 6.9 month median survival 
after LITT, relatively better than the historical control; no permanent neurologic deficits 
were reported [17]. More recently, Sloan et al conducted a phase I trial with 10 patients 
with high-grade glioma, using NeuroBlate for the LITT procedure.  Median OS was 10.5 
months after LITT; no deaths were reported related to the procedure [19]. The authors 
conclude from their phase I study that LITT therapy for recurrent glioblastoma is safe.  In 
the largest series to date, Mohammadi et al retrospectively reviewed 34 patients with high-

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grade glioma who underwent the LITT procedure with NeuroBlate, either as upfront or 
salvage treatment. This study showed some improvement in median progression free 
survival, although the median overall survival was not yet reached [13]. This study found 
that more complete coverage of tumor by TDT lines improved PFS and suggested that this 
can be likened to the extent of resection concept in surgery. 
 
There is little data in the literature regarding the role of the extent of tumor coverage by 
LITT thermal energy on outcomes for patients with glioblastoma. However, there is 
literature reporting improved outcomes in patients with extensive surgical resections. 
There is a suggestion that the improved survival correlated with “extent of surgical 
resection” can be achieved by the “extent of hyperthermic ablation.” [13] 
 
2.3  Salvage treatment of recurrent glioblastoma 
 
Second-line chemotherapy is the most common treatment modality in recurrent 
glioblastoma.  At recurrence, a minority of patients are eligible for repeat resection or re-
irradiation which may pose challenges, although repeat resection may be associated with a 
survival advantage [6]. Necrosis and cognitive impairment can occur with re-irradiation, 
and increased risk of infection and worsening neurologic status is more likely in patients 
undergoing repeat resection. Efficacy of second-line chemotherapy, as noted above, is very 
limited. Options include treatment with bevacizumab (FDA approved humanized 
monoclonal antibody that targets the vascular endothelial growth factor), rechallenging 
with temozolomide or other cytotoxic drugs including lomustine, and experimental 
targeted therapies and immunotherapies.  
 
Nitrosoureas are commonly used as treatment for glioblastoma.  Beginning in 1968, 
investigators studied single-agent chemotherapy in the treatment of brain tumors [24]. In 
the 1970s, the Brain Tumor Study group defined carmustine, a nitrosourea agent, as the 
standard against which newer forms of therapy were compared. Unfortunately, most 
patients quickly develop resistance to carmustine, and thus there have been modest 
improvements in survival rates with its use [2].  Lomustine (CCNU), also a nitrosourea 
agent, is pharmacologically similar to carmustine and is used in the treatment of certain 
neoplastic diseases.  Lomustine has been shown to be useful as a single agent or in 
combination therapy with other approved chemotherapy agents in both primary and 
metastatic brain tumors.   Study results for single-agent use of lomustine in the treatment 
of recurrent malignant gliomas in adults have been summarized by Hildebrand [9] with 
overall tumor response rates of 19% to 44% (partial response [PR] + stable disease [SD]) 
with length of remission of 6 to 8 months.  A recent large meta-analysis of 364 studies 
describing 24,193 patients with high-grade glioma treated with lomustine either as single 
agent or in combination with other agents revealed a survival gain of 5.3 months [25].  
 
Although lomustine alkylates DNA and RNA, this agent is not cross resistant with other 
alkylators.  In a recent phase III trial of enzastaurin versus lomustine in the treatment of 
recurrent glioblastoma, some temozolomide resistant glioblastoma patients responded to 
lomustine treatment (response rate of 4.3% but a 6-month PFS of 19% [23]; indicating 

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there is non-overlapping resistance with temozolomide.  Due to high lipid solubility and 
the relative lack of ionization at physiological pH, lomustine crosses the blood-brain barrier 
quite effectively. Common and severe adverse events include bone marrow suppression 
(most notably thrombocytopenia and leukopenia).  
 
2.4  
Rationale for this trial 
 
Surgical extent of resection has been shown to have an impact on glioma outcomes, with 
patients with unresectable or subtotally resected tumors being at a suspected disadvantage 
with regard to outcomes. Tumor progression may be heralded by new imaging changes 
and/or neurologic symptoms. These symptoms may require additional medications such as 
corticosteroids which may lead to additional symptoms (e.g. steroid myopathy) and a 
reduction in quality of life. A multi-institutional nonrandomized retrospective study 
suggests LITT may improve progression free survival in patients with unresectable 
glioblastoma, and a first-in-humans phase I trial found LITT to be safe, and promising in 
terms of efficacy [19].  Improving progression-free survival may prevent degradation of 
quality of life. 
 
With this in mind, we propose treating patients with recurrent glioblastoma, with LITT 
followed by salvage chemotherapy with lomustine, a second-line chemotherapy agent in 
patients with recurrent glioblastoma who have failed temozolomide treatment. Patients 
with known IDH-wildtype anaplastic astrocytomas (grade 3 gliomas), with suspected 
recurrence, will also be considered for inclusion, as these tumors may be similarly 
aggressive and lack viable treatment options. The aim of the study is to improve disease 
control rate at 6 months in this cohort of patients with recurrent glioblastoma.  
 
2.5 
Rationale for secondary objectives 
 
2.5.1  Rationale for evaluating survival  
 
It has been suggested that the cytoreductive effect of hyperthermia may be equivalent to 
surgical debulking [13], in other words, extent of ablation is potentially equivalent to extent 
of resection. 
 
2.5.2  Rationale for analyzing volumetric data consisting of thermal damage threshold (TDT) 
lines and overall tumor volume.   
 
 
The goal is to correlate the extent of laser thermal ablation with outcome (OS and TTP). 
Volumetric data will allow a quantitative measurement of extent of ablation. 
 
2.5.3  Rationale for imaging correlates  
 
 
LITT’s mode of action induces tissue damage by thermal ablation. Some tissue damage 
continues to occur even after the completion of the procedure. A systematic analysis of the 
evolution of these changes over time on imaging studies, and their correlation with 

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outcome, will help us evaluate how these changes evolve and impact the assessment of 
tumor progression.  
 
2.5.4  Rationale for evaluating the safety profile 
 
 
Previous studies have found LITT to be a safe procedure for patients with brain tumors. 
We will gather more data on the safety of LITT, in the context of recurrent glioblastoma, 
and salvage chemotherapy. 
 
2.5.5  Rationale for analyzing quality of life, functional status, and health care utilization 
 
Patients with recurrent brain tumors often experience reduced quality of life, poor 
functional status and increased health care utilization.  We will determine whether the use 
of LITT can preserve quality of life and functional status in recurrent disease, and lower 
the extent of hospitalization and health care utilization. 
 
 
2.6  Rationale for exploratory objectives  
 
Tumor tissue and peripheral blood will be evaluated in our trial with the objective of 
identifying correlative biomarkers of response and outcome. Collection of tumor tissue 
may allow for the evaluation of molecular and immunologic markers linked to response to 
therapy and survival in subsets of patients.  Tumor tissue (biopsy) will be collected 
immediately pre- and post-procedure to inform the changes imparted on brain tumor tissue 
by thermal ablation. 
 
3.0  
DRUG AND DEVICE INFORMATION  
 
3.1  
Device name: NeuroBlate System® 
 
The laser probe is available in two diameters (3.3 mm and 2.2 mm) and is internally cooled 
using CO2 gas. The laser energy (1064 nm) exits the probe almost perpendicularly (side-
firing probe) through a sapphire tip. The laser source is a 12-W pulse mode diode laser 
(1064 nm, cycle of 1.6 seconds in on mode and 2.2 seconds in off mode). 
 
The NeuroBlate System monitors and visually reports the temperature of tissue and the 
thermal dose. By convention the temperature commonly used in reporting experimental 
thermal dosage equivalence is 43°C. Tissues exposed to temperatures of 43°C or higher 
for ≥ 60 minutes initiate apoptosis and die within 48 hours. Tissues exposed to 43°C for 
shorter periods of time have a decreased level of damage, which has been refined 
empirically through preclinical testing and canine and porcine models (unpublished data, 
Monteris Medical, Inc.).  
 
The NeuroBlate software determines the likelihood of eventual cell death across the 
monitored tissue following laser thermal therapy [17]. 
 

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3.1.1  Risks 
 
The risks of LITT therapy are low in the treatment of brain tumors, as has been documented 
in several small studies (Hawasli, 2012; Schroeder, 2013, Missios, 2013). In a few patients, 
temporary or permanent mild neurological deterioration (typically some manifestation of 
paresis) was observed, along with occasionally focal seizures. In general, the overall 
functionality (Karnofsky scores) was not reduced by the LITT treatment. Improvements in 
survival have been suggested following LITT therapy, equivalent to those observed 
following surgical resection (median = 11.2 months). With the recent availability (FDA 
clearance and market release) of the NeuroBlate® System, neurosurgeons managing this 
group of patients have an additional option. The minimally invasive approach of the 
NeuroBlate® System procedure with the non-ionizing ablation is an attractive alternate 
intervention to address the therapeutic needs of these subjects. In the NeuroBlate® System 
therapy First-in-Humans Phase 1 Clinical Trial for Recurrent Glioblastoma, the procedure 
appeared to be a new, safe method of ablating deep hemispheric recurrent GBM (Sloan, 
2013). The device offers neurosurgeons precise control over thermal dosing into target 
tissues sufficient to induce near immediate tissue necrosis. The procedure was well 
tolerated and most subjects could be safely discharged after 24-48 hours without significant 
pain in the surgical area, nausea or headache. No infections related to the LITT procedure 
were observed within 6 months of the procedure (Hawasli, 2012; Schroeder, 2013, Missios, 
2013). The impact of the NeuroBlate® System procedure on the QoL of patients with brain 
tumors or brain metastases is limited by the small collective clinical experience using the 
NeuroBlate® System therapy. Due to the recent introduction of NeuroBlate® System 
therapy, its effective incorporation in standard clinical practice of patients with newly 
diagnosed glioblastoma is unknown. 
 
Risks are classified as follows: 
 
Risk  
Mild  
Moderate  
Severe  
Likely risks  
(>5% ) 
Fever  
Low or high blood 
pressure  
Headache  
Fatigue, drowsiness  
Bleeding into or around 
the brain 
Swelling of the tissue in 
the brain 
Increased size of abnormal 
area due to the treatment 
Pain at the biopsy site 
Nausea or vomiting 
 
Less likely 
risks  
(1-5%) 
Depression of anxiety  
Agitation  
Blurry vision  
Small transient strokes 
(TIA)  
Reaction to anesthesia or 
other drugs  
Seizures 
Difficulty speaking 
Loss of muscle 
coordination to one or 
more parts of the body 
Injury to blood vessels 
Pneumonia 
 
Injury to brain tissue  
Loss of nerve 
function to a part of 
the body  
Stroke  
Blood clots to other 
parts of the body  

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Wound healing 
difficulties  
Fluid in the lungs or other 
lung abnormalities 
Infection, local or general 
Air bubbles to the 
lungs or other parts 
of the body  
Rare risks  
(<1%)  
Anemia  
Abnormal blood cell 
counts  
Loss of mental function 
Personality changes 
Unconsciousness 
Heart attack 
Death  
Failure of brain to 
regulate body 
systems  
 
 
As with any surgical procedure, the NeuroBlate® System involves some risks.  The 
following potential risks or discomforts may be associated with the surgical procedure or 
the NeuroBlate System. In addition, the list includes possible risks associated with the use 
of the NeuroBlate System in the GBM population. The frequency and severity of adverse 
events can vary, and may necessitate additional medical intervention, including surgery.  
 
• Agitation 
• Anemia 
• Aneurysm 
• Anxiety 
• Aphasia 
• Ataxia or loss of body coordination 
• Atelectesis 
• Bacteremia or sepsis 
• Bleeding into or around the brain  
• Blurry vision/visual disturbance 
• Cerebral infarction 
• Coma 
• Complete or incomplete hemiparesis 
• Death 
• Decrease energy 
• Deep venous thrombosis 
• Depression  
• Difficulty hearing 
• Difficulty speaking 
• Difficulty swallowing 
• Difficulty walking 
• Drowsiness 
• Edema 
• Failure of central regulation 
• Fever 
• Headache 
• Hypertension 
• Hypotension 

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• Increased seizures frequency/duration or severity 
• Infection, local or generalized 
• Injury to blood vessels 
• Injury to brain tissue 
• Insomnia (e.g. sleep problems) 
• Intestinal toxicity 
• Loss of mental function 
• Muscle weakness  
• Myocardial infarction 
• Nausea/vomiting 
• Nerve paralysis 
• Obtundation 
• Paralysis 
• Personality or cognitive changes (e.g. mood, memory, attention and thinking ability) 
• Permanent neurological deficit 
• Pneumonia 
• Presence of new type of seizure 
• Pain at incision site 
• Pulmonary or other air embolism 
• Reaction to anesthesia or other drugs 
• Status epilepticus 
• Stroke or transient ischemic attack (TIA) 
• Thromboembolism 
• Tingling or numb sensations in the body 
• Tissue damage 
• Unconsciousness 
• Wound dehiscence 
 
3.1.2   The training for the operator to use LITT equipment 
 
LITT is FDA-approved for intracranial use. All users undergo standard training provided 
by the company, Monteris. The surgeons performing this procedure are already 
experienced users of LITT (over 120 cases combined).  Deployment of the laser probe into 
the tumor is exactly the same as performing a stereotactic biopsy (i.e. using computer-
assisted navigation technique for implanting a stereotactic biopsy needle), which is 
standard training during neurosurgery residency. As far as mitigating damage to normal 
tissue, thermal damage maps are monitored in real time and points are selected on normal 
tissue that enable the user to immediately stop treatment should those structures reach 
damaging temperatures.  
 
3.2   
Drug Name: Lomustine (CCNU) 
 

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Lomustine is one of the nitrosoureas used in the treatment of certain neoplastic diseases. It 
is 1-(2-chloro-ethyl)-3-cyclohexyl-1-nitrosourea. It is a yellow powder with the empirical 
formula of C9H16ClN3O2 and a molecular weight of 233.71. Lomustine is soluble in 10% 
ethanol (0.05 mg per mL) and in absolute alcohol (70 mg per mL). Lomustine is relatively 
insoluble in water (<0.05 mg per mL).  Inactive ingredients in lomustine capsules are 
magnesium stearate and mannitol, and may additionally contain wheat starch and talc. 
Lomustine is commercially available in 10 mg, 40 mg and 100 mg capsules for oral 
administration.  Doses of lomustine should be rounded down to the nearest 10 mg. 
 
3.2.1 Chemical Name: 1-(2-chloro-ethyl)-3-cyclohexyl-1-nitrosourea 
 
3.2.2 Molecular Formula: C9H16ClN3O2 
 
3.2.3 Molecular Weight: 233.71 
 
3.2.4 Appearance: yellow powder  
 
3.2.5 How Supplied: Lomustine is commercially available in 10 mg, 40 mg and 100 mg capsules 
for oral administration. 
 
3.2.6 Formulation:  Lomustine is soluble in 10% ethanol (0.05 mg per mL) and in absolute 
alcohol (70 mg per mL). It is relatively insoluble in water (<0.05 mg per mL).  Inactive 
ingredients in lomustine capsules are magnesium stearate and mannitol, and may 
additionally contain wheat starch and talc.  
 
3.2.7 Mechanism of Action:  Nitrosourea antineoplastic agents are alkylating agents.  
This class of drugs work by inhibiting DNA replication, RNA transcription, and nucleic 
acid function. The drug is believed to inhibit DNA replication, RNA transcription, and 
nucleic acid function. Lomustine also may modify cellular proteins. Specifically, lomustine 
possesses a chloroethyl group that alkylate nucleic acids and cell proteins and form DNA-
DNA or DNA-protein crosslinks, which lead to the global effects of impaired nucleic acid 
functioning. As compared to carmustine, lomustine is less likely to form isocyanates 
leading to diminished carbamoylation effects; although lomustine metabolites exhibit 
increased alkylating activity. Cells resistant to other alkylating agents are probably resistant 
to lomustine. 
 
3.2.8 Pharmacology/Pharmacokinetics: 
A. Absorption: The drug is rapidly absorbed across the GI tract following oral 
administration, or across the skin following topical administration. The exact 
bioavailability is unknown, but nearly complete oral absorption occurs in 30 minutes. 
Orally-administered lomustine is rapidly and totally converted to metabolites by first-pass 
metabolism in the liver. Essentially all of an oral dose is metabolized within 1 hour; some 
of these metabolites may be active 
 
 

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B. Distribution: The drug distributes throughout the body tissues. Because of the high lipid 
solubility and the relative lack of ionization at physiologic pH, lomustine crosses the blood-
brain barrier quite effectively; however, only lomustine's metabolites can be detected in 
the CSF. CSF concentrations are >= 50% of plasma concentrations. 
 
C. Metabolism & Elimination: The half-life of lomustine metabolites ranges from 16 hours 
to 2 days 
 
 
D. Excretion: Following the administration of radio-labeled lomustine at oral doses of 30—
100 mg/m2, about half of the radioactivity was excreted in the urine in the form of 
metabolites within 24 hours. Most of the metabolites are eliminated slowly in the urine. 
 
E. Effect of Renal Impairment: There is no dosage adjustment provided in the 
manufacturer’s labeling. 
 
F. Effect of Hepatic Impairment: There is no dosage adjustment provided in the 
manufacturer’s labeling. 
 
 
3.2.9 Human Toxicology: 
 
 
A. Bone marrow suppression (e.g., thrombocytopenia, leukopenia, and anemia) has been 
commonly reported with lomustine therapy; thrombocytopenia and leukopenia are dose-
limiting toxicities. Patients receiving lomustine are at increased risk for serious bleeding 
and infection. Delayed and cumulative myelosuppression (pancytopenia) may occur, 
typically between 4 to 6 weeks following a dose, and may persist for 1 to 2 weeks; 
therefore, do not administer recommended doses of lomustine sooner than every 6 weeks. 
Monitor blood counts weekly for at least 6 weeks after a dose. Duration of suppression 
may be longer after repeated doses. A lomustine dose reduction may be necessary based 
on nadir blood counts. Following a lomustine 130 mg/m2 dose, 65% of patients 
experienced white blood cell (WBC) counts below 5000 cells/mm3 and 36% had WBC 
counts less than 3000 cells/mm3.  
 
B. Gastrointestinal (GI) adverse events such as nausea and vomiting have been reported 3 
to 6 hours after oral lomustine doses; loss of appetite (anorexia) may also occur. Symptoms 
usually last less than 24 hours. Prophylactic antiemetic administration and taking lomustine 
on an empty stomach may help to prevent these GI side effects. Stomatitis has also been 
reported infrequently with lomustine therapy. 
 
C.  Elevated hepatic enzymes (e.g., increased transaminase and alkaline phosphatase 
levels) and hyperbilirubinemia have been reported with lomustine therapy. Hepatotoxicity 
was typically reversible. Monitor liver function tests periodically during lomustine therapy. 
 
D.  Renal adverse events (e.g., progressive azotemia, decrease in kidney size, and renal 
failure (unspecified)) have been reported in patients receiving large cumulative doses after 
prolonged lomustine therapy. Kidney damage has also been reported infrequently in 

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patients receiving lower total lomustine doses. Monitor kidney function tests periodically 
during lomustine therapy. 
 
E.  Pulmonary toxicity (e.g., pulmonary infiltrate and/or pulmonary fibrosis) has been 
reported rarely with lomustine therapy. Pulmonary toxicity typically occurs 6 months or 
longer after starting lomustine therapy; however, delayed onset pulmonary fibrosis has 
been reported up to 17 years after treatment in patients who received related nitrosoureas 
in childhood and early adolescence (1—16 years) combined with cranial radiotherapy for 
intracranial tumors. Additionally, pulmonary toxicity has been typically reported following 
cumulative lomustine doses of greater than 1100 mg/m2, but there was 1 report of 
pulmonary toxicity occurring at a cumulative dose of 600 mg. Obtain baseline pulmonary 
function studies and monitor pulmonary function tests frequently tests during treatment. 
Patients with baseline predicted Forced Vital Capacity (FVC) or Carbon Monoxide 
Diffusing Capacity (DLCO) below 70% are particularly at risk for toxicity. 
 
F.  Secondary malignancy (e.g., acute leukemia and bone marrow dysplasia) has been 
reported with prolonged nitrosourea therapy. 
 
G.  Alopecia has also been reported infrequently with lomustine therapy. 
 
H.  Optic atrophy and visual impairment (e.g., blindness) have been reported infrequently 
with lomustine therapy. 
 
I.  Neurological adverse reactions such as disorientation, lethargy, ataxia, and dysarthria 
have occurred with lomustine therapy. 
 
 
3.2.10 Clinical Pharmacokinetic Properties:  See Section 3.2.8 
 
 
3.2.11 Administration: Lomustine will be administered orally as described in the treatment plan.  
 
3.2.12 Supplier: Lomustine (Gleostine) is available commercially. 
 
 
3.2.13 Agent Distribution: Lomustine (Gleostine) will be supplied through the patients’ insurance 
provider. 
 
4.0  
ELIGIBILITY CRITERIA  
 
This study was designed to include women and minorities, but was not designed to measure 
differences of intervention effects with regards to gender or race.  Males and females will 
be recruited with no preference to gender.  No exclusion to this study will be based on race.   
All patients who meet the following eligibility criteria must be registered with the 
 
University of Texas MD Anderson Cancer Center. 
 
   
4.1  
General Inclusion Criteria  
 

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A. 
Patients must have suspected recurrent supratentorial grade IV glioblastoma (or 
grade III IDH-wildtype anaplastic astrocytoma), for which a complete surgical 
resection is unsafe due to location, shape, or size of the tumor.  
 
Diagnosis of recurrence will be established by biopsy and frozen section 
immediately prior to initiating LITT procedure. If findings on frozen section are 
not consistent with recurrence (glioblastoma or recurrent IDH-wildtype anaplastic 
astrocytoma), decision to proceed with LITT procedure will be at the discretion of 
the neurosurgeon  (only patients with histologically-proven recurrent tumor will be 
evaluable for efficacy). 
 
B.  
All patients must sign an informed consent indicating that they are aware of the 
investigational nature of this study.  Patients must have signed an authorization for 
the release of their protected health information. Patients must be registered prior 
to treatment on study. 
 
 
C.  
Patients must be > 18 years old. 
 
D.   
Patients must have a Karnofsky Performance Score (KPS) >60. 
 
 
 
E.   
Patients must have received standard of care therapy with chemoradiation with 
temozolomide followed by adjuvant chemotherapy with temozolomide. Patients 
may have received one additional chemotherapy regimen (other than lomustine) in 
addition to adjuvant temozolomide prior to study entry (patients at either first or 
second recurrence are eligible). 
 
 
 
F.   
In the context of this clinical trial, a lesion suitable for LITT is single, enhancing, 
supratentorial, at least 2 cm from inner table of skull over the hemispheric 
convexity, and >1 cm, but <= 5 cm in cross-sectional dimension, including thalamic 
tumor (≤ 3 cm). 
 
G.   
Patients must have stable cardiovascular, neurovascular and neurological status, 
and be considered surgical candidates, as determined by any relevant pre-operative 
assessments, at the neurosurgeon’s discretion. 
 
H.   
Patients must not be receiving concurrent anti-tumor treatment and must have 
recovered from toxicity of prior treatment. Minimum interval required: 1) >6 weeks 
following nitrosourea chemotherapy; 2) >4 weeks after recovering from any non-
nitrosourea drug or systemic investigational agent; 3) >2 weeks after receiving any 
non-cytotoxic anti-tumor drug; 4) > 4 weeks after receiving radiation therapy (>12 
weeks following upfront concurrent chemoradiation); 5) >2 weeks following 
Optune device use. 
 
I.   
Patients must not have previously undergone an intracranial LITT procedure. 
 

2016-0443 
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J.  
Patients must have adequate bone marrow function (WBC > 3,000/µl, ANC >  
 
1,500/mm3, platelet count of > 100,000/mm3, and hemoglobin > 10 gm/dl),  
 
adequate liver function (SGOT and  bilirubin < 2 times ULN), and adequate  
 
renal function (creatinine < 1.5 mg/dL) before starting therapy.  These tests  
 
must be performed within 14 days (+ 3 working days) prior to registration.  
 
Eligibility level for hemoglobin and platelets may be reached by transfusion.  
 
K.  
Women of childbearing potential must have a negative B-HCG documented 
within 7 days prior to registration and must agree to practice adequate 
contraception as defined below. 
 
 
Non-childbearing potential (i.e., physiologically incapable of becoming pregnant), 
includes any female who has had: 
1. 
A hysterectomy 
2. 
A bilateral oophorectomy 
3. 
A bilateral tubal ligation 
4.  
Is post-menopausal: 
Subjects not using hormone replacement therapy (HRT) must have 
experienced total cessation of menses for ≥ 1 year and be greater than 45 
years in age, OR, in questionable cases, have a follicle stimulating hormone 
(FSH) value >40 mIU/mL and an estradiol value < 40pg/mL (<140 pmol/L).  
 
Subjects using HRT must have experienced total cessation of menses for >= 
1 year and be greater than 45 years of age OR have had documented 
evidence of menopause based on FSH and estradiol concentrations prior to 
initiation of HRT. 
 
Childbearing potential includes any female who has had a negative serum 
pregnancy test within 7 days of study registration, and agrees to use adequate 
contraception.  Acceptable contraceptive methods, when used consistently and in 
accordance with both the product label and the instructions of the physician, are as 
follows: 
1.  
Complete abstinence from sexual intercourse for 14 days before starting 
treatment, through the treatment, and for at least 1 month after the last dose 
of temozolomide.  
2.  
Oral contraceptive, either combined or progestogen alone. A second barrier 
method is required during the first month of treatment with oral 
contraceptives. 
3.  
Injectable progesterone 
4.  
Implants of levonorgestrel. 
5.  
Estrogenic vaginal ring.   
6.  
Percutaneous contraceptive patches.  
7.  
Intrauterine device (IUD) or intrauterine system (IUS) with a documented 
failure rate of less than 1% per year. 
8.  
Male partner sterilization (vasectomy with documentation of azoospermia) 

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prior to the female subject's entry into the study, and this male is the sole 
partner for that subject.   
9.  
Double barrier method: condom and an occlusive cap (diaphragm or 
cervical/vault 
caps) 
with 
a 
vaginal 
spermicidal 
agent 
(foam/gel/film/cream/suppository). 
 
 
Female participants who are lactating should discontinue nursing prior to the first  
 
dose of temozolomide and should refrain from nursing throughout the treatment  
 
period and for 42 days following the last dose of lomustine. 
 
 
 
 
4.2  
General Exclusion Criteria  
 
A.   
Patients must not have received treatment with bevacizumab.  
 
B.   
Patients must not have had prior treatment of glioblastoma with stereotactic 
radiosurgery, brachytherapy, or carmustine-impregnated wafers (Gliadel).   
 
C.   
Patients must not have symptoms attributed to mass effect of the tumor (despite 
corticosteroid treatment) that would be better treated with debulking surgery, or 
wherein surgical debulking in the first 30 days following LITT procedure would be 
anticipated for symptom management. 
 
 
 
D.   
Patients unable to undergo MRI are not eligible. 
 
 
 
E.   
Patients with progression of multifocal tumors or tumors involving the posterior 
fossa (brainstem and cerebellum) will be excluded,  as will patients where the 
anticipated treatment margin will be within 5 mm of critical intracranial structures 
(e.g., primary branches of cerebral vessels, dural sinuses, hypophysis or cranial 
nerves). 
 
F.   
Patients may not have undergone previous treatment with lomustine. 
 
G.   
Patients must not have any significant medical illnesses that in the investigator’s 
opinion cannot be adequately controlled with appropriate therapy or would 
compromise the patient’s ability to tolerate this therapy. 
 
H.   
Patients with a history of any other cancer (except non-melanoma skin cancer or 
carcinoma in-situ of the cervix), unless in complete remission and off of all therapy 
for that disease for a minimum of 3 years are ineligible. 
 
I.   
Patients must not have active infection or serious intercurrent medical illness. 
 
J.   
Patients must not be pregnant/breast feeding and must agree to practice adequate 
contraception (see 4.1.K) 

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K.   
Patients must not have uncontrolled hypertension (systolic >180 mm hg or diastolic 
> 100 mg Hg), angina pectoris, cardiac dysrhythmia, or recent (within 6 weeks) 
intracranial hemorrhage 
 
 
 
5.0  
STATISTICAL FACTORS 
 
 
There will be an accrual of approximately 34 patients. Accrual to the trial may be increased 
to 37 (10%) patients to ensure a sufficient number of evaluable patients for the primary 
objective of the study. Patients removed due to toxicity are evaluable and these patients 
will be considered treatment failures for the primary efficacy outcome. Patients who 
undergo LITT but do not complete salvage chemotherapy will still be evaluable. However, 
patients with pre-LITT biopsy not consistent with recurrent glioblastoma or recurrent IDH-
wildtype anaplastic astrocytoma will not be evaluable for efficacy and will be replaced.   
 
 
6.0  
TREATMENT PLAN  
 
6.1 
General 
 
All patients who meet eligibility criteria must be registered before initiating the study 
procedure. 
 
A.  
Patients will be monitored for hematologic or serologic evidence of 
myelosuppression, hepatic injury, renal injury, and electrolyte  
 
disturbances and for clinical evidence of other toxicity as is described in    
 
section 8.0. 
 
 
B.   
G-CSF Administration: 
 
Routine prophylactic use of G-CSF is not permitted. However, therapeutic use in 
patients with serious neutropenic complications, such as sepsis, may be considered 
at the investigator’s discretion. 
 
C.   
Supportive Care: 
 
a.  
Corticosteroids should be used in the smallest dose to control symptoms of cerebral 
edema and mass effect, and discontinued if possible. 
 
b.    
Anti-seizure medications should be used as indicated.  
  
c.  
Febrile neutropenia may be managed according to the institution's Infectious 
Disease guidelines.  Measures may include appropriate laboratory testing, 
including blood and urine cultures and the institution of broad-spectrum antibiotics.  
If a source for the fever is not identified or the fever resolves when the neutrophil 

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count recovers, antibiotics may be discontinued and the patient observed. 
 
d.  
Antiemetics. The use of antiemetics will be left to the investigators’ discretion. 
Prophylactic treatment with 5-HT3 receptor antagonists is recommended.  
 
e. 
Other Concomitant Medications.  
 
Therapies considered necessary for the well-being of the patient may be given at 
the discretion of the investigator. Other concomitant medications should be avoided 
except for analgesics, chronic treatments for concomitant medical conditions, or 
agents required for life-threatening medical problems. All concomitant medications 
must be recorded. Pneumocystis jiroveci pneumonia (PJP, previously carinii, PCP) 
– prophylaxis is required ONLY for patients during concurrent chemoradiation. 
During adjuvant and salvage chemotherapy, all patients, particularly if on steroids, 
should be observed closely for lymphopenia. Prophylaxis for PJP may be 
considered at the investigator’s discretion if the total lymphocyte count is ≤ 200. 
 
D.     Other Anticancer or Experimental Therapies: 
 
No other anticancer therapy (including chemotherapy, hormonal treatment or 
immunotherapy) of any kind is permitted during the study period. No other drug 
under investigation may be used concomitantly with the study drug. 
 
E.  
Surgery: 
 
If neurosurgical management is required for reasons other than tumor progression, 
these procedures must be documented, including the indications for surgery, the 
surgical operative note and pathology report. If surgery is required for suspected 
progression and pathology reveals only treatment effect, the patient can continue 
treatment with lomustine at the discretion of the treating physician, once recovered 
from surgery. 
 
6.2  
Treatment Plan Overview 
 
This will be a prospective, single-center study. All eligible participants with recurrent 
glioblastoma (see study criteria, section 4.0) will undergo thermal ablation of tumor 
utilizing the LITT procedure. Diagnosis of glioblastoma will be determined histologically 
(frozen section) by biopsy, prior to LITT procedure. Diagnosis will be confirmed upon full 
neuropathological review (for determination of evaluability for efficacy). It is acceptable 
for biopsy to occur immediately prior to LITT procedure, establishing presence of viable 
tumor by histological analysis of frozen section performed by a neuropathologist. If there 
is uncertainty as to the exact pathological diagnosis, or if frozen section is not consistent 
with glioblastoma, LITT procedure will either proceed at the discretion of the neurosurgeon 
or be delayed until full neuropathological review is completed. Blood (within 24 hours of 
procedure) and tissue (pre-ablation biopsy) will be obtained and banked for corollary 

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studies. If possible, post-ablation biopsy will also be obtained, immediately following the 
procedure, for comparison of tissue and banking for corollary studies. LITT procedure will 
be followed by salvage lomustine. 
 
The surgeon will perform the LITT procedure in the MD Anderson Cancer Center MRI 
BrainSuite operating room, using real-time MRI with thermography (heat mapping) and 
proprietary software. The patient will undergo post-procedural neurologic assessment and 
follow up MRI within 48 hours of the procedure.  The patient will present for outpatient 
follow up neurological assessment 14 days (+/- 3 business days) following the procedure. 
The patient will be evaluated for appropriateness to begin salvage therapy with lomustine, 
to start 14-35 days following the procedure. Choice of salvage chemotherapy is limited to 
lomustine, to standardize the treatment plan. The patient’s neurological status MRI scans 
will be reassessed at regular intervals. The patient will complete a quality of life self-
assessment at regular intervals. Steroid dose will be documented at time of each neurologic 
assessment/MRI scan. Toxicity will be monitored.  Should the patient’s tumor progress per 
the RANO criteria, or the patient develop toxicity on treatment regimen, further 
management decisions will be made per the treating physician. 
 
6.3  
Number of Patients and Study Duration 
 
An estimated 3 patients can be accrued per month, with accrual completed in about 12 
months, with an additional 12 months of follow-up. 
 
Total accrual to the trial will be increased by 10% to ensure a sufficient number of 
evaluable patients for the primary objective of the study. 
 
The total study duration is estimated at 24 months. 
 
 
6.4  
Study Design/Treatment Schedule 
 
Within 24 hours prior to the procedure, the patient will undergo pre-operative trajectory 
site and skull entry point planning MRI. MRI sequences will include FLAIR, T2*, 
diffusion-weighted, and T1-weighted volume spoiled gradient-recalled acquisition in the 
steady state, and in some cases diffusion tensor imaging, to further evaluate nearby critical 
white matter tracts. The eloquence of the tumor will be graded according to the criteria of 
Sawaya et al (see Appendix), and tumor dimensions and volume will be calculated (see 
below). 
 
In the MD Anderson Cancer Center MRI BrainSuite operating room, after induction of 
general anesthesia, a Mayfield 3-point fixation apparatus is attached to the patient’s head 
and a trajectory guidance device, modified to secure the laser probe control mechanism, is 
attached to the skull.  The patient then undergoes a brain biopsy. Standard biopsy technique 
will be used. Approximately 4 cores will be obtained from each biopsy.  Before proceeding 
with LITT, the diagnosis will be established by histological analysis of frozen section. If 
there is uncertainty as to the exact pathological diagnosis, LITT procedure will either 

2016-0443 
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proceed at the discretion of the neurosurgeon or delayed until full neuropathological review 
is completed. Diagnosis will be confirmed upon full neuropathological review (for 
determination of evaluability for efficacy). Blood (within 24 hours of procedure) and tissue 
(at pre-ablation biopsy) will be obtained and banked for corollary studies. If possible, post-
ablation biopsy will also be obtained, immediately following the procedure, for comparison 
of tissue and banking for corollary studies. These studies will include exploratory 
determination of tumor markers and blood-based biomarkers. 
 
LITT will be delivered directly to the tumor by a neurosurgeon, using the rigid, gas-cooled, 
side-firing or diffusion tip NeuroBlate laser probe.  The surgeon manually segments the 
tumor using NeuroBlate software and the T1-weighted planning images.  Temperature 
reference points are identified. Treatment is monitored using real-time MRI thermometry 
as well as proprietary software providing predictive thermal feedback.  The surgeon will 
control the rotation and depth of the probe, to tailor tissue coagulation. The surgeon will 
optimize the delivery of the dose to the tumor, while minimizing dose to surrounding brain 
tissue. Disposition of thermal energy outside the tumor into the cisterns, ventricles, sulci, 
and subarachnoid space is permitted at the discretion of the surgeon. Application of laser 
energy at multiple angles and depths as required is permitted. The probe is advanced and 
retracted to treat planes within the tumor until maximum coverage of the prescribed thermal 
injury is achieved.   Laser ablation is stopped manually by the surgeon when it is thought 
that the predicted thermal ablation zone is sufficient, or stopped automatically if any 
monitored limits are exceeded.  
 
The patient will undergo post-operative follow-up neurologic assessment (including KPS) 
and MRI (details of sequences outlined below) within 48 hours of the procedure. If the 
patient is stable, they may be discharged within 48 hours of the procedure, following MRI.  
Symptomatic, treatment-related edema may be treated with corticosteroids.  
 
All patients will be monitored throughout the study for safety and toxicityIf the patient 
reports new or worsening neurologic deficits, signs/symptoms of increased intracranial 
pressure, or a decline in KPS, CT head will be performed as indicated.  If there is evidence 
of new or worsening edema, a trial of steroids may be prescribed, per the treating physician. 
Hemorrhage or other clinical or radiographic evidence of toxicity will be managed as 
appropriate.  Toxicity will be graded 1-5 according to the National Cancer Institute 
Terminology Criteria for Adverse Events v4.0, with a score of 1 indicating mild adverse 
effects, a score of 2 moderate adverse effects, a score of 3 severe adverse effects, and a 
score of 4 life-threatening adverse effects (see Appendix).  
 
Patients will be monitored for toxicity in the 2 week period following LITT and then for 
an additional 4 weeks, which may include a period during which a patient is receiving 
chemotherapy. 
 
Patients will undergo followup clinic visit on post-operative day 14 (+/- 3 days). 
 
Following a 14-35 day post-surgical interval, patients may be eligible to initiate treatment 

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with single-agent lomustine for up to 6 cycles. 
 
For all patients, RANO criteria will be used to determine response to treatment.   
 
Patients will undergo follow-up evaluation including neurologic examination, adverse 
effects, and MRI sequences at intervals as detailed below. Patients will be followed until 
death. KPS and steroid dose will be documented at time of each neurologic assessment. 
 
Beginning with the first post-operative scan, all MRI imaging will incorporate the 
conventional MRI (T1 pre and post-contrast images, T2-weighted images (T2WI), Fluid 
attenuating inversion recovery (FLAIR) images) and advanced MRI (MR perfusion 
[dynamic susceptibility contrast (DSC), dynamic contrast enhancement (DCE) and arterial 
spin labeling (ASL)], MR- diffusion, and MR spectroscopy) sequences. Imaging post-
processing and evaluation will include but is not be limited to modified RANO criteria, 
advanced quantitative imaging and volume tumor metrics, and voxel-by-voxel (texture, 
heterogeneity, energy, etc) imaging analysis. Pre-operative imaging will include contrast-
enhanced T1-weighted volumetric images, which are transferred to proprietary software, 
and probe trajectory and skull entry point are planning. DTI-FT may be added to identify 
nearby critical white matter tracts. Intra-operative imaging will include MR-thermography 
and TDT lines. For all imaging, the amount of edema will be graded quantitatively with a 
score of 0 (no detectable edema), 1 (moderate edema without significant shift), or 2 (severe 
regional edema with mass effect or shift). Tumor dimensions and volume (detailed below) 
will also be calculated.  Tumor progression will be defined according to the RANO criteria 
(see section 9.3). 
 
6.5  
Evaluation and treatment schedule for salvage chemotherapy  
 
14-35 days following the procedure, if deemed medically stable, participants will initiate 
treatment with lomustine. The baseline examination before initiation of chemotherapy will 
include MRI (within 48 hours post-procedure and 14 days (+/- 3 days) post-procedure), 
full blood counts and blood chemistry tests (BUN, creatinine, electrolytes, liver function 
tests), and a physical examination that includes KPS.  
 
 
 
One cycle of lomustine is defined as 6 weeks.  Patients will undergo comprehensive 
evaluation with MRI scan along with neurologic assessment to include KPS following each 
cycle (6 weeks) of lomustine. Chemotherapy prescription or orders will be provided based 
on outlined parameters and assessment of toxicities during the previous cycle.  
 
 
6.6  
CBC Monitoring Parameters 
 
Lomustine 
CBC and differential and BUN/creatinine will be checked every 2 weeks during a 6 week 
cycle, and must be checked on day 42 (+/- 2 days), prior to initiating a new cycle.  LFTs 
will be performed on day 42 (+/- 2 days), prior to initiating a new cycle. 

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6.7  
Post-procedural inflammatory changes 
 
If prior to the next scheduled MRI, the patient develops signs of increased intracranial 
pressure (ie. confusion, new/worsening headache, nausea & vomiting), new or worsening 
of neurological deficits, and/or KPS decreases to < 70 and likely is attributable to the 
experimental treatment, the patient will undergo CT head or MRI brain with and without 
contrast to ensure there is no hemorrhage, new/worsening edema or other acute event. 
Corticosteroids may be initiated in the case of symptomatic edema. If CT head is negative 
for a hemorrhage, significant edema or cerebrospinal fluid obstruction, and the addition or 
increase of dexamethasone does not improve symptoms, an MRI brain with and without 
contrast is warranted to better assess for signs of edema or other abnormalities.  
 
6.8  
Disease Progression 
 
If disease progression occurs outside of the area of the initial LITT procedure, further 
management will be at the discretion of the treating physician. Repeat LITT therapy near 
to prior LITT site may be performed but patients will be considered to have progression 
according to the protocol endpoints. Data on subsequent therapy will be collected when 
possible.  
 
 
6.9  
Doses 
 
1.   
Salvage Therapy  
 
A.   
Lomustine  
Lomustine will be administered orally on an empty stomach before bed (2 hours 
after or 1 hour before food).  Lomustine will be administered every six weeks on 
day 1 of every 6 week cycle. While the recommended dose of lomustine for patients 
with recurrent GBM is 100-130 mg/m2 (Wick, 2010), we chose to initiate 
lomustine at 90 mg/m2 for the first cycle, as this is the routine initial dose in our 
clinical practice for patients with recurrent GBM.  This is the dose typically 
tolerated in our patient population, in terms of myelosuppression. The dose of 
lomustine may be increased to 110 mg/m2 starting with the second cycle, at the 
treating physician’s discretion, as long as patient has not required dose modification 
for toxicity. A treatment window of +/- 3 days is acceptable. Patients receiving 
lomustine should receive premedication with ondansetron, granisetron or other 
anti-emetic medication at the treating physician’s discretion. Doses of lomustine 
will be rounded down to the nearest 10 mg. 
 
Dose Level 
Lomustine 
+1 
110 mg/m2 
0 (Starting) 
90 mg/m2 
-1 
67.5 mg/m2 
-2 
45 mg/m2 

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6.10 
Dose modifications for toxicity  
 
6.10.1  Salvage Treatment with Lomustine 
 
For hematological toxicity 
A repeat course of lomustine should not be given until circulating blood elements have 
returned to acceptable levels (platelets above 100,000/mm3; or absolute neutrophil count 
≥ 1500/mm3).  This usually occurs within 6 weeks.  Blood counts should be monitored 
weekly and repeat courses should not be given before 6 weeks because the hematologic 
toxicity is delayed and cumulative. Growth factor support is permitted.  Lomustine may be 
dose reduced a maximum of 2 times. 
 
For nonhematologic toxicity 
 
For nonhematologic toxicity ≥CTCAE Grade 3, treatment should be delayed until 
resolution to less than or equal to the patient’s baseline value before proceeding. Dose 
reductions for nonhematologic toxicities will be based on the previous dose level 
administered. If, after restarting therapy, the patient does not have recurrence of the event 
after 42 days of therapy, the patient may be reescalated to the full dose at the discretion of 
the investigator.  Upon toxicity resolution to Grade 1 or less, lomustine treatment will 
resume as follows: 
a. Nausea and/or vomiting: treatment may resume without dose reduction.  Grade 
3 or 4 nausea and/or vomiting should be managed with appropriate changes in 
antiemetic regimen.  Additionally, the dose of lomustine may be split over 3 days 
if necessary. 
b. Grade 3 transaminase elevations that return to baseline by Day 1 of the next 
cycle: treatment may resume without delay or dose reduction. 
c. For pulmonary toxicities:  Patients will be assessed with pulmonary function 
tests, discontinuation and as clinically indicated during the course of therapy. 
Nadir After Prior Dose  
 
 
Percentage of Starting  
Absolute Neutrophil Count (ANC) 
Platelets 
 
Dose to be Given 
 
(x109/L) 
 
 
(x109/L) 
 
 
 
 
 
> 100,000 
 
 
100% 
LLN - 1.5 
 
 
 
75,000-99,999   
 
100% 
1.5 – 1.0  
 
 
 
25,000-74,999   
 
75% 
<1.0  
 
 
 
 
< 25,000  
 
 
50% 

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d. Other Grade 3 or 4 nonhematologic toxicities considered study drug related: a 
25% dose reduction should be administered for the first dose reduction and a 
50% dose reduction for the second reduction, if deemed appropriate by the 
treating physician. 
 
7.0 
PRE-TREATMENT EVALUATION 
 
7.1  
General Requirements 
 
7.1.1 A complete history and neurological examination (to include documentation of 
KPS as well as MRI (see section 6).  
 
 
7.1.2 Pre-study laboratory tests shall include CBC, differential, platelets, BUN, serum 
creatinine, bilirubin, ALT, AST, PT/INR, and serum pregnancy test for women of 
childbearing potential. Pre-study laboratory tests must be obtained within 14 days 
of registration. HCG must be obtained within 14 days of registration, in women of 
child-bearing potential. Further pre-operative labs will be obtained at the discretion 
of the surgeon. 
 
 
7.1.3 Patients must undergo pre-operative risk stratification/evaluation. 
 
 
7.1.4  Documentation of suspected recurrent tumor diagnosis. Following biopsy (which 
may be performed immediately prior to LITT procedure), tissue slides must be 
submitted for neuropathologic review (See section 12). Decision to proceed with 
LITT will be per the discretion of the neurosurgeon. If there is uncertainty as to the 
exact pathological diagnosis, or if frozen section is not consistent with 
glioblastoma, LITT procedure will either proceed or be delayed until full 
neuropathological review is completed. 
 
 
8.0 
EVALUATION DURING STUDY 
 
(See Study Calendar in Appendix)  
8.1     General Requirements 
 
 
8.1.1  Within 24 hours prior to the procedure, the patient will undergo pre-operative 
trajectory site and skull entry point planning MRI. If taking corticosteroids, the 
patient must be on a stable or decreasing dose for at least 5 days, prior to MRI. 
 
8.1.2  A real-time brain MRI with heat mapping will be performed during the LITT 
procedure, along with proprietary software providing predictive thermal damage 
feedback. 
 
 
8.1.2   Blood will be collected within 24 hours prior to the LITT procedure. Blood will be 
banked for exploratory analysis. Blood will also be collected approximately every 
2 weeks while the patient is undergoing treatment with lomustine. 

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8.1.3 Tumor tissue will be collected at pre-ablation and post-ablation biopsy (when 
feasible) and banked for correlative analysis. 
 
8.1.4  A brain MRI and neurologic assessment including KPS will be performed within 
48 hours following completion of the LITT procedure. 
 
     
8.1.5   A brain MRI and neurologic assessment including KPS will be performed on day 
14 (+/- 3 days) following completion of the LITT procedure.  
 
 
  
 8.1.6   A brain MRI and neurologic assessment including KPS will be performed every 6 
weeks (every cycle) while on lomustine chemotherapy. 
 
8.1.7  All relevant information regarding drug doses, concomitant medications, and doses, 
measurable lesions with measurements, tumor response, laboratory examinations, 
and treatment-related toxicities will be documented in the patient’s medical record 
and flow sheets. Corticosteroid use must be documented. 
 
8.1.8   A complete physical and neurologic exam (to include documentation of KPS) will 
be performed prior to initiation of every cycle of chemotherapy.  
 
8.1.9   Determination of progression of disease (as defined in Section 9.4). 
 
a. RANO criteria will be used to determine progression. 
 
b. Patients who discontinue treatment due to progression will be followed for 
survival every 3 months (+/- 14 days)*. 
 
c. Patients who come off therapy for reasons other than progression will be 
followed every 3 months (+/- 6 weeks) until progression or institution of new anti-
tumor therapy.  They should then be followed for survival every 3 months (+/- 14 
days)*. 
 
* if the patient is unable to return for a clinic visit, the follow up may be conducted 
via letter or phone call from research staff to inquire regarding interim health 
history.  Information will be recorded. All patients will be followed until death or 
loss-to-follow-up.  Attempts to avoid loss of follow-up, including letters and phone 
call, will be implemented by research nurse.   
 
 
 8.1.10 Laboratory Assessment  
 
During the salvage chemotherapy phase with lomustine, CBC with differential and 
BUN/creatinine will be obtained every 2 weeks (+/- 3 days), and LFTs will be 
performed prior to each (6 week) cycle.  
 

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8.1.11 An end-of treatment visit will ideally include history and exam, and MRI to 
document status of disease. 
 
 
9.0 
CRITERIA FOR EVALUATION AND ENDPOINT DEFINITIONS 
 
9.1 
Primary Endpoint 
 
 
9.1.1  Disease control rate at 6 months:  Defined as the percentage of evaluable (See Section 5.0) 
patients that have at least stable disease or better at 6 months after the LITT procedure. 
RANO criteria will be used to determine progression.  
 
9.2  
Secondary Endpoints 
 
       
9.2.1  Overall survival time, defined as the time from the enrollment until the time of death.  
Patients who are alive will be censored at the time of last contact.  . 
 
9.2.2   Time to progression (TTP) is defined as the time from study enrollment until the time of 
first disease progression, relapse, or death due to disease (event). Patients who are alive 
without progression or relapse will be censored at the time of last contact.  Patients who 
died without progression will be censored at death. 
 
9.2.3 Safety and toxicity of LITT by determination of adverse events and surgical complications 
within 2 weeks of the procedure, plus an additional 4 weeks (to account for potential 
delayed inflammatory changes and initiation of subsequent treatment).  Safety for LITT 
procedure will be defined as the absence of severe clinical toxicity as determined by the 
CTCAE version 4.0, within 6 weeks of the procedure, and/or absence of acute events (ie, 
significant hemorrhage or brain herniation) documented on imaging. Severe toxicity will 
also be defined as a drop of 20 points or more in KPS and not amenable to corticosteroids, 
and likely attributable to the procedure, or symptomatic hemorrhage, increased brain 
edema resulting in herniation/impending herniation, and/or significant neurologic decline 
not amenable to corticosteroids. Safety and toxicity will be reassessed again throughout the 
duration of the study.   
 
9.2.4  Analysis of volumetric data consisting of thermal damage threshold lines and overall tumor 
volume and analysis of radiographic evolution of LITT treated glioblastoma, by serial MRI 
for analysis of the chronological sequence of the lesion’s evolution.  
 
9.2.5  Evaluate functional status and the occurrence of symptoms, using the Karnofsky 
Performance Score (KPS) and the MDASI-BT (English) self-reporting tool, respectively. 
 
9.2.6   Analysis of health care utilization as measured by length of hospital stay post-op, 
readmission, and time to home (include inpatient rehab care). 
 
9.3  
Exploratory Endpoints 

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9.3.1  To identify peripheral blood and tumor tissue molecular biomarkers associated with 
response to LITT based therapy, as measured by progression-free survival and overall 
survival, and to obtain exploratory data regarding tumor tissue inflammatory/immunologic 
profile. 
 
9.3.2  To determine changes in tumor tissue pre- and post-procedure, to evaluate the impact of 
the procedure on brain tumor tissue. 
 
9.4       Definitions of Response (Based on RANO Criteria) 
 
RANO Criteria: 
 
Criterion                                 
CR 
PR 
SD 
PD*** 
 
 
 
 
 
T1 gadolinium enhancing disease  
 None       
> 50%  ↓ 
< 50% ↓ but  < 25% ↑ 
> 25%↑ 
T2/FLAIR 
Stable or  
↓  
Stable or  
↓  
Stable or  ↓  
↑* 
New Lesion 
None   
None   
None   
Present 
Corticosteroids 
None 
Stable or  
↓  
Stable or  ↓  
NA** 
Clinical Status 
Stable or  
↑  
Stable or  
↑  
Stable or  ↑  
↓* 
Requirement for Response 
All 
All 
All 
Any* 
 
 
Abbreviations: RANO, Response Assessment in Neuro-Oncology; CR, complete response; 
PR, partial  response; SD, stable disease; PD, progressive disease; FLAIR, fluid-attenuated 
inversion  recovery; NA, not  applicable. 
 
* Progression occurs when this criterion is present. To be considered progressive disease, 
increase in T2/FLAIR should occur on stable or increasing doses of corticosteroids 
compared to baseline scan or best response following initiation of therapy, and should not 
be due to co-morbid events (e.g. radiation therapy, demyelination, ischemic injury, 
infection, seizures, post-operative changes, or other treatment effects). 
 
**Increase in corticosteroids alone will not be taken into account in determining 
progression in the absence of persistent clinical deterioration. 
 
*** this criteria only pertains to assessment of progression >12 weeks following 
completion of chemoradiation. 
 

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The primary measure of imaging response will be based on serial measures of the product 
of the two largest cross-sectional diameters.  For patients with <0.5mm of enhancing tissue 
in two cross-sectional diameters in each of two perpendicular slices on the baseline scan, 
progression will be defined when enhancement is >1cm in two cross-sectional diameters 
in each of two perpendicular slices. 
 
9.4.1. Measurable Disease: Bidimensionally measurable lesions with clearly defined 
margins by MRI scan. 
 
9.4.2 Evaluable Disease: Unidimensionally measurable lesions, masses with margins not 
clearly defined.  
 
9.4.3    Non-Evaluable Disease: Not Applicable for response evaluation. 
 
9.4.4. Objective Status, To Be Recorded at Each Evaluation: If there are too many 
measurable lesions to measure at each evaluation, choose the largest two to be 
followed before a patient is entered on study.  The remaining lesions will be 
considered evaluable for the purpose of objective status determination.  Unless 
progression is observed, objective status can only be determined when ALL 
measurable and evaluable sites and lesions are assessed. 
 
9.5  
Best Response: This will be calculated from the sequence of objective statuses. 
 
 
For patients with all disease sites assessed every evaluation period, the best response will 
be defined as the best objective status as measured according to Section 9.4  If the response 
does not persist at the next regular scheduled MRI, the response will still be recorded based 
on the prior scan, but will be designated as a non-sustained response.  If the response is 
sustained, e. g. still present on the subsequent MRI, it will be recorded as a sustained 
response, lasting until the time of tumor progression.  Best response is unknown if the 
patient does not qualify for a best response or increasing disease and if all objective status 
determinations before progression are unknown. 
 
 
 
9. 6 
Neurological Exam: Although not used for determining response, it is useful to evaluate 
improvement in the neurologic exam, (as compared to the baseline assessment), that should 
coincide with objective measurement of tumor size.  
 
 
 
+1 
Better 
0 
Unchanged 
-1 
Worse 
B 
Baseline 
 

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9.7 
 Performance Status: Patients will be graded according to Karnofsky  
 
Performance Status (see Appendix 16.2). 
 
9.8   
Time to Progression:  From date of enrollment in study to the date of first observation of 
progressive disease, death due to disease (event), or early discontinuation of treatment.  
 
9.9    Overall Survival:   Time from initial tumor diagnosis (definitive surgical resection or 
biopsy) to death from any cause. 
 
10.0 
CRITERIA FOR REMOVAL FROM STUDY 
 
10.1 
Criteria for Removal from Study: 
 
 a.  Biopsy sample prior to planned LITT procedure does not meet pathological inclusion 
criteria.  
 
b. Administration of 6 cycles of salvage therapy with lomustine. 
 
c. Progression of disease (as defined in Section 9.4) 
 
Patients must be followed by MRI and will be removed from study if unequivocal 
progression (per RANO criteria) is documented after any cycle of treatment.  Patients with 
stable disease, partial or complete response will continue on therapy as defined in Section 
6.0. 
 
d. Unacceptable toxicity (see Section 6.10) 
 
e. The patient may withdraw from the study at any time for any reason. 
 
f. 
Medical or psychiatric illness which in the investigator's judgment renders the patient 
incapable of further therapy. 
 
g. Treatment delay due to toxicity greater than 8 weeks measured from the start of the 
preceding cycle. 
 
10.2 
All reasons for discontinuation of treatment must be documented in the flow sheets. 
 
 
11.0 
STATISTICAL CONSIDERATIONS 
 
11.1  Overview 
 

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In this prospective, single-arm phase II study, we will estimate the disease control rate 
at 6 months in patients with recurrent GBM, who are treated with LITT and followed 
by salvage therapy with lomustine. 
 
 
Simon's optimal two-stage design (Simon, 1989) will be employed to evaluate the 
effect of the study regimen on disease control rate at 6 months. A disease control rate 
of 10% or lower is considered a failure and the new regimen will be rejected under this 
circumstance, and we would like to improve this rate to 25%. Given type I error rate of 
0.1 and type II error rate of 0.20, Simon’s optimal two-stage design requires to enroll 
13 patients in the first stage. Up to 6 months of suspension of accrual is needed to 
evaluate the disease control in these 13 patients. The study will be stopped and the new 
regiment will be declared as ineffective if 0 or 1 patient remains disease control at 6 
months. The accrual will only continue when at least 2 disease controls at 6 months 
have been observed, at which time 21 additional patients will be accrued to reach a 
total of 34 patients. By the end of the study, the null hypothesis will be rejected if 6 or 
more patients remain disease control and the study regimen will be considered 
promising. Given these boundaries, the probability of stopping the trial early is 62% 
and the expected sample sizes will be 21 if the true disease control rate is 10%. 
 
11.2  Toxicity Monitoring 
 
 
Patients will be monitored by cohorts of 10 patients for severe toxicities (drop in KPS 
> 20 points which is attributed to the procedure and not amenable to corticosteroids, 
and/or 
symptomatic hemorrhage 
or 
increased 
brain 
edema 
resulting 
in 
herniation/impending herniation attributed to the procedure and not amenable to 
corticosteroids, and/or National Cancer Institute Terminology Criteria for Adverse 
Events v4.0 grade of 3-4 attributable to the procedure or procedure and chemotherapy) 
within 2 weeks + 6 weeks in which period that patients receive the LITT procedure and 
1  cycle of chemotherapy (total of 8 to 10 weeks). Specifically, we will stop the trial if 
there is a high probability of observing the severe toxicity rate TOXE >30%, i.e., 
Pr(TOXE > 30%|Data)>90%.   
 
Given this rule and the prior for severe toxicity rate as beta(0.3, 0.7), we will stop the study 
and claim the treatment is too toxic if the number of patients in each group with severe 
toxicities/total of number of patients treated >= 6/10, 9/20, and 13/30. The operating 
characteristics of for these stopping rules are in Table 2. 
 
Table 2: Operating Characteristics for the Stopping Rule (5000 Simulations) 
 
True Toxicity Rate Probability Stop Early Average Sample Size 
0.20 
1.4% 
33.7 
0.30 
15.0% 
31.7 
0.40 
52.8% 
25.9 

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11.3  Analysis Plan: 
 
Data of variables of interest including patients’ demographic, clinical characteristics, 
length of hospital stay following LITT, peripheral blood and tumor tissue molecular 
biomarkers, and inflammatory/immunologic profile will be summarized using standard 
descriptive statistics, such as mean, standard deviation, median, and range for continuous 
variables, frequency and proportion for categorical variables. Correlation will be assessed 
among continuous variables using Pearson or Spearman correlation coefficient, whichever 
is appropriate. Association between categorical variables will be examined by Chi-Squared 
test or Fisher’s exact test when appropriate. Wilcoxon rank-sum test or Kruskal-Wallis test 
will be used to examine the difference on continuous variables between or among patient’s 
characteristic groups. Overall survival (OS) and Time to progression (TTP) will be 
estimated using the Kaplan-Meier method and the comparison between or among patient’s 
characteristic groups will be evaluated by log-rank test. The Cox regression model may be 
applied to assess the effect of covariates of interest on OS and TTP. The disease control 
rate at 6 months will be estimated along with 95% confidence intervals. Toxicity data and 
the long-term steroid requirements will be summarized by frequency tables.  KPS and 
MDASI-BT data will be obtained at baseline, after procedure, and with every imaging visit 
thereafter.  We will summarize the MDASI-BT at each time point using descriptive 
statistics and evaluate the change of MDASI-BT over time and its correlation with response 
and/or treatment tolerance using linear mixed models, where random effects will be used 
to account for within-subject correlations. The radiographic evolution of LITT-treated 
glioblastoma quantitatively measured by MRI and ABTI, tumor metrics, peripheral blood 
and tumor tissue molecular biomarkers, and inflammatory/immunologic profile at each 
time point will be summarized using descriptive statistics and presented graphically and 
the change of it will also be evaluated using linear mixed models. We may also evaluate 
the association between the change in peripheral blood/tumor tissue molecular 
biomarkers/inflammatory/immunologic profile and response status.   
Other statistical methods may be applied when appropriate. 
 
References:  
 
1. Thall, PF, Simon, R, Estey, EH: Bayesian sequential monitoring designs for single-arm 
clinical trials with multiple outcomes. Statistics in Medicine 14:357-379, 1995.  
2. Thall, PF, Simon, R, Estey, EH: New statistical strategy for monitoring safety and efficacy 
in single-arm clinical trials. J. Clinical Oncology 14:296-303, 1996.  
3. Thall, PF and Sung, H-G: Some extensions and applications of a Bayesian strategy for 
monitoring multiple outcomes in clinical trials. Statistics in Medicine 17:1563-1580, 1998.  
4. Thall PF, Wooten LH, Tannir N. Monitoring event times in early phase clinical trials: some 
practical issues. Clinical Trials, 2:467-478, 2005.   
 
11.4  Evaluability 
 
The study will be conducted as an intent-to-treat study. All patients who had the laser probe 

2016-0443 
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inserted into the brain will be evaluable for inclusion in the analysis, provided that 
histology confirms recurrent glioblastoma or IDH wildtype-anaplastic astrocytoma (per the 
criteria outlined in section 12). This is the case regardless of losses before the outcome is 
measured due to dropout or noncompliance.  To be evaluable for inclusion in the toxicity 
stopping rule patients must have had the laser probe inserted into the brain.  
 
12.0   DISCIPLINE REVIEW  
 
12.1  Pathology Review 
 
a. 
Following LITT, slides from the biopsy must be submitted for review if not 
previously done.  The purpose of this review is to verify the histologic diagnosis. 
b.  
Biopsy tissue must be verified by the neuropathologist to represent viable 
glioblastoma (or anaplastic astrocytoma, if IDH-wildtype). 
c.  
For samples representing  mixed viable tumor and radiation necrosis, biopsy tissue 
must be verified by the neuropathologist to contain at least 30% viable, mitotically-
active glioblastoma (or anaplastic astrocytoma, if IDH-wildtype) to be considered 
representative of recurrent disease.  If unable to obtain percentage, recurrent disease 
will be determined per expert opinion of neuropathologist. 
 
12.2  Radiology Review 
 
All MRI scans will be obtained and interpreted at MD Anderson Cancer Center. 
 
13.0 SAFETY ASSESSMENTS AND TOXICITY MONITORING 
 
All patients will be evaluated for safety.  The safety parameters include all laboratory tests 
and hematological abnormalities, CNS observations, physical examination findings, and 
spontaneous reports of adverse events reported to the investigator by patients.  All toxicities 
encountered during the study will be evaluated according to the NCI Common 
Terminology Criteria for Adverse Events (CTCAE) version 4.0 and recorded prior to each 
course of therapy.  Life-threatening toxicities that are unexpected and assessed to be 
possibly related to the study agent should be reported immediately to the study coordinator, 
Institutional Review Board (IRB), and those that are unexpected and assessed to be 
possibly related to the study agents should also be reported to the FDA. 
 
Adverse Device Effect 
 
An adverse device effect (ADE) is an AE related to the use of the study device. This 
definition includes AEs resulting from insufficient or inadequate instructions for use, 
deployment or operation, or any malfunction of the medical device. This definition also 
includes any event from an error in usage or from intentional misuse of the medical device. 
 
Serious Adverse Device Effect 
 

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A serious adverse device effect (SADE) is an adverse device effect that has resulted in any 
of the consequences characteristic of a serious adverse event. 
Anticipated Serious Adverse Device Effect 
 
An anticipated serious adverse device effect is an effect which by its nature, incidence, 
severity or outcome, has been identified in the risk analysis report. 
 
Unanticipated Serious Adverse Device Effect 
 
An unanticipated serious adverse device effect (USADE) is a serious adverse effect, which 
by its nature, incidence, severity or outcome, has not been identified in the current version 
of the risk analysis report, protocol or application (including a supplementary plan or 
application). USADEs are also commonly called unanticipated adverse device effects 
(UADE), as defined in 21 CFR 812.3 (s). 
 
Device Malfunction 
 
A device malfunction is defined as a failure of a device to meet its performance 
specification or otherwise perform as intended per IFU. 
 
Information about all adverse events, whether volunteered by the subject, discovered by 
investigator questioning, or detected through physical examination, laboratory test or other 
means, will be collected and recorded on the Adverse Event Case Report Form and 
followed as appropriate. An adverse event is any undesirable sign, symptom or medical 
condition occurring after starting study drug (or therapy) even if the event is not considered 
to be related to study drug. 
 
Medical conditions/diseases present before starting study treatment are only considered 
adverse events if they worsen after starting study treatment (any procedures specified in 
the protocol). Adverse events occurring before starting study treatment but after signing 
the informed consent form are recorded on the Baseline Evaluations_Adverse Events Case 
Report Form. Abnormal laboratory values or test results constitute adverse events only if 
they induce clinical signs or symptoms or require therapy, and are also recorded on the 
Adverse Events Case Report Form. 
 
A serious adverse event is any adverse drug experience at any dose that results in any of 
the following outcomes: Death, a life-threatening adverse drug experience, inpatient 
hospitalization or prolongation of existing hospitalization, a persistent or significant 
disability/incapacity, or a congenital anomaly/birth defect.  Important medical events that 
may not result in death, be life-threatening, or require hospitalization may be considered 
serious when, based upon appropriate medical judgment, they may jeopardize the patient 
or may require medical or surgical intervention to prevent one of the outcomes listed in 
this definition.  Examples of such medical events include allergic bronchospasm requiring 
intensive treatment in an emergency room or at home, blood dyscrasias or convulsions in 
a patient who has never had seizure activity in the past that do not result in inpatient 

2016-0443 
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hospitalization, or the development of drug dependency or abuse. 
 
Events not considered to be serious adverse events are hospitalizations for the purposes of 
this protocol and include:  
 
- 
Routine treatment or monitoring of the studied indication not associated with any 
deterioration in condition;  
- 
Treatment, which was elective or pre-planned, for a pre-existing condition that did 
not worsen; 
- 
Treatment on an emergency, outpatient basis for an event not fulfilling any of the 
definitions of serious given above and not resulting in hospital admission. 
 
Pregnancy, although not itself a serious adverse event, should also be reported on serious 
adverse event form and be followed up to determine outcome, including spontaneous or 
voluntary termination, details of birth, and the presence or absence of any birth defects or 
congenital abnormalities. 
 
The study will utilize the Cancer Therapy Evaluation Program (BTTC) Common 
Terminology Criteria for Adverse Events (CTCAE) Version 4.0 for Toxicity and Adverse 
Event reporting.   
 
All serious adverse events that are unexpected and assessed to be possibly related to the 
study agents must be reported to the FDA by the lead investigator (or their designee) as a 
15-day post-marketing ‘Alert Report’. An unexpected adverse event is one that is not 
already described in the study agent Investigator Brochure(s). The lead principal 
investigator (or their designee) also has the obligation to report serious adverse events to 
their IRB, This includes serious, related, labeled (expected) and serious, related, unlabeled 
(unexpected) adverse experiences. 
SAEs should be recorded on a MedWatch Form FDA 3500A. The MedWatch form can be 
downloaded from the www at:  
 
http://www.fda.gov/medwatch/how.htm 
 
 
 
MedWatch 3500A Reporting Guidelines: 
 
In addition to completing appropriate patient demographic and suspect medication 
information, the report should include the following information within the Event 
Description (section 5) of the MedWatch 3500A form: 
 
• 
Treatment regimen (dosing frequency, combination therapy) 
• 
Protocol description (and number, if assigned) 
• 
Description of event, severity, treatment, and outcome, if known 
• 
Supportive laboratory results and diagnostics 

2016-0443 
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• 
Investigator’s assessment of the relationship of the adverse event to each 
investigational product and suspect medication 
 
 
Follow-up information:   
 
Additional information may be added to a previously submitted report by any of the 
following methods: 
 
• 
Adding to the original MedWatch 3500A report and submitting it as follow-up 
• 
Adding supplemental summary information and submitting it as follow-up with the 
original MedWatch 3500A form  
• 
Summarizing new information and faxing it with a cover letter including subject 
identifiers (i.e. D.O.B. initial, subject number), protocol description and number, if 
assigned, suspect drug, brief adverse event description, and notation that additional 
or follow-up information is being submitted  (The subject identifiers are important 
so that the new information is added to the correct initial report) 
 
 
Assessing Causality: 
 
Investigators are required to assess whether there is a reasonable possibility that the study 
agent/s caused or contributed to an adverse event.  The following general guidance may be 
used. 
 
Yes: 
If the temporal relationship of the clinical event to the study agent/s 
administration makes a causal relationship possible, and other drugs, therapeutic 
interventions or underlying conditions do not provide a sufficient explanation for 
the observed event. 
 
No: 
If the temporal relationship of the clinical event to the study agent/s 
administration makes a causal relationship unlikely, or other drugs, therapeutic 
interventions or underlying conditions provide a sufficient explanation for the 
observed event. 
 
Adverse events will be classified as follows: 
 
• 
Definitive (certain): conclusive evidence beyond reasonable doubt that the AE can 
be attributed to radiation and/or temozolomide. 
• 
Probable (likely): evidence is clearly in favor of attributing the AE to radiation 
and/or temozolomide. 
• 
Possible (indeterminate): evidence is indeterminate for attributing the AE to 
radiation and/or temozolomide or an alternate cause. 
• 
Not related: conclusive evidence beyond reasonable doubt that the AE can be 
attributed to causes other than radiation and/or temozolomide.  

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14.0   REFERENCES 
 
1. Bown SG. Phototherapy in tumors. World J Surg. 1983 Nov;7(6):700-9. 
 
2. Bredel M, Zentner J. Brain-tumour drug resistance: the bare essentials. Lancet Oncol. 2002 Jul; 
3(7):397-406. 
 
3. Carpentier A, McNichols RJ, Stafford RJ, Guichard JP, Reizine D, Delaloge S, Vicaut E, Payen 
D, Gowda A, George B. Laser thermal therapy: real-time MRI-guided and computer-controlled 
procedures for metastatic brain tumors. Lasers Surg Med. 2011 Dec; 43(10):943-50.  
 
4. Carpentier A, Chauvet D, Reina V, Beccaria K, Leclerq D, McNichols RJ, Gowda A, Cornu P, 
Delattre JY. MR-guided laser-induced thermal therapy (LITT) for recurrent glioblastomas. Lasers 
Surg Med. 2012 Jul;44 (5):361-8. 
 
5. Cerullo LJ, Burke LP. Use of the laser in neurosurgery. Surg Clin North Am. 1984 
Oct;64(5):995-1000. 
 
6. Chaichana et al. J Neurosurg. 2013 Apr;118(4):812-20. 
 
7. Chaichana et al. World Neurosurg 2014 Jul-Aug82 (1-2). 
 
8. De Poorter J, De Wagter C, De Deene Y, Thomsen C, Ståhlberg F, Achten E. Noninvasive MRI 
thermometry with the proton resonance frequency (PRF) method: in vivo results in human muscle. 
Magn Reson Med. 1995 Jan;33 (1):74-81. 
 
9. Hildebrand J, De Witte O, Sahmoud T. Response of recurrent glioblastoma and anaplastic 
astrocytoma to dibromodulcitol, BCNU and procarbazine--a phase-II study. J Neurooncol. 1998 
Apr;37 (2):155-60. 
 
10. Kahn T, Bettag M, Ulrich F, Schwarzmaier HJ, Schober R, Fürst G, Mödder U. MRI-guided 
laser-induced interstitial thermotherapy of cerebral neoplasms. J Comput Assist Tomogr. 1994 Jul-
Aug; 18(4):519-32. 
 
11. Lacroix, M., et al. A multivariate analysis of 416 patients with glioblastoma multiforme: 
prognosis, extent of resection, and survival. J. Neurosurg 2001. 95: 190-98. 
 
12. McGirt, M., et al. Independent association of extent of resection with survival in patients with 
malignant brain astrocytoma. J. Neurosurg 2009. 110: 156-162.  
 
13. Mohammadi AM, Hawasli AH, Rodriguez A, Schroeder JL, Laxton AW, Elson P, Tatter SB, 
Barnett GH, Leuthardt EC. The role of laser interstitial thermal therapy in enhancing progression-

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free survival of difficult-to-access high-grade gliomas: a multicenter study. Cancer Med. 2014 
Aug; 3(4):971-9. 
 
14. Mrugala MM, Crew LK, Fink JR, Spence AM. Carboplatin and bevacizumab for recurrent 
malignant glioma. Oncol Lett. 2012 Nov; 4(5):1082-1086. 
 
15. Rahmathulla G, Recinos PF, Kamian K, Mohammadi AM, Ahluwalia MS, Barnett GH. MRI-
guided laser interstitial thermal therapy in neuro-oncology: a review of its current clinical 
applications. Oncology. 2014; 87(2):67-82. 
 
16. Schober R, Bettag M, Sabel M, Ulrich F, Hessel S. Fine structure of zonal changes in 
experimental Nd:YAG laser-induced interstitial hyperthermia. Lasers Surg Med. 1993; 13(2):234-
41. 
 
17. Schwarzmaier HJ, Eickmeyer F, von Tempelhoff W, Fiedler VU, Niehoff H, Ulrich SD, Yang 
Q, Ulrich F. MR-guided laser-induced interstitial thermotherapy of recurrent glioblastoma 
multiforme: preliminary results in 16 patients. Eur J Radiol. 2006 Aug; 59 (2):208-15. 
 
18. Simpson, JR, et al. Influence of location and extent of surgical resection on survival of patients 
with glioblastoma multiforme: results of three consecutive Radiation Therapy Oncology Group 
(RTOG) clinical trials. Int J Radiat Oncol Biol Phys. 1993 May 20;26(2):239-44 
 
19. Sloan AE, Ahluwalia MS, Valerio-Pascua J, Manjila S, Torchia MG, Jones SE, Sunshine JL, 
Phillips M, Griswold MA, Clampitt M, Brewer C, Jochum J, McGraw MV, Diorio D, Ditz G, 
Barnett GH. Results of the NeuroBlate System first-in-humans Phase I clinical trial for recurrent 
glioblastoma. J Neurosurg. 2013 Jun;118(6):1202-19. 
 
20. Stafford RJ, Fuentes D, Elliott AA, Weinberg JS, Ahrar K. Laser-induced thermal therapy for 
tumor ablation. Crit Rev Biomed Eng. 2010;38 (1):79-100.  
 
21. Stupp, R., et al. Effects of radiotherapy with concomitant and adjuvant temozolomide versus 
radiotherapy alone on survival in glioblastoma in a radomised phase II study: 5-year analysis of 
the EORTC-NCIC trial. Lancet Oncol 2009; 10: 459-66.  
 
22. Sugiyama K, Sakai T, Fujishima I, Ryu H, Uemura K, Yokoyama T. Stereotactic interstitial 
laser-hyperthermia using Nd-YAG laser. Stereotact Funct Neurosurg. 1990; 54-55:501-5. 
 
23. Wick W, Puduvalli VK, Chamberlain MC, van den Bent MJ, Carpentier AF, Cher LM, Mason 
W, Weller M, Hong S, Musib L, Liepa AM, Thornton DE, Fine HA. Phase III study of enzastaurin 
compared with lomustine in the treatment of recurrent intracranial glioblastoma. J Clin Oncol. 
2010 Mar 1;28 (7):1168-74. 
 
24. Wilson CB, Gutin P, Boldrey EB, Drafts D, Levin VA, Enot KJ. Single-agent chemotherapy 
of brain tumors. A five-year review. Arch Neurol. 1976 Nov; 33(11):739-44. 
 

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25. Wolff JE, Berrak S, Koontz Webb SE, Zhang M. Nitrosourea efficacy in high-grade glioma: a 
survival gain analysis summarizing 504 cohorts with 24193 patients. J Neurooncol. 2008 May; 
88(1):57-63. 
 
26. Wong, ET., et al. Outcomes and prognostic factors in recurrent glioma patients enrolled onto 
phase II clinical trials. J Clin Oncol 1999 Aug; 17(8): 2572-8. 
 
14.1 Statistical References 
 
Thall, PF, Simon, R, Estey, EH: Bayesian sequential monitoring designs for single-arm clinical 
trials with multiple outcomes. Statistics in Medicine 14:357-379, 1995.  
 
Thall, PF, Simon, R, Estey, EH: New statistical strategy for monitoring safety and efficacy in 
single-arm clinical trials. J. Clinical Oncology 14:296-303, 1996.  
 
Thall, PF and Sung, H-G: Some extensions and applications of a Bayesian strategy for monitoring 
multiple outcomes in clinical trials. Statistics in Medicine 17:1563-1580, 1998.  
 
Thall PF, Wooten LH, Tannir N. Monitoring event times in early phase clinical trials: some 
practical issues. Clinical Trials, 2:467-478, 2005.   
 
Simon R. Optimal Two-Stage Designs for Phase II Clinical Trials, Controlled Clinical Trials 10: 
1-10, 1989.   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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15.0  APPENDIX 
 
15.1 
NCI Common Terminology Criteria for Adverse Events 
 
15.2 
Karnofsky Performance Status (KPS) and Neurologic Function 
 
15.3 
Summary of Specimen Requirements  
 
15.4  
Standard monitoring plan to be used for all Phase I/II protocols at M. D.    
Anderson Cancer Center 
 
15.5  
Guidelines for Filing Reports of Adverse Experiences at M. D. Anderson  
 
15.6         Classification of Tumor Eloquence 
 
 
   15.7 
Informed Consent 
 
 
 
 
   15.8 
Study Calendar 
 
 
 
 
15.1 
NCI Common Terminology Criteria for Adverse Events 
 
This study will utilize the CTCAE version 4.0 for Toxicity and Adverse Event reporting.  
A copy of the CTCAE version 4.0 can be downloaded from the www at 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm 
 
 
 
 
 
 

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15.2 
Karnofsky Performance Status (KPS) and Neurological Function 
 
Patient's performance status and Neurologic Functions will be graded according to 
the following scales: 
 
 
 
Karnofsky Performance Status 
 
KPS 100 
Normal; no complaints; no evidence of disease 
KPS   90 
Able to carry on normal activity; minor signs or symptoms of 
disease 
KPS   80 
Normal activity with effort; some sign or symptoms of disease 
KPS   70 
Cares for self; unable to carry on normal activity or do active work 
KPS   60 
Requires occasional assistance, but is able to care for most personal 
needs 
KPS   50 
Requires considerable assistance and frequent medical care 
KPS   40 
Disabled; requires special care and assistance 
KPS   30 
Severely disabled; hospitalization is indicated, although death no 
imminent 
KPS   20 
Very sick; hospitalization necessary; active support treatment is 
necessary 
KPS   10 
Moribund; fatal processes progressing rapidly 
KPS     0 
Dead 
 
 
 
 
 
Neurologic Function 
 
 
+1 
Better 
 
 0 
Unchanged 
 
-1 
Worse 
 
 B 
Baseline 
 
 
 

2016-0443 
January 15, 2020 
Page 42 of 49 
 
15.3  Summary of specimen requirements and collection 
 
 
Tissue or Specimen 
Time of Collection  
Plasma 
Baseline and then every 6 or 8 
weeks. 
PBMCs 
Baseline, and then every 6 or 8 
weeks. 
Tumor tissue (also collect plasma and 
PBMCs) 
At the time of surgery 
 
 
PBMC and Plasma Collection and Processing: 
Collect 2-8 mL CPT tubes into a BD Vacutainer CPT™ tube with Sodium Citrate 
(Becton Dickinson product #362761). Plasma and PBMC aliquots will be generated 
using standard laboratory processing procedures. Please contact research technician 
from Dr. de Groot’s laboratory when samples are collected.  Pager number 713-
834-6209, or 713-606-0213. 
 
 
 
Tumor tissue collection and processing 
At the time of tumor resection, the collaborating neurosurgeon will collect fresh 
tumor tissue (depending on tissue availability given the likelihood that the patient 
will have a limited tumor biopsy) along with a sample of patient blood as described 
above.  DNA and RNA will be extracted from tumor tissue and analyzed for 
genomic alterations, when possible.  
 
 

2016-0443 
January 15, 2020 
Page 43 of 49 
 
15.4 
Standard monitoring plan to be used for all Phase II protocols at M. D. Anderson 
Cancer Center 
 
The Institutional Review Board of the University of Texas M. D. Anderson Cancer Center 
(Cancer Center) has reviewed and approved the following Data and Safety Monitoring Plan 
for all Phase I and Phase II clinical trials conducted at the Cancer Center. 
 
During the protocol review and approval process, the IRB determines the level of safety 
monitoring required for each protocol on a case by case basis. The minimum monitoring 
requirements include investigator monitoring of patient safety, adverse event (AE) 
reporting in compliance with IRB, NCI and FDA guidelines and participation in the 
Continuing Review process with the IRB.  For protocols that are determined by the IRB to 
be of higher risk, the investigator will be required to report on patient safety after treating 
a small number of patients before being allowed to accrue more participants. This number 
will be determined at the time the protocol is approved by the IRB. Studies that are blinded, 
multi-center, high-risk or involve vulnerable populations will be monitored by our Data 
and Safety Monitoring Board (DSMB).  The outcome of IRB and DSMB safety reviews 
are conveyed to the Principal Investigator (PI) via the administrative support staff in the 
Office of Protocol Research (OPR). 
 
For all protocols conducted at the Cancer Center, the principal investigator is responsible 
for submitting AEs to the IRB.  The Cancer Center’s policy for AE submission has been 
defined and approved by the IRB and must be included as an appendix to all protocols. 
AEs are submitted to OPR, entered into the Protocol Data Management System (PDMS) 
and forwarded to the designated IRB vice chairperson for review.   Attached to each AE, 
is a listing of all prior AEs submitted for that protocol.  Any comments, questions or 
changes the IRB requests to the protocol as a result of this review are conveyed to the 
investigator.  The investigator response and protocol modification process is monitored by 
the IRB vice chairperson and OPR support staff.  The vice chairperson presents the report 
on AE review to the full committee at the next IRB meeting. 
 
All protocol participants must be registered in the PDMS.  Eligibility questions for each 
protocol are databased and must be answered in the system before it will accept each 
registration.  If any answer indicates the participant does not completely meet eligibility 
PDMS provides a prompt and an explanation is required.  These are reviewed monthly by 
the Vice President for Research Administration to assure each explanation addresses the 
appropriate eligibility issue. For NCI sponsored studies, the system does not allow 
registration of participants with less than complete eligibility. The date in the current 
informed consent document is displayed to ensure only the most current IRB approved 
version is used.  Consent date, registration date, off study date, and evaluability data are 
required for all registrants.  
 
 
 
 

2016-0443 
January 15, 2020 
Page 44 of 49 
 
 
 
15.5    Guidelines for Filing Reports of Adverse Experiences at M. D. Anderson  
 
A. 
21 CFR 312.32   
 
Serious Adverse Experience (SAE) –Any adverse drug experience occurring at any dose 
that results in any of the following outcomes:  
• Death 
 
• A life-threatening adverse drug experience – any adverse experience that places 
the patient, in the view of the initial reporter, at immediate risk of death from 
the adverse experience as it occurred. It does not include an adverse experience 
that, had it occurred in a more severe form, might have caused death. 
 
• Inpatient hospitalization or prolongation of existing hospitalization 
 
• A persistent or significant disability/incapacity – a substantial disruption of a 
person’s ability to conduct normal life functions. 
 
• A congenital anomaly/birth defect.  
 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered a serious adverse drug experience when, based upon 
appropriate medical judgment, they may jeopardize the patient or subject and may require 
medical or surgical intervention to prevent one of the outcomes listed in this definition. 
Examples of such medical events include allergic bronchospasm requiring intensive 
treatment in an emergency room or at home, blood dyscrasias or convulsions that do not 
result in inpatient hospitalization, or the development of drug dependency or drug abuse. 
  
Unexpected Adverse Drug Experience - Any adverse drug experience, the specificity or 
severity of which is not consistent with the current investigator brochure; or, if an 
investigator brochure is not required or available, the specificity or severity of which is not 
consistent with the risk information described in the general investigational plan or 
elsewhere in the current application, as amended.  Unexpected, as used in this definition, 
refers to an adverse drug experience that has not been previously observed (e.g., included 
in the investigator brochure) rather than from the perspective of such experience not being 
anticipated from the pharmacological properties of the pharmaceutical product. 
 
B.  
MDA Policy and Procedure for reporting of adverse experiences (Includes 
both commercial and investigational drugs): 
 
• 
All clinical protocols should include a list of the expected and anticipated events or 
hospitalizations relating to the study regimen.  If an expected or anticipated event 
is documented in the protocol, then it does not have to be reported as an SAE. 

2016-0443 
January 15, 2020 
Page 45 of 49 
 
(Example: Expected Grade 4 myelosuppression needs only to be reported as part of 
the study results) 
 
• 
All events falling under the definition of serious adverse event that are not listed in 
the  
protocol as being expected or anticipated, and occurring within 30 days 
following the last treatment date, must be reported to the sponsor within the 
specified time frame stated in the protocol.  
 
• 
All deaths with possible, probable or definite attribution to the study drug, device, 
or intervention must have a written report submitted to the Institutional Review 
Board (IRB) via OPR within one working day (24 hours) of knowledge of the event.  
 
• 
All serious adverse events other than that stated above must have a written report 
submitted to the Institutional Review Board (IRB) via OPR within 5 working days 
of knowledge of the event.  
 
• 
If necessary, the sponsor is then required to notify the Food and Drug 
Administration (FDA) within 7 calendar days. 
 
• 
All unexpected adverse experiences that are classified as Grade 4 must be reported 
by following the guidelines listed above. 
 
• 
Known reactions classified as Grades 1-3 do not need to be reported. However, 
these toxicities should be submitted as part of the study results. 
 
C. 
Adverse Experience Reporting Forms: 
  
Attached is the MDACC severe adverse event reporting form.  This form should be utilized 
if MDACC is the sponsor, the study is a non-sponsored study, or the sponsor does not 
provide an appropriate reporting form.   
 
If the study sponsor requires a protocol specific SAE form to be completed, then that form 
may be use for IRB submission as long as the MDACC protocol number and patient 
medical record number is written at the top of the front page.   
 
D.  
External Adverse Experiences / Safety Reports 
 
All external adverse events/safety reports received from the sponsor should be submitted 
to the IRB through the Office of Protocol Research.   The “External Adverse Event Report” 
can be located under section 1 of the OPR Forms Manual, and should be utilized as the 
cover sheet for this submission. 
 
 
 
15.6 Classification of Tumor Eloquence (from Sawaya et al, 1998) 

2016-0443 
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15.7 Informed Consent  
 
 
 
 
 
 
 

2016-0443 
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15.8 Study Calendar 
 
 
 
 
 
Salvage Chemotherapy** 
End of 
Treatment 
Follow-up10 
 
 
 
 
Cycles 1 -6 
 
Screening 
LITT 
Post-LITT 
clinic visit 
Day 
1*** 
Day 15 
Day 
29 
3 
Mons 
6 Mons 
9 Mons 
12 
Mons 
 
<28 days 
prior to 
registration 
≤ 7 days 
following 
registration 
14 days post-
LITT (±3) 
 
± 3 
days 
± 3 
days 
±6 weeks 
±6 
weeks 
±6 weeks 
±6 
weeks 
±6 
weeks 
Eligibility 
Assessment1 
X 
 
 
 
 
 
 
 
 
 
 
Informed 
Consent 
X 
 
 
 
 
 
 
 
 
 
 
Medical 
History 
Review 
X 
 
X 
X 
 
 
X 
X 
X 
X 
X 
Medications 
Review 
X 
 
X 
X 
 
 
X 
X 
X 
X 
X 
Serum 
Pregnancy 
Test (bHCG)3 
X2 
 
X 
X 
 
 
 
 
 
 
 
Physical 
Exam 
X 
X 
X 
X 
 
 
X 
X 
X 
X 
X 
Neurological 
Exam 
X 
X4 
X 
X 
 
 
X 
X 
X 
X 
X 
KPS 
X 
X4 
X 
X 
 
 
X 
X 
X 
X 
X 
MRI 
X 
X5, X6, X7 
X 
X 
 
 
X 
X 
X 
X 
X 
Hematology2 
X2 
 
X 
X 
X 
X 
 
 
 
 
 
Chemistry2 
X2 
 
X 
X 
X 
X 
 
 
 
 
 

2016-0443 
January 15, 2020 
Page 48 of 49 
 
LFTs 
X2 
 
X 
X 
 
 
 
 
 
 
 
MDASI-BT 
(English)  
X 
 
X 
X 
 
 
X 
X 
X 
X 
X 
NeuroBlate 
System 
procedure 
(LITT/thermal 
ablation) 
 
X 
 
 
 
 
 
 
 
 
 
Blood sample 
for corollary 
studies (5-10 
ml) 
 
X8 
 
 
 
 
 
 
 
 
 
Tissue 
samples for 
corollary 
studies 
 
X9 
 
 
 
 
 
 
 
 
 
Lomustine 
 
 
X* 
X 
 
 
 
 
 
 
 
Adverse 
Event 
Assessment 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
*Lomustine to start between 14-35 days following LITT (at physician’s discretion); Tests/procedures (except MRI)  indicated under 
“Day 1” must be repeated if lomustine initiated > 3 days following Day 14 visit 
 
** Up to 6 cycles of lomustine, on day 1 of a 42 day cycle 
 
***a) Tests/procedures within 3 days before starting; b) a) Cycle 1 day 1 to start between 14-35 days following LITT; For C1D1, 
tests/procedures (except MRI)  indicated under “Day 1” must be repeated if lomustine initiated > 3 days following Day 14 visit 
 
1. Recurrent GBM will be confirmed by biopsy prior to or on day of LITT procedure 
 
2. Labs (including bHCG) should be obtained within 14 days prior to registration 
 
3. Serum Pregnancy test (bHCG) only required for females of child-bearing potential unless the patient is confirmed as post-
menopausal or surgically sterile 
 
4. Post-operative follow-up neurologic assessment (including KPS) within 48 hours of procedure 
 
5. Within 24 hours prior to the procedure, the patient will undergo pre-operative trajectory site and skull entry point planning MRI 

2016-0443 
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Page 49 of 49 
 
 
6. Intra-op MRI will be completed as part of the LITT set-up 
 
7. Post-LITT MRI should be completed within 48 hours after LITT procedure 
 
8. Blood sample to be obtained within 24 hours of procedure, for banking and corollary studies 
 
9. Pre- and post-ablation biopsy tissue samples, when feasible, for banking and corollary studies 
 
10. For patients discontinuing therapy for reasons other than tumor progression. Patients who discontinue therapy for tumor 
progression will be contacted by research staff every 3 months (+/- 14 days)  to inquire regarding interim health history(if unable to 
return for a clinic visit)