Clinical trial NCT02285855
Conditions: Lung Cancer
Keywords: Lung Cancer Non small cell lung cancer Stereotactic body radiotherapy SBRT XRT Radiation therapy Metformin Metformin ER Placebo Sugar pill Lung adenocarcinoma Genotypes Genetic mutations
Sponsor: M.D. Anderson Cancer Center
Start date: 2015-02-20; Completion date: 2019-01-05
Enrollment: 27 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The goal of this clinical research study is to learn if giving metformin in combination with radiation therapy is more effective than radiation therapy alone. In this study, participants will receive either metformin or a placebo. A placebo is not a drug. It looks like the study drug but is not designed to treat any disease or illness. It is designed to be compared with a study drug to learn if the study drug has any real effect.

This is an investigational study. Metformin is FDA approved for the treatment of diabetes. Its use in this study to be given with radiation therapy to treat lung cancer is investigational. The study doctor can explain how the study drug is designed to work.

Up to 70 participants will be enrolled in this study. All will take part at MD Anderson.

Detailed description:

Arms: arm 1: Participants randomized to Metformin treatment receive Metformin for 3 weeks prior to SBRT treatment and for 1 week during SBRT treatment. Metformin administered at a dose of 2000 mg by mouth in divided dose daily (500 mg am, 1000 mg noon, 500 mg pm). To reduce GI toxicity, participants start Metformin at 1000 mg daily in a divided dose (500mg am, 500 mg pm) for 1 week. SBRTdelivered per standard of care practice. arm 2: Participants randomized to placebo treatment 3 weeks prior to SBRT treatment and for 1 week during SBRT treatment. Placebo administered by mouth three times a day. SBRT delivered per standard of care practice.
Interventions: intervention 1: Metformin intervention 2: Placebo intervention 3: Stereotactic body Radiotherapy (SBRT)
Intervention descriptions: intervention 1: Metformin treatment given at a dose of 2000 mg by mouth in divided dose daily (500 mg am, 1000 mg noon, 500 mg pm). To reduce GI toxicity, participants start Metformin at 1000 mg daily in a divided dose (500mg am, 500 mg pm) for 1 week. intervention 2: Placebo treatment given 3 weeks prior to SBRT treatment and for 1 week during SBRT treatment. Placebo administered by mouth three times a day. intervention 3: SBRT delivered per standard of care practice as determined by participant's physician.

Protocol documents:
Prot_000.pdf: 
2014-0255 protocol  
Version 11 
Accepted on 1/26/2017 
THE UNIVERSITY OF TEXAS 
M. D. ANDERSON CANCER CENTER 
 
 
Tumor mutation status will predict metabolic response to metformin in NSCLC 
 
 
 
 
 
Eligibility Check 
 
1.0 
Introduction 
2.0 
Objectives 
3.0 
Recruitment & Selection 
4.0 
Pre- & Post-treatment Evaluation 
5.0 
Neoadjuvant Metformin 
6.0 
18F-FDG PET/CT Imaging 
7.0 
SBRT Treatment 
8.0 
Registration Procedures 
9.0 
Statistical Considerations  
10.0 
Potential Risks 
11.0 
Long Term Goals 
12.0 
Data Monitoring & Adverse Event Reporting 
13.0 
Data Confidentiality Plan 
14.0 
References 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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ELIGIBILITY CHECK 
 
 
  
 
_____(Y) 
1. 
Does the patient have histologic proof of lung cancer documented by 
biopsy sufficient for mutational analysis? 
 
_____(Y) 
2. 
Does the patient have non-small cell lung cancer documented by FDG 
PET/CT and negative brain MRI? 
 
_____(Y) 
3. 
Is the patient medically inoperable or refuse thoracic surgery? 
 
_____(N) 
4. 
Does the patient have a random blood glucose >200 mg/dl or is the 
patient currently on metformin or other hypoglycemic agent? 
 
 
_____(N) 
5. 
Does the patient have a creatinine > normal institutional limits or a 
diagnosis of chronic kidney disease? 
 
_____(N) 
6. 
Has the patient ever had lactic acidosis? 
 
_____(Y) 
7. 
Does the patient plan to receive hypofractionated RT at MD Anderson? 
 
_____(Y) 
8. 
Has the patient signed a study-specific informed consent form? 
 
 
 
 
 
 
__________________________ Patient's Name 
__________________________ Verifying Physician 
__________________________ Patient ID# 
__________________________ Birth date 
__________________________ Sex 
__________________________ Race 
__________________________ Radiotherapy Completion Date 
__________________________ PET/CT Schedule Date 
 
 
 
Completed by _______________________________ 
Date _________________
 
 


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1.0 
Introduction 
Stereotactic Body Radiotherapy (SBRT) for NSCLC 
Lung cancer remains the leading cause of cancer death in the United States in 2010 (Jemal, 
Siegel et al. 2010). SBRT for stage I lung cancer in medically inoperable patients appears 
promising, the RTOG 0236 phase II multi-institutional study achieved 3-year survival and 
local control rates of 55.8% and 90.6% (Timmerman, Paulus et al. 2010). The goal of SBRT 
is the delivery of higher doses per treatment over fewer treatments, otherwise known as 
hypofractionated RT. In comparison, the local control rate for conventional RT was 
reported as 30 to 40% (Armstrong and Minsky 1989; Dosoretz, Katin et al. 1996). 
However, as tumor size increases, both local and distant failure rates increase, with local 
failure rates of close to 40% in some series (Chi, Liao et al. 2010).  Thus, additional therapy 
for these patients is required.   
18F-FDG PET/CT after SBRT for NSCLC 
One difficulty in utilizing SBRT or hypofractionated RT for therapy is determining 
response to treatment.  CT scans following SBRT are difficult to interpret due to post-
SBRT lung consolidation, making accurate estimations of local failure difficult (Bradley, 
Moughan et al. 2010). Retrospective review has suggested the utility of using post-
treatment FDG-PET/CT scans for determining local failure following SBRT (Henderson, 
Hoopes et al. 2010; Chang, Liu et al. 2012), with a post-SBRT maximum SUV threshold 
of 5 associated with a negative predictive value of 100%. However, the utility of PET/CT 
in this context, as well as the optimum timing of imaging following SBRT has yet to be 
determined. 
Metformin as an anti-cancer agent 
Several epidemiologic studies have shown significantly decreased rates of non-small cell 
lung cancer (NSCLC) in diabetics taking metformin (Hsieh, Lee et al. 2012; Mazzone, Rai 
et al. 2012).  Although this phenomenon is not universal (Smiechowski, Azoulay et al. 
2012), a recent meta-analysis of over 210,000 total patients and 21,000 diabetics found that 
lung cancer incidence was significantly decreased in metformin users (RR 0.67, 
p=0.05)(Noto, Goto et al. 2012).  Data from similar populations implicate this drug in 
improved survival following a cancer diagnosis.  Specifically, in the meta-analysis 
described above, metformin was found to be associated with a decrease in cancer mortality 
in all sites (RR 0.66, p=0.005)(Noto, Goto et al. 2012).  Additionally, several studies have 
linked improved survival following a lung cancer diagnosis and metformin use.  
Specifically, Tan and colleagues showed that patients with locally advanced NSCLC taking 
metformin had a median overall survival (OS) of 20 months (Tan, Yao et al. 2011).  The 
remaining patients were then stratified by glucose control regimen (insulin vs. other); with 
median OS being approximately 13 months in both groups.   This is in line with our own 
observations, with metformin use being independently associated with improved OS on 
multivariate analysis in both HNSCC and NSCLC (Skinner, Sandulache et al. 2012). There 
are significant pre-clinical data showing that metformin exerts an anti-neoplastic effect on 
a variety of lung cancer cell lines as well as in preclinical animal models (Algire, Zakikhani 
et al. 2008; Algire, Amrein et al. 2011; Zaugg, Yao et al. 2011; Ashinuma, Takiguchi et al. 
2012; Chaudhary, Kurundkar et al. 2012; Javeshghani, Zakikhani et al. 2012; Kato, Gong 
et al. 2012; Luo, Hu et al. 2012; Menendez, Oliveras-Ferraros et al. 2012; Salani, Maffioli 
et al. 2012; Sikka, Kaur et al. 2012; Wu, Li et al. 2012).  
Metformin is also a potent radiosensitizer. This phenomenon was first described by Sanli 
and colleagues, with metformin acting to radiosensitize NSCLC cells independent of LKB1 
activation (Sanli, Rashid et al. 2010).  We and other groups have found similar effects in 


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multiple tumor types in the aero-digestive tract, including cancer of the head and neck 
(HNSCC), esophagus, and lung (Liu, Scholz et al. 2012; Song, Lee et al. 2012). 
Biomarkers of metformin sensitivity 
The mechanisms underlying the anti-neoplastic function of metformin are complex, 
although AMPK activation and mTOR inhibition are thought to play an important role. 
Metformin as well as another biguanide, phenformin, were found to have a much more 
striking effect in tumors with absent LKB1 (Algire, Amrein et al. 2011; Shackelford, Abt 
et al. 2013).  However, this observation may not be universal, as a separate study showed 
the effectiveness of metformin in LKB1 intact cells (Xiao, He et al. 2012). The anti-
neoplastic effects of metformin have also been found to be limited to tumor cells with non-
functional p53 (Buzzai, Jones et al. 2007), a finding that is consistent with work in our 
laboratory (Sandulache, Skinner et al. 2012; Skinner, Sandulache et al. 2012).  Tumor cells 
with dysfunctional p53 and/or LKB1 lack the capability of responding appropriately to 
metabolic stress, leading to cell death following treatment with a metabolically targeted 
agent like metformin, while sparing normal surrounding cells (Pollak 2012).  
Metformin and FDG-PET/CT  
It is known that metformin alters the uptake of FDG in normal tissues.  Specifically, 
metformin causes a selective increase in FDG-uptake in normal bowel (Gontier et al., 2008; 
Massollo et al., 2013; Ozülker et al., 2010), as well as in colon cancer cells in 
vitro(Habibollahi et al., 2013).  However, metformin administration significantly 
decreased cell proliferation and FDG uptake in neoplastic tissue in mice fed a high fat diet 
(Mashhedi et al., 2011).  On retrospective review we have observed that metformin use 
does not preclude the use of FDG-PET/CT as a surrogate response for response in 
esophageal cancer (Skinner et al., 2012b) following chemoradiation.       
 
Hypothesis:  Tumor mutation status (genotype) versus glucose uptake (phenotype) 
will more accurately predict metformin therapy response in lung cancer. 
 
Significance and summary 
This is a prospective trial evaluating the use of the imaging of glucose uptake via FDG-
PET/CT scan as well as mutations associated with pre-clinical sensitivity to the drug 
metformin as possible clinical useful indicators of tumor sensitivity to this drug.  We will 
perform a 1:6 randomization of patients stratified by tumor size (≥4 cm vs. <4cm), with a 
goal of 60 patients treated with open label metformin and hypofractionated RT as described 
below and 10 patients treated with hypofractionated RT alone.  Subjects will have a core 
 
 
Figure 1. Protocol timeline. [70 non-diabetic study subjects will enroll in this early phase II study. Each 
will receive a 18F-FDG PET/CT imaging of their lung tumor on entry. Biopsy material will tested for 
mutations. Patients will be stratified by tumor size (≥4 cm vs. <4 cm) and randomized at 1:6 weighted 
to metformin treatment. Subsequently, patients randomized to metformin treatment will receive 3 weeks 
of metformin followed by repeat 18F-FDG PET imaging. All patients will receive their primary SBRT 
treatment per our standard practice. They will take metformin until completion of RT.  They will have 


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biopsy of the primary tumor and FDG-PET/CT scans at baseline and 6 months after 
hypofractionated RT as well as an additional FDG-PET/CT scan 3 week after starting 
metformin. Although multiple groups are investigating the use of metformin as an adjunct 
to cancer therapy, its effects as an cancer therapeutic remain to be tested.  Additionally, it 
is unclear what tumor biomarkers will be predictive for tumor response to this agent.  
Further, metformin has an unclear effect on FDG uptake, with both decreases and increases 
reported in the literature (Gontier et al., 2008; Habibollahi et al., 2013; Mashhedi et al., 
2011; Massollo et al., 2013; Ozülker et al., 2010).  As FDG-PET/CT is commonly used to 
asses response to therapeutic agents in cancer, it is important to determine the effect of 
metformin on this imaging modality in the prospective setting.  Combining genetic and 
imaging profiles may also be useful to enrich for patients likely to respond to this agent. 
(Gontier et al., 2008; Massollo et al., 2013; Ozülker et al., 2010) 
 
 
 
 
2.0 
Objectives 
2.1 
To determine the effect of metformin on response in NSCLC patients 
treated with hypofractionated RT 
2.2 
To characterize the effect of metformin on tumor FDG-avidity. 
2.3 
Secondary objectives: 
2.3.1 To evaluate mutations that lead to increased sensitivity to 
metformin.  
2.3.2 To compare the anatomic versus metabolic response to metformin 
and hypofractionated treatment. 
 
 
3.0 
RECRUITMENT AND SELECTION 
Patients with a pathologic diagnosis of NSCLC who are scheduled to receive 
thoracic hypofractionated RT will be recruited for this study. 70 patients will be 
involved in this single-blinded randomized study.  All patients will undergo a FDG-
PET/CT scan at baseline, following 3 weeks of metformin and at 6 months post-
SBRT.   Subjects will not be excluded based on age, gender, economic status, or 
race.    
3.1 
Patients will sign consent for the imaging procedure. 
3.1.1 Patient will be registered on protocol in CORe. 
3.1.1.1 Inclusion Criteria 
3.1.1.1.1 Patients with pathologic diagnosis of lung 
NSCLC or squamous cell carcinoma. 
3.1.1.1.2 Patients are to be treated with hypofractionated 
RT. 
3.1.1.1.3 Patient is not a surgical candidate due to medical 
comorbidities determined by a thoracic surgeon 
or patient refusal. 
3.1.1.1.4 Patient plans to receive treatment at MD 
Anderson. 
3.1.1.1.5 Patients must sign informed consent. 
3.1.1.1.6 Patient must have adequate renal function within 
30 days prior to registration, defined as serum 
creatinine within normal institutional limits or 
creatinine clearance at least 60 ml/min 


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3.1.1.2 Exclusion Criteria 
3.1.1.2.1 Patient has: random glucose >200 mg/dl or is 
taking an oral hypoglycemic agent or insulin at 
the time of study entry.  
3.1.1.2.2 Patient has a history of lactic acidosis, chronic 
kidney disease or a creatinine ≥ 1.2 mg/dl 
3.1.1.2.3 Women who are pregnant or breast feeding, as 
treatment involves unforeseeable risks to the 
participant, embryo, fetus, or nursing infant. 
3.1.1.2.4 Patients with history of allergic reaction to 
metformin 
 
3.1.2 Patients will complete the study on the day of the 6 month follow-
up RT visit.  They will not require additional follow-up. 
 
4.0 
PRE- AND POST-TREATMENT EVALUATION 
4.1 
All patients will provide informed consent prior to study entry. 
4.2 
All patients should have sufficient tumor tissue for mutational studies. 
4.2.1 Archival tumor tissue will be evaluated for TP53, KRAS and STK11 
mutations using the CMS50 available under the existing IPCT 
Clearinghouse Protocol (PA11-0852)  
4.3 
All patients will receive FDG-PET/CT scan at baseline (prior to metformin 
start), prior to RT and at 6 months (+/- 30 days) following RT. 
4.4 
All patients will have baseline (prior to starting metformin or placebo) and 
weekly laboratory studies while taking metformin or placebo: 
4.4.1 Blood glucose 
4.4.2 Creatinine 
4.4.3 BUN 
4.5 
A one-time optional blood sample (10 ml) for circulation tumor DNA 
analysis collected either at baseline or during radiation treatment 
 
5.0 
NEOADJUVANT METFORMIN 
5.1 
All study subjects randomized will receive metformin or placebo for 3 
weeks (+/- seven days) prior to RT treatment and for up to 2 weeks during 
RT treatment.  
5.2 
Metformin will be administered at a dose of 2000 mg in divided dose daily 
(500 mg am, 1000 mg noon, 500 mg pm). To reduce GI toxicity, patients 
will start metformin at 1000 mg daily in a divided dose (500mg am, 500 mg 
pm) for 1 week. If patients are not able to tolerate advancing the dose to 
2000mg daily after one week, patients may take between 1000mg to 
1500mg daily for the duration of the trial.  If this dose is not tolerable, the 
patient will stop study medication. 
5.3 
Study subjects will be instructed to stop taking metformin/placebo and 
contact the study PI if they develop any of the following symptoms of lactic 
acidosis: unusual tiredness, dizziness, severe drowsiness, chills, blue/cold 
skin, muscle pain, fast/difficult breathing, slow/irregular heartbeat, stomach 
pain with nausea, vomiting, or diarrhea. 
 
6.0 
 18F-FDG PET/CT ACQUISITIONS 


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6.1 
The study coordinator will identify patients and confirm informed consent. 
PET/CT imaging sessions will be performed at the CABI General Electric 
Discovery 690 FX PET/CT scanner. In the event PET/CT scans cannot be 
performed at CABI, electronic copies of PET scans will be allowed for 
image analysis. 
6.2 
The patients will be imaged lying supine and flat on the scanner bed in 
approximately the same position as their radiotherapy.  
6.3 
The patients will undergo PET/CT imaging using [18F]-2-fluoro-2-
deoxyglucose positron emission tomography (18F-FDG), using a standard 
approved radiopharmaceutical dose and administration selected by the 
nuclear medicine physician (120 min). 
Each study subject will receive 18F-FDG PET/CT imaging 3 times: at 
baseline (prior to metformin start), prior to radiotherapy, and 6 months (+/- 
30 days) following completion of radiotherapy. Patient preparation prior to 
imaging will follow the NCI consensus recommendations (Shankar, 
Hoffman et al. 2006). Each patient will receive between 5.18 and 7.77 MBq 
per kilogram of body weight of 18F-FDG injected 65 (+/-5) minutes prior to 
initiation of imaging (Shankar, Hoffman et al. 2006). Patient will receive 
their PET/CT imaging on a General Electric Discovery 690 FX PET/CT 
scanner with the same arm positioning (up/down) as utilized in their CT 
radiotherapy planning. 4D acquisition techniques will be utilized. An 
average CT will be acquired and utilized for attenuation correction (Pan, 
Mawlawi et al. 2006). 
6.4 
The uptake time, time between injection of 18F-FDG and initiation of the 
PET emission acquisition, will be between 60 to 70 minutes. An average 
CT will be acquired for attenuation correction purposes. 
 
 
7.0 
SBRT TREATMENT 
7.1 
At MD Anderson, we have treated > 600 lung SBRT cases since 2004 with 
a 3-year average of 130 cases per year. 
7.2 
All patients in this study are medically inoperable (or refuse thoracic 
surgery) and have non-small cell lung cancers in whom the standard of care 
at MD Anderson is SBRT to a total dose of 50-70 Gy in 4-15 daily treatment 
fractions. The radiation treatment planning, prescription radiation dose, and 
administration will be determined by their attending radiation oncology 
physician. It is expected each patient in this study will receive RT per our 
standard of care practice.  
7.3 
Tissue heterogeneity correction should be applied for planning. Daily on-
board imaging using CT on-rail or cone beam CT is required before each 
fraction for stereotactic delivery. Orthogonal portal films should be taken to 
verify the treatment isocenter before each treatment.  
 
8.0 
REGISTRATION PROCEDURES 
8.1 
Informed consent is required prior to participation in this study. The study 
coordinator will inform potential subjects about the study opportunity and 
ask if they would like to participate. If the patient is interested, they will be 
given an opportunity to read the informed consent and authorization 
document specific to the study and ask questions of the study coordinator. 
The patient will be informed about: 1) the rationale for the study; 2) the 


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logistics of the study; 3) the risks of the study; 4) how the data will be used. 
Consent will be obtained by study coordinator.  The patient will be given a 
copy of the consent, and asked to sign another copy for our records. 
8.2 
Patients will be registered in CORe after pretreatment evaluation is 
completed and eligibility criteria are met. 
8.3 
The principal investigator and all key personnel have completed NIH 
approved institutional and HIPAA training in the conduct of medical 
research studies 
 
9.0 
STATISTICAL CONSIDERATIONS 
9.1 
Objectives 
The primary objectives are to compare tumor response by PERCIST 
between metformin and placebo cohorts and between genotypes of three 
candidate genes for metformin patients. Secondary objectives will consider 
the correspondence of the RECIST and PERCIST tumor response methods 
and the predictive power of pre-treatment glucose utilization.  In addition, 
we will evaluate the predictive power of pre-treatment glucose utilization 
with mutation status for resultant metformin disease control (DC) using 
RECIST and PERCIST criteria. 
 
9.2 
Study Design. 
Patients will be randomized 6:1 to metformin versus placebo in the Clinical 
Oncology Research system (CORe). All patients will undergo a FDG-
PET/CT scan at baseline (prior to metformin start), prior to RT and at 6 
months (+/- 30 days) post-RT.  Response will be determined at 6 months 
post-treatment via relative change from pre-treatment tumor SUV of [18F]-
FDG-PET after 3 weeks induction metformin or placebo to the tumor SUV 
at 6 months post-treatment. Subjects will not be excluded based on age, 
gender, economic status, or race. 
 
9.3 
Power and Sample Size Calculations.  
9.3.1 Metformin versus Placebo 
The metformin versus placebo (N=60 metformin vs N=10 placebo) 
comparison attains 80% power to detect a difference in magnitude 
of at least 1 standard deviation using a two-sided Mann-Whitney test 
at the 0.05 significance level.  
9.3.2 Genotype Comparisons 
Among the N=60 patients treated with metformin, we expect 40-
50% patients to present disruptive TP53 mutations, 25-50% to 
present Kras activating mutations, and 15-30% to present 
inactivating STK11 mutations.  A two-sided test at the 0.05 
significance level attains at least 81-84% power to detect a 
difference in magnitude of at least 0.8 standard deviations between 
cohorts of patients with functional and disruptive TP53 mutations; 
at least 80-90% power to detect a difference in magnitude of at least 
0.9 standard deviations between cohorts of patients with activated 
and inactivated Kras mutations; at least 80-96% power to detect a 
difference in magnitude of at least 1.1 standard deviations between 
cohorts of patients with functional and inactivated STK11 
mutations. Among the cohort of patients that present disruptive 


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TP53 mutations, the test attains at least 80-96% power to detect a 
difference in magnitude of at least 1.5 standard deviations between 
cohorts of patients with activated and inactivated Kras mutations 
and at least 80-94% power to detect a difference in magnitude of at 
least 1.7 standard deviations between cohorts of patients with 
functional and inactivated STK11 mutations. 
 
9.4 
Analysis Plan. 
9.4.1 Primary Objectives 
Mann-Whitney tests will be used to test for genotype effects of 
within each of the three candidate genes and between study arms 
(control versus metformin treated). Among the N=70, we will 
compare tumor response at 6 months post-treatment between study 
arms (N=60 metformin vs N=10 placebo).  
9.4.2 Secondary Aim 1 
The first secondary objective will evaluate the correspondence of 
the RECIST and PERCIST tumor response methods. Each tumor’s 
relative change in maximum transaxial diameter on CT after 3 
weeks induction metformin (N=60) will be matched with the 
corresponding relative change at 3-weeks from pre-treatment 
tumor SUV of [18F]-FDG-PET. The relationship among the pairs 
will be assessed for linear dependence using Pearson's product 
moment correlation coefficient. The sample size of N=60 patients 
provides 80% power to detect a positive correlation of at least 0.32 
using a one-sided test of null hypothesis of independence. 
9.4.3 Secondary Aim 2 
The second secondary objective will consider the predictive power 
of pre-treatment glucose utilization with mutation status for 
resultant metformin disease control (DC) using RECIST and 
PERCIST criteria. DC for RECIST will require CR, PR, or SD 
after 3 weeks induction metformin. DC for PERCIST will require a 
reduction in tumor SUV of [18F]-FDG-PET after 3 weeks induction 
metformin. The accuracy of pre-treatment SUV of [18F]-FDG-PET 
in predicting DC will be evaluated using area under the receiver 
operator characteristic curve (AUROC) for each tumor genotype 
independently and combined. For a one-sided test of the null 
hypothesis of indiscriminate prediction (AUROC=0.5), the sample 
size of N=60 patients provides at least 80% power to detect an 
AUROC of at least 0.71 at the 0.05 significance level given that 
the resultant disease control rate is at least 25% in the combined 
analysis. In addition, inference with multivariate logistic regression 
will be used to assess the effect of pre-treatment SUV of [18F]-
FDG-PET in the presence of genotype status.  Confounders of 
post-radiation chemotherapy and steroid use will be adjusted for 
using linear mixed regression modeling. 
 
  
10.0 
POTENTIAL RISKS 
10.1 
CT risks.  The patients recruited to this study will receive three CT imaging 
sessions in combination with FDG-PET scan for this study. The major risk 


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from multiple CT scans is from the radiation.  Each CT scan will deliver 
approximately 0.05 Gy to the patient.  However, each patient will undergo 
radiation therapy that will deliver at least 45 Gy to the tumor and scatter 
doses of at least 2.5 Gy (5% of the prescribed dose) to the entire chest.   
10.2 
FDG-PET risks.  The patients recruited to this study will receive two 
PET/CT imaging sessions for this study.  The radiation dose from the 
PET/CT scans described in sections 5.3 and 5.4, is still quite small relative 
to radiation dose from a standard CT scan.     
10.3 
Radiation dose. The total radiation dose from the procedures in this study 
will be predominately from the three 4D CT scans, which is about 0.15 Gy 
for the three scans. The additional radiation of patients undergoing several 
CT scans as defined in this protocol will result in negligible additional dose. 
The additional risk is thus likely to be immeasurable. 
10.4 
Metformin treatment. Metformin has a well-established safety profile and 
is used clinically, not only in diabetics, but also in non-diabetic patients with 
polycyctic ovarian syndrome(Tang et al., 2012).  Metformin is not 
associated with hypoglycemia in non-diabetic patients(Harborne et al., 
2003).  Although a clinical concern during metformin treatment is lactic 
acidosis (which limits the use of this drug to patients without impaired renal 
function), a recent meta-analysis found the incidence of this being 
4.4/100,000 patient years and less than that observed in patients using other 
hypoglycemic regimens(Salpeter et al., 2010).  Metformin is associated 
with acute GI side effects (loose stools, nausea), however these effects are 
mitigated by gradual dose-escalation and usually resolve within the first few 
weeks of treatment.    
 
11.0 
LONG TERM GOALS 
SBRT or hypofractionated RT is an effective treatment for many medically 
inoperable patients with stage I lung NSCLC.  However, with larger (T2) tumors 
local and distant failure is as high as 40% in some series (Chi et al., 2010).  For 
many of these patients medical comorbidities limit adjuvant or concurrent systemic 
therapy.  The current study seeks to investigate the minimally toxic agent 
metformin as an adjunct to SBRT or hypofractionated RT.  Our goal is to compare 
the response of lung NSCLC to metformin with RECIST versus PERCIST criteria. 
Secondarily, we will compare tumor mutation status versus tumor metabolic 
activity to predict tumor sensitivity to metformin.  Secondarily, we hope to examine 
the genetic profile of these tumors to determine markers of sensitivity to metformin.    
 
12.0 
DATA MONITORING & ADVERSE EVENT REPORTING 
12.1 
Data Monitoring. The Data and Safety Monitoring Plan (DSMP) is 
established to ensure the safety of research participants and the integrity of 
the study data.  This study is an intervention study with a known minimally 
toxic agent that is routinely used in the clinic. As such, this is a relatively 
low risk study and data monitoring will occur on an occurrence basis with 
regular review by the PI. The study staff (PI, Clinical research coordinator, 
research nursing, etc.) is responsible for collecting and recording all clinical 
data.  As these results are collected, all > 3 toxicities and adverse events will 
be identified, graded for severity and assigned causality, reported to the 
required entities, and compiled for periodic review.  After assigning 
causality, the PI will decide the course of action for the study 


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participant.  The PI will evaluate all AE’s and determine whether the 
adverse event affects the risk/benefit ratio of the study and whether 
modifications to the protocol or informed consent form are required.  
Throughout this process, the PI will inform and collaborate with the IRB 
and Clinical Research Compliance. 
12.2 
Toxicity Grading. The Common Terminology Criteria for Adverse Events 
version 4.0 will be used to grade all > 3 (CTCAE v4.0; available at 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.ht
m) treatment-related adverse events. All patient encounter or treatment 
areas should have access to a copy of these criteria. 
12.3 
Adverse Events. All > 3 adverse events (AE) must be reported to the 
Protocol PI.  All serious adverse events, defined as grade 4 or 5 toxicity, 
will be reported to the institutional review board (IRB) of The University of 
Texas M. D. Anderson Cancer Center according to institutional reporting 
guidelines and using institutional reporting forms (see Appendix C). 
Reports of serious adverse events will be delivered to Clinical Research 
Compliance and will be submitted to the U.S. Food and Drug 
Administration by the safety coordinator according to 21CFR 312.32. 
12.4 
AE Reporting. The following AEs experienced by patients accrued to this 
protocol and attributable to the protocol treatment (definitely, probably, or 
possibly related) should be reported (from the start of protocol treatment to 
30 days after protocol treatment): 
12.4.1 Death on study. 
12.4.2 Hospitalization or prolongation of hospitalization on study 
12.4.3 Life-threatening event 
12.4.4 Persistent or significant disability or incapacity 
 
13.0 
DATA CONFIDENTIALITY PLAN 
All patient-reported outcome, laboratory, radiographic, and clinical data gathered 
in this protocol will be stored in a password-protected database. All patient 
information will be handled using anonymous identifiers. Linkage to patient 
identity is only possible after accessing a password-protected database. Access to 
the database is only available to individuals directly involved in the study. 
Information gathered for this study will not be reused or disclosed to any other 
person or entity, or for other research. Once the research has been completed, 
identifiers will be retained for as long as is required by law and by institutional 
regulations, and at that point will be destroyed. 
 
 
 
 
 
 
 
14.0 Study Calendar 
 
Procedures 
Baseline 
         Treatment Phase 
 
Follow-up 
Wk 
1 
Wk 
2 
Wk 
3 
Wk 
4 
Wk 
5 
Wk  
6 
Month 62 


2014-0255 
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PET/CT (at CABI) 
X3 
  
  
  
X 
  
 
X3 
Metformin/Placebo7 
  
X 
X 
X 
X 
X5 
X 
  
SBRT (50 Gy in 4 fx) 
  
  
  
  
X 
  
 
  
SBRT (70 Gy in 10 fx) 
  
  
  
  
X 
X 
 
  
Hypofractionated RT (45-60 Gy 
in 15 fx 
 
 
 
 
X 
X 
 
X 
 
Blood chem (Glucose, Cr, BUN)  
X1 
X4 
X4 
X4 
X4 X4,5 X4,8 
  
Optional blood for circulating 
DNA 
X6 
  
  
  
  
  
 
  
Toxicity Evaluation 
  
X 
X 
X 
X 
X5,8 X8 
  
Drug diary 
  
X 
X 
X 
X 
X5 
X8 
  
  
 
  
1 Within 30 days prior to registration 
 
  
2  Within +/- 30 days 
  
 
  
3  As part of SOC prior to study 
entry 
 
  
4  While taking 
metformin/placebo 
 
  
5 For 70 Gy in 10 treatment 
 
  
6 One 10 ml purple top collected once either at BL or during treatment phase 
7 +/- 7 days for the first 3 week period 
8  For 45-60 Gy in 15 treatment 
  
  
  
  
  
 
  
 
 
 
15.0 REFERENCES: 
 
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Menendez, J. A., C. Oliveras-Ferraros, S. Cufí, B. Corominas-Faja, J. Joven, B. Martin-
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M. Nhiri, R. Cordera and D. Maggi (2012). "Caveolin-1 is essential for metformin 
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: official publication of the Federation of American Societies for Experimental 
Biology 26(2): 788-798. 
Sandulache, V. C., H. D. Skinner, T. J. Ow, A. Zhang, X. Xia, J. M. Luchak, L.-J. C. Wong, 
C. R. Pickering, G. Zhou and J. N. Myers (2012). "Individualizing antimetabolic 
treatment strategies for head and neck squamous cell carcinoma based on tp53 
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SAP_001.pdf: 
2014-0255 protocol  
 Version 11 
Accepted on 1/26/2017 
 
2014-0255: Tumor mutation status will predict metabolic response to metformin in NSCLC 
Version 11 
Accepted on 1/26/2017 
Statistical analysis plan 
The objective will evaluate the correspondence of the RECIST and PERCIST tumor response methods. 
Each tumor’s relative change in maximum transaxial diameter on CT after 3 weeks induction metformin 
(N=60) will be matched with the corresponding relative change at 3-weeks from pre-treatment tumor 
SUV of [18F]-FDG-PET. The relationship among the pairs will be assessed for linear dependence using 
Pearson's product moment correlation coefficient. The sample size of N=60 patients provides 80% 
power to detect a positive correlation of at least 0.32 using a one-sided test of null hypothesis of 
independence. 
The objective will consider the predictive power of pre-treatment glucose utilization with mutation 
status for resultant metformin disease control (DC) using RECIST and PERCIST criteria. DC for RECIST will 
require CR, PR, or SD after 3 weeks induction metformin. DC for PERCIST will require a reduction in 
tumor SUV of [18F]-FDG-PET after 3 weeks induction metformin. The accuracy of pre-treatment SUV of 
[18F]-FDG-PET in predicting DC will be evaluated using area under the receiver operator characteristic 
curve (AUROC) for each tumor genotype independently and combined. For a one-sided test of the null 
hypothesis of indiscriminate prediction (AUROC=0.5), the sample size of N=60 patients provides at least 
80% power to detect an AUROC of at least 0.71 at the 0.05 significance level given that the resultant 
disease control rate is at least 25% in the combined analysis. In addition, inference with multivariate 
logistic regression will be used to assess the effect of pre-treatment SUV of [18F]-FDG-PET in the 
presence of genotype status.  Confounders of post-radiation chemotherapy and steroid use will be 
adjusted for using linear mixed regression modeling.