Clinical trial NCT03520842
Conditions: KRAS Gene Mutation Metastatic Malignant Neoplasm in the Brain Recurrent Non-Small Cell Lung Carcinoma Stage IV Non-Small Cell Lung Cancer AJCC v7
Sponsor: Stanford University
Start date: 2018-08-14; Completion date: 2022-06-15
Enrollment: 22 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This phase II trial studies how well regorafenib works together with methotrexate in treating participants with metastatic non-squamous non-small cell lung cancer with tumors that harbor a KRAS mutation. Regorafenib is a targeted therapy that works on different cancer pathways to stop the growth of tumor cells and stop them from spreading. Methotrexate may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving regorafenib and methotrexate together may work in treating participants with KRAS mutated non-small cell lung cancer.

Detailed description:
PRIMARY OBJECTIVES:

I. To determine the progression free survival (PFS) of the combination of regorafenib and methotrexate for metastatic KRAS mutated non-small cell lung cancer (NSCLC) patients who have received at least 1 prior systemic therapy.

SECONDARY OBJECTIVES:

I. To determine the objective response rate (ORR) of the combination of regorafenib and methotrexate for metastatic KRAS mutated NSCLC patients who have received at least 1 prior systemic therapy.

II. To determine the disease control rate (DCR) at 8 weeks of the combination of regorafenib and methotrexate for metastatic KRAS mutated NSCLC patients who have received at least 1 prior systemic therapy.

III. To determine the safety of the combination of regorafenib and methotrexate in metastatic KRAS mutated NSCLC patients who have received at least 1 prior systemic therapy, assessed as the number of subjects that experience a treatment-emergent adverse event.

IV. To determine the safety of the combination of regorafenib and methotrexate in metastatic KRAS-mutated NSCLC patients who have received at least 1 prior systemic therapy, assessed as the number (percent) of participants experiencing any dose-limiting toxicity (DLT).

V. To determine the pharmacokinetic parameters of methotrexate when combined with regorafenib (i.e., trough and maximum serum concentration \[Cmax\]).

OUTLINE:

Participants receive regorafenib orally (PO) once daily (QD) and methotrexate PO twice weekly with 2-3 days apart on a 3 week on / 1 week off schedule. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, participants will come in for an end of study treatment visit.

Arms: arm 1: Participants receive regorafenib PO QD on days 1-21, and methotrexate PO twice weekly with 2-3 days apart on a 3 week on/ 1 week off cycle. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Interventions: intervention 1: Methotrexate intervention 2: Pharmacokinetic Study intervention 3: Regorafenib
Intervention descriptions: intervention 1: Given PO intervention 2: Correlative studies intervention 3: Given PO

Protocol documents:
Prot_SAP_000.pdf: 
 
 
 
 
Study of Regorafenib in Combination With Oral Methotrexate for KRAS 
Mutated Non-Small Cell Lung Cancer (NSCLC) 
Study Protocol and Statistical Analysis Plan 
NCT03520842 
January 7, 2022 


 
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Study of Regorafenib in combination with Oral Methotrexate for 
KRAS Mutated Non-Small Cell Lung Cancer (NSCLC)       
 
 
Document History 
Notes 
30 January 2017 
Draft Protocol to Bayer 
27 June 2017 
First Round Bayer Comments 
21 August 2017 
Protocol to Bayer 
17 November 2017 
Protocol to SRC 
13 December 2017 
Protocol SRC Approved; Title Updated 
7 February 2018 
Adds statement of non-significant risk (NSR) regarding 
KRAS testing 
9 August 2018 
Eliminates specificity of methotrexate packaging 
18 January 2019 
2019 Continuing Review 
07 May 2019 
Dosing schedule and DLT modifications, initial Bayer review 
14 June 2019 
Dosing schedule and DLT modifications, secondary Bayer review 
05 Jan 2021 
Personnel update; PI changed 
07 Jan 2022 
Corrected administrative discrepancies on sample size and 
exclusion criteria 


 
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Study of Regorafenib in combination with Oral Methotrexate for KRAS Mutated 
Non-Small Cell Lung Cancer (NSCLC) 
Coordinating Center 
Stanford Cancer Institute 
875 Blake Wilbur Drive 
Stanford, CA 94305 
Protocol Director  
Heather A. Wakelee, MD 
Stanford Cancer Institute 
875 Blake Wilbur Drive 
Stanford, CA 94305 
P: 
 
F: 
 
 
Co-Investigators 
Joel W. Neal, MD PhD 
Stanford Cancer Institute 
875 Blake Wilbur Drive, 
 
Stanford, CA 94305 
P: 
 
F:
 
 
Kavitha Ramchandran, MD 
Stanford Cancer Institute 
875 Blake Wilbur Drive  
Stanford, CA 94305 
Stanford, CA 94305 
P: 
 
F: 
 
  
Millie Das, MD 
Stanford Cancer Institute 
875 Blake Wilbur Drive  
Stanford, CA 94305 
P: 
 
F:
 
 
Study Coordinator 
 
Stanford Cancer Institute 
Cancer Clinical Trials Office 
 
 
P: 
 
F: 
 
Biostatistician 
 PhD 
Stanford University  
 
  
 
P: 
 
F:
 
 
 
Version #4.0 / Version Date: 07 Jan 2022 


 
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TABLE OF CONTENTS 
 
PROTOCOL SYNOPSIS ............................................................................................................. 7 
SCHEMA ..................................................................................................................................... 16 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ............................................ 17 
1. OBJECTIVES ...................................................................................................................... 19 
1.1 PRIMARY OBJECTIVE ........................................................................................................ 19 
1.2 SECONDARY OBJECTIVES .................................................................................................. 19 
1.3 EXPLORATORY OBJECTIVES .............................................................................................. 19 
2. BACKGROUND .................................................................................................................. 19 
2.1 KRAS MUTATED NON-SMALL CELL LUNG CANCER ......................................................... 19 
2.2 REGORAFENIB AND METHOTREXATE ................................................................................ 21 
2.2.1  REGORAFENIB .................................................................................................................. 22 
2.2.1.1  REGORAFENIB MECHANISM OF ACTION AND PRE-CLINICAL STUDIES .......................... 22 
2.2.1.2  REGORAFENIB CLINICAL TRIALS IN CANCER, INCLUDING LUNG CANCER .................... 22 
2.2.1.3  REGORAFENIB NONCLINICAL AND CLINICAL TOXICOLOGY .......................................... 24 
2.2.1.4  REGORAFENIB PHARMACOKINETICS, METABOLISM, MAJOR ROUTE OF ELIMINATION, 
AND POTENTIAL DRUG INTERACTIONS ...................................................................................... 28 
2.2.1.5  REGORAFENIB RATIONALE FOR THE STARTING DOSE AND REGIMEN CHOSEN .............. 29 
2.2.2 METHOTREXATE ............................................................................................................... 29 
2.2.2.1  METHOTREXATE MECHANISM OF ACTION AND PRE-CLINICAL STUDIES IN LUNG 
CANCER ..................................................................................................................................... 29 
2.2.2.2  METHOTREXATE CLINICAL TRIALS IN LUNG CANCER ................................................... 30 
2.2.2.3  METHOTREXATE CLINICAL TOXICOLOGY ..................................................................... 31 
2.2.2.4  METHOTREXATE PHARMACOKINETICS, METABOLISM, MAJOR ROUTE OF ELIMINATION, 
AND POTENTIAL DRUG INTERACTIONS ...................................................................................... 33 
2.2.2.5  METHOTREXATE RATIONALE FOR THE STARTING DOSE AND REGIMEN CHOSEN .......... 35 
2.3 RATIONALE ....................................................................................................................... 35 
2.4 STUDY DESIGN ................................................................................................................. 38 
2.5 CORRELATIVE STUDIES BACKGROUND ............................................................................. 38 
2.5.1  DETECTING CIRCULATING TUMOR DNA (CTDNA) AND TUMOR MUTATIONS USING 
CAPP-SEQ ................................................................................................................................. 38 
2.5.2  COMPUTATIONAL SIMULATION MODEL ........................................................................... 38 
3. PARTICIPANT SELECTION AND ENROLLMENT PROCEDURES ....................... 38 
3.1 INCLUSION CRITERIA ........................................................................................................ 39 
3.2 EXCLUSION CRITERIA ....................................................................................................... 40 
3.3 INFORMED CONSENT PROCESS .......................................................................................... 41 
3.4     RANDOMIZATION PROCEDURES ........................................................................................ 42 
3.5 STUDY TIMELINE .............................................................................................................. 42 
3.5.1  PRIMARY COMPLETION .................................................................................................... 42 
3.5.2  STUDY COMPLETION ........................................................................................................ 42 
4. TREATMENT PLAN .......................................................................................................... 42 
4.1 GENERAL CONCOMITANT MEDICATION AND SUPPORTIVE CARE GUIDELINES .................. 43 


 
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4.1.1  PROHIBITED THERAPIES ................................................................................................... 43 
4.1.2  THERAPIES TO AVOID (TO THE EXTENT POSSIBLE) .......................................................... 43 
4.1.3  THERAPIES THAT MAY REQUIRE ADDITIONAL MONITORING ........................................... 43 
4.1.4  PERMITTED MEDICATIONS ............................................................................................... 42 
4.2 CRITERIA FOR REMOVAL FROM STUDY ............................................................................. 45 
4.2.1  WITHDRAWAL OF CONSENT ............................................................................................. 45 
4.2.2  DISCONTINUING STUDY TREATMENT ............................................................................... 45 
4.2.3  PREMATURE TERMINATION OF THE STUDY ...................................................................... 46 
4.2.4  SPECIAL SITUATIONS REQUIRING PI PERMISSION ............................................................ 46 
4.3 ALTERNATIVES ................................................................................................................. 46 
5. INVESTIGATIONAL AGENT/DEVICE/PROCEDURE INFORMATION ................ 46 
5.1 
 INVESTIGATIONAL AGENT/DEVICE/PROCEDURE .............................................................. 47 
5.1.1  REGORAFENIB .................................................................................................................. 47 
5.1.2  METHOTREXATE .............................................................................................................. 48 
5.2 AVAILABILITY .................................................................................................................. 48 
5.3 AGENT ORDERING ............................................................................................................ 49 
5.3.1  REGORAFENIB .................................................................................................................. 49 
5.3.2  METHOTREXATE .............................................................................................................. 49 
5.4 AGENT ACCOUNTABILITY ................................................................................................. 49 
5.4.1  REGORAFENIB .................................................................................................................. 49 
5.4.2  METHOTREXATE .............................................................................................................. 49 
6. DOSE MODIFICATIONS .................................................................................................. 49 
6.1 
 DOSE LIMITING TOXICITY DEFINITIONS (FIRST 28-DAY PERIOD) .................................... 50 
6.2 
 DOSE MODIFICATIONS ..................................................................................................... 52 
6.2.1  REGORAFENIB .................................................................................................................. 53 
6.2.1.1  REGORAFENIB DOSE LEVELS ........................................................................................ 53 
6.2.1.2  REGORAFENIB-RELATED TOXICITIES (GENERAL) ......................................................... 53 
6.2.1.3  REGORAFENIB-RELATED HAND-FOOT SKIN REACTION (HFSR) ................................... 54 
6.2.1.4  REGORAFENIB-RELATED HYPERTENSION ...................................................................... 57 
6.2.2  METHOTREXATE .............................................................................................................. 59 
6.2.2.1  METHOTREXATE DOSE LEVELS ..................................................................................... 59 
6.2.2.2  METHOTREXATE-RELATED CYTOPENIAS ...................................................................... 59 
6.2.2.3  METHOTREXATE OVERDOSE MANAGEMENT ................................................................. 61 
6.2.3  OVERLAPPING TOXICITIES BETWEEN REGORAFENIB AND METHOTREXATE..................... 62 
6.2.3.1  LIVER FUNCTION ABNORMALITIES ................................................................................ 62 
6.2.3.2  PREVENTION/MANAGEMENT STRATEGIES FOR DIARRHEA, NAUSEA, AND VOMITING, 
AND MUCOSITIS/STOMATITIS ..................................................................................................... 63 
7. ADVERSE EVENTS AND REPORTING PROCEDURES ............................................ 67 
7.1 POTENTIAL ADVERSE EVENTS .......................................................................................... 67 
7.2 ADVERSE EVENT REPORTING............................................................................................ 67 
7.2.1  DEFINITION OF ADVERSE EVENT ...................................................................................... 67 
7.2.2  GRADING, RELATIONSHIP, EXPECTEDNESS OF ADVERSE EVENTS .................................... 67 
7.2.3 RECORDING ADVERSE EVENTS ......................................................................................... 67 
7.2.4  SERIOUS ADVERSE EVENTS .............................................................................................. 67 
7.2.5  ADVERSE EVENT REPORTING ........................................................................................... 67 


 
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7.2.5.1  SERIOUS ADVERSE EVENTS, STANFORD REPORTING ..................................................... 68 
7.2.5.2  BAYER REPORTING ........................................................................................................ 68 
8. PLANNED RESEARCH STUDIES ................................................................................... 71 
8.1 BLOOD SAMPLES FOR CORRELATIVE RESEARCH STUDIES ................................................ 71 
8.1.1  CAPP-SEQ CIRCULATING TUMOR DNA .......................................................................... 71 
8.1.2  COMPUTATIONAL SIMULATION MODEL ........................................................................... 71 
9. STUDY CALENDAR .......................................................................................................... 71 
10. MEASUREMENT................................................................................................................ 73 
10.1  PRIMARY OUTCOME MEASUREMENT ................................................................................. 73 
10.2  SECONDARY OUTCOME MEASUREMENTS ......................................................................... 73 
10.2.1  TO DETERMINE THE OBJECTIVE RESPONSE RATE USING RECIST V1.1 CRITERIA OF THE 
ORAL COMBINATION OF REGORAFENIB AND METHOTREXATE FOR PATIENTS WITH PRE-TREATED 
METASTATIC KRAS MUTATED NON-SQUAMOUS NSCLC ........................................................... 73 
10.2.2  TO DETERMINE THE DISEASE CONTROL RATE AT 8 WEEKS USING RECIST V1.1 CRITERIA 
OF THE ORAL COMBINATION OF REGORAFENIB AND METHOTREXATE FOR PATIENTS WITH 
PRE-TREATED METASTATIC KRAS MUTATED NON-SQUAMOUS NSCLC ..................................... 74 
10.2.3  TO DETERMINE THE SAFETY USING CTCAE V4.03 CRITERIA OF THE ORAL COMBINATION 
OF REGORAFENIB AND METHOTREXATE FOR PATIENTS WITH PRE-TREATED METASTATIC KRAS 
MUTATED NON-SQUAMOUS NSCLC ........................................................................................... 74 
10.2.4  TO DETERMINE THE PHARMACOKINETIC PARAMETERS OF METHOTREXATE 
WHENCOMBINED WITH REGORAFENIB (I.E., CMAX) .................................................................... 75 
10.3  EXPLORATORY ENDPOINT ................................................................................................. 75 
10.3.1  TO CORRELATE KRAS CIRCULATING TUMOR DNA (CTDNA) USING CAPP-SEQ 
PRE-TREATMENT AND THROUGHOUT TREATMENT WITH CLINICAL OUTCOME MEASURES, 
INCLUDING RESPONSE RATE AND PROGRESSION-FREE SURVIVAL ............................................... 75 
11. REGULATORY CONSIDERATIONS ............................................................................. 76 
11.1 INSTITUTIONAL REVIEW OF PROTOCOL ............................................................................. 76 
11.2 DATA AND SAFETY MONITORING PLAN ............................................................................ 76 
11.3 DATA MANAGEMENT PLAN .............................................................................................. 76 
12. STATISTICAL CONSIDERATIONS ............................................................................... 78 
12.1 STATISTICAL DESIGN ........................................................................................................ 78 
12.1.1  RANDOMIZATION ........................................................................................................... 78 
12.2 INTERIM ANALYSES ........................................................................................................... 78 
12.3 DESCRIPTIVE STATISTICS AND EXPLORATORY DATA ANALYSIS ...................................... 78 
12.4 PRIMARY ANALYSIS .......................................................................................................... 78 
12.5 SECONDARY ANALYSIS ..................................................................................................... 79 
12.5.1  SECONDARY ANALYSIS POPULATION ............................................................................. 80 
12.6  SAMPLE SIZE ..................................................................................................................... 80 
12.6.1  ACCRUAL ESTIMATES .................................................................................................... 80 
12.6.2  SAMPLE SIZE JUSTIFICATION .......................................................................................... 80 
12.6.3  EFFECT SIZE JUSTIFICATION ........................................................................................... 81 
12.7 CRITERIA FOR FUTURE STUDIES ........................................................................................ 81 
12.8 EXPLORATORY OBJECTIVE................................................................................................ 81 
13. REFERENCES ..................................................................................................................... 83 


 
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APPENDICES ............................................................................................................................. 90 
APPENDIX A: ECOG PERFORMANCE STATUS ........................................................................ 90 
APPENDIX B: RECIST VERSION 1.1 CRITERIA ....................................................................... 91 
APPENDIX C: CYP3A4 INHIBITORS/INDUCERS ...................................................................... 94 
APPENDIX D: EXAMPLES OF CLINICAL SUBSTRATES FOR THE CYTOCHROME ENZYMES 
CYP2B6, CYP2C8, AND CYP2C9 ............................................................................................ 96 
 
APPENDIX E: PARTICIPANT ELIGIBILIY CHECKLIST ...................................................97 
 
APPENDIX F: CELLWORKS MODELING OVERVIEW ...................................................101 
 


 
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PROTOCOL SYNOPSIS 
 
TITLE 
Study of Regorafenib in combination with Oral Methotrexate for KRAS 
Mutated Non-Small Cell Lung Cancer (NSCLC) 
STUDY PHASE 
Phase 2 
INDICATION 
KRAS mutated NSCLC Patients who have previously received one line of 
systemic therapy 
INVESTIGATION-
AL PRODUCT  
Regorafenib in combination with Oral Methotrexate 
PRIMARY 
OBJECTIVE 
•To determine the progression-free survival (PFS) of the combination of 
regorafenib and methotrexate for metastatic KRAS mutated NSCLC patients 
who have received at least 1 prior systemic therapy 
SECONDARY 
OBJECTIVE(S) 
•To determine the objective response rate (ORR) of the combination of 
regorafenib and methotrexate for metastatic KRAS mutated NSCLC patients 
who have received at least 1 prior systemic therapy 
•To determine the disease control rate (DCR) at 8 weeks of the combination 
of regorafenib and methotrexate for metastatic KRAS mutated NSCLC 
patients who have received at least 1 prior systemic therapy 
•To determine the safety of the combination of regorafenib and methotrexate 
for metastatic KRAS mutated NSCLC patients who have received at least 1 
prior systemic therapy  
•To determine the pharmacokinetic parameters of methotrexate when 
combined with regorafenib (i.e., trough and Cmax)  
EXPLORATORY 
OBJECTIVES 
•To correlate circulating tumor DNA (ctDNA) using CAncer Personalized 
Profiling by Deep Sequencing (CAPP-Seq)1 pre-treatment and throughout 
treatment with clinical outcomes 
•To correlate computational simulation model prediction of sensitivity to the 
combination of regorafenib and methotrexate based on genomic data with 
clinical outcomes 
INCLUSION/ 
EXCLUSION 
CRITERIA 
(Appendix E) 
Inclusion Criteria 
In order to be eligible for participation in this trial, the patient must meet ALL 
of the following criteria (i.e., mark “yes” or “N/A” to all criteria): 
1. Histologic or cytologic confirmed diagnosis of non-squamous 
non-small cell lung cancer that is recurrent or metastatic. 
Adenosquamous is allowed provided the patient has confirmed 
adenocarcinoma component.  
2. Documentation of pathogenic KRAS mutation  


 
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3. Previous receipt of at least one systemic therapy for recurrent or 
metastatic disease OR previous receipt of adjuvant systemic therapy 
within 6 months of enrollment.  There is no limit on number of prior 
therapies allowed.   
4. Prior systemic therapy must be completed at least 2 weeks prior to 
study treatment, with either improvement of clinically significant 
treatment-related toxicities to grade 0 to 1 OR stabilized to a new 
baseline.   
5. Previously treated OR asymptomatic non-progressing < 1 cm 
untreated brain metastases are allowed 
6. Measurable disease based on RECIST version 1.1 criteria (Appendix 
B) 
7. Ability to understand and the willingness to sign a written informed 
consent document  
8. Age ≥ 18 years-old 
9. ECOG performance status of 0 or 1 (Appendix A) 
10. Adequate bone marrow, liver, and renal function as assessed by the 
following laboratory requirements: 
a. Absolute neutrophil count (ANC) ≥ 1500/mm3 
b. Platelet count ≥ 100,000 /mm3 
c. Hemoglobin (Hb) ≥ 9 g/dL  
d. Serum creatinine ≤ 1.5x upper limit of normal (ULN) OR 
calculated (Cockcroft-Gault formula) or measured creatinine 
clearance ≥ 50 mL/min for patients with creatinine levels 
> 1.5x ULN 
e. Total bilirubin ≤ 1.5x ULN OR Direct bilirubin ≤ ULN for 
patients with total bilirubin levels > 1.5x ULN  
f. Alanine aminotransferase (ALT) and aspartate 
aminotransferase (AST) ≤ 3x ULN (≤ 5x ULN for patients 
with liver involvement of their cancer) 
11. Must be able to swallow and retain oral medication. 
12. Women patients of childbearing potential and men patients with 
women partners of childbearing potential must agree to use adequate 
contraception or agree to abstain from heterosexual activity beginning 
at the time of signing informed consent until at least 3 months after the 
last dose of study treatment.  Post-menopausal women (defined as no 
menses for at least 1 year) and surgically sterilized women are not 
considered childbearing.   


 
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Exclusion Criteria 
In order to be eligible for participation in this trial, the patient must NOT meet 
the following criteria (i.e., mark “no” or “N/A” to all criteria): 
1. Previously treated with regorafenib  
2. Known allergy to regorafenib or methotrexate  
3. Currently receiving another systemic standard or investigational 
anti-cancer therapy. Prior investigational therapy must be completed 
within 4 half-lives (if known) or 2 weeks, whichever is longer.  The 
maximal washout of investigational therapy will not exceed 4 weeks 
prior to study treatment. Bone medications such as bisphosphonates 
and RANK ligand inhibitors permitted.   
4. Leptomeningeal disease as documented by CSF cytology. 
5. Clinically significant cardiovascular-related disease including: 
a. Uncontrolled hypertension (systolic pressure >150 mm Hg or 
diastolic pressure > 90 mm Hg on repeated measurements that 
does not resolve prior to study treatment on C1D1 despite 
optimal medical management) 
b. Congestive heart failure – New York Heart Association 
(NYHA) Class III or greater 
c. Active coronary artery disease (i.e., unstable or new onset 
angina within 3 months of study treatment; myocardial 
infarction within 6 months of study treatment) 
d. Clinically significant cardiac arrhythmias other than atrial 
flutter/fibrillation  
e. Stroke, including transient ischemic attacks, within 6 months 
of study treatment  
f. Other clinically significant arterial events, except for controlled 
asymptomatic pulmonary embolism, within 6 months of study 
treatment 
6. Clinically significant hemorrhage or bleeding event within 1 month of 
study treatment  
7. Uncontrolled symptomatic pleural effusion or ascites  
8. Known active additional malignancy that is undergoing or expected to 
undergo systemic treatment during duration of study participation.   


 
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9. Known history of human immunodeficiency virus (HIV) infection or 
known current active hepatitis B (i.e., Hep B DNA positive in prior 
3 months) or hepatitis C infection (i.e., Hep C RNA positive in prior 
3 months, with the exception of patients who have completed curative 
therapy and are Hep C RNA negative on retest).   
10. Major surgical procedure (e.g., involving the opening of a major body 
cavity) within 4 weeks of study treatment.  This does not apply to 
low-risk procedures (i.e., thoracentesis; dparacentesis; chest 
tube/PleurX catheter placement; line placement; needle biopsy of 
tumor; and bronchoscopy).   
11. Presence of a clinically significant non-healing wound or non-healing 
ulcer. 
12. Concomitant therapy required at time of first dose of study treatment, 
including: 
a. Strong CYP3A4 inhibitors and CYP3A4 inducers (Appendix 
C) 
a. Regular use of NSAIDs, proton pump inhibitors, and 
probenecid 
13. Women who are pregnant or breast-feeding. 
14. Any condition which, in the investigator’s opinion, including 
substance abuse, medical, psychological or social conditions that 
makes the patient unsuitable for trial participation or may interfere 
with the patient’s participation in the study.   
TREATMENT 
SUMMARY 
Treatment:  
Study treatment (regorafenib and methotrexate) will be administered 3 weeks 
ON/1 week OFF of each 28-day cycle, ongoing until disease progression or 
intolerable toxicity.    
 
Regorafenib will begin on Cycle 1 Day 1 and will be self-administered at 
80 mg oral daily 3 weeks on/1 week off of the 28-day cycle with a low-fat 
meal. Regorafenib will NOT be dose escalated during Cycle 1. If a patient 
requires a dose reduction below 80 mg daily due to a treatment-related 
toxicity, the patient should discontinue study treatment. If a patient requires 
>4 week delay for treatment-related toxicity, it is encouraged that the patient 
discontinue study treatment, unless the patient may derive ongoing benefit by 
resuming treatment as per investigator discretion and after discussion with the 
study PI. 


 
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Regorafenib can be dose escalated to 120 mg oral daily (same schedule of 3 
weeks on/1 week off of the 28-day cycle) according to strict criteria beginning 
at Cycle 2 Day 1. The strict criteria for escalation include no evidence of 
significant drug-related toxicities (SDRT), defined as any event that would 
require a dose modification of regorafenib (i.e., interruption only, reduction 
only, or interruption followed by reduction) according to the toxicity 
guidelines/tables in Section 6.2.1 (regorafenib toxicities) and Section 6.2.3 
(overlapping regorafenib and methotrexate toxicities). If after the first two 
cycles a patient has not yet escalated or is considering re-escalation to 
regorafenib 120 mg, this is permitted as long as all treatment-related toxicities 
have resolved to grade 0-1 or to the patient’s baseline and at the discretion of 
the investigator. However, a patient is not required to dose escalate 
regorafenib to 120 mg during the course of study treatment and is 
permitted to remain at the 80 mg dose if it is better tolerated and per 
investigator discretion.   
Methotrexate will begin on Cycle 1 Day 1 and is self-administered during the 
same weeks as regorafenib (i.e., 3 weeks on /1 week off each 28-day cycle). 
The initial starting dose during Cycle 1 Week 1 of methotrexate is 10 mg oral 
twice weekly. Methotrexate doses will be separated by at least 2 days each 
week (doses separated by 3 days preferred). Methotrexate will be dose 
escalated in the following manner as tolerated weekly (+/- 1 day): Cycle 1 
Week 1: 10 mg oral twice weekly, Cycle 1 Week 2: 15 mg oral twice weekly, 
Cycle 1 Week 3: 20 mg oral twice weekly. Beginning in Cycle 2, 
methotrexate will be self-administered at doses ranging from 10 to 20 mg oral 
twice weekly, depending on tolerability, with 2-3 days between doses. Dose 
escalation of methotrexate can continue after Cycle 1 depending on the 
patient’s tolerability, if the patient has not dose escalated to 20 mg by the end 
of Cycle 1. 
 
Methotrexate will be taken within 30 minutes of regorafenib, if feasible, 
during Cycle 1 for ease of pharmacokinetic studies. Beginning in Cycle 2, 
patients may take regorafenib and methotrexate at different times of day 
depending on their preference. Self-administration with food is encouraged to 
improve tolerability. 


 
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Schedule of Events: 
Please see Study Calendar in Section 9 for further details such as 
windows allowed for study procedures. 
Screening: Performed within 30 days of Cycle 1 Day 1 or on Cycle 1 Day 1 if 
prior to the first dose of study treatment.  Exception includes brain MRI, 
which can be performed within 45 days of Cycle 1 Day 1.  Screening studies 
include: informed consent, documentation of patient demographics and 
medical history, beta-HCG (for women of childbearing potential), EKG (as 
indicated), review of concurrent medications, physical examination, vital 
signs (including height and weight), ECOG performance status, complete 
blood count with differential, serum chemistry, random urine 
protein:creatinine ratio (as a baseline, not for eligibility), CT chest + 
abdomen/pelvis with contrast (unless contraindicated), brain MRI (or CT 
head), archival tumor tissue (if available).   
 
Clinic Visit with Physical Exam/Vitals: Patients will be evaluated in clinic 
weekly during Cycle 1, and during Week 1 and Week 3 of Cycle 2.  Starting 
with Cycle 3, patients will be evaluated in clinic once per cycle.  During these 
scheduled clinic visits, a physical exam will be performed and vital signs will 
be documented.  During Cycle 2 Week 2, patients will document blood 
pressure locally and report to investigator team if blood pressure is >140/90.   
 
Weight/ECOG Performance Status: Patient’s weight and ECOG Performance 
Status will be recorded once per cycle. 
 
 
Medications/Adverse Events/Pill Count: Concurrent medications and adverse 
events will be documented throughout study.  Pill count will be performed on 
remaining patient supplies of regorafenib and methotrexate weekly during 
Cycle 1, and thereafter once per cycle.   
 
Labs: Complete blood count with differential and serum chemistry will be 
measured weekly during Cycle 1, and Week 1 and Week 3 during Cycle 2.  
Thereafter, these studies will be performed once per cycle.  Serum 
amylase/lipase and thyroid studies (TSH/free T4) will be measured once per 
cycle.   
 
Pharmacokinetic (PK) Studies: Blood samples for methotrexate PK studies 
will be measured during Cycle 1 prior to self-administration of study 
treatment and one hour post-self administration of methotrexate during Weeks 


 
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1, 2, and 3.  Cycle 1 Week 4 will only include a single methotrexate 
measurement (to check the trough since this is an off week).   
 
Circulating Tumor DNA (ctDNA) Studies: Blood samples for ctDNA will be 
collected at baseline (Week 1) and Week 3 of Cycle 1, and thereafter, once 
per cycle for Cycles 2 and 3.  Thereafter, ctDNA samples will be collected at 
a timepoint that is closest to time of radiologic imaging.   
 
Imaging:  
CT chest + abdomen/pelvis with contrast (unless contraindicated): Image all 
known baseline sites of disease. Perform every 8 weeks + 1 week for the first 
1 year and then after 1 year, every 12 weeks + 1 week. For patients who come 
off study for toxicity or any other reason, obtaining interval imaging (i.e., 
unscheduled scan) will be strongly encouraged to monitor response. 
 
Brain MRI: Screening study for all patients.  For patients with untreated brain 
metastases at baseline, perform every 8 weeks + 1 week at baseline for the 
first 1 year and then after 1 year, every 12 weeks + 1 week.  If patient has 
history of treated brain metastases or no history of brain metastases, frequency 
of brain imaging follow-up is per the investigator discretion, although it is 
encouraged to perform the imaging every 8-16 weeks (+ 1 week). 
  
Chest X-ray (2 view): For patients with a history of pleural effusion, perform 
once per cycle because methotrexate can accumulate in pleural effusions.  For 
patients with adequate chest imaging with re-staging CT prior to cycle, it is 
permitted to omit Chest X-ray imaging. C1D1 chest X-ray may be omitted by 
the treating physician if baseline chest imaging (completed within 30 days of 
C1D1) is deemed adequate. 
 
Refer to Section 9 Study Calendar for further details.   
 
Dose Limiting Toxicities (DLT) will be monitored during Cycle 1 (first 28 
days). During Cycle 1, patients will be on regorafenib 80 mg oral daily 3 
weeks on/1 week off and methotrexate with doses ranging three dose levels 
between 10-20 mg oral twice weekly 3 weeks on/1 week off. A patient will be 
eligible for DLT assessments if he/she has received at least 80% of the 
planned doses of study treatment, which will be calculated by dosing days of 
regorafenib in case a patient is off treatment during Cycle 1 for a reason other 
than toxicity.   
 


 
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A DLT will be generally defined as any Grade 3 or 4 toxicity occurring during 
Cycle 1 (first 28 days), which is regarded as clinically significant and related 
to study treatment with clarifications and exceptions for adverse event terms 
noted below. The NCI‑CTCAE version 4.03 will be used to assess toxicities.   
 
Only the following hematologic toxicities will be considered a DLT: 
• Absolute Neutrophil Count (ANC) < 500/mm3 for > 7 days despite 
dose interruption 
• Febrile neutropenia [ANC <1000/mm3 with a single temperature of 
> 38.3 degrees C (101 degrees F) or a sustained temperature of 
≥ 38 degrees C (100.4 degrees F) for more than one hour] 
• Platelets < 25,000/mm3 or ≥ Grade 3 thrombocytopenia associated 
with clinically significant bleeding 
 
Non-hematologic Grade 3 or Grade 4 toxicity considered clinically significant 
and study treatment-related is a DLT, except for the following, permitting 
protocol therapy can resume according to the toxicity guidelines in Section 
6.2. (Note: If patient declines to resume protocol therapy despite being able 
to, this will not be considered a DLT). 
• Grade 3 nausea, vomiting, or diarrhea that improves to grade 2 or less 
with dose interruption and appropriate supportive care within 5 days   
• Grade 3 mucositis or stomatitis that improves to grade 0-1 with dose 
interruption and appropriate supportive care within 28 days 
• Grade 3 hypertension that improves to grade 2 or less with dose 
interruption and appropriate supportive care within 7 days 
• Grade 3-4 electrolyte abnormalities that are asymptomatic and can be 
corrected with supplementation and/or appropriate supportive care 
(e.g., hypomagnesemia, hypokalemia, hypocalcemia, hyponatremia, 
hypophosphatemia) or any grade of electrolyte abnormality that is 
related to another adverse event such as diarrhea, nausea, or vomiting 
• Grade 3 asymptomatic maculo-papular rash that improves to grade 2 
or less with dose interruption and appropriate supportive care within 
28 days 
 
The following will not be considered a DLT: 
• ≥ Grade 3 lipase and amylase that is asymptomatic 
• Grade 3 unconjugated/indirect bilirubin secondary to Gilbert’s disease 
or equivalent 


 
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Miscellaneous: In case an unexpected drug-related toxicity (even at a lower 
grade) is seen more frequently than expected or beyond the DLT time period, 
this toxicity may be declared as a DLT for the remainder of the study after 
consultation with the PI. 
SAMPLE SIZE  
18 patients, with at least 15 evaluable for PFS 
STATISTICAL 
CONSIDERATION
S 
Efficacy: 
Our null hypothesis is that the median PFS is 2 months. We wish to have 80% 
power at the alternative hypothesis of a median PFS of 8 months. Assuming a 
horizon for PFS of 2.0 months and exponential PFS, the probability of being 
PFS-free at that time is 50.0% under the null hypothesis and 8% under the 
alternative hypothesis. With 18 informative patients, we would have 
approximately 80% power to reject the null hypothesis at a one-sided 
significance level of 5%. 
 
The null hypothesis for this study is based on two major references: 1) 
Median PFS with regorafenib alone in pre-treated metastatic NSCLC (KRAS 
mutation not specified) was 84 days (approximately 2-3 months), and 2) 
Median PFS with a similar agent to regorafenib, sorafenib, in pre-treated 
metastatic KRAS mutated NSCLC was 2.3 months (95% CI 1.6-3.0)2. A 
clinically meaningful alternative hypothesis would be 8 months. 
 
Safety Stopping Rule: 
We will consider the number of patients with dose limiting toxicity (DLT), 
defined in section 6.1, to ensure there is not excessive toxicity. If 2 or more 
of the first 6 patients have a DLT, or if 3 or more out of the first 12 
patients have a DLT, we will suspend enrollment to the trial and reconsider 
the dosing strategy (including dose and schedule of regorafenib and/or 
methotrexate). Finally, if at the final analysis, 3 or more patients have DLT, 
we will take this as an indication that the regimen may be too toxic and 
additional dose and schedule may be considered for future development of the 
combination. The table below shows the probability of stopping early (pstop) 
and the probability of declaring the regimen too toxic at an interim look or at 
the final analysis (pcross), for various value of the probability of DLT (ptox); 
the expected sample size under each scenario is also shown (ess). 
 
Ptox pcross  pstop   ess 
0.05  0.012  0.004  18.0 
0.10  0.102  0.033  17.7 


 
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0.14  0.243  0.089  17.2 
0.18  0.417  0.175  16.5 
0.22  0.588  0.284  15.5 
0.26  0.731  0.406  14.5 
0.30  0.838  0.530  13.3 


 
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SCHEMA 
 
PATIENTS 
 
18 KRAS mutated metastatic and/or recurrent NSCLC patients who received at least 
1 prior systemic therapy 
OBJECTIVES 
Primary:  
• 
Progression Free Survival 
Secondary:  
• 
Objective response rate (CR plus PR; RECIST v1.1) 
• 
Disease control rate at 8 weeks (CR+PR+SD at 8 weeks; RECIST v1.1); 
• 
Safety (dose limiting toxicities; CTCAE v4.03) 
• 
Pharmacokinetic parameters of methotrexate (trough, Cmax) 
TREATMENT 
 
 
 
Dosing Strategies  
(3 Weeks ON/1 Week OFF of 28-Day Cycle) 
Regorafeniba 
80 mg 
Daily 
Regorafenibb 
80 mg or 120 mg as tolerated  
Daily 
MTX Dose Level 1* 
10 mg 
Twice Weekly 
MTX Dose Level 2 
15 mg (escalate as tolerated) 
Twice Weekly 
MTX Dose Level 3 
20 mg (escalate as tolerated) 
Twice Weekly 


 
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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
 
AE 
Adverse event 
AHA 
Alpha hydroxyl acid 
ALK 
Anaplastic lymphoma kinase 
ALT 
Alanine aminotransferase 
ANR 
Absolute neutrophil count 
ASCO 
American Society of Clinical Oncology 
AST 
Aspartate aminotransferase 
AUC 
Plasma concentration vs.  time curve 
BCRP 
Breast Cancer Resistance Protein 
Beta-HCG 
Beta human chorionic gonadotropin 
BP 
Blood pressure 
CAPP-Seq 
Cancer Personalized Profiling by Deep Sequencing 
C 
Celsius 
CI 
Confidence interval 
Cmax 
Maximum serum concentration 
CRF 
Case report form 
CR 
Complete response 
CSF 
Cerebrospinal fluid 
CT 
Computerized tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
ctDNA 
Circulating tumor DNA 
Cys 
Cysteine 
DCE 
Dynamic contrast enhanced 
DCR 
Disease control rate 
DHFR 
Dihydrofolate reductase 
DLT 
Dose limiting toxicity 
DSMC 
Data and Safety Monitoring Committee 
EGFR 
Epidermal growth factor receptor 
EKG 
Electrocardiogram 
F 
Fahrenheit 
FDA 
Food and Drug Administration 
FOLT 
Folate transporter 1 
FPGS 
Folylpolyglutamyl synthetase 
G-CSF 
Granulocyte colony-stimulating factor 
GCP 
Good Clinical Practice 
GIST 
Gastrointestinal solid tumor 
GMP 
Good Manufacturing Practices 
GTPase 
Guanosine triphosphatases 
Hb 
Hemoglobin 
HFSR 
Hand-foot skin reaction 
HIV 
Human Immunodeficiency Virus 
HR 
Hazard ratio 
IB 
Investigator’s brochure 


 
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IM 
Intramuscular 
IRB 
Institutional Review Board 
KRAS 
Kirsten rat sarcoma 
mCRC 
Metastatic colorectal cancer 
mg 
milligrams 
MRI 
Magnetic resonance imaging 
MTX 
Methotrexate 
N/A 
Not applicable 
NCI 
National Cancer Institute 
NSAID 
Nonsteroidal anti-inflammatory drug 
NSCLC 
Non-small cell lung cancer 
NYHA 
New York Heart Association 
ORR 
Objective response rate 
OS 
Overall survival  
PD-L1 
Programmed death-ligand 1 
PFS 
Progression free survival  
PI 
Principal Investigator 
PK 
Pharmacokinetic 
PPE 
Palmar-plantar erythrodysesthesia 
PPI 
Proton pump inhibitor 
PR 
Partial response 
RANKL 
Receptor activator of nuclear factor kappa-B ligand 
RECIST 
 
Response evaluation criteria in solid tumors 
RFC 
Reduced folate carrier 
RPLS 
Reversible Posterior Leukoencephalopathy Syndrome 
SAE 
Serious adverse event 
SD 
Stable disease 
SDRT 
Significant drug-related toxicities 
TKI 
Tyrosine kinase inhibitor 
ULN 
Upper limit of normal 
VEGFR 
Vascular endothelial growth factor receptor 


 
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OBJECTIVES 
1.1. 
Primary Objective  
• To determine the progression-free survival (PFS) of the combination of regorafenib and 
methotrexate for metastatic KRAS mutated NSCLC patients who have received at least 1 
prior systemic therapy 
1.2. 
Secondary Objectives 
 
• To determine the objective response rate (ORR) of the combination of regorafenib and 
methotrexate for metastatic KRAS mutated NSCLC patients who have received at least 1 
prior systemic therapy 
• To determine the disease control rate (DCR) at 8 weeks of the combination of regorafenib 
and methotrexate for metastatic KRAS mutated NSCLC patients who have received at 
least 1 prior systemic therapy 
• To determine the safety of the combination of regorafenib and methotrexate for 
metastatic KRAS mutated NSCLC patients who have received at least 1 prior systemic 
therapy  
• To determine the pharmacokinetic parameters of methotrexate when combined with 
regorafenib (i.e., trough and Cmax)  
1.3  
Exploratory Objectives 
• To correlate circulating tumor DNA (ctDNA) using CAncer Personalized Profiling by 
Deep Sequencing (CAPP-Seq)1 pre-treatment and throughout treatment with clinical 
outcomes 
• To correlate computational simulation model prediction of sensitivity to the combination 
of regorafenib and methotrexate based on genomic data with clinical outcomes 
2. 
BACKGROUND 
In the United States, lung cancer is the number one cause of cancer-related deaths, with an 
estimated 222,500 new cases of lung cancer and 155,870 lung cancer-related deaths in 20173,4.  
Non-small cell lung cancer (NSCLC) accounts for over 85% of all lung cancer cases, and 
includes adenocarcinoma, squamous cell carcinoma, and large cell carcinoma.  With the rise of 
precision medicine, NSCLC care has transitioned from treatment based on histology to a focus 
on targetable genetic driver mutations5, with the most successful stories to date including 
epidermal growth factor receptor (EGFR)-mutated and anaplastic lymphoma kinase (ALK)-gene 
rearranged NSCLC.  However, for the most common oncogenic driver mutation, KRAS (Kirsten 
murine sarcoma viruses), targeted therapy has been elusive6,7.   
2.1 
KRAS Mutated Non-Small Cell Lung Cancer 
KRAS-mutant NSCLC comprises approximately 30% of NSCLC adenocarcinomas and 5% of 
squamous carcinomas8,9.  It is significantly associated with a history of smoking, an older age of 
diagnosis, and a higher prevalence among Caucasians8.  To date, the impact of KRAS on 
prognosis is unclear.  Initially, KRAS mutations were identified as negative prognostic factors for 
patients with adenocarcinoma10.  Subsequent studies, however, have reported mixed results11-16.  


 
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One recent meta-analysis concluded that although the association was weak, KRAS mutation 
remained a valid predictor for poor prognosis and treatment outcomes in NSCLC17.   
KRAS belongs to the family of RAS genes that encode small guanosine triphosphatases 
(GTPases) located at the inner surface of the cellular membrane18.  The KRAS enzyme functions 
primarily to relay signaling from activated transmembrane receptors, such as EGFR, into the 
cytoplasm.  Important downstream signaling pathways include RAF-MEK-ERK and 
PI3K-AKT-mTOR, both of which mediate cellular growth, proliferation, motility, and 
survival19,20.  Mutations in the KRAS gene constitutively activate these pathways, and are thought 
to occur as an early event in lung cancer tumorigenesis21.  The most common KRAS mutations 
are found on codons 12, 13, and, less frequently, on 6122-24.  Notably, a group of irreversible oral 
allosteric inhibitors for KRAS G12C have been developed that selectively bind to the mutant Cys 
12, leaving the wild-type protein unaffected25.  Experiments have shown that these 
cysteine-reactive molecules successfully impair KRAS(G12C) function and reduce the viability 
of KRAS(G12C)-mutant lung cancer cell lines, thus representing one promising area of 
development for KRAS-specific therapies.  Given that KRAS mutations are easily identifiable and 
highly prevalent in NSCLC, they are an appealing target for therapeutic intervention.   
Current management of metastatic KRAS-mutant NSCLC resembles that for NSCLC without 
known currently “actionable” mutations (i.e., EGFR/ALK/ROS1 negative).  First-line therapies 
include immunotherapy with pembrolizumab for patients with PD-L1 expression on at least 50% 
of tumor cells26, and platinum-based doublet chemotherapy for patients with less than 50% 
PD-L1 expression27.  Second-line immunotherapy options include pembrolizumab for patients 
with PD-L1 expression greater than or equal to 1%28, as well as nivolumab29,30 and 
atezolizumab31, irrespective of PD-L1 expression.  Second-line FDA-approved 
chemotherapeutics include single-agent docetaxel +/- ramucirumab32 and pemetrexed33,34, among 
other non-FDA approved chemotherapeutics (i.e., gemcitabine, irinotecan).  Active investigation 
for combination therapies in the second-line setting for EGFR/ALK negative NSCLC is currently 
ongoing, although there have yet to be any major changes in the standard of care based on these 
studies35.   
Considerable attention has turned to the search for an intervention that offers patients with 
KRAS-mutated NSCLC a targeted therapy of their own.  Since KRAS itself is not currently 
clinically targetable, efforts have focused largely on modulating the activity of its downstream 
effectors.  Inhibitors of mTOR36, BRAF37, and MEK38 are currently being evaluated in clinical 
trials.  However, limitations of MEK inhibition have been revealed through a lack of specificity 
and sub-optimal responses39-42.  Unfortunately, the phase III randomized SELECT-1 study 
examining docetaxel versus docetaxel plus selumetinib failed to show benefit in KRAS-mutant 
NSCLC41, highlighting the need for therapies for this lung cancer subtype.  KRAS-mutant 
NSCLC is resistant to EGFR TKI treatment12,43, although there were some responses to 
combination erlotinib and bexarotene and combination gefitinib and everolimus44,45.  Recent 
studies demonstrate a considerable amount of heterogeneity among KRAS-mutant lung cancer 
that may ultimately affect therapeutic responses, and may be part of the reason this genomic 
subset has been so difficult to target.  For example, one study identified subsets of KRAS-mutant 
lung adenocarcinoma with differing co-mutations in LKB1, TP53, and CDKN2A/B that had 
altered cellular and immune profiles46.  Recent studies have also revealed unique differences in 
KRAS-mutant NSCLC metabolism, such as enhanced dependency on folate metabolism47, that 
suggest other possibilities for therapeutic targeting.  Given the prevalence and the current 


 
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treatment landscape of KRAS-mutated NSCLC outlined above, there is a dire need for improved 
treatment options.     
2.2 
Regorafenib and Methotrexate 
2.2.1    Regorafenib 
Please see Regorafenib Investigational Brochure48 for further details. 
2.2.1.1 Regorafenib Mechanism of Action and Pre-Clinical Studies 
Regorafenib is an oral small molecule inhibitor of multiple membrane-bound and intracellular 
kinases involved in normal cellular functions and in pathologic processes such as oncogenesis, 
tumor angiogenesis, and maintenance of the tumor microenvironment. Regorafenib has potent 
preclinical anti-tumor activity and long-lasting anti-angiogenic activity, as measured by dynamic 
contrast enhanced (DCE) – magnetic resonance imaging (MRI)49.   
In in vitro biochemical or cellular assays, regorafenib or its major human active metabolites, M-2 
and M-5, inhibited the activity of RET, VEGFR1, VEGFR2, VEGFR3, KIT, PDGFR-alpha, 
PDGFR-beta, FGFR1, FGFR2, TIE2, DDR2, Trk2A, Eph2A, RAF-1, BRAF, BRAFV600E, 
SAPK2, PTK5, and Ab1 at concentrations of regorafenib that have been achieved clinically.  In 
in vivo models, regorafenib demonstrated anti-angiogenic activity in a rat tumor model, and 
inhibition of tumor growth, as well as anti-metastatic activity in several mouse xenograft models, 
including some for human colorectal carcinoma. 
In vivo, regorafenib exhibited anti-angiogenic and anti-proliferative effects in human colon and 
breast xenografts as demonstrated by a reduction in microvessel area, reduced Ki-67 staining, 
and reduced pERK1/2 staining in tissue sections from tumor xenografts, and dose-dependent 
inhibition of growth in multiple xenograft models (breast, colon, renal, NSCLC, melanoma, 
pancreatic, thyroid, ovarian)49.  Immunohistochemical ex-vivo studies with a phospho-specific 
monoclonal anti-ERK 1/2 antibody demonstrated inhibition of the MAPK pathway five days 
after treatment with regorafenib in 2 of 3 tumor models examined (MDA-MB 231 and BxPC-3), 
but not in NSCLC (H460). 
In addition, all tested human tumor xenografts (MDA-MB-231, H460 (lung), BxPC-3, and 
Colo-205) demonstrated a significant reduction in new blood vessels by histomorphometry as 
detected in tumor samples using a murine CD31 antibody49.  These data suggest that regorafenib 
can target the tumor cell MAPK pathway (tumor cell survival) and tumor vasculature in some 
but not all tumors. 
2.2.1.2 Regorafenib Clinical Trials in Cancer, Including Lung Cancer 
FDA-Approved Indications for Regorafenib (3):  
1) Colorectal Cancer: Regorafenib is currently FDA-approved at a dose of 160 mg oral once 
daily for the first 21 days of each 28-day cycle for patients with metastatic colorectal cancer 
(mCRC) who have been previously treated with fluoropyrimidine-, oxaliplatin- and 
irinotecan-based chemotherapy, an anti-VEGF therapy, and, if KRAS-wild type, an anti-EGFR 
therapy.  This September 2012 approval was supported by two phase III global randomized 
studies, including the CORRECT study50 (North America, Europe, Asia, and Australia) and the 
CONCUR Study51 (Asia Pacific).  The CORRECT study was an international, multicenter, 
randomized, double-blind, placebo-controlled study of regorafenib that enrolled 760 patients 


 
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with mCRC whose disease has progressed after approved standard therapies, with a primary 
endpoint of overall survival (OS).  At a pre-planned second interim analysis, there was a 
statistically significant survival benefit for regorafenib (OS, median OS was 6.4 months vs.  5.0 
months, hazard ratio [HR] = 0.773 [95% confidence interval (CI) 0.635 to 0.941; 1-sided p = 
0.0051]).  In addition to improved OS, progression-free survival (PFS) and disease control rate 
(DCR) were superior.  Regorafenib demonstrated comparable efficacy benefits across patient 
subgroups including KRAS status.   
2) Gastrointestinal Stromal Tumor (GIST): Regorafenib is currently FDA-approved at a dose 
of 160 mg oral once daily for the first 21 days of each 28-day cycle for patients with locally 
advanced, unresectable, or metastatic gastrointestinal stromal tumor (GIST) who have been 
previously treated with imatinib mesylate and sunitinib malate.  This 2013 FDA approval was 
supported by the Phase III GRID randomized study of regorafenib vs.  placebo in patients with 
GISTs who had exhausted all other treatment options, with statistically significant 3.9-month 
improvement in PFS, compared with placebo (4.8 months vs.  0.9 months; HR = 0.27;     
p<.0001)52.  OS rate was similar and DCR was also improved. 
3) Hepatocellular Carcinoma (HCC): Regorafenib is currently FDA-approved at a dose of 
160 mg oral once daily for the first 21 days of each 28-day cycle for patients with hepatocellular 
carcinoma (HCC) who have been previously treated with sorafenib.  This April 2017 approval 
was supported by the phase III RESORCE randomized trial of regorafenib vs.  placebo in 
patients with HCC who progressed on previous treatment with sorafenib, with a primary 
endpoint of OS53.  Regorafenib demonstrated a statistically significant improvement in OS 
compared with placebo (HR = 0.63; 95% CI 0.50 to 0.79; 1-sided p<0.0001), with a median OS 
of 10.6 months (95% CI 9.1 to 12.1) for regorafenib compared to 7.8 months (95% CI 6.3 to 8.8) 
for placebo.  PFS and time to progression were also significantly improved with regorafenib. 
Clinical Trials in Lung Cancer:  
Regorafenib has been studied in lung cancer as a single agent and in combination with 
cisplatin/pemetrexed chemotherapy54,55.   
The study extension of the phase I study of regorafenib in NSCLC was last presented at the 
American Society of Clinical Oncology (ASCO) meeting in 201054.  Regorafenib was 
administered orally once daily continuously in repeating cycles of 21 days, with 22 patients 
receiving 100 mg (recommended phase II dose) and one patient receiving 120 mg.  The mean 
treatment duration was 84.6 days +/-61 days (2-281 days).  The majority of patients were heavily 
pre-treated with a median number of 3 regimens received, including 57% receiving a prior EGFR 
inhibitor small molecule.  There was a high DCR of 83% (N= 15 of 18 patients evaluable had 
best response of stable disease).  However, the median PFS was only 84 days, although one 
patient had a PFS of 259 days (range 30-259 days).  Efficacy was examined by EGFR and KRAS 
mutation status when available.  Of the 9 patients tested for EGFR, 2 had an EGFR mutation, 
subtype unknown, and of the 6 patients tested for KRAS, all were negative—none of these 
patients were part of the 5 patients who had the longest PFS on study.  In the waterfall plot, there 
were 8 patients with some decrease in tumor burden, and only 3 had molecular data available, 
including one EGFR/KRAS negative, one EGFR negative/KRAS unknown, and one KRAS 
negative/EGFR unknown. 


 
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Regorafenib was also studied in combination with cisplatin and pemetrexed for the first-line 
treatment of metastatic NSCLC55.  Regorafenib 60 mg daily was administered continuously on 
days 1-21 of each cycle.  After completion of 6 cycles of chemotherapy, regorafenib as a single 
agent or in combination with pemetrexed was dosed until progression.  A total of 9 patients were 
treated on the study before termination.  All patients were tested for EGFR and KRAS, and 3 
patients had a KRAS mutation, 1 had an exon 20 EGFR mutation, and 5 patients were 
EGFR/KRAS wild-type.  The objective response rate (ORR) was 55.6%, with 5 partial responses, 
3 stable disease, and one progressive disease.  Of the 3 KRAS codon 12 mutations (2 KRAS 
G12V and 1 KRAS G12A), there were 2 partial responses with a 38% and 44% reduction in 
tumor target lesions.  One patient with a KRAS mutation had progressive disease in the nontarget 
lesions but had a 44% decrease in the target lesions.  The overall median PFS for the study was 7 
months.  In the KRAS mutated subgroup, the PFS range was from 1.5 months in the patient with 
progressive disease to 12.4 months.  The OS ranged from 13.1 months to 56.7 months.  The 
patient with the second longest PFS and OS in this study had a KRAS mutation. 
2.2.1.3 Regorafenib Nonclinical and Clinical Toxicology 
Nonclinical Toxicology:  
Carcinogenesis and Mutagenesis: Studies examining the carcinogenic potential of regorafenib 
have not been conducted.  Regorafenib itself did not demonstrate genotoxicity in in vitro or in 
vivo assays; however, a major human active metabolite of regorafenib, (M-2), was positive for 
clastogenicity, causing chromosome aberration in Chinese hamster V79 cells. 
Impairment of Fertility: Dedicated studies to examine the effects of regorafenib on fertility have 
not been conducted; however, there were histological findings of tubular atrophy and 
degeneration in the testes, atrophy in the seminal vesicle, and cellular debris and oligospermia in 
the epididymides in male rats at doses similar to those in human at the clinical recommended 
dose based on the plasma concentration vs.  time curve (AUC).  In female rats, there were 
increased findings of necrotic corpora lutea in the ovaries at the same exposures.  There were 
similar findings in dogs of both sexes in repeat dose studies at exposures approximately 83% of 
the human exposure at the recommended human dose based on AUC.  These findings suggest 
that regorafenib may adversely affect fertility in humans. 
Animal Toxicology and/or Pharmacology: In a chronic 26-week repeat dose study in rats, there 
was a dose-dependent increase in the finding of thickening of the atrioventricular valve.  At a 
dose that resulted in an exposure of approximately 12% of the human exposure at the 
recommended dose, this finding was present in half of the examined animals. 
Clinical Toxicology: 
Toxicity in Gastrointestinal Cancer Studies: 
In the CORRECT study of metastatic colorectal cancer, the most frequent grade 3+ adverse 
events in the regorafenib group were hand-foot skin reaction (17%), fatigue (15%), diarrhea 
(8%), hyperbilirubinemia (8%), and hypertension (7%)50.  Adverse events in CONCUR were 
consistent with the known safety profile of regorafenib in metastatic colorectal cancer51.  In the 
GIST study, the most common grade ≥3 adverse events associated with regorafenib were 
hand-foot skin reaction (56.1%), hypertension (48.5%), and diarrhea (40.9%)52.  In the 


 
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RESORCE study, the most common grade ≥3 adverse events associated with regorafenib were 
hypertension (15%), hand-foot skin reaction (13%), fatigue (9%), and diarrhea (3%)53. 
In response to the toxicities observed in the CORRECT and CONCUR trials, the randomized 
phase II Regorafenib Dose Optimization Study (ReDos) was conducted in 116 patients with 
refractory metastatic colorectal cancer in which a weekly dose escalation of regorafenib from 80 
mg oral daily, 120 mg oral daily, to a target of 160 mg oral daily during cycle one was compared 
with the standard dose of 160 mg oral daily56. In this study, 43% of patients in the dose-
escalation arm versus 24% of patients in the standard-dose arm completed two cycles of 
treatment and intended to initiate cycle three (p=0.0281). The most common grade 3+ adverse 
events occurring in the dose-escalation arm versus the standard-dose arm included fatigue (13% 
vs 17.7%), hand-foot skin reaction (14.8% vs 16.1%), abdominal pain (16.7% vs 6.5%), 
hypertension (7.4% vs 14.5%), increased alkaline phosphatase (5.6% vs 1.6%), and lymphopenia 
(7.4% vs 0%). 
A follow-up dose titration study of regorafenib in metastatic colorectal cancer used 120 mg as a 
starting dose during cycle one, and found similar efficacy compared to the standard 160 mg dose. 
In this trial of 60 patients, DCR was 36.7%, with a median PFS of 2.3 months (95% CI 1.8 to 
2.8)57. About 42% (25/60) of patients needed a dose reduction to 80 mg due to adverse events, 
and that dose reduction was needed in 10% (6/60) of patients at the first cycle. Overall grade 3-4 
adverse events were observed in 55% (33/60) of patients. 
Toxicity in Lung Cancer Studies: 
Regorafenib at 100 mg oral daily dosed continuously had similar side effects in 23 NSCLC 
patients54.  Regorafenib was relatively well-tolerated in NSCLC patients, with 
treatment-emergent study drug-related adverse events including 35% hand-foot skin reaction, 
30% pain in extremity, 26% rash/desquamation, 22% hypothyroidism, 17% each of nausea, 
hypertension, dry skin, neuropathy, fatigue, and 13% each of muscular pain, mucositis, anorexia, 
voice changes, diarrhea, and 9% each of low platelets, vomiting, hypophosphatemia, mucositis 
on clinical exam, constipation, elevated amylase, taste alteration.  Grade 3 adverse events 
included 3 hand-foot skin reactions, 1 hypertension, 1 sensory neuropathy, 1 diarrhea, 1 low 
platelets, and 2 hypophosphatemias.  Five out of the 23 patients had dose interruptions, while 
only 2 out of 23 had dose reductions. 
Additional Clinical Safety Information from Package Insert (revision 04/2017) (in addition, 
please Refer to the Investigator’s Brochure): 
The frequency of adverse events comes from the large gastrointestinal studies outlined below. 
Most Common Adverse Events: In randomized placebo-controlled trials (CORRECT, GRID, 
RESORCE and CONCUR), the most frequently observed adverse drug reactions (≥20%) in 
patients receiving regorafenib are pain (including gastrointestinal and abdominal pain), HFSR, 
asthenia/fatigue, diarrhea, decreased appetite/food intake, hypertension, infection, dysphonia, 
hyperbilirubinemia, fever, mucositis, weight loss, rash, and nausea. 
Most Common Serious Adverse Events: The most serious adverse reactions in patients receiving 
regorafenib are hepatotoxicity, hemorrhage, and gastrointestinal perforation. 
Hepatotoxicity: Severe drug-induced liver injury with fatal outcome occurred in 
regorafenib-treated patients in clinical trials.  In most cases, liver dysfunction occurred within the 


 
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first 2 months of therapy and was characterized by a hepatocellular pattern of injury.  In the 
CORRECT study, fatal hepatic failure occurred in 1.6% of patients in the regorafenib arm and in 
0.4% of patients in the placebo arm, and all the patients with hepatic failure had metastatic 
disease in the liver.  In the GRID study, fatal hepatic failure occurred in 0.8% of patients in the 
regorafenib arm.  In the RESORCE study, there was no increase in the incidence of fatal hepatic 
failure as compared to placebo. 
Infections: Regorafenib caused an increased risk of infections.  The overall incidence of infection 
(Grades 1-5) was higher (32% vs.  17%) in 1142 regorafenib-treated patients as compared to the 
control arm in randomized placebo-controlled trials.  The incidence of grade 3 or greater 
infections in regorafenib treated patients was 9%.  The most common infections were urinary 
tract infections (5.7%), nasopharyngitis (4.0%), mucocutaneous and systemic fungal infections 
(3.3%) and pneumonia (2.6%).  Fatal outcomes caused by infection occurred more often in 
patients treated with regorafenib (1.0%) as compared to patients receiving placebo (0.3%); the 
most common fatal infections were respiratory (0.6% in regorafenib-treated patients vs 0.2% in 
patients receiving placebo). 
Hemorrhage: Regorafenib caused an increased incidence of hemorrhage in clinical trials.  The 
overall incidence (Grades 1-5) was 18.2% in 1142 patients treated with regorafenib and 9.5% in 
patients receiving placebo in randomized, placebo-controlled trials.  The incidence of grade 3 or 
greater hemorrhage in patients treated with regorafenib was 3.0%.  The incidence of fatal 
hemorrhagic events was 0.7%, involving the central nervous system or the respiratory, 
gastrointestinal, or genitourinary tracts.   
Dermatologic Toxicity: In randomized, placebo-controlled trials, adverse skin reactions occurred 
in 71.9% of patients in the regorafenib arm and in 25.5% of patients in the placebo arm, 
including hand-foot skin reaction (HFSR) also known as palmar-plantar erythrodysesthesia 
syndrome (PPES), and severe rash requiring dose modification.  In the randomized, 
placebo-controlled trials, the overall incidence of HFSR was higher in 1142 regorafenib-treated 
patients (53%) than in the placebo-treated patients (8%).  Most cases of HFSR in 
regorafenib-treated patients appeared during the first cycle of treatment.  The incidences of 
Grade 3 HFSR (16% versus <1%), Grade 3 rash (3% versus <1%), serious adverse reactions of 
erythema multiforme (<0.1% vs.  0%) and Stevens-Johnson Syndrome (<0.1% vs.  0%) were 
also higher in regorafenib-treated patients.  Across all trials, a higher incidence of HFSR was 
observed in Asian patients treated with regorafenib (all grades: 72%; Grade 3: 18%).  Toxic 
epidermal necrolysis occurred in 0.02% of 4518 regorafenib-treated patients across all clinical 
trials of regorafenib administered as a single agent. 
Hypertension: In randomized, placebo-controlled trials, hypertensive crisis occurred in 0.2% of 
patients in the regorafenib arms and in none of the patients in the placebo arms.  Regorafenib 
caused an increased incidence of hypertension (30% versus 8% in CORRECT, 59% versus 27% 
in GRID, and 31% versus 6% in RESORCE).  The onset of hypertension occurred during the 
first cycle of treatment in most patients who developed hypertension (67% in randomized, 
placebo-controlled trials).   
Elevated Lipase: Regorafenib increased lipase levels in 9.2% (46/500) of treated patients in the 
CORRECT study, 1.8% (9/500) of patients to a Grade 3 level, and 0.4% (2/500) of patients to a 
Grade 4 level.  Regorafenib increased lipase levels in 10.6% (14/132) of treated patients in the 
GRID study, 0% of patients to a Grade 3 level, and 0.8% (1/132) of patients to a Grade 4 level.   


 
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Cardiac Ischemia and Infarction: Regorafenib increased the incidence of myocardial ischemia 
and infarction (0.9% vs 0.2%) in randomized placebo-controlled trials.   
Reversible Posterior Leukoencephalopathy Syndrome (RPLS, also known as posterior reversible 
encephalopathy syndrome): RPLS occurred in one of 4800 regorafenib-treated patients across all 
clinical trials.   
Gastrointestinal Perforation or Fistula: Gastrointestinal perforation occurred in 0.6% of 4518 
patients treated with regorafenib across all clinical trials of regorafenib administered as a single 
agent; this included eight fatal events.  Gastrointestinal fistula occurred in 0.8% of patients 
treated with regorafenib and 0.2% of patients in placebo arm across randomized, 
placebo-controlled trials. 
Wound Healing: No formal studies of the effect of regorafenib on wound healing have been 
conducted, although vascular endothelial growth factor receptor (VEGFR) inhibitors such as 
regorafenib can impair wound healing. 
Specific Populations: 
Pregnant Women: Based on animal studies and its mechanism of action, regorafenib can 
cause fetal harm when administered to a pregnant woman.  There are no available data on 
regorafenib use in pregnant women.  Regorafenib was embryolethal and teratogenic in rats 
and rabbits at exposures lower than human exposures at the recommended dose, with 
increased incidences of cardiovascular, genitourinary, and skeletal malformations. 
Lactation: There are no data on the presence of regorafenib or its metabolites in human milk, 
the effects of regorafenib on the breastfed infant, or on milk production.  In rats, regorafenib 
and its metabolites are excreted in milk. 
Females and Males of Reproductive Potential: There are no data on the effect of regorafenib 
on human fertility.  Results from animal studies indicate that regorafenib can impair male 
and female fertility. 
Geriatric Patients: Of the 1142 regorafenib-treated patients enrolled in randomized, 
placebo-controlled trials, 40% were 65 years of age and over, while 10% were 75 and over.  
No overall differences in efficacy were observed between these patients and younger 
patients.  There was an increased incidence of Grade 3 hypertension (18% versus 9%) in the 
placebo-controlled trials among regorafenib-treated patients 65 years of age and older as 
compared to younger patients.  In addition, one Grade 4 hypertension event has been reported 
in the 65 years and older age group and none in the younger age group. 
Hepatic and Renal Impairment: Regorafenib does not require dose adjustment for mild or 
moderate hepatic impairment (Child-Pugh Class A or B) or for mild, moderate, or severe 
renal impairment.  However, the investigator should refer to the eligibility (Sections 3.1 and 
3.2) and adverse event management section (Section 7) for protocol requirements.   
Race: Based on pooled data from three placebo-controlled trials (the CORRECT, CONCUR, 
and GRID studies), a higher incidence of HFSR and liver function test abnormalities 
occurred in Asian patients treated with regorafenib as compared with Whites. 


 
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2.2.1.4 Regorafenib Pharmacokinetics, Metabolism, Major Route of Elimination, and 
Potential Drug Interactions 
Information in this section was obtained from regorafenib package insert v.4-2017.  Please see 
Investigator’s Brochure for more information. 
Pharmacokinetics:  
Absorption: After a single 160 mg dose of regorafenib in patients with advanced solid tumors, 
regorafenib reaches a geometric mean peak plasma level (Cmax) of 2.5 μg/mL at a median time 
of 4 hours and a geometric mean area under the plasma concentration vs.  time curve (AUC) of 
70.4 μg*h/mL.  The AUC of regorafenib at steady-state increases less than dose proportionally at 
doses greater than 60 mg.  At steady-state, regorafenib reaches a geometric mean Cmax of 3.9 
μg/mL and a geometric mean AUC of 58.3 μg*h/mL.  The coefficient of variation of AUC and 
Cmax is between 35% and 44%.  The mean relative bioavailability of tablets compared to an oral 
solution is 69% to 83%. 
In a food-effect study, 24 healthy men received a single 160 mg dose of regorafenib on three 
separate occasions: under a fasted state, with a high-fat meal and with a low-fat meal.  A high-fat 
meal (945 calories and 54.6 g fat) increased the mean AUC of regorafenib by 48% and decreased 
the mean AUC of the M-2 and M-5 metabolites by 20% and 51%, respectively, as compared to 
the fasted state.  A low-fat meal (319 calories and 8.2 g fat) increased the mean AUC of 
regorafenib, M-2 and M-5 by 36%, 40% and 23%, respectively as compared to fasted conditions.  
Regorafenib was administered with a low-fat meal in the CORRECT and GRID studies. 
Distribution: Regorafenib undergoes enterohepatic circulation with multiple plasma 
concentration peaks observed across the 24-hour dosing interval.  Regorafenib is highly bound 
(99.5%) to human plasma proteins. 
Metabolism: Regorafenib is metabolized by CYP3A4 and UGT1A9.  The main circulating 
metabolites of regorafenib measured at steady-state in human plasma are M-2 (N-oxide) and M-5 
(N-oxide and N-desmethyl).  Both metabolites have similar in vitro pharmacological activity and 
steady-state concentrations as regorafenib.  M-2 and M-5 are highly protein bound (99.8% and 
99.95%, respectively). 
• Elimination: Following a single 160 mg oral dose of regorafenib, the geometric mean 
(minimum to maximum) elimination half-lives for regorafenib and the M-2 metabolite in 
plasma are 28 hours (14 to 58 hours) and 25 hours (14 to 32 hours), respectively.  M-5 
has a longer mean (minimum to maximum) elimination half-life of 51 hours (32 to 70 
hours). 
• Excretion: Approximately 71% of a radiolabeled dose was excreted in feces (47% as 
parent compound, 24% as metabolites) and 19% of the dose was excreted in urine (17% 
as glucuronides) within 12 days after administration of a radiolabeled oral solution at a 
dose of 120 mg. 
Drug Interactions: 
Extracted directly from package insert v.4-2017.  Please refer to Investigator’s Brochure for 
more information.  Please refer to section 4.1 for contraindicated medications while on study or 
medications that should be used with caution. 


 
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In vitro studies suggested that regorafenib is an inhibitor of CYP2C8, CYP2C9, CYP2B6, 
CYP3A4 and CYP2C19; M-2 is an inhibitor of CYP2C9, CYP2C8, CYP3A4 and CYP2D6, and 
M-5 is an inhibitor of CYP2C8.  In vitro studies suggested that regorafenib is not an inducer of 
CYP1A2, CYP2B6, CYP2C19, and CYP3A4 enzyme activity.  Relevant drug interactions are 
listed below. 
• Strong CYP3A4 Inducers: Co-administration of a strong CYP3A4 inducer with 
regorafenib decreased the plasma concentrations of regorafenib, increased the plasma 
concentrations of the active metabolite M-5, and resulted in no change in the plasma 
concentrations of the active metabolite M-2, and may lead to decreased efficacy. 
• Strong CYP3A4 Inhibitors: Co-administration of a strong CYP3A4 inhibitor with 
regorafenib increased the plasma concentrations of regorafenib and decreased the plasma 
concentrations of the active metabolites M-2 and M-5, and may lead to increased toxicity. 
• Breast Cancer Resistance Protein (BCRP) Substrates: Co-administration of regorafenib 
with a BCRP substrate increased the plasma concentrations of the BCRP substrate. 
2.2.1.5 Regorafenib Rationale for the Starting Dose and Regimen Chosen 
Regorafenib is FDA-approved at a dose of 160 mg (four 40-mg tablets) orally once daily for the 
first 21 days of each 28-day cycle for metastatic colorectal cancer patients, gastrointestinal 
stromal tumor patients, and hepatocellular carcinoma patients.  The drug has been evaluated 
previously in patients with NSCLC without known KRAS mutations at doses of 100 mg daily 
continuously, and had expected toxicity with few dose modifications required54. Since 
regorafenib has not been investigated in combination with low-dose oral methotrexate, there is 
potential for overlapping toxicity (gastrointestinal, liver, and skin). Frequent dose modifications 
required of single agent regorafenib at the 160 mg dose based on prior studies (i.e., CORRECT 
and GRID) have resulted in efforts to optimize dosing strategies when initiating regorafenib. 
Among these, a weekly dose escalation (REDOS) has demonstrated improvements in 
continuation rates and a trend towards improved overall survival56. Based on these data, 
regorafenib will be administered at an initial dose of 80 mg oral daily 3 weeks on/1 week off of a 
28-day cycle. Beginning in Cycle 2, patients may dose escalate to a target dose of 120 mg (same 
schedule of 3 weeks on/1 week off of 28-day cycle) according to strict criteria, including no 
evidence of significant drug-related toxicities (SDRT), defined as any event that would require a 
dose modification of regorafenib (i.e., interruption only, reduction only, or interruption followed 
by reduction) according to the guidelines/tables in Section 6.2.1 (regorafenib toxicities) and 
Section 6.2.3 (overlapping regorafenib and methotrexate toxicities). 
2.2.2  Methotrexate 
Please see Methotrexate Investigational Brochure58 (Generic, Mylan Pharmaceuticals) for 
further details. 
2.2.2.1 Methotrexate Mechanism of Action and Pre-Clinical Studies in Lung Cancer 
Methotrexate (4-amino-10-methyl-folic acid) is an anti-folate that is frequently used in the 
treatment of head and neck cancers, leukemia, and lymphoma.  In smaller doses, it is a common 
immunomodulatory agent used to treat autoimmune diseases, such as rheumatoid arthritis.  
Methotrexate acts as a competitive inhibitor of the enzyme dihydrofolate reductase (DHFR), 
which normally reduces dihydrofolate to tetrahydrofolate that is essential for purine nucleotide 


 
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and thymidylate synthesis.  As a result, methotrexate disrupts DNA synthesis, causes cell-cycle 
arrest in the S phase, and ultimately leads to cellular apoptosis.   
Rapidly dividing cells are particularly sensitive to the effects of methotrexate.  These cells 
exhibit a higher rate of methotrexate uptake and lower rate of efflux compared to slow-growing 
and resting-state cells59.  Intracellularly, methotrexate binds with a much greater affinity to 
DHFR compared to the endogenous dihydrofolate substrate60, and is converted to its 
polyglutamated metabolite by folylpolyglutamyl synthetase (FPGS).  Methotrexate 
polyglutamates (with up to 8 glutamate residues) inhibit DHFR with at least as much potency as 
the monoglutamate form, and function additionally as potent antagonists of thymidylate 
synthase, AICAR transformylase, and GAR transformylase to further deplete the supply of 
reduced folates61.  Furthermore, pre-clinical studies have shown that methotrexate may interfere 
with single-carbon transfer reactions, generate reactive oxygen species, and engage in other 
processes that contribute to its cytotoxicity60.  One key aspect of methotrexate function that 
makes it appealing as a chemotherapeutic agent is its selectivity for malignant cells that are 
actively proliferating.  This selectivity may be due, at least in part, to the greater accumulation of 
methotrexate polyglutamates in tumor cells compared to normal human tissue62,63.   
Pre-clinical studies of methotrexate in lung cancer are few in number, with the majority of the 
drug’s pre-clinical work having been conducted in relation to leukemia and lymphoma.  
However, a couple of in vitro studies in the 1980s examined its properties in small cell lung 
cancer, which described a general association between methotrexate polyglutamate retention and 
drug sensitivity64,65.  In 1991, another in vitro study explored the combination effects of 
methotrexate and 5-fluorouracil in two human NSCLC cell lines (NCI-H23 and NCI-358), 
revealing an interaction that was highly schedule-dependent in terms of whether it was 
antagonistic or cytotoxic66.  Over the past decade, a series of independent studies have evaluated 
methotrexate action in the A549 cell line (notably a KRAS-mutated NSCLC cell line), which 
together have highlighted its strong anti-proliferative activity and induction of cellular 
differentiation and apoptosis along specific molecular pathways67-69.  In 2013, the antagonistic 
relationship between methotrexate and aspirin was demonstrated in two human lung 
adenocarcinoma cell lines, CL1-0 and A54970.  Methotrexate alone reduced cell viability by 
75%, whereas combination methotrexate and aspirin treatment resulted in a 46% decrease in cell 
numbers.  The addition of aspirin also reversed the accumulation of CL1-0 cells in the S phase 
and prevented methotrexate-mediated apoptosis, but did not affect DHFR levels or function. 
2.2.2.2 Methotrexate Clinical Trials in Lung Cancer 
Although methotrexate is not commonly used for the treatment of lung cancer, it was studied 
extensively from the 1970s to 1980s with some evidence of activity based on cruder chest x-ray 
imaging and response criteria.   
One of the first studies in lung cancer involved "low" doses of methotrexate (80 to 800 mg) and 
high doses of methotrexate (3 to 18 g), with 7 out of 8 responses (6/6 patients with squamous cell 
carcinoma and 1/2 patients with anaplastic carcinoma) seen at the higher dose71.  In another 
study of high-dose methotrexate (6 to 10 g/m²) administered in patients with NSCLC, there were 
2 responses seen, lasting 13 and 17 weeks72.  Another study examined the effect of a 30-hour 
continuous IV infusion of methotrexate at 1.5 g/m² compared to a dose escalation from 
1.5 to 12 g/m² of IV methotrexate over 6 hours, both followed by leucovorin rescue, with 3/17 
partial responses among the patients treated with 30-hour continuous methotrexate73.  Another 


 
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phase II study of high-dose methotrexate with citrovorum rescue resulted in one patient 
responding with a partial regression of tumor out of 28 patients with NSCLC, suggesting 
response rate of less than 20%74.  Methotrexate has also been studied in small cell lung cancer 
with variable activity.75,76 
The following studies at least included doses that more closely approximate the dosing schedule 
of this protocol (i.e., much lower doses than studies listed above).  There was a retrospective 
study of 195 patients treated with methotrexate using a variety of dosing schedules 
(0.2 to 0.9 mg/kg oral twice a week, 5 to 10 mg/kg IV every 3 weeks)77.  Of the 29 patients with 
lung adenocarcinoma, 5 had a response, and a median OS of 8 months.  There was a prospective 
randomized study that compared twice weekly IM (intramuscular) injections of methotrexate at a 
high dose of 0.6 mg/kg or a low dose 0.2 mg/kg with placebo in 239 lung cancer patients78.  The 
investigators found an ORR of 21% in patients with measurable disease receiving the high dose 
(N = 48) and an ORR of 11% in patients receiving the low dose (N = 37).  Patients with a 
response also had a longer survival.  Together these data suggest some but limited efficacy of 
single agent methotrexate in lung cancer.   
2.2.2.3 Methotrexate Clinical Toxicology 
In a lung cancer study with similar dose used in our trial of methotrexate IM twice weekly 0.2 
mg/kg and 0.6 mg/kg, there was a leukopenia rate (<4500/mm3) of 26% at the low-dose and 53% 
at the high-dose, thrombocytopenia (< 100,000/mm3) rate of 21% at the high-dose and 13% at the 
low-dose, oral ulcerations of 50% at the high-dose and 14% at the low-dose, and diarrhea and 
vomiting of 18% at the high-dose and 26% at the low dose78.   
In general, the most common adverse reactions following methotrexate administration include 
ulcerative stomatitis, leukopenia, nausea, abdominal distress, malaise, fatigue, fever and chills, 
dizziness, and decreased resistance to infection.   
The toxicities below emphasize rheumatologic related toxicity since doses in this study 
more approximate rheumatologic oral methotrexate dosing. 
At rheumatologic dosing of methotrexate (low dose oral (7.5 to 15 mg/week) pulse methotrexate 
for rheumatoid arthritis, most common adverse events include: 
• Incidence Greater Than 10%: Elevated liver function tests 15%, nausea/vomiting 10%. 
• Incidence 3% to 10%: Stomatitis, thrombocytopenia, (platelet count less than 
100,000/mm). 
• Incidence 1% to 3%: Rash/pruritus/dermatitis, diarrhea, alopecia, leukopenia (WBC less 
than 3000/mm3), pancytopenia, dizziness. 
• Incidence of interstitial pneumonitis 1% 
This is similar also for psoriasis studies, which uses slightly higher doses of 25 mg weekly.  With 
the exception of alopecia, photosensitivity, and "burning of skin lesions" (each 3% to 10%), the 
adverse reaction rates in these reports were very similar to those in the rheumatoid arthritis 
studies. 


 
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Summary of Methotrexate Toxicity by Organ System: 
Gastrointestinal: Methotrexate can cause vomiting, diarrhea, or stomatitis occur, which may 
result in dehydration. 
Hematologic: Methotrexate can suppress hematopoiesis and cause anemia, aplastic anemia, 
pancytopenia, leukopenia, neutropenia, and thrombocytopenia.  In clinical trials in rheumatoid 
arthritis (n=128), leukopenia (WBC <3000/mm3) was seen in 2 patients, thrombocytopenia 
(platelets <100,000/mm3) in 6 patients, and pancytopenia in 2 patients. 
Hepatic: Methotrexate may cause acute (elevated transaminases) and chronic (fibrosis and 
cirrhosis) hepatotoxicity.  Chronic toxicity is potentially fatal, and generally has occurred after 
prolonged use (about 2+ years) and after a total dose of at least 1.5 grams.  In studies in psoriatic 
patients, hepatotoxicity was found to be a function of total cumulative dose, and was enhanced 
by alcoholism, obesity, diabetes, and advanced age.  An accurate incidence rate has not been 
determined; the rate of progression and reversibility of lesions is not known.  Persistent 
abnormalities in liver function tests may precede appearance of fibrosis or cirrhosis in this 
rheumatoid arthritis patients.  There is a combined reported experience in 217 rheumatoid 
arthritis patients with liver biopsies both before and during treatment (after a cumulative dose of 
at least 1.5 g) and in 714 patients with a biopsy only during treatment.  There are 64 (7%) cases 
of fibrosis and 1 (0.1%) case of cirrhosis.  Of the 64 cases of fibrosis, 60 were deemed mild. 
Infection or Immunologic Studies: Immunization may be ineffective when given during 
methotrexate therapy.  Hypogammaglobulinemia has been reported rarely.  Potentially fatal 
opportunistic infections, especially Pneumocystis carinii pneumonia, may occur with 
methotrexate therapy.   
Pulmonary: Pulmonary symptoms (especially a dry non-productive cough) or a non-specific 
pneumonitis occurring during methotrexate therapy may develop.  Although clinically variable, 
the typical patient with methotrexate-induced lung disease presents with fever, cough, dyspnea, 
hypoxemia, and an infiltrate on chest X-ray.  This can occur at all dosages. 
Renal: Methotrexate may cause renal damage that may lead to acute renal failure.  
Nephrotoxicity is due primarily to the precipitation of methotrexate and 7-hydroxymethotrexate 
in the renal tubules. 
Skin: Severe, occasionally fatal, dermatologic reactions, including toxic epidermal necrolysis, 
Stevens-Johnson syndrome, exfoliative dermatitis, skin necrosis, and erythema multiforme, have 
been reported in children and adults, within days of oral, intramuscular, intravenous, or 
intrathecal methotrexate administration.  Reactions were noted after single or multiple, low, 
intermediate or high doses of methotrexate in patients with neoplastic and non-neoplastic 
diseases.  Radiation dermatitis and sunburn may be "recalled" by the use of methotrexate. 
Specific Populations: 
• Pregnant Women: Methotrexate can cause fetal death or teratogenic effects when 
administered to a pregnant woman. 
• Lactation: Methotrexate has been detected in human breast milk, with the highest breast 
milk to plasma concentration ratio reached at 0.08:1.   


 
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2.2.2.4 Methotrexate Pharmacokinetics, Metabolism, Major Route of Elimination, and 
Potential Drug Interactions 
Pharmacokinetics 
Absorption: In adults, oral absorption of methotrexate is rapid and dose-dependent, and occurs 
primarily through the proton-coupled folate transporter in the small intestine.  Peak serum levels 
are typically reached within 1-2 hours.  At doses of 30 mg/m2 or less, methotrexate is 
well-absorbed, giving a mean bioavailability of about 60%.  However, at doses greater than 
80 mg/m2 in adults, and greater than 40 mg/m2 in children, absorption is significantly less, 
possibly due to saturation.  Administration with food may delay absorption and reduce peak 
concentrations.   
Distribution: About 50% of methotrexate in serum is protein-bound.  Laboratory studies have 
shown that it may be displaced from plasma albumin by sulfonamides, salicylates, tetracyclines, 
chloramphenicol, and phenytoin.  Methotrexate does not penetrate the blood-cerebrospinal fluid 
barrier in therapeutic amounts when given orally or parenterally. 
Half-life: The plasma half-life of high-dose methotrexate varies from 8-15 hours, whereas the 
half-life for low-dose methotrexate for the treatment of rheumatoid arthritis, psoriasis, or 
low-dose antineoplastic therapy (less than 30 mg/m2) ranges from 3-10 hours.   
Metabolism:  Cellular uptake of methotrexate occurs via active transport mediated by the 
reduced folate carrier (RFC) family, folate transporter 1 (FOLT, also known as RFC1 encoded 
by SLC19A1) in particular.  The RFC system transports reduced folates and antifolates like 
methotrexate much more efficiently compared to the transport of folic acid (Kt = 0.7 to 6.0 
µmol/L versus Kt = 200 µmol/L)79,80.  Additional cellular influx is mediated by the α and β 
isoforms of the folate receptor and the proton-coupled folate transporter.  In general, the level of 
cellular proliferation and activity as well as the extracellular temperature and pH influence the 
rate of methotrexate influx into the cells. 
After absorption, methotrexate undergoes hepatic and intracellular metabolism to polyglutamated 
forms, which can be converted back to methotrexate by hydrolase enzymes.  Methotrexate may 
bind to and inhibit DHFR or undergo polyglutamation by FPGS.  Polyglutamation of folates and 
antifolates facilitates their intracellular retention, extends the substrate half-life, and occurs as a 
typical process in most tumors63,81.  Polyglutamation of methotrexate occurs progressively over 
several hours.  After 24 hours, more than 80% of intracellular methotrexate appears in its 
polyglutamated form82.  Methotrexate deglutamation is catalyzed by the lysosomal γ-glutamyl 
hydrolase.  A number of ATP-binding cassette transporters, including ABCC1-ABCC5 and 
ABCG1/2, and the breast cancer resistance protein (BCRP) mediate methotrexate exportation 
from cells.  However, methotrexate polyglutamates with more than three glutamate residues are 
not substrates for these transporters, and are not typically exported.  As a result, the retention and 
accumulation of methotrexate polyglutamates provides sustained inhibition of DHFR long after 
blood levels have decreased61.   
One metabolite of methotrexate, 7-OH-methotrexate, is produced in the liver by the enzyme 
aldehyde oxidase, and is secreted into bile.  7-OH-methotrexate may accumulate in plasma, 
reaching peak levels between 24-48 hours following high-dose methotrexate administration, and 
is readily excreted in urine.  Notably, intracellular 7-OH-methotrexate polyglutamates inhibit 
thymidylate synthase and AICAR transformylase with a similar potency as methotrexate 


 
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polyglutamates.  7-OH-methotrexate itself may also bind to DHFR, but acts weakly as an 
inhibitor compared to methotrexate.  DAMPA is another minor metabolite of methotrexate that is 
produced in the gastrointestinal tract by bacterial carboxypeptidases, and by hydrolysis of 
methotrexate by the rescue agent carboxypeptidase G2.  DAMPA is considered an inactive 
metabolite of methotrexate since it does not effectively inhibit DHFR.   
Elimination: Methotrexate is excreted primarily through the kidneys, by both glomerular 
filtration and active tubular secretion.  Renal excretion of single daily doses ranges from 55-88% 
or higher within 24 hours.  Biliary excretion is limited, and accounts for less than 10% of the 
administered dose.  Elimination may be non-linear due to saturation of renal tubular 
reabsorption, and has been observed in patients with psoriasis at doses between 7.5 to 30 mg.  
Impaired renal function can rapidly increase methotrexate serum levels, which may remain 
elevated for extended periods.  In general, methotrexate clearance rates are widely variable, and 
usually decrease at higher doses.  Delayed drug clearance, either through impaired renal 
function, a third space effusion, or from other causes, is a major contributor to methotrexate 
toxicity.   
Drug Interactions:  
• Nonsteroidal Anti-inflammatory Drugs (NSAIDS): Concomitant administration of some 
NSAIDs with high dose methotrexate therapy has been reported to elevate and prolong 
serum methotrexate levels, resulting in deaths from severe hematologic and 
gastrointestinal toxicity.  Given potential of toxicity, caution should also be used when 
NSAIDs and salicylates are administered concomitantly with lower doses of methotrexate 
such as in this study.  These drugs have been reported to reduce the tubular secretion of 
methotrexate in an animal model and may enhance its toxicity.  Despite the potential 
interactions, studies of methotrexate in patients with rheumatoid arthritis have usually 
included concurrent use of constant dosage regimens of NSAIDs, without apparent 
problems.  It should be appreciated, however, that the doses used in rheumatoid arthritis 
(7.5 to 20 mg/week) are somewhat lower than those used in psoriasis and that larger 
doses such as in this study could lead to unexpected toxicity. 
• Drugs Highly Bound to Plasma Proteins: Methotrexate is partially bound to serum 
albumin, and toxicity may be increased because of displacement by certain drugs, such as 
salicylates, tetracyclines, chloramphenicol, phenylbutazone, phenytoin, and 
sulfonamides.   
• Probenecid: Renal tubular transport is also diminished by probenecid. 
• Oral Antibiotics: Oral antibiotics such as tetracycline, chloramphenicol, and 
nonabsorbable broad spectrum antibiotics, may decrease intestinal absorption of 
methotrexate or interfere with the enterohepatic circulation by inhibiting bowel flora and 
suppressing metabolism of the drug by bacteria. 
• Penicillins: Penicillins may reduce the renal clearance of methotrexate; increased serum 
concentrations of methotrexate with concomitant hematologic and gastrointestinal 
toxicity have been observed with methotrexate. 
• Theophylline: Methotrexate may decrease the clearance of theophylline.   


 
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• Trimethoprim/sulfamethoxazole: Trimethoprim/sulfamethoxazole has been reported 
rarely to increase bone marrow suppression in patients receiving methotrexate, probably 
by an additive antifolate effect. 
2.2.2.5 Methotrexate Rationale for the Starting Dose and Regimen Chosen 
Previous studies in patients with NSCLC have evaluated single-agent methotrexate at doses 
approximating 12 to 36 mg intramuscularly twice weekly, which produced responses and were 
well-tolerated.  In vitro cell line studies, discussed in rationale Section 2.3, suggest our target 
Cmax should be achieved with the doses of methotrexate used in this study.  The dosing 
frequency of methotrexate twice weekly provides reasonable exposure based on pharmacokinetic 
(PK) data during regorafenib administration, as methotrexate is hypothesized to enhance the 
activity of regorafenib.  Methotrexate is a known substrate of the BCRP efflux transporter in the 
intestinal epithelia with the end result of increasing bioavailability.  Methotrexate elimination is 
primarily via the kidneys where it is filtered but is potentially also excreted by the BCRP 
transporter.  Given that regorafenib impairs BCRP activity, methotrexate pharmacokinetics may 
be affected resulting in a) increased bioavailability and b) decreased renal clearance.  To 
determine the extent of this drug-drug interaction for this novel combination, abbreviated 
pharmacokinetic studies will be performed as detailed in the study calendar (section 9).  In 
addition, the methotrexate doses used in this study should provide an adequate therapeutic index 
despite this potential drug interaction given: 1) methotrexate dose is lower than standard doses 
used as a single agent for cancer therapy and, 2) methotrexate is generally at most 60% 
bioavailable when administered by mouth. An intrapatient weekly dose escalation of 
methotrexate will be performed as detailed in the study calendar, Section 9, with a target dose of 
20 mg oral twice weekly 3 weeks on/1 week off of a 28-day cycle. 
For clinicaltrials.gov compliance 
Regorafenib is a FDA approved drug for (1) metastatic colorectal cancer patients who have been 
previously treated with fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapy, an 
anti-VEGF therapy, and, if KRAS wild type, an anti-EGFR therapy and (2) locally advanced, 
unresectable or metastatic gastrointestinal stromal tumor (GIST) who have been previously 
treated with imatinib mesylate and sunitinib malate.  Regorafenib is not approved for the 
indication studied in this protocol.  Methotrexate is used as anti-cancer therapies and 
autoimmune diseases such as rheumatoid arthritis but not for the indication studied in this 
protocol.  Regorafenib and methotrexate as a combination therapy is not FDA approved for any 
indication. 
The protocol director will submit clinical trial information as required using ClinicalTrials.gov to 
fulfill the requirements of FDAAA 801. 
2.3 
Rationale 
Regorafenib 
As detailed in Section 2.2.1, regorafenib49 has been studied in lung cancer as a single agent and 
also in combination with cisplatin/pemetrexed chemotherapy83,84.  In the single agent study, 
regorafenib achieved a high disease control rate (DCR) of 83% (n=15/18) in heavily pre-treated 
patients83.  The median progression free survival (PFS) was 84 days.  This trial studies the 
combination of regorafenib and methotrexate in a molecularly defined subset of lung 


 
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cancer- KRAS mutated NSCLC.  Despite the modest activity of regorafenib in an unselected 
NSCLC population, there were no tumors with known KRAS mutations represented.  We 
hypothesize that regorafenib will be more effective in NSCLC patients whose tumors harbor 
a KRAS mutation based on computational modeling (outlined below).   
In addition, regorafenib was also studied in combination with cisplatin and pemetrexed for the first 
line treatment of metastatic NSCLC, with an objective response rate (ORR) of 55.6%, (N=5/9), 
median PFS of 7 months, and overall survival (OS) of 13.1 months to 56.7 months .11 Three 
patients had a KRAS mutation, of whom two had a partial response and all had a decrease in target 
lesions.  In addition, the patient with the second longest PFS and OS in this study had a KRAS 
mutation.  There is a suggestion that regorafenib in combination with platinum-pemetrexed 
chemotherapy may have enhanced activity in KRAS mutated NSCLC.  Pemetrexed is 
mechanistically different from methotrexate but it is also an anti-folate chemotherapy.  
Based on this data, we hypothesize that regorafenib in combination with anti-folate-based 
methotrexate therapy will result in improved clinical activity in patients with KRAS mutated 
NSCLC.   
The data of regorafenib in NSCLC builds upon the data of sorafenib in NSCLC, particularly in the 
KRAS mutated subgroup.  Regorafenib has a different structure from sorafenib by the addition of 
a fluorine atom in the center phenyl ring and has similar targets as sorafenib but is considerably 
more potent85.  Sorafenib has clinical activity in KRAS mutated NSCLC2,86,87.  Sorafenib was the 
most active agent in the BATTLE trial (Biomarker-Integrated Targeted Therapy Study) and it has 
been incorporated as one of the treatment arms for BATTLE-286,88.  In a phase II trial of sorafenib 
in heavily pretreated KRAS mutated NSCLC patients, the ORR was 10.5%, the DCR was 52.6%, 
the median PFS was 2.3 months (95% CI 1.6-3.0), and the median OS was 5.3 months (95% CI 
3.6-7.0)2.  In addition, other vascular endothelial growth factor-receptor (VEGFR) oral tyrosine 
kinase inhibitors (TKI) are useful for the treatment of lung cancer such as nintedanib, which is 
approved in Europe.89 PFS was significantly improved in the docetaxel plus nintedanib group 
compared with the docetaxel plus placebo group (median 3.4 vs 2.7 months; hazard ratio 0.79 
[95% CI 0.68-0.92], p=0.0019).  In summary, there is a role for VEGFR inhibition in lung 
cancer.  Sorafenib, a VEGFR inhibitor, has single agent activity in KRAS mutated NSCLC.  
Based on this data, we hypothesize that a more potent version of sorafenib, regorafenib, will 
have enhanced activity in KRAS mutated NSCLC, when combined with methotrexate.   
Methotrexate 
As detailed in Section 2.2.2, although methotrexate is not commonly used for the treatment of 
NSCLC, it was studied extensively from the 1970s to 1980s with some evidence of activity based 
on cruder chest x-ray imaging and response criteria.  There was a retrospective study of 195 
patients treated with methotrexate using a variety of dosing schedules, including 0.2 to 0.9 mg/kg 
oral twice a week, for which 5 of 29 patients with lung adenocarcinoma had a response77.  There 
was also prospective randomized study comparing twice weekly IM injections of methotrexate at 
a high dose of 0.6 mg/kg or a low dose 0.2 mg/kg with placebo in 239 lung cancer patients, with 
an ORR of 21% in patients receiving the high dose and an ORR of 11% in patients receiving the 
low dose and response was associated longer survival78.  Single agent oral methotrexate in an 
average patient of 60 kg at doses ranging from 12 to 36 mg intramuscular twice weekly 
produced responses in patients with NSCLC.  Molecular status of KRAS was not known at 
this time. 


 
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Repurposing Methotrexate in Combination with Regorafenib for the Treatment of KRAS 
Mutated NSCLC based on Synergy in a Computational Model and Cell Lines 
In an experimental proprietary simulation model by Cellworks which models millions of cancer 
pathway interactions at the genomic, transcriptional, and proteomic level simultaneously, 
regorafenib and methotrexate were found to be synergistic in KRAS mutated lung cancer cell lines.  
More details on the Cellworks simulation model and the methodology to identify the combination 
of regorafenib and methotrexate are detailed in Appendix F.  The simulation model prediction of 
synergy of this combination was confirmed in vitro in KRAS mutated cell lines (i.e., A549, H2122, 
H358).  The synergy at low doses of regorafenib (3.3 uM) and methotrexate (0.25 uM) was 
differential, with synergy only seen in KRAS mutated cell lines (i.e., H2122) but not KRAS wild 
type cell lines (i.e., CALU3) (Figure 2 of Appendix F).  With methotrexate at a very low 
concentration of 0.25 uM, there was a dose response with increasing concentrations of regorafenib 
from 1-10 uM.  Synergy with methotrexate was seen at doses of regorafenib as low as 1 uM.  The 
dose of oral methotrexate required for synergy with regorafenib is significantly lower than the dose 
traditionally used in the treatment of cancer, consistent with the repurposing of methotrexate for 
use in combination with regorafenib in a molecularly defined subset of KRAS mutated NSCLC.  
The target Cmax for methotrexate can be achieved with an oral dose as low as 7.5 mg90,91.  The 
Cmax of regorafenib from 1 to 10 uM can be achieved with doses of ≤ 100 mg given 
non-proportional pharmacokinetic increases83,92.  Based on preclinical in vitro cell line data, our 
target Cmax is at least 0.25 uM for methotrexate and this should be achieved with oral doses as 
low as 7.5 mg daily90.  Our target Cmax for regorafenib is ≥ 1 uM and this is easily achieved at 
the dose studied in this protocol at 120 mg83. 
The mechanism of the proposed synergy of regorafenib and methotrexate is outlined below and in 
Figure 1 of Appendix F.  Regorafenib inhibits RAF, which is downstream of activated KRAS.  
Methotrexate inhibits dihydrofolate reductase, which is involved in methionine, purine, and 
pyrimidine synthesis pathways, affecting the S-phase of the cell cycle.  One of the main converging 
nodes of synergy of this combination is proposed via SP193,94 and the transcription factor for 
dihydrofolate reductase.  Methotrexate also causes upregulation of DUSP6 and NF195,96, which 
are inhibitors of the RAF-RAS-ERK pathway.  It has been shown that KRAS mutated lung cancer 
cell lines have increased dependency on folate pathways for survival, and therefore, are more 
sensitive to anti-folate therapies like methotrexate and pemetrexed compared to KRAS wild-type 
lung cancer47.  Methotrexate has also been shown to decrease KRAS mRNA expression.   
The reason methotrexate was found to be more advantageous for combination with regorafenib 
than alternative anti-folate pemetrexed in the Cellworks proprietary simulation model is outlined 
below.  Although pemetrexed and methotrexate have the potential to target several enzymes in the 
folate pathway, methotrexate primarily inhibits dihydrofolate reductase while pemetrexed 
primarily inhibits thimidylate synthase97-100.  Via dihydrofolate reductase inhibition, methotrexate 
mainly works via s-adenosylmethionine and DNA methylation machinery while pemetrexed 
mainly works via pyrimidine synthesis pathway and also via the purine synthesis pathway at a 
higher concentration.  Methotrexate, unlike pemetrexed, also has a unique property of inhibiting 
isoprenylcysteine carboxyl methyltransferase, which is key regulator of prenylation, an important 
step for the functionality of RAS isoforms101,102.  Therefore, its effect will be specific for RAS 
mutant tumors. 


 
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Although not specifically examined in the Cellworks model, methotrexate may also have 
beneficial immunomodulatory effects.  Methotrexate effects may be prolonged more than the 
half-life (~ 3 hours) suggests due to accumulation of polyglutamate metabolites in tissues, which 
can take weeks to months to achieve steady state (6.2 weeks-139.8 weeks)103.  These may have 
lasting immunomodulatory effects that are beneficial.  For example, methotrexate inhibits 
polyamines (small organic cations) that are required for tumor growth104-106; methotrexate 
increases adenosine, which has pleiotropic effects and in some studies when interacting through 
A3 receptors, inhibits proliferation and promotes apoptosis in tumors106-108; methotrexate has been 
shown to decrease levels of interleukin-1 and tumor necrosis factor, which are involved in cancer 
progression106,109,110.  In addition, this more attractive oral combination of methotrexate and 
regorafenib is positioned for the 2nd/3rd line setting and beyond, and majority of patients will have 
already been treated with pemetrexed.  There is no published data that failure to pemetrexed would 
result in failure to methotrexate.  The purpose of methotrexate in this trial is to at low doses 
synergistically enhance the activity of regorafenib.   
In summary, the significant crosstalk of pathways explains the synergy of regorafenib and 
methotrexate in KRAS mutated NSCLC. Methotrexate is also the ideal anti-folate given 
ability of oral administration, direct impact on RAS via prenylation, and potential beneficial 
immunomodulatory effects. 
2.4 
Study Design 
This is a prospective open-label non-randomized single-arm treatment trial of regorafenib in 
combination with oral methotrexate for metastatic KRAS mutated non-squamous NSCLC 
patients who have received at least 1 systemic therapy, with a primary endpoint of progression 
free survival.   
2.5 
Correlative Studies Background 
2.5.1  Detecting Circulating Tumor DNA (ctDNA) and Tumor Mutations using CAPP-Seq 
Peripheral blood monitoring of cancer while on treatment is attractive.  CAncer Personalized 
Profiling by Deep Sequencing (CAPP-Seq) is a method to measure ctDNA using a selector of 
biotinylated DNA oligonucleotides that detect recurrent mutations in cancers111.  The initial 
design of the CAPP-Seq selector was created for NSCLC.  The initial selector targeted 521 exons 
and 13 introns from a total of 139 mutated genes, and could identify 96% of patients with 
NSCLC.  Using CAPP-Seq for noninvasive monitoring of cancer in the initial publication, had 
an impressive receiving operating characteristic (AUC 0.95), with a sensitivity of 85% and 
specificity of 96%.  The sensitivity was higher in tumors of more advanced stage, reaching 100% 
in stage II-IV tumors.  Newman et al (Diehn/Alizadeh labs, Stanford University, Stanford, CA) 
were able to correlate ctDNA levels with tumor volumes determined radiographically by PET 
and/or CT (R2 = 0.89, P = 0.0002).  ctDNA levels were also shown to fall dramatically in 
patients responding to chemotherapy and targeted therapeutics.  ctDNA was also helpful in 
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after radiotherapy is often difficult to interpret.  ctDNA was also useful in surveillance 
monitoring after curative intent therapy for early stage NSCLC.  In addition, ctDNA by 
CAPP-Seq has the ability to detect resistance mechanisms to oral targeted therapeutics.  For 
example, in 43 NSCLC patients treated with a 3rd generation EGFR inhibitor rociletinib, there 
were multiple resistance mechanisms detected with CAPP-Seq in almost half of the patients 
including MET, EGFR, PIK3CA, ERBB2, KRAS, and RB1 along with novel EGFR mutations 
(L798I and C797S)112.  Therefore, CAPP-Seq is also a robust platform to study resistance 
mechanisms. 
ctDNA as measured by CAPP-Seq technology may serve as a useful surrogate biomarker of 
clinical activity to regorafenib and methotrexate using baseline levels of ctDNA or change 
in levels of ctDNA longitudinally.  In this trial, we will measure ctDNA levels as surrogate 
biomarkers of response.  ctDNA may be able to distinguish at early timepoints which 
patients will benefit from the combination of regorafenib and methotrexate.  CAPP-Seq 
may also identify resistance mutations to this oral combination targeted therapy. 
2.5.2  Computational Simulation Model 
The Cellworks computational model is described in Section 2.3.  We will send available 
de-identified genomic data to Cellworks via secure encrypted communication.  Sources of 
genomic data may have been collected from blood, tissue, urine, or other body fluid (i.e., pleural 
fluid).  Genomic data may include copy number variation, targeted gene sequencing, whole 
exome sequencing, are whole genome sequencing.  The genomic data may have been generated 
previously for standard of care management of the patient.  In addition, de-identified genomic 
data from circulating tumor DNA may be shared for modeling.  Therefore, prediction of 
sensitivity to this therapy based on the patient's available genomic data, which may go beyond 
KRAS, can then potentially be correlated with clinical outcomes of the patient on study. 
3. 
PARTICIPANT SELECTION AND ENROLLMENT PROCEDURES 
3.1 
Inclusion Criteria  
In order to be eligible for participation in this trial, the patient must meet ALL of the following 
criteria (i.e., mark “yes” or “N/A” to all criteria): 
1. Histologic or cytologic confirmed diagnosis of non-squamous non-small cell lung cancer 
that is recurrent or metastatic. Adenosquamous is allowed provided the patient has 
confirmed adenocarcinoma component. 
2. Documentation of pathogenic KRAS mutation  
3. Previous receipt of at least one systemic therapy for recurrent or metastatic disease OR 
previous receipt of adjuvant systemic therapy within 6 months of enrollment.  There is no 
limit on number of prior therapies allowed.   
4. Prior systemic therapy must be completed at least 2 weeks prior to study treatment, with 
either improvement of clinically significant treatment-related toxicities to grade 0-1 OR 
stabilized to a new baseline.   


 
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5. Previously treated OR asymptomatic non-progressing < 1 cm untreated brain metastases 
are allowed 
6. Measurable disease based on RECIST version 1.1 criteria (Appendix B) 
7. Ability to understand and the willingness to sign a written informed consent document  
8. Age ≥ 18 years-old 
9. ECOG performance status of 0 or 1 (Appendix A) 
10. Adequate bone marrow, liver and renal function as assessed by the following laboratory 
requirements: 
a. Absolute neutrophil count (ANC) ≥ 1500/mm3 
b. Platelet count ≥ 100,000 /mm3 
c. Hemoglobin (Hb) ≥ 9 g/dL  
d. Serum creatinine ≤ 1.5x upper limit of normal (ULN) OR calculated 
(Cockcroft-Gault formula) or measured creatinine clearance ≥ 50 mL/min for 
patients with creatinine levels > 1.5x ULN 
e. Total bilirubin ≤ 1.5x ULN OR Direct bilirubin ≤ ULN for patients with total 
bilirubin levels > 1.5x ULN  
f. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3x ULN 
(≤ 5x ULN for patients with liver involvement of their cancer) 
11. Must be able to swallow and retain oral medication. 
12. Women patients of childbearing potential and men patients with women partners of 
childbearing potential must agree to use adequate contraception or agree to abstain from 
heterosexual activity beginning at the time of signing informed consent until at least 3 
months after the last dose of study treatment.  Post-menopausal women (defined as no 
menses for at least 1 year) and surgically sterilized women are not considered 
childbearing.   
3.2  
Exclusion Criteria 
In order to be eligible for participation in this trial, the patient must NOT meet the following 
criteria (i.e., mark “no” or “N/A” to all criteria): 
1. Previously treated with regorafenib  
2. Known allergy to regorafenib or methotrexate  
3. Currently receiving another systemic standard or investigational anti-cancer therapy.  
Prior investigational therapy must be completed within 4 half-lives (if known) or 2 
weeks, whichever is longer.  The maximal washout of investigational therapy will not 
exceed 4 weeks prior to study treatment.  Bone medications such as bisphosphonates and 
RANK ligand inhibitors permitted.   
4. Leptomeningeal disease as documented by CSF cytology. 
5. Clinically significant cardiovascular-related disease including: 


 
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a. Uncontrolled hypertension (systolic pressure >150 mm Hg or diastolic pressure 
> 90 mm Hg on repeated measurements that does not resolve prior to study 
treatment on C1D1 despite optimal medical management 
b. Congestive heart failure – New York Heart Association (NYHA) Class III or 
greater 
c. Active coronary artery disease (i.e., unstable or new onset angina within 3 months 
of study treatment; myocardial infarction within 6 months of study treatment) 
d. Clinically significant cardiac arrhythmias other than atrial flutter/fibrillation  
e. Stroke, including transient ischemic attacks, within 6 months of study treatment  
f. Other clinically significant arterial events, except for controlled asymptomatic 
pulmonary embolism, within 6 months of study treatment 
6. Clinically significant hemorrhage or bleeding event within 1 month of study treatment  
7. Uncontrolled symptomatic pleural effusion or ascites  
8. Known active additional malignancy that is undergoing or expected to undergo systemic 
treatment during duration of study participation.   
9. Known history of human immunodeficiency virus (HIV) infection or known current 
active hepatitis B (i.e., Hep B DNA positive in prior 3 months) or hepatitis C infection 
(i.e., Hep C RNA positive in prior 3 months, with the exception of patients who have 
completed curative therapy and are Hep C RNA negative on retest).   
10. Major surgical procedure (e.g., involving the opening of a major body cavity) within 4 
weeks of study treatment.  This does not apply to low-risk procedures (i.e., thoracentesis; 
paracentesis;  chest tube/PleurX catheter placement;  line placement;  needle biopsy of 
tumor;  and bronchoscopy).   
11. Presence of a clinically significant non-healing wound or non-healing ulcer 
12. Concomitant therapy required at time of first dose of study treatment, including: 
a. Strong CYP3A4 inhibitors and CYP3A4 inducers (Appendix C) 
b. Regular use of NSAIDs, proton pump inhibitors, and probenecid 
13. Women who are pregnant or breast-feeding. 
14. Any condition which, in the investigator’s opinion, including substance abuse, medical, 
psychological or social conditions that makes the patient unsuitable for trial participation 
or may interfere with the patient’s participation in the study.   
See Participant Eligibility Checklist in Appendix E. 
3.3 
Informed Consent Process 
All participants must be provided a consent form describing the study with sufficient information 
for participants to make an informed decision regarding their participation.  Participants must 
sign the IRB approved informed consent prior to participation in any study specific procedure.  
The participant must receive a copy of the signed and dated consent document.  The original 
signed copy of the consent document must be retained in the medical record or research file.   


 
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Special Informed Consent Circumstances: 
1. If the patient is not physically capable of providing a signature, a verbal statement of 
consent can also be given in the presence of an impartial witness (independent of the 
investigator).  This is to be documented by a signature from the informing physician as 
well as by a signature from the witness. 
2. For adults under legal protection, consent shall be given by the legal guardian(s).  The 
consent of an adult under legal protection shall also be requested where such a person is 
able to express his/her own will.  His/her refusal or the withdrawal of his/her consent may 
not be disregarded. 
3. In emergency situations, when prior consent of the patient is not possible, the consent of 
the patient’s legal representative(s) or proxy consenter, if present, should be requested.  
The patient should be informed about the study as soon as possible and his/her consent to 
continue the study should be requested. 
The informed consent form provided to patients/legal representatives or proxy consenters will be 
revised whenever important new information becomes available that may be relevant to the 
patient’s consent, or if there is an amendment to the protocol that necessitates a change to the 
content of the patient information and/or the written informed consent form.  The investigator 
will inform the patient/legal representative or proxy consenter of changes in a timely manner and 
will ask the patient to confirm his/her participation in the study by signing the revised informed 
consent form.  Any revised written informed consent form must receive the IRB`s approval in 
advance of use. 
3.4       Randomization Procedures 
There is no randomization for this study. 
3.5 
Study Timeline 
3.5.1  Primary Completion 
Assuming no dose limiting criteria are met, with a sample size of 18 patients, with at least 15 
evaluable for PFS, and an accrual rate of 2 patients per month, the time for the study to reach 
primary completion for the primary endpoint of progression-free survival will take 12-15 months 
(from the time study opens to accrual).   
3.5.2  Study Completion 
The study will reach study completion 24 months from the time the study opens to accrual. 
4. 
TREATMENT PLAN 
• Screening, study visits, and end of treatment visit will be conducted as outlined in the 
Study Calendar (Section 9).   


 
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• Study treatment will be administered in 28-day cycles.  Refer to Section 5.1 for dose and 
schedule. 
4.1 
General Concomitant Medication and Supportive Care Guidelines 
4.1.1  Prohibited Therapies 
• Other concurrent systemic standard or investigational anti-cancer therapy, with the 
exception of bone strengthening medications such as RANK ligand inhibitors or 
bisphosphonates 
• Concurrent radiation therapy, with the exception of: 
o 1) Central nervous system radiation, either stereotactic radiotherapy or whole 
brain radiation, as long as there is evidence of systemic disease control per 
investigator-assessment 
o 2) Palliative radiation therapy, as long as (1) the target lesion(s) are not 
included within the radiation field (or can be replaced with an alternative 
target lesion), and (2) that the radiation is not required due to progression per 
investigator-assessment. 
o Of note, study treatment (both regorafenib and methotrexate) should be held 
on the days of radiation. 
 
4.1.2  Therapies to Avoid (To the Extent Possible) 
The following therapies should be avoided to the extent possible, particularly during 
Cycle 1. 
• Regorafenib-related 
o Strong CYP3A4 inducers (decrease exposure of regorafenib).  Examples 
include rifampin, phenytoin, carbamazepine, phenobarbital, and St.  John’s 
Wort.  (Appendix C) 
o Strong CYP3A4 inhibitors (increase exposure of regorafenib).  Examples 
include clarithromycin, grapefruit juice, itraconazole, ketoconazole, 
posaconazole, nefazodone, telithromycin, and voriconazole.  (Appendix C) 
• Methotrexate-related 
o Regular use of non-steroidal anti-inflammatories (NSAIDs)  
o Regular use of proton pump inhibitors (PPIs) 
o Regular use of Probenecid  
• Regorafenib and methotrexate-related 
o Regular or excessive use of alcohol 
4.1.3  Therapies that May Require Additional Monitoring 
The following therapies may require additional monitoring per institutional guidelines. 
• Regorafenib-related 
o Medication that is metabolized by the cytochrome enzymes CYP2C8, 
CYP2B6, and CYP2C9 (Appendix D) 


 
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o Therapeutic anticoagulation with Vitamin-K antagonists (i.e., warfarin) or 
with other anticoagulants (i.e., heparins, low molecular weight heparin, oral 
direct anti-XA inhibitors)  
 Of note, warfarin is metabolized by the cytochrome enzyme CYP2C9 
and its levels may be affected by regorafenib. 
o BCRP substrates such as statins, prazosin, glyburide, nitrofurantoin, and 
cimetidine. 
 Regorafenib is an inhibitor of BCRP transporters and the investigator 
should be aware of the potential increased serum concentrations of 
BCRP substrates.  Of note, methotrexate (investigational compound in 
this study) is a BCRP substrate, and dose limiting toxicity definitions, 
drug levels, and safety monitoring have been incorporated in this 
study.  However, the target dose for this study is relatively low at 
20 mg oral methotrexate twice weekly.  This dose is lower dose than 
the dose used in other cancers such as head and neck at 40 mg/m2 iv 
weekly, which is well-tolerated.113,114 Not only is the target dose of 
methotrexate for this study lower, there will also be decreased 
absorption due to route of administration, oral, compared to 
intravenous, subcutaneous, or intramuscular.   
• Methotrexate-related.  Drugs that can affect methotrexate levels.   
These should be avoided in Cycle 1 to the extent possible. 
o Can increase methotrexate levels 
 Penicillins (can reduce renal clearance of methotrexate) 
 Drugs highly bound to plasma protein such as such as salicylates, 
phenylbutazone, phenytoin, and sulfonamides (can decrease amount of 
methotrexate bound to serum albumin) 
o Can decrease methotrexate levels 
 Oral antibiotics such as tetracycline and chloramphenicol (can 
decrease intestinal absorption or interfere with metabolism by 
inhibiting bowel flora)  
• Methotrexate-related (other) 
o Trimethoprim/sulfamethoxazole has been reported rarely to increase bone 
marrow suppression  
4.1.4  Permitted Medications 
• All medications and therapies that are considered necessary for the patient’s welfare (i.e., 
concurrent medical conditions, supportive care), and which are not expected to interfere 
with the study treatment, may be given at the discretion of the investigator.   
• Aspirin use up to 325 mg daily is permitted.  Daily aspirin doses above 325 mg may be 
permitted under investigator discretion.  Previous studies of rheumatoid arthritis report no 
increases in methotrexate-induced pulmonary disease or major toxic reactions in those 


 
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receiving aspirin115-119.  Another study found no increase in adverse events or effect on 
laboratory parameters in those on 975 mg aspirin four times per day for one week120.  
Subjects who regularly use aspirin will be monitored closely in this trial. 
• Granulocyte colony-stimulating factor (G-CSF) and other hematopoietic growth factors 
may be used in the management of acute toxicity, such as febrile neutropenia, when 
clinically indicated or at the investigator’s discretion.   
• Chronic erythropoietin 
• Bisphosphonates or RANK-ligand inhibitors 
4.2 
Criteria for Removal from Study 
4.2.1  Withdrawal of Consent 
Patient (or his/her legally acceptable representative) may choose to discontinue the trial at any 
time, for any reason, and without prejudice to further treatment and care.  A patient who 
withdraws consent from study participation will be asked to state the level of withdrawal: 
• 1) Withdrawal from study treatment only; in this case, follow up data will continue as 
planned.   
• 2) Withdrawal from study, including study treatment and post-treatment follow-up. 
In the event of withdrawal of consent, the study staff and/or investigator must make every 
effort to ascertain the level of consent withdrawn.  The type of consent withdrawal must be 
noted in source documents. 
4.2.2  Discontinuing Study Treatment 
Patients will stop study treatment for any of the following reasons (bullets below).  These 
patients will be followed for outlined outcomes until the end of the study.  To the extent possible, 
they should be followed for safety until improvement to grade 0-1 or stabilization to new 
baseline (i.e., potentially permanent sequelae) of toxicities attributable to the study treatment. 
• Withdraws consent for study treatment 
o If a patient withdraws from study treatment, the investigator should promptly notify the 
Stanford Medical Monitor and will make every effort to complete the End-of-Treatment 
visit.  Every effort must be made to ascertain if patients will permit follow-up. 
• Unacceptable toxicity  
• Pregnancy 
• Investigator decision  
• Lost to follow-up 
o Before a patient is considered “lost to follow-up”, study personnel should contact the 
patient at least twice by phone and once by mail and document these attempts.  Study 


 
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personnel may use public records to check for mortality for any patients considered “lost 
to follow-up,” as permitted by applicable laws or regulations. 
• Disease progression (Refer to Section 4.2.4 for further details) 
• Death 
• Consistent and significant non-compliance with study treatment, protocol-mandated 
procedures, or both 
• The study is terminated by the investigator or Bayer.  (Refer to Section 4.2.3) 
4.2.3  Premature Termination of the Study  
The premature termination of the study may occur (but is not limited to) the following: 
-If risk-benefit ratio becomes unacceptable owing to, for example: safety findings from this study 
(e.g., SAEs); results of any interim analysis; results of parallel clinical studies 
-If the study conduct (e.g., recruitment rate; drop-out rate) does not suggest a proper completion 
of the trial within a reasonable time frame. 
-The investigator has the right to close his/her center at any time. 
-For any of the above closures, the following applies: 
 Closures should occur only after consultation between involved parties. 
 All affected institutions.  (e.g., IRB(s); competent authority(ies); study center; head of 
study center) should be informed as applicable according to local law. 
 In case of a partial study closure, ongoing patients, including those in post study 
follow-up, should be taken care of in an ethical manner. 
4.2.4  Special Situations Requiring PI Permission  
Patients may continue on study therapy with permission of the overall study PI in the following 
situations:  
• Patients with progression of disease as determined by the investigator should generally 
discontinue study therapy.  However, if the patient is having clinical benefit (for example, 
response or stable disease systemically, with mild progression in central nervous system), 
patients may be considered to continue on therapy post-progression.  The patient should 
have permission from the overall study PI to receive post-progression therapy before the 
second week of post-progression study treatment is given (i.e., patient can receive 1 week 
of study treatment post-progression without prospective permission).   
• For patients who require > 28 days delay of regorafenib secondary to a treatment-related 
adverse event or for another reason (starting from the time the study treatment was 
supposed to be administered), they will proceed with the End-of-Treatment visit, unless, 
in the investigator’s opinion, continuing on study treatment is of benefit for the patient.  


 
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In this case, the reason of continuation should be documented and there should be 
permission from the overall study PI before resuming treatment.   
o If there is a methotrexate-related toxicity that requires discontinuation of 
methotrexate but the patient is tolerating regorafenib, regorafenib may be 
continued without methotrexate (permission not required by study PI). 
4.3 
Alternatives 
All patients will sign informed consent.  To minimize potential risks related to potential 
overlapping toxicities from regorafenib and methotrexate, patients will undergo an intra-patient 
weekly dose escalation of methotrexate and be followed very closely in the first two cycles for 
safety.  Peripheral blood research studies will be drawn with every effort to coincide with 
scheduled safety blood draws.  Patients may withdraw from the study at any time without 
prejudice to their further care.  Patients with progressing cancer may be offered a variety of 
alternate treatment options.  They may also be offered palliative and supportive care services. 
5. 
INVESTIGATIONAL AGENT/DEVICE/PROCEDURE INFORMATION 
Please refer to Section 2 and investigator’s brochure (IB) for regorafenib, and Section 2 and 
package insert for methotrexate for details regarding mechanism of action, summaries of animal 
and clinical studies, non-clinical and clinical pharmacokinetics, major route of elimination, and 
safety profile.   
5.1 
 Investigational Agent/Device/Procedure   
5.1.1  Regorafenib 
Regorafenib will begin on Cycle 1 Day 1 and will be self-administered at 80 mg oral daily for 3 
weeks on /1 week off of a 28-day cycle. Regorafenib is provided as 40 mg tablets. Regorafenib 
will NOT be dose escalated during Cycle 1.   
Regorafenib can be dose escalated to 120 mg oral daily (same schedule of 3 weeks on/1 week off 
of the 28-day cycle) according to strict criteria beginning on Cycle 2 Day 1. The strict criteria  
for escalation include no evidence of significant drug-related toxicities (SDRT), defined as any 
event that would require a dose modification of regorafenib (i.e., interruption only, reduction 
only, or interruption followed by reduction) according to the toxicity guidelines/tables in Section 
6.2.1 (regorafenib toxicities) and Section 6.2.3 (overlapping regorafenib and methotrexate 
toxicities). If after the first two cycles a patient has not yet escalated or is considering re-
escalation to regorafenib 120 mg, this is permitted as long as all treatment-related toxicities have 
resolved to grade 0-1 or to the patient’s baseline and at the discretion of the investigator. 
However, a patient is not required to dose escalate regorafenib to 120 mg during the course 
of study treatment and is permitted to remain at the 80 mg dose if it is better tolerated and 
per investigator discretion.   
Regorafenib should be taken ideally at a similar time each day and with approximately 8 fluid 
ounces (240 mL) of water after a low-fat (<30% fat) meal. Some examples of low-fat meals are: 


 
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• Two slices of white toast with 1 tablespoon of low-fat margarine and 1 tablespoon of 
jelly and 8 ounces (240 mL) of skim milk (approximately 319 calories and 8.2 g of 
fat). 
• One cup of cereal, 8 ounces (240 mL) of skim milk, one piece of toast with jam (no 
butter or marmalade), apple juice, and one cup of coffee or tea (2 g fat, 17 g protein, 
93 g of carbohydrate, 520 calories. 
5.1.2  Methotrexate 
Methotrexate will be self-administered during the study twice weekly during the same weeks as 
regorafenib (i.e., a schedule of 3 weeks on/1 week off of a 28-day cycle).  Methotrexate is 
provided as 2.5 mg tablets.  The initial starting dose during Cycle 1 Week 1 is 10 mg oral twice 
weekly.  Doses of methotrexate should be separated by at least 2 days each week. However, it is 
preferred that methotrexate doses are separated by 3 days.  During Cycle 1, methotrexate and 
regorafenib will be taken at a similar time of day to allow for ease of pharmacokinetic sampling. 
During Cycle 1, methotrexate will be taken within 30 minutes of regorafenib, and therefore, will 
be taken with a low-fat meal. 
Methotrexate will be dose escalated each week during Cycle 1 as tolerated to a maximum dose of 
20 mg oral twice weekly:  
• Cycle 1 D1 (+ 1 day): 10 mg (i.e., 4 tablets) oral twice weekly   
• Cycle 1 D8 (+ 1 day): 15 mg  (i.e., 6 tablets) oral twice weekly 
• Cycle 1 D15 (+ 1 day): 20 mg (i.e., 8 tablets) oral twice weekly 
• Cycle 1 D22 (+ 1 day): OFF 
Beginning in Cycle 2, methotrexate will be self-administered at doses ranging from 10 to 20 mg 
oral twice weekly, depending on tolerability, with 2-3 days between doses and on the same 
weeks as regorafenib (3 weeks on/1 week off of a 28 day cycle). Dose escalation of methotrexate 
can continue after Cycle 1 depending on the patient’s tolerability, if the patient has not dose 
escalated to 20 mg by the end of Cycle 1. Beginning in Cycle 2, methotrexate may be taken at a 
different time of day than regorafenib per patient preference. Methotrexate may be taken with or 
without food per patient preference. Although methotrexate administration with food may delay 
absorption and reduce peak concentrations of methotrexate, it may improve tolerability and is 
therefore encouraged.   
5.2 
Availability 
BAYER U.S.  LLC will provide regorafenib. 
Methotrexate (generic) will be purchased through the Stanford Research Pharmacy.  Bayer will 
supply funding for purchase of methotrexate.   


 
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5.3 
Agent Ordering 
5.3.1  Regorafenib 
Supply of regorafenib will occur through direct contact with the supplier, BAYER U.S.  LLC.   
BAYER U.S.  LLC  
 
 
Phone: 
 
5.3.2  Methotrexate 
An Interdepartmental Request Form, which can be obtained from the Standard Register, will be 
filled out and submitted to the Stanford Research Pharmacy for supply of methotrexate.   
Stanford Hospital & Clinics 
Department of Pharmacy 
 
Stanford, CA 
 
Phone: 
 
Fax: 
 
5.4 
Agent Accountability 
All study drugs will be stored at the investigational site in accordance with Good Clinical 
Practice (GCP) and Good Manufacturing Practices (GMP) requirements and the instructions 
given by the clinical supplies department of the Institution and will be inaccessible to 
unauthorized personnel. 
5.4.1  Regorafenib 
Regorafenib tablets will be packaged in high density polyethylene bottles with a white child 
resistant closure and induction seal. Each bottle contains 28 tablets and a 3-gram desiccant.  The 
bottles will have a label affixed containing study identification, product identification, and 
quantity of tablets.  Once the drug has been received it should be kept in a secure, dry location.  
Study drug should be stored in its original bottle at a temperature not above 25°C (77°F).  The 
study drug must be exclusively used for the investigation specified in this protocol and it will 
only be accessible to authorized staff. 
The investigator, or a responsible party designated by the investigator (i.e., site pharmacist), will 
maintain a careful record of the inventory and disposition of the agent using the NCI Drug 
Accountability Record or another comparable drug accountability form.   
At the end of the study, unused supplies of regorafenib should be destroyed according to 
institutional policies. Destruction will be documented in the Drug Accountability Record Form.  
The certificate of destruction for regorafenib should be sent to Bayer. 


 
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A completed “Unused Study Drug Disposition Form Destruction or Return Confirmation” 
should be sent to Bayer at the following address:   
E-mail: 
  
  OR 
Mail: (VP of Medical Affairs named in contract) at 
BAYER U.S.  LLC  
 
 
5.4.2  Methotrexate 
Methotrexate tablets (2.5 mg each) will be packaged in a tight, light-resistant container using a 
child-resistant closure. The methotrexate packages  will have a label affixed containing study 
identification, product identification, and quantity of tablets.  Once methotrexate  has been 
received, it will be kept in a secure, dry location.  Methotrexate will be stored in its original 
package  at a temperature not above 25°C (77°F).  Methotrexate will be exclusively used for the 
investigation specified in this protocol, and it will only be accessible to authorized staff. 
At the end of the study, unused supplies of methotrexate will be destroyed according to 
institutional policies. 
6. 
DOSE MODIFICATIONS 
6.1   
Dose Limiting Toxicity Definitions (First 28-Day Period) 
Dose Limiting Toxicities (DLT) will be monitored during Cycle 1 (first 28 days). During 
Cycle 1, patients will be on regorafenib 80 mg oral daily 3 weeks on/1 week off and 
methotrexate with doses ranging three dose levels between 10-20 mg oral twice weekly 3 weeks 
on/1 week off. A patient will be eligible for DLT assessments if he/she has received at least 80% 
of the planned doses of study treatment, which will be calculated by dosing days of regorafenib 
in case a patient is off treatment during Cycle 1 for a reason other than toxicity.   
A DLT will be generally defined as any Grade 3 or 4 toxicity occurring during Cycle 1 (first 28 
days), which is regarded as clinically significant and related to study treatment with clarifications 
and exceptions for adverse event terms noted below. The NCI‑CTCAE version 4.03 will be used 
to assess toxicities.   
 
Only the following hematologic toxicities will be considered a DLT: 
• Absolute Neutrophil Count (ANC) < 500/mm3 for > 7 days despite dose interruption 
• Febrile neutropenia [ANC <1000/mm3 with a single temperature of > 38.3 degrees C 
(101 degrees F) or a sustained temperature of ≥ 38 degrees C (100.4 degrees F) for more 
than one hour] 
• Platelets < 25,000/mm3 or ≥ Grade 3 thrombocytopenia associated with clinically 
significant bleeding 


 
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Non-hematologic Grade 3 or Grade 4 toxicity considered clinically significant and study 
treatment-related is a DLT, except for the following, permitting protocol therapy can resume 
according to the toxicity guidelines in Section 6.2. (Note: If patient declines to resume protocol 
therapy despite being able to, this will not be considered a DLT). 
• Grade 3 nausea, vomiting, or diarrhea that improves to grade 2 or less with dose 
interruption and appropriate supportive care within 5 days   
• Grade 3 mucositis or stomatitis that improves to grade 0-1 with dose interruption and 
appropriate supportive care within 28 days 
• Grade 3 hypertension that improves to grade 2 or less with dose interruption and 
appropriate supportive care within 7 days 
• Grade 3-4 electrolyte abnormalities that are asymptomatic and can be corrected with 
supplementation and/or appropriate supportive care (e.g., hypomagnesemia, 
hypokalemia, hypocalcemia, hyponatremia, hypophosphatemia) or any grade of 
electrolyte abnormality that is related to another adverse event such as diarrhea, nausea, 
or vomiting 
• Grade 3 asymptomatic maculo-papular rash that improves to grade 2 or less with dose 
interruption and appropriate supportive care within 28 days 
 
The following will not be considered a DLT: 
• ≥ Grade 3 lipase and amylase that is asymptomatic 
• Grade 3 unconjugated/indirect bilirubin secondary to Gilbert’s disease or equivalent 
 
Miscellaneous: In case an unexpected drug-related toxicity (even at a lower grade) is seen more 
frequently than expected or beyond the DLT time period, this toxicity may be declared as a DLT for the 
remainder of the study after consultation with the PI. 
6.2  
Dose Modifications  
The guidelines in this section (applies to all text and tables listed under the Section 6.2) are 
STRICT for adverse event management for the FIRST TWO CYCLES of therapy. After 
the first two cycles of therapy, the final adverse event management decision is per investigator 
discretion, although these guidelines should be strongly considered  
Separate guidelines are given for (1) regorafenib-related adverse event management, (2) 
methotrexate-related adverse event management, and (3) potential overlapping toxicities of the 
two investigational agents including dermatologic (rash), gastrointestinal (diarrhea, nausea, 
vomiting, stomatitis), and hepatitis.   
In general, if regorafenib dose is interrupted, methotrexate dose should be interrupted.  However, 
if methotrexate dose is interrupted, regorafenib dose does not necessarily need to be interrupted 
if the toxicity is thought to be unrelated to regorafenib (i.e., cytopenias).  In general, for 


 
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overlapping toxicities of both study drugs that necessitate dose reduction, both regorafenib and 
methotrexate should be dose reduced, although some toxicities may allow for stepwise reduction 
upon resuming treatment (i.e., dose reducing one drug first and keeping the other study drug at 
the same dose).  Re-escalation of one or both drugs in certain circumstances can be considered 
per guidelines below. Monitoring should be performed following dose interruption or 
modification of regorafenib and/or methotrexate, in a manner consistent with the local clinical 
standard of care.   
6.2.1  Regorafenib 
6.2.1.1 Regorafenib Dose Levels  
The starting dose of regorafenib is 80 mg oral once daily on a 3 weeks on/1week off schedule 
of a 28-day cycle with a low-fat meal during Cycle 1. Regorafenib will NOT be dose escalated 
during Cycle 1. Regorafenib can be dose escalated to 120 mg starting at Cycle 2 based on 
absence of significant-drug related toxicities (SDRT), defined as any event that would require a 
dose modification of regorafenib (i.e., interruption only, reduction only, or interruption followed 
by reduction) according to the guidelines/tables in this Section 6.2.1 (regorafenib toxicities) and 
Section 6.2.3 (overlapping toxicities with methotrexate).  
Doses will be delayed or reduced for clinically significant hematologic and non-hematologic 
toxicities that are related to study treatment according to the guidelines shown in the Dose 
Delays/Dose Modifications tables that follow. Dose modifications will follow predefined dose 
levels.   
The modifications of regorafenib will follow the following predefined dose levels: 
Dose level 0 (starting 
dose) 
80 mg oral daily 
Two 40-mg tablets of regorafenib 
Dose level 1 
120 mg oral daily 
Three 40-mg tablets of regorafenib 
If after the first two cycles, a patient has not yet escalated or is considering re-escalation to 
regorafenib 120 mg oral daily, this is permitted as long as all treatment-related toxicities 
have resolved to grade 0-1 or to the patient’s baseline and at the discretion of the 
investigator.  
If a patient requires a dose reduction below 80 mg daily due to a treatment-related toxicity, the 
patient should discontinue study treatment. If a patient requires >4 week delay for treatment-
related toxicity, it is encouraged that the patient discontinue study treatment, unless the patient 
may derive ongoing benefit by resuming treatment as per investigator discretion and after 
discussion with the overall study PI. 


 
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6.2.1.2 Regorafenib-Related Toxicities (General) 
The following table outlines dose adjustments for clinically significant toxicities (hematologic 
and non-hematologic) related to regorafenib except hand-foot skin reaction (HFSR), 
hypertension, mucositis/stomatitis, and liver function test abnormalities.    
In addition to these recommended dose modifications, subjects who develop diarrhea, mucositis 
or stomatitis, anorexia or other events predisposing to fluid loss or inadequate fluid intake should 
be carefully monitored and rehydrated as clinically necessary. Dose reductions when 
recommended are only permitted for those patients who have already escalated to the 120 mg 
oral daily dose. No dose reductions below 80 mg are permitted and if this is required, patients 
should go off protocol treatment.  
Patients do not necessarily need to discontinue protocol therapy if intolerable or severe 
toxicity occurs at the regorafenib 80 mg dose if it is possible for (i) a treatment-related 
toxicity to improve to a lower grade with dose interruption alone +/- maximal supportive 
care and the patient is able to resume regorafenib at a dose of 80 mg oral daily or (ii) if the 
toxicity is thought to be at least contributed to methotrexate whereby a dose reduction of 
only methotrexate may improve the toxicity per investigator discretion. These scenarios are 
further described in tables below. 
Recommended dose modification for Regorafenib treatment-related toxicities except hand-foot-skin 
reaction, hypertension and ALT/AST/bilirubin 
NCI-CTCAE v4.03a 
Dose Interruption 
Dose  
Modificationb 
Dose for Subsequent 
Cycles 
Grade 0-2 
Treat on time 
No change 
No change 
Grade 3 
Delay until ≤ Grade 2c 
Reduce by 1 dose level 
(if patient on 120 mg 
dose)d 
If toxicity remains < 
Grade 2, dose 
re-escalation can be 
considered at the 
discretion of the treating 
investigator.   
 
If dose is re-escalated 
and toxicity (≥ Grade 3) 
recurs, institute 
permanent dose 
reduction. 
Grade 4 
Delay until ≤ Grade 2 c 
Reduce by 1 dose level 
(if patient on 120 mg 
dose)d 
 
Permanent 
discontinuation 
can be considered at 
treating investigator’s 
discretion. 
Dose escalation not 
recommended. 


 
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a.  NCI-CTCAE = National Cancer Institute - Common Terminology Criteria for Adverse Events, 
    version 4.03 
b.  Excludes (1) alopecia; (2) non-refractory nausea/vomiting, diarrhea responsive to supportive care; (3) non-refractory 
hypersensitivity reaction responsive to supportive care; (4) laboratory abnormalities except those specifically 
noted in Section 6.2. See separate toxicity table for mucositis/stomatitis. 
c.  If no recovery after a 28-day delay, treatment should be permanently discontinued unless patient is deriving clinical 
benefit per-investigator assessment and after discussion with overall study PI. (Refer to Section 4.2.4) 
d. Patients requiring dose reduction of regorafenib below 80 mg daily should go off protocol therapy. The 
maximum daily dose of regorafenib is 120 mg. 
 
6.2.1.3 Regorafenib-Related Hand-Foot Skin Reaction (HFSR) 
Grading for Hand-Foot-Skin-Reaction 
 
Grade 1 
Grade 2 
Grade 3 
NCI-CTCAE v4.03 
Palmar-plantar 
erythrodysesthesia 
syndromea 
Minimal skin changes or 
dermatitis (e.g., erythema, 
edema, or hyperkeratosis) 
without pain 
Skin changes 
(e.g., peeling, blisters  
bleeding, edema, or 
hyperkeratosis) with 
pain 
Severe skin changes 
(e.g., peeling, blisters, 
bleeding, edema, or 
hyperkeratosis) with 
pain 
Further description / 
examples of skin 
changes 
Numbness, dysesthesia / 
paresthesia tingling, 
painless swelling, or 
erythema of the hands 
and/or feet 
Painful erythema and 
swelling of the hands 
and/or feet 
Moist desquamation, 
ulceration, blistering, 
or severe pain of the 
hands and/or feet 
Effect on activities 
Does not disrupt normal 
activities 
Limiting instrumental 
activities of daily life 
(e.g., preparing meals, 
shopping for groceries 
or clothes, using the 
telephone, managing 
money) 
Limiting self-care 
activities of daily life 
(e.g., bathing, dressing 
and undressing, feeding 
self, using the toilet, 
taking medications) 
and not bedridden 
a.  Palmer-planter erythrodysesthesia syndrome is a disorder characterized by redness, marked 
    discomfort, swelling, and tingling in the palms of hands or the soles of the feet. 
 


 
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Recommended dose modification for Regorafenib-related hand-foot-skin reaction (HFSR) a,e 
Grade of event 
(NCI-CTCAE v4.0) 
Occurrence 
Suggested Dose Modification 
Grade 1 
Any 
Maintain dose level and immediately institute supportive measures for 
symptomatic relief 
Grade 2 
 
1st occurrence 
Immediately institute supportive measures and consider decreasing 
dose by one dose level (i.e., if patient is on 120 mg dose)b,d.  If no 
improvement or dose level maintained (i.e., particularly if patient is 
only on 80 mg dose), interrupt therapy for a minimum of 7 days, until 
toxicity resolves to Grade 0 to 1. 
No improvement 
within 7 days or 
2nd occurrence 
Interrupt therapy until toxicity resolves to Grade 0 to 1. 
When resuming treatment, treat at reduced dose level b,d 
3rd occurrence 
Interrupt therapy until toxicity resolves to Grade 0 to 1.  
When resuming treatment, can consider continuing treatment at 
reduced dose level.b, d However, discontinuing therapy strongly 
encouraged. 
4th occurrence 
Discontinue therapy 
Grade 3 
 
1st occurrence 
Institute supportive measures immediately.  Interrupt therapy for a 
minimum of 7 days until toxicity resolves to Grade 0 to 1.c When 
resuming treatment, decrease dose by one dose level.b, d 
2nd occurrence 
Institute supportive measures immediately.  Interrupt therapy for a 
minimum of 7 days until toxicity resolves to Grade 0 to 1.c When 
resuming treatment, can consider continuing treatment at reduced 
dose level.b, d However, discontinuing therapy strongly 
encouraged.   
3rd occurrence 
Discontinue treatment  
a. More conservative management is allowed if judged medically appropriate by the investigator. 
b. If toxicity returns to Grade 0 to 1 after dose reduction, dose re-escalation is strongly discouraged. However, it is 
permitted at the discretion of the investigator after the patient has completed one cycle at reduced dose without 
recurrence of event. 
c. If no recovery after a 28 day delay, treatment should be permanently discontinued unless patient is deriving 
clinical benefit per-investigator assessment and after discussion with overall study PI.  (Refer to Section 4.2.4) 
d. Patients requiring dose reduction of regorafenib below 80 mg daily should go off protocol therapy. The 
maximum daily dose of regorafenib is 120 mg. 
e. It should be noted that oral methotrexate can cause dermatologic toxicity including alopecia, dermatitis, 
erythema multiforme, erythroderma, photosensitivity, pruritus, rash, sensation of burning skin, skin necrosis, 
skin plaque erosion, Steven-Johnson syndrome, tissue necrosis, and toxic epidermal necrolysis.  However, 
methotrexate does not generally cause HFSR.  In general, when adverse management guidelines suggest 
interrupting therapy with regorafenib, methotrexate therapy should also be interrupted.  If the investigator 
cannot rule out relatedness to methotrexate, if it is recommended to reduce regorafenib by one dose level, 
methotrexate can also be reduced by one dose level (Refer to Section 6.2.2.1 for methotrexate dose levels). 


 
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At first occurrence of HFSR, independent of grade, prompt institution of supportive 
measures such as topical emollients, low potency steroids, or urea-containing creams 
should be administered. Early referral to supportive dermatology is strongly encouraged 
for all patients given the relatively high incidence of this toxicity with regorafenib.  
Recommended prevention/management strategies for skin toxicities consistent with HFSR are 
summarized below: 
Control of calluses 
Before initiating treatment with regorafenib: 
• Check condition of hands and feet. 
• Suggest a manicure/pedicure, when indicated. 
• Recommend pumice stone use for callus or ‘rough spot’ removal, when indicated. 
During regorafenib treatment, patient should: 
• Avoid pressure points. 
• Avoid items that rub, pinch or create friction. 
Use of creams 
• Non-urea based creams may be applied liberally. 
• Keratolytic creams (e.g., urea-based creams, salicylic acid 6%) may be used sparingly 
and only to affected (hyperkeratotic) areas. 
• Alpha hydroxyl acids (AHA) based creams may be applied liberally 2 times a day.  
Approximately 5% to 8% provides gentle chemical exfoliation. 
• Topical analgesics (e.g., lidocaine 2%) are to be considered for pain control. 
• Topical corticosteroids like clobetasol 0.05% should be considered for subjects with 
Grade 2 or 3 HFSR.  It is preferable to avoid systemic steroids. 
Tender areas should be protected as follows: 
• Use socks/gloves to cover moisturizing creams 
• Wear well-padded footwear 
• Use insole cushions or inserts (e.g., silicon, gel) 
• Foot soaks with tepid water and Epson salts 
6.2.1.4 Regorafenib-Related Hypertension 
Hypertension is a known adverse event associated with regorafenib treatment.  Patients will have 
their blood pressure measured per Study Calendar (Section 9).  If additional blood pressure 
measurements are done outside the study site, and the blood pressure is > 150 mm Hg systolic or 
> 90 mm Hg diastolic (NCI CTCAE v4.03), then the patient should contact study personnel for 
guidance.  The management of hypertension, including the choice of antihypertensive 
medication, will be performed according to local standards and to the usual practice of the 
investigator.  Every effort should be made to control blood pressure by medical means other 


 
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than study drug dose modification.  If necessary, the following table outlines suggested dose 
reductions. 


 
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Recommended Management of Regorafenib Related Treatment-Emergent Hypertension 
Grade  
 
(CTCAE v4.03) 
Antihypertensive Therapy 
Regorafenib Dosing 
1 
Prehypertension (systolic BP 
120 - 139 mmHg or diastolic 
BP 80 - 89 mmHg) 
None 
• Continue regorafenib 
• Consider increasing blood pressure (BP) 
monitoring 
2 
Systolic BP 140 - 159 mmHg 
or diastolic BP 90 - 99 
mmHg, 
OR 
Symptomatic increase by 
> 20 mmHg (diastolic) if 
previously within normal 
limits 
• Treat with the aim to achieve 
diastolic BP ≤ 90 mm Hg: 
• If BP previously within normal 
limits, start anti-hypertensive 
monotherapy 
• If patient already on 
anti-hypertensive medication, 
titrate up the dose. 
• Continue regorafenib 
 
• If symptomatic, hold regorafenib until 
symptoms resolve AND diastolic BP ≤ 90 
mm Hga.  When regorafenib is restarted, 
continue at the same dose level. 
 
3 
Systolic BP ≥ 160 mmHg or 
diastolic BP ≥ 100 mmHg 
OR 
More than one drug or more 
intensive therapy than 
previously used indicated 
Treat with the aim to achieve 
diastolic BP ≤ 90 mm Hg: 
Start anti-hypertensive medication  
 
AND/OR 
Increase current anti-hypertensive 
medication 
 
AND/OR  
Add additional anti-hypertensive 
medications.   
• Hold regorafenib until diastolic BP ≤ 90 
mm Hg, and if symptomatic, until 
symptoms resolve.a 
 
• When regorafenib is restarted, continue at 
the same dose level. If Grade 3 
hypertension recurs, reduce by 1 dose 
level.b,c  
 
• If BP is not controlled with the addition of 
new or more intensive therapy, reduce by 
1 dose level.b,c 
 
• If Grade 3 hypertension recurs despite 
dose reduction and appropriate 
antihypertensive therapy, discontinue 
therapy. 
4 
Life-threatening 
consequences 
(e.g., malignant hypertension, 
transient or permanent 
neurologic deficit, 
hypertensive crisis) 
Per institutional guidelines 
Discontinue therapy 
a. If no recovery after a 28-day delay, treatment should be permanently discontinued unless patient is deriving 
clinical benefit per-investigator assessment and after discussion with overall study PI.  (Refer to Section 4.2.4) 
b. After the patient’s BP remains controlled for at least one cycle, dose re-escalation permitted per investigator’s 
discretion. 
c.  Patients requiring dose reduction of regorafenib below 80 mg daily should go off protocol therapy. 


 
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6.2.2  Methotrexate 
6.2.2.1 Methotrexate Dose Levels 
Methotrexate is given at low doses, no more than 20 mg oral twice weekly, separated by at least 
2 days (preferably 3 days), 3 weeks on/1 week off of a 28-day cycle.  
The modifications of methotrexate will follow the predefined dose levelsa:  
Dose level 0 
20 mg oral twice weekly 
Eight, 2.5-mg tablets 
Dose level -1 
15 mg oral twice weekly 
Six, 2.5-mg tablets 
Dose level -2 
10 mg oral twice weekly 
Four, 2.5-mg tables 
a Of note, methotrexate will be dose escalated weekly from dose level -2 to dose level 0 during 
Cycle 1 to each individual patient’s maximum tolerated dose. 
In general, if regorafenib dose is interrupted, methotrexate dose should be interrupted. However, 
if methotrexate dose is interrupted, regorafenib dose does not necessarily need to be interrupted 
if the toxicity is thought to be unrelated to regorafenib (i.e., cytopenias). In general, for 
overlapping toxicities of both study drugs that necessitate dose reduction, both regorafenib and 
methotrexate should be dose reduced, although some toxicities may allow for stepwise reduction 
upon resuming treatment (i.e., dose reducing one drug first and keeping the other study drug at 
the same dose). Dose reduction for methotrexate is usually decreased by one dose level but can 
be decreased by two dose levels per investigator discretion. Re-escalation of one or both drugs 
can be considered according to toxicity tables and where noted, investigator discretion.   
Methotrexate may cause cytopenias, with guidelines for methotrexate dose management in 
Section 6.2.2.2. Regorafenib does not necessarily need to be dose interrupted or reduced for 
cytopenias. For severe cytopenias, the investigator should check a methotrexate level (Refer 
to Section 6.2.2.3 for Methotrexate Overdose). If a patient requires discontinuation of 
methotrexate due to cytopenias, regorafenib may be continued alone at the discretion of the 
investigator.  


 
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6.2.2.2 Methotrexate-Related Cytopenias  
Neutrophil Count Decreased 
CTCAE v.  4.03 
Definition 
Methotrexate Dosing 
Grade 1 
<LLN-1500/mm3; <LLN -1.x 
10e9/L 
Continue methotrexate 
Grade 2 
<1500-1000/mm3; <1.5-1.0x10e9/L 
Continue methotrexate and follow 
blood counts 
Grade 3 
<1000-500/mm3; <1.0-0.5x 10e9/L 
Interrupt methotrexate until 
≤ Grade 2 and resume at one lower 
dose levela,b; check methotrexate 
level 
Grade 4 
<500/mm3; <0.5 x 10e9/L 
Interrupt methotrexate until 
≤ Grade 2 and resume at one lower 
dose levela,b; check methotrexate 
level 
a: If there is an interruption of methotrexate recommended to manage cytopenias, it is 
recommended to resume at one lower dose level (i.e., dose reduction from 20 mg  15 mg). 
However, it is permitted to resume at two lower dose levels per investigator discretion (i.e., 20 
mg  10 mg). If a dose reduction is made for cytopenia, the dose of methotrexate should not 
be escalated, unless a patient has decreased by more than one dose level. 
b: If patient is already on the lowest dose of methotrexate (10 mg), methotrexate should be 
discontinued and regorafenib may be continued per investigator discretion. 
Febrile Neutropenia 
CTCAE v.  4.03 
Definition 
Methotrexate Dosing 
Grade 3 
ANC < 1000/mm3 with single 
temperature of >38.3 degrees C 
(101 degrees F) or sustained 
temperature of >= 38 degrees C 
(100.4 degrees F) for more than one 
hour 
Interrupt methotrexate until 
neutrophil count recovers to 
≤ Grade 2, fevers resolve, and 
resume at one lower dose levela,b; 
check methotrexate level 
Grade 4 
Life-threatening consequences; 
urgent intervention indicated 
Interrupt methotrexate until 
neutrophil count recovers to 
≤ Grade 2, fevers resolve, and 
resume at one lower dose levela,b; 
check methotrexate level 


 
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a: If there is an interruption of methotrexate recommended, it is recommended to resume at 
one lower dose level (i.e., dose reduction from 20 mg  15 mg). However, it is permitted to 
resume at two lower dose levels per investigator discretion (i.e., 20 mg  10 mg). If a dose 
reduction is made, the dose of methotrexate should not be escalated, unless a patient has 
decreased  by more than one dose level. 
b: If patient is already on the lowest dose of methotrexate (10 mg), methotrexate should be 
discontinued and regorafenib may be continued per investigator discretion. 
Anemia 
CTCAE v.  4.03 
Definition 
Methotrexate Dosing 
Grade 1 
Hemoglobin (hb) <LLN-10.0 g/dl 
Continue methotrexate 
Grade 2 
Hemoglobin (hb) <10.0-8.0 g/dl 
Continue methotrexate and follow 
blood counts 
Grade 3 
Hemoglobin (hb) <8.0 g/dl; 
transfusion indicated 
Interrupt methotrexate until Hb 
resolves to ≤ Grade 2, consider red 
blood cell transfusion, and resume 
at one lower dose levela,b 
Grade 4 
Life-threatening consequences; 
urgent intervention indicated 
Interrupt methotrexate until Hb 
resolves to ≤ Grade 2, transfuse, 
and resume at one lower dose 
levela,b; check methotrexate level 
a: If there is an interruption of methotrexate recommended to manage cytopenias, it is 
recommended to resume at one lower dose level (i.e., dose reduction from 20 mg  15 mg). 
However, it is permitted to resume at two lower dose levels per investigator discretion (i.e., 20 
mg  10 mg). If a dose reduction is made for cytopenia, the dose of methotrexate should not 
be escalated, unless a patient has decreased more than one dose level. 
b: If patient is already on the lowest dose of methotrexate (10 mg), methotrexate should be 
discontinued and regorafenib may be continued per investigator discretion. 


 
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Platelet count decreased (Thrombocytopenia) 
CTCAE v.  4.03 
Definition 
Methotrexate Dosing 
Grade 1 
<LLN-75,000/mm3 
Continue methotrexate 
Grade 2 
<75,000-50,000/mm3 
Interrupt methotrexate until platelet 
count recovers to ≤ Grade 1 and 
resume at one lower dose levela,b 
Grade 3 
<50,000-25,000/mm3 
Interrupt methotrexate until platelet 
count recovers to ≤ Grade 1 and 
resume at one lower dose levela,b; 
check methotrexate level 
Grade 4 
<25,000/mm3 
Interrupt methotrexate until platelet 
count recovers to ≤ Grade 1 and 
resume at one lower dose levela,b; 
consider transfusing platelets for 
clinically significant bleeding; 
check methotrexate level 
a: If there is an interruption of methotrexate recommended to manage cytopenias, it is 
recommended to resume at one lower dose level (i.e., dose reduction from 20 mg  15 mg). 
However, it is permitted to resume at two lower dose levels per investigator discretion (i.e., 20 
mg  10 mg). If a dose reduction is made for cytopenia, the dose of methotrexate should not 
be escalated, unless a patient has decreased more than one dose level. 
b: If patient is already on the lowest dose of methotrexate (10 mg), methotrexate should be 
discontinued and regorafenib may be continued per investigator discretion. 
6.2.2.3 Methotrexate Overdose Management 
Given low doses of oral methotrexate used in this protocol, leucovorin is very unlikely to be 
necessary.  However, if there is a suspected methotrexate overdose, check methotrexate level 
promptly.  Leucovorin is indicated to diminish the toxicity and counteract the effect of 
inadvertently administered overdosages of methotrexate per institutional guidelines, with 
leucovorin administration beginning as promptly as possible.  As the time interval between 
methotrexate administration and leucovorin initiation increases, the effectiveness of leucovorin 
in counteracting toxicity decreases.  Monitoring of the serum methotrexate concentration is 
essential in determining the optimal dose and duration of treatment with leucovorin. 
In cases of massive overdosage, hydration and urinary alkalinization may be necessary to prevent 
the precipitation of methotrexate and/or its metabolites in the renal tubules.  Generally speaking, 
neither hemodialysis nor peritoneal dialysis have been shown to improve methotrexate 
elimination.  However, effective clearance of methotrexate has been reported with acute, 
intermittent hemodialysis using a high-flux dialyzer and consultation with nephrology may be 


 
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useful.  Another option for toxic plasma methotrexate concentrations (>1 micromole per liter) is 
glucarpidase in patients with delayed methotrexate clearance due to impaired renal function.  
Leucovorin should not be administered within 2 hours before or after dose of glucarpidase.  For 
48 hours after glucarpidase administration, leucovorin dose is based on pre-glucarpidase 
concentrations. 
6.2.3 Overlapping Toxicities Between Regorafenib and Methotrexate  
Potential overlapping toxicities of methotrexate and regorafenib include dermatologic (rash), 
gastrointestinal (diarrhea, nausea, vomiting, stomatitis), and hepatitis.   
6.2.3.1 Liver Function Abnormalities 
For patients with observed worsening of serum liver tests considered related to regorafenib 
and/or methotrexate (i.e., where no alternative cause is evident, such as post-hepatic cholestasis 
or disease progression), the dose modification and monitoring advice below can be followed.   
Methotrexate has been described to cause cirrhosis of liver (0.1%), hepatic fibrosis (7%), acute 
hepatitis, other hepatotoxicity, liver failure, abnormal liver function tests (15%).  Manifestations 
of hepatotoxicity or abnormal liver function tests may include elevations in AST/ALT, alkaline 
phosphatase, or bilirubin.  Regorafenib has resulted in severe drug induced liver injury in 0.3% 
across clinical trials.  Regorafenib is a UGT1A1 inhibitor.  Mild, indirect (unconjugated) 
hyperbilirubinemia may occur in patients with Gilbert’s syndrome. 
Recommended Dose Modification/interruption for alanine aminotransferase and/or aspartate 
aminotransferase increases related to study treatment (regorafenib and/or methotrexate)a 
Increases in ASL/ALT (per 
NCI-CTCAE v 4.03) 
1st Occurrence 
Restart 
Recurrence 
AST and/or ALT ≤ 5x ULN 
(<Grade 3) 
- 
Baseline Grade 0 
Grade 1 (>ULN-3x 
ULN) 
- 
Baseline Grade 1 
(>ULN-3x ULN) 
Grade 2 (>3-5x 
ULN) 
Continue dosing of regorafenib 
and methotrexate, with weekly 
monitoring of liver function 
until transaminases return to 
≤ 3x ULN (< Grade 1) or 
baseline. 
 
 
AST and/or ALT ≤ 5x ULN 
(<Grade 3) 
- 
Baseline Grade 0 
Grade 2 (>3.0-5.0 x 
ULN) 
Interrupt dosing of regorafenib 
and methotrexate, with at least 
weekly monitoring of liver 
function until transaminases 
return to ≤ 3x ULN (< 
Grade 1). 
Consider dose reducing 
regorafenib and 
methotrexate by one dose 
level, with at least weekly 
monitoring of liver 
function.b 
 
ALT and/or AST > 5 x ULN 
(> Grade 3)a 
Interrupt dosing of regorafenib 
and methotrexate, with weekly 
monitoring until transaminases 
return to < 3x ULN (< Grade 1)  
or baseline. 
If the potential benefit of 
reinitiating regorafenib and 
methotrexate is considered 
to outweigh the risk of 
hepatotoxicity: reduce 1 
Discontinue 
regorafenib 
and 
methotrexate 


 
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6.2.3.2 Prevention/Management Strategies for Diarrhea, Nausea, Vomiting, 
Mucositis/Stomatitis, and Maculo-Papular Rash 
Both regorafenib and methotrexate have overlapping gastrointestinal toxicities.  Many of these 
toxicities can be managed with appropriate supportive care.   
NAUSEA, VOMITING, DIARRHEA DOSE MANAGEMENT: 
• If the toxicity (diarrhea, nausea, vomiting) is severe (CTCAE v.  4.03 grade 3-4), 
interrupt regorafenib and methotrexate.   
o Grade 3: Dose reduction is not always necessary, although the dose should 
generally be reduced by one dose level for each study drug if it is refractory to 
maximum supportive care after 5 days. Upon improvement of toxicity to < grade 
dose level of both drugs and 
measure serum 
transaminases weekly for at 
least 4 weeks.a If 
methotrexate at lowest dose 
of 10 mg, it is permitted to 
only dose reduce 
regorafenib one dose level 
when considering resuming 
treatment. 
ALT and/or AST > 20 x 
ULN (> Grade 4) 
Discontinue regorafenib and 
methotrexate and follow serum 
transaminases closely until 
resolution. 
 
 
ALT or AST >3x ULN (> 
Grade 2), with concomitant 
rise in bilirubin (>2x ULN), 
primarily direct bilirubin, if 
grade 0-1 baseline AST 
and/or ALT (< 3 x ULN) 
 
ALT or AST >8x ULN, with 
concomitant rise in bilirubin 
(>2x ULN), primarily direct 
bilirubin, if grade 2 baseline 
AST and/or ALT (> 3- 5x 
ULN) 
Discontinue regorafenib and 
methotrexate and follow serum 
transaminases closely until 
resolution (at least weekly).   
 
Exception: subjects with 
Gilbert's syndrome who 
develop elevated transaminases 
should be managed as per the 
recommendations outlined 
above for ALT/AST elevations. 
 
 
a: It will not always clear whether regorafenib or methotrexate or both caused the hepatotoxicity.  Regorafenib is 
more likely to contribute to severe hepatotoxicity than low dose methotrexate.  After an adverse event of grade 3 
hepatotoxicity, regorafenib should generally not be dose escalated.  However, after one cycle of both regorafenib 
and methotrexate at reduced dose level, methotrexate can be escalated with weekly monitoring of liver function 
tests. 
b: Patients requiring dose reduction below regorafenib 80 mg should go off protocol therapy. The maximum daily 
dose of regorafenib is 120 mg.  


 
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2, can consider stepwise dose reduction when resuming treatment (i.e., reduce 
methotrexate by one dose level and continue regorafenib at same dose level or 
vice versa). In general, if dose reduction is performed, dose should not be re-
escalated until the patient has completed one cycle at reduced dose without 
recurrence of the event at the discretion of the investigator.  
o Grade 4: Upon improvement of toxicity to < grade 2, dose reduction by one dose 
level of both drugs (or at least regorafenib if methotrexate at lowest 10 mg dose) 
is recommended and consideration should be given to discontinuing protocol 
treatment. The dose should not be re-escalated. 
DIARRHEA: Diarrhea can be a common side effect of regorafenib (43-47%).  Diarrhea can also 
occur with oral methotrexate (1-3%).  The preventive/management strategies for diarrhea should 
be consistent with local standards (e.g., anti-diarrheals and optimized hydration status).  
Anti-diarrhea medications may be introduced if symptoms occur.  Previous trials have shown 
that the diarrhea could be managed with loperamide.  The dose of loperamide is two tablets 
(4 mg) initially, then 2 mg after each unformed stool, not to exceed 16 mg/day for ≤2 days.  
Diphenoxylate (Lomotil) or tincture of opium are additional agents. 
NAUSEA/VOMITING: Nausea and vomiting can occur with both regorafenib (17-20%) and 
methotrexate (>20%).  Anti-emetics per institutional standards including but not limited to 
ondansetron, metoclopramide, prochlorperazine.  The patient may also be pre-medicated with 
anti-emetics prior to dosing regorafenib and/or methotrexate. 
MUCOSITIS/STOMATITIS: Mucositis/stomatitis can occur with both regorafenib (33-40%) 
and methotrexate (2-10%).   


 
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Recommended dose modification for mucositis or stomatitisa 
Grade of event 
(NCI-CTCAE v4.0) 
Occurrence 
Suggested Dose Modification 
Grade 1 
Any 
Maintain dose level of regorafenib and methotrexate and immediately 
institute supportive measures for symptomatic relief 
Grade 2 
 
1st occurrence 
Immediately institute supportive measures and consider decreasing 
dose by one dose level of regorafenib (if patient on 120 mg dose 
level) and methotrexate (if patient on >10 mg dose level) b,d. If no 
improvement or dose level maintained (i.e., particularly if patient is 
only on a 80 mg dose of regorafenib or 10 mg dose of methotrexate), 
interrupt regorafenib and methotrexate for a minimum of 7 days, until 
toxicity resolves to Grade 0 to 1  
No improvement 
within 7 days or 
2nd occurrence 
Interrupt regorafenib and methotrexate until toxicity resolves to 
Grade 0 to 1. 
When resuming treatment, treat at reduced dose level of regorafenib 
and methotrexateb,d. Can also consider stepwise approach when 
resuming treatment of first decreasing dose level of methotrexate and 
only decreasing dose level of regorafenib if required (or vice versa). 
3rd occurrence 
Interrupt regorafenib and methotrexate until toxicity resolves to 
Grade 0 to 1.   
When resuming treatment, decrease dose by one dose level for 
regorafenib and methotrexate OR can consider continuing treatment at 
the lowest dose levels regorafenib (i.e., 80 mg) and methotrexate (i.e., 
10 mg) if further dose reduction not possible.b,d However, 
discontinuing therapy strongly encouraged. 
4th occurrence 
Discontinue therapy 
Grade 3 
 
1st occurrence 
Institute supportive measures. Interrupt regorafenib and methotrexate 
for a minimum of 7 days until toxicity resolves to Grade 0 to 1.c 
When resuming regorafenib and methotrexate, decrease dose by one 
dose level for both regorafenib and methotrexate.b,d Can also carefully 
consider stepwise approach when resuming treatment of first 
decreasing dose level of methotrexate and only decreasing dose level 
of regorafenib if required (or vice versa). 
2nd occurrence 
Interrupt regorafenib and methotrexate for a minimum of 7 days until 
toxicity resolves to Grade 0 to 1.c Can consider continuing treatment 
at the lowest dose levels of regorafenib (i.e., 80 mg) and methotrexate  
(i.e., 10 mg) if further dose reduction not possible.b,d However, 
discontinuing therapy strongly encouraged.   
3rd occurrence 
Discontinue treatment. 
Grade 4 
Any occurrence 
Discontinue treatment. 


 
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a. More conservative management is allowed if judged medically appropriate by the investigator. 
b. If toxicity returns to Grade 0 to 1 after dose reduction, dose re-escalation is strongly discouraged. However, it is 
permitted at the discretion of the investigator after the patient has completed one cycle at reduced dose without 
recurrence of event. 
c. If no recovery after a 28-day delay, treatment should be permanently discontinued unless patient is deriving 
clinical benefit per-investigator assessment and after discussion with overall study PI. (Refer to Section 4.2.4) 
d. Patients requiring dose reduction below regorafenib 80 mg should go off protocol therapy. The maximum daily 
dose of regorafenib is 120 mg.  
Treatment is per institutional standards and may include: 
• Routine mouth care, including: 
o  removal of dentures 
o oral rinses with weak solution of salt and baking soda (i.e., one-half teaspoon of 
salt and one teaspoon of baking soda in a quart of water) every four hours 
o avoidance of acidic, salty, dry foods 
• Topical lidocaine solutions including “Magic Mouthwash”, with variety of ingredients 
(examples listed below), swish and spit (or swallow depending on extent) four –six times 
daily 
o One consists of viscous lidocaine (50 mL of a 2 percent solution), sodium 
bicarbonate (100 mL of a 1 mEq/mL solution), and diphenhydramine (50 mL of a 
12.5 mg/5 mL solution) in 500 mL normal saline (resultant fluid volume 700 mL) 
with instructions to swish and expectorate 10 to 15 mL four to six times per day.   
o Another type consists of a mixture of equal parts of viscous lidocaine, 
diphenhydramine, and magnesium aluminum hydroxide (Maalox).  
• Steroid solution rinses (i.e., dexamethasone elixirs) 
• Systemic opiates including morphine (oral route preferred)  
MACULO-PAPULAR RASH 
• Grade 3 AND symptomatic: Interrupt regorafenib and methotrexate and institute 
supportive measures. Dose reduction is not always necessary, although the dose should 
generally be reduced by one dose level for each study drug if it is refractory to supportive 
care after 7 days. Upon improvement of toxicity to < grade 2, can consider stepwise dose 
reduction when resuming treatment (i.e., reduce methotrexate by one dose level and 
continue regorafenib at same dose level or vice versa). In general, if dose reduction is 
performed, dose should not be re-escalated until the patient has completed one cycle at 
reduced dose without recurrence of the event at the discretion of the investigator.  
• Grade 3 AND asymptomatic: Continue regorafenib and methotrexate at current dose 
level and institute supportive measures. 


 
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7. 
ADVERSE EVENTS AND REPORTING PROCEDURES 
7.1 
Potential Adverse Events 
Refer to Section 2.2 for detailed adverse events of regorafenib and methotrexate.  Refer also to 
investigator’s brochure for Regorafenib and generic package insert for Methotrexate.   
7.2 
Adverse Events 
7.2.1  Definition of Adverse Event  
Adverse events are defined as clinically significant untoward medical event that occurs during 
the course of the use of a study treatment, both laboratory and non-laboratory, irrespective of 
relatedness to study treatment.   
Non-clinically significant lab values as determined by the treating investigator or designee are 
not considered adverse events.  In more detail, elective surgical or medical procedures are not 
considered adverse events.  Conditions that started before initiation of study therapy are 
considered baseline medical history and not adverse events.  However, baseline conditions that 
worsen in frequency or severity after initiation of study therapy will be documented as adverse 
events.    
7.2.2  Grading, Relationship, Expectedness of Adverse Events 
Adverse events will be graded according to NCI-CTCAE v4.03.  In general, it should be noted if 
the adverse event is a serious adverse event (Refer to Section 7.2.5).  For all events, the 
relationship to treatment and the grade of the event should be determined by the investigator and 
as much as possible, the causality assessment should be done separately for each study treatment.  
For example, distinction should be made between relatedness to regorafenib, methotrexate, or 
both.  In order to determine relatedness, the following factors may be useful: 1) temporal 
sequence from drug administration (i.e., the event occurs after study treatment is given); 2) 
recovery on drug discontinuation OR, recurrence on study treatment re-introduction 
(re-challenge): 3) underlying, concomitant, intercurrent diseases or concomitant medication or 
treatment; 4) the pharmacology and pharmacokinetics of the study treatment (i.e., absorption, 
distribution, metabolism and excretion).  Usually, if an adverse event is not deemed related is  
because there is the existence of an alternative explanation.   
Investigators should refer to the Safety Information section (2.2) along with the current IB for 
regorafenib, including the DCSI (development core safety information for the expected side 
effects of regorafenib.  Overview listings of frequent events that have occurred so far in the 
clinical development are shown in the current IB.  As with any agent, there is always the 
potential for unexpected AEs, including hypersensitivity reactions.  Given current knowledge of 
regorafenib toxicities, adverse events of special interest may include: acute renal failure 
(NCI-CTCAE version 4.03 ≥ grade 3) or severe proteinuria (NCI-CTCAE version 4.03 ≥ 
grade 3); interstitial lung disease; acute cardiac failure; clinically significant bleeding 
(NCI-CTCAE version 4.03 ≥ grade 3); Stevens-Johnson Syndrome and erythema multiforme; 


 
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hepatic failure; reversible posterior leukoencephalopathy syndrome; and gastrointestinal 
perforation or fistula For methotrexate, investigators should refer to the Safety Information 
(Section 2.2) of the protocol.  The Protocol Director (PD) or designee will assess each Adverse 
Event (AE) to determine whether it is unexpected according to the Informed Consent, Protocol 
Document, or Investigator’s Brochure, and related to the investigation. 
CTCAE v4.03 (Refer to official guide for more details per each adverse event term): 
• Grade 1: mild; asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention is not indicated. 
• Grade 2: moderate; minimal, local, or noninvasive intervention is indicated; limiting 
to age-appropriate instrumental activities of daily living (ADL; instrumental ADL 
refers to preparing meals, shopping for groceries or clothes, using the telephone, 
managing money, etc.). 
• Grade 3: Severe or medically significant but not immediately life threatening; 
hospitalization or prolongation of hospitalization is indicated; disabling; limiting to 
self care ADL (self care ADL refers to bathing, dressing and undressing, feeding self, 
using the toilet, taking medications, and not bedridden). 
• Grade 4: life-threatening consequences; urgent intervention is indicated. 
• Grade 5: death due to an AE. 
7.2.3   Recording Adverse Events 
Both Serious and Non-Serious Adverse Events will be clearly noted in source documentation and 
listed on study specific Case Report Forms (CRFs).  In general, in the source documentation, 
adverse events should include adverse event term (i.e., diagnosis), start/stop dates, action taken 
[i.e., study treatment (regorafenib or methotrexate or both) withdrawn, interrupted; dose reduced, 
not changed, increased or both)] and outcome (i.e., ongoing, resolving, resolved).  All AEs 
regardless of seriousness or relatedness to either study drug  will be documented from the start of 
therapy (C1D1) until the end of treatment visit.  SAEs will also be documented from the time of 
informed consent until 30 days after the last dose of either study drug regardless of relatedness.   
7.2.4  Serious Adverse Events (SAE) 
An SAE is classified as any untoward medical occurrence that meets any of the following criteria 
(a – f): 
• Fatal: Adverse event (AE) results in death. 
• Life-threatening: AE placed patient at immediate risk of death.  This classification does 
not refer to an event, which hypothetically might have caused death if it were more 
severe. 
• Hospitalization: AE that required or prolonged inpatient hospitalization.  Hospitalizations 
for elective medical treatments or surgical procedures are not considered SAEs.  


 
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Treatments planned before enrolment in study or routine check-ups are not considered 
SAEs.  Admission to palliative unit or hospice facility is not considered hospitalization. 
• If progressive disease leads to signs and symptoms that meet the criteria for an 
SAE (i.e., hospitalization, disability, death, or important medical event), the signs 
and symptoms should be reported as an SAE and not the underlying progressive 
disease. 
• Disabling / incapacitating: AE that resulted in substantial and permanent disruption of a 
person’s ability to conduct normal life’s functions. 
• Congenital anomaly / birth defect: AE outcome in a child or fetus of a patient exposed to 
the treatment regimen before conception or during pregnancy.   
• Medically Significant: The AE did not meet any of the above criteria, but could have 
jeopardized the patient and might have required medical or surgical intervention to 
prevent one of the outcomes listed above as judged by the investigator. 
All Serious Adverse Events (SAEs) will be tracked until resolution, or until 30 after the 
last dose of the study treatment, whichever is earlier.   
7.2.5  Adverse Event Reporting 
Throughout the course of the study, the Principal Investigator and study personnel agree to 
comply with the obligations of adverse event reporting as set forth below and with FDA 
regulations.   
7.2.5.1 Serious Adverse Events, Stanford Reporting 
SAEs CTCAE Grade 3 and above, and all subsequent follow-up reports will be reported to the 
Stanford Cancer Institute Data and Safety Monitoring Committee (DSMC) using the study 
specific CRF regardless of the event’s relatedness to the investigation.  Following review by the 
DSMC, events meeting the IRB definition of ‘Unanticipated Problem’ will be reported to the 
IRB using eProtocol within 10 working days of DSMC review, or within 5 working days for 
deaths or life-threatening experiences.  (DSMC plan detailed in Section 11.2). 
7.2.5.2 Bayer Reporting 
Additionally, the Stanford University shall within 24 hours from the time of awareness of the event 
report to BAYER by fax or and/or email.   
1) All Serious Adverse Events occurring after start of administration of BAYER product, 
independent of their causal relationship to the study treatment (Details Below) 
-- if linked to a serious adverse event, reports of misuse, abuse, overdose, medication error and 
other uses outside what is foreseen in the protocol, with respect to the study treatment 
2) Reports of drug exposure via mother / father with and without adverse events, such as exposure 
during conception, pregnancy, childbirth and breastfeeding, including their outcome (if it is 
patient’s partner, outcome is subject to partner’s consent). 


 
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3) Communication concerning safety related information to regulatory authorities or ethics 
committees including but not limited to (This is exempt from 24 hour reporting from time of 
awareness but should be reported in an expedited manner): 
o Development Safety Update Reports / relevant parts of IND reports for the study; 
o Other safety related reports, issues and queries that are either raised by or 
communicated to regulatory authorities or ethics committees (e.g., reportable 
non-serious cases) 
4) If a patient dies during the trial or within 30 days of the end-of-treatment visit, the investigator 
will inform Bayer and record the cause of death if available (using the SAE Form). 
Details for Reporting of Serious Adverse Events: 
All SAEs should be reported to Bayer within 24 hours of the Principal Investigator’s awareness 
and should include the following minimum information:  
1.  The name and contact information of the reporter 
2.  The name of the study drug(s) 
3.  A description of the reported SAE 
4.  A patient identified by one or more of the following:  
a.  Patient initials 
b.  Patient number  
c.  Knowledge that a patient who experienced the adverse event exists 
d.  Age 
e.  Sex 
5.  An investigator assessment of study drug causality.  A separate causality assessment should 
be provided for each study drug (i.e., regorafenib, methotrexate). 
The Investigator/Sponsor may report SAEs using: 
A MedWatch form available at http://www.fda.gov/medwatch/ 
All reports shall be sent electronically to one of the following methods of contact: 
Electronic Mailbox: 
  
Facsimile:                  
  
Address:                 
Global Pharmacovigilance - USA  
Mail only         
BAYER U.S.  LLC 
                         
  


 
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Address: 
 
 
FDX or UPS only 
 
Reports for all Bayer products can also be phoned in via our Medical Communications 
Department 
Phone:                  
 
8. 
Planned Research Studies 
Additional/alternative correlative exploratory research may be performed pending development 
of new technology and scientific advances.  Archival tissue may be retrieved for additional 
correlative exploratory research.  This may require the cooperation of other laboratories. 
8.1 
Blood Samples for Correlative Research Studies  
8.1.1 CAPP-Seq Circulating Tumor DNA1 
Blood will be drawn (goal of 20 to 50 mL whole blood at each timepoint) at the timepoints listed 
in Section 9 Study Calendar.  The blood will be brought to the Diehn/Alizadeh labs as soon as 
possible, but always within 4 hours of collection, for further processing.   
Blood samples will be hand-transported to the Diehn/Alizadeh lab within 4 hours of draw.   
 
We do not anticipate shipping of specimens.   
 CAPP-Seq will be performed by Diehn/Alizadeh labs (Stanford Campus).  CAPP-Seq result will 
be reported as circulating tumor DNA (ctDNA) either as a percentage of total circulating free 
DNA and/or ctDNA titer (a continuous variable in units pg/mL).  The assay can identify less 
than 0.005% ctDNA, though many advanced NSCLC tumors have greater than 1% ctDNA, 
resulting in a wide dynamic range for analysis. 
All specimens will be de-identified with a unique code identifier.   
Tissue and blood samples will be retained and used for future research.  For example, CAPP-Seq 
can also be performed on archival or fresh tissue.   
8.1.2  Computational Simulation Model (Refer to Section 2.5.2) 
We will send available de-identified genomic data to Cellworks via secure encrypted 
communication.  In addition, de-identified genomic data from circulating tumor DNA may be 
shared for modeling.   


 
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9. 
STUDY CALENDAR* 
   
Screeninga 
(Day -30 to 
Day 1) 
Cycle 1 
Cycle 2 
Cycle 3* 
Off Studym 
D1 
 
D8 
 
D15 
 
D22 
 
D1 
 
D8 
 
D15 
 
D22 
 
D1  
D8  
D15  D22  
Regorafenibb 
 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
 
 
Methotrexatec 
 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Beta-hCGd 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
EKG (as indicated) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concurrent Medications 
X 
X----------------------------------------------------------------------------------------------X 
X 
Physical Exam 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
 
 
X 
Vital Signse 
X 
X 
X 
X 
X 
X 
Xe 
X 
 
X 
 
 
 
X 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
ECOG Performance Status 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
Pill Count 
 
X 
X 
X 
X 
X 
 
 
 
X 
 
 
 
 
Complete Blood Count with 
Differential 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
 
 
X 
Serum Chemistryf 
X 
X 
X 
X 
X 
X 
  
X 
 
X 
 
 
 
X 
Random Urine 
Protein:Creatinine Ratio g 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum Amylase/Lipase and 
TSH/Free T4 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
Pharmacokinetic Sample: 
Methotrexateh 
 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
Circulating Tumor DNA 
(ctDNA)i 
 
X 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
Radiologic Evaluation (CT)j 
X 
Radiologic measurements will be performed every 8 weeks + 1 week for the first 1 
year and then after 1 year, every 12 weeks +  1 week  
X 
Brain MRI (or CT head)k 
X 
Brain MRI every 8 weeks + 1 week if untreated brain metastases at baseline for the 
first 1 year and then after 1 year, every 12 weeks + 1 week 
X 
Chest XRAY 2-Viewl 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
Archival Tumor Tissue (if 
available) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse Event Evaluation 
 
X --------------------------------------------------------------------------------------------X 
X 


 
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*Study treatment is given 3 weeks ON/ 1 week OFF of a 28-day cycle, ongoing until disease progression or intolerable toxicity.   
1) WINDOWS:  
 
Unless otherwise specified, each cycle with its associated study-specific procedures has the following window: (-3 days/+7 days).  
 
Specific to Cycle 1, the required weekly visits have a + 1 day window.   
 
If there is a clinic holiday or other unforeseen circumstance that prevents the performance of study specific procedures in the 
specified timeframe, a longer window should be approved by PI prior to scheduled visit with a clear reason stated. 
2) DOSE INTERRUPTIONS:  
 
For dose interruptions, patients will continue on cycles as scheduled (e.g., patient will start Cycle 2 28 days after Cycle 1 regardless 
of any dose interruptions).   
 
If patient has dose interruption, protocol-specified procedures should be followed as feasible and applicable. 
 
If patient has a dose interruption during Cycle 1 but still requires first time intrapatient dose escalation of methotrexate, the weekly 
protocol-specified procedures specified during Cycle 1 should be followed until the dose is maximally escalated (i.e., weekly 
CBC+diff, CMP, vital signs, physical exam, and PK sampling). 
a: 
Screening studies must be performed within 30 days of Cycle 1 D1.  Exceptions include brain MRI, which can be performed within 
45 days of Cycle 1 D1.  Screening studies may be completed on Cycle 1 D1 as long as they are completed prior to the first dose of 
study treatment. 
b: 
Regorafenib will begin on Cycle 1 D1 and be self-administered at 80 mg oral daily 3 weeks on/1 week off of a 28-day cycle. 
Regorafenib may be dose escalated to 120 mg oral daily (3 weeks on/1 week off of a 28-day cycle) beginning on Cycle 2 D1 
according to strict criteria, including no evidence of significant drug-related toxicities (SDRT), defined as any event that would 
require a dose modification of regorafenib (i.e., interruption only, reduction only, or interruption followed by reduction) according 
to the toxicity guidelines/tables in Section 6.2.1 (regorafenib toxicities) and Section 6.2.3 (overlapping regorafenib and methotrexate 
toxicities). Refer to Section 5.1.1 for more details on self-administration of regorafenib and Section 6.2.1 for regorafenib dose 
modifications. 
c: 
Methotrexate will begin on Cycle 1 D1 and is self-administered during the same weeks as regorafenib (i.e., 3 weeks on /1 week off).  
The initial starting dose during Cycle 1 Week 1 of methotrexate is 10 mg oral twice weekly.  Methotrexate doses should be separated 
by at least 2 days.  However, it is preferred that methotrexate dosing is separated by 3 days.  Methotrexate will be dose escalated in 
the following manner as tolerated weekly: Cycle 1 Week 1: 10 mg oral twice weekly, Cycle 1 Week 2: 15 mg oral twice weekly, 
Cycle 1 Week 3: 20 mg oral twice weekly. Beginning in Cycle 2, methotrexate will be self-administered at doses ranging from 
10 to 20 mg oral twice weekly (depending on tolerability), with at 2-3 days between doses. Refer to Section 5.1.2 for more details 
on self-administration of methotrexate and Section 6.2.2 for methotrexate dose modifications. When methotrexate is scheduled, it 
should be taken together with regorafenib (within 30 minutes, if feasible) during Cycle 1 for ease of pharmacokinetic studies.  
Beginning in Cycle 2, patients may take regorafenib and methotrexate at different times of day.   
d: 
Urine or serum pregnancy test (women of childbearing potential) must be performed and confirmed negative prior to 
self-administration of study treatment on Cycle 1 D1.   
e: 
Patient needs to document blood pressure locally anytime during the week of Cycle 2 D8 (i.e., week 2 cycle 2) and only report to 
investigator team if blood pressure is >140/90.   
f: 
Serum chemistry includes electrolytes (bicarbonate, chloride, potassium, sodium, calcium) along with phosphorus; liver function 
including albumin, alkaline phosphatase, total bilirubin, total protein, SGOT[AST], and SGPT[ALT]; renal function including BUN 
and creatinine; and glucose.   
g: 
We will check urine protein:creatinine ratio at screening as a baseline measure for comparison in the event of subsequent 
development of proteinuria, but not for eligibility.  We will periodically assess ratio throughout the study depending on patient’s 
symptoms.   
h:  Methotrexate: PK blood samples will be measured during Cycle 1 prior to self-administration of study treatment (i.e., baseline for 
Cycle 1 D1, trough) and 1 hour post-self administration  (+15 minutes)  (i.e., Cmax) of methotrexate during Weeks 1, 2, and 3 of 
cycle 1.  Cycle 1 Week 4 will only include a single methotrexate level.  Methotrexate will be taken within 30 minutes of regorafenib 
on days of PK sampling. 
i: 
Blood samples for ctDNA will be collected at the specified timepoints in study calendar and then only at a timepoint that is closest 
to time of radiologic imaging.  Refer to Section 8.1 for further details on procedures for sample collection. 
j.   Computed tomography (CT) chest + abdomen/pelvis with contrast (unless contraindicated) to image all known baseline sites of 
disease.  To the extent possible, the same imaging modality should be used for follow-up studies.  If CT is not best suited for 
following the patient’s cancer, any study that conforms to RECIST 1.1 criteria is allowed.  Imaging will be performed every 8 
weeks + 1 week irrespective of dose interruptions.  If the patient is on study for > 1 year, imaging frequency can be decreased to 
as infrequent as every 12 weeks (+ 1 week). For patients who come off study for toxicity or any other reason, obtaining interval 
imaging (i.e., unscheduled scan) will be strongly encouraged to monitor response.  
k: 
Brain MRI (preferred over CT head) will be performed every 8 week + 1 week if patient has untreated brain metastases at baseline; 
imaging will be performed every 8 weeks + 1 week irrespective of dose interruptions.  If the patient is on study for > 1 year, 
imaging frequency can be decreased to as infrequent as every 12 weeks (+ 1 week).  If patient has history of treated brain metastases 
or no history of brain metastases, frequency of brain imaging follow-up is per the investigator discretion, although it is encouraged 


 
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to perform the imaging every 8-16 weeks (+ 1 week).  Imaging the brain as well as systemic sites of disease at the same time is 
strongly encouraged.   
l: 
Chest X-ray (2 view) will be performed once per cycle for patients with a history of pleural effusion because methotrexate can 
accumulate in pleural effusions.  For patients with adequate chest imaging with re-staging CT prior to cycle, it is permitted to omit 
Chest X-ray imaging. C1D1 chest X-ray may be omitted by the treating physician if baseline chest imaging (completed within 30 
days of C1D1) is deemed adequate. 
m: Off-study evaluation.  There is no requirement to repeat imaging at off-study visit if patient comes off for adverse event, although 
it is strongly encouraged. 
10. 
MEASUREMENTS 
10.1  Primary Outcome Measurement 
To determine the progression-free survival (PFS) of the oral combination of regorafenib 
and methotrexate for patients with pre-treated metastatic KRAS mutated non-squamous 
NSCLC  
• Title: Progression-free survival 
• Time Frame:  See Study Calendar (Section 9) 
• Safety Issue:  This outcome is not a safety issue. 
• Relevant Subset: All patients treated with at least one dose of regorafenib and 
methotrexate.   
• Measurement Definition  
o Progression free survival is measured from the time of first study treatment until 
objective tumor progression as determined by RECIST 1.1 criteria or death from 
any cause, whichever comes earlier.  Refer to Section 12.4 for censoring rules. 
• Measurement Methods 
o RECIST version 1.1 criteria  (Appendix B)121 Investigators on the trial will 
perform tumor measurements based on RECIST v1.1 criteria.  There will be no 
independent review.   
o Death will be indicated as occurred or not occurred.  Study personnel may use 
public records to check for mortality for any patients, especially those considered 
lost-to-follow-up. 
o Measurement Timepoints 
o Refer to Study Calendar Section 9  
10.2 
Secondary Outcome Measurements 
10.2.1 To determine the objective response rate using RECIST v1.1 criteria of the oral 
combination of regorafenib and methotrexate for patients with pre-treated metastatic 
KRAS mutated non-squamous NSCLC  
• Relevant Subset: All patients treated with at least one dose of regorafenib and 
methotrexate.   


 
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• Measurement Definition  
o Proportion of complete responses + partial responses as determined by 
RECIST v1.1 criteria 
• Measurement Methods 
o RECIST version 1.1 criteria (Appendix B) 
• Measurement Timepoints 
o Refer to Study Calendar Section 9 
10.2.2 To determine the disease control rate at 8 weeks using RECIST v1.1 criteria of the 
oral combination of regorafenib and methotrexate for patients with pre-treated 
metastatic KRAS mutated non-squamous NSCLC  
• Relevant Subset: All patients treated with at least one dose of regorafenib and 
methotrexate.   
• Measurement Definition  
o Proportion of complete responses + partial responses + stable disease as 
determined by RECIST v1.1 criteria at 8 weeks 
• Measurement Methods 
o RECIST version 1.1 criteria (Appendix B) 
• Measurement Timepoints 
o Refer to Study Calendar Section 9 
10.2.3 To determine the safety using CTCAE v4.03 criteria of the oral combination of 
regorafenib and methotrexate for patients with pre-treated metastatic KRAS 
mutated non-squamous NSCLC  
• Relevant Subset: All patients treated with at least one dose of regorafenib and 
methotrexate.   
• Measurement Definition  
o Incidence of adverse events 
• Measurement Methods 
o Common Terminology Criteria for Adverse Events (CTCAE v4.03) 
• Measurement Timepoints  
o From time of first study treatment through the end-of-treatment visit 
10.2.4 To determine the pharmacokinetic parameters of methotrexate when combined 
with regorafenib  (i.e., Cmax)  
• Relevant Subset: For trough level, all patients with at least one evaluable baseline 
pharmacokinetic sample and one follow-up trough pharmacokinetic sample treated with 
at least one dose of regorafenib and methotrexate.  For Cmax level, all patients with at 
least one evaluable pharmacokinetic sample at the time that approximates the Cmax (1 
hour-post dose) treated with at least one dose of regorafenib and methotrexate.   


 
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• Measurement Definition  
o Concentration of methotrexate (measured generally as micromolar/L) 
o Cmax is measured one hour (+15 minutes) after ingestion of regorafenib and 
methotrexate 
o Trough concentrations are measured at least ~2 days after a dose of oral 
methotrexate 
• Measurement Methods 
o Methotrexate assay is a fluorescent polarization immunoassay 
• Measurement Timepoints  
o Refer to Study Calendar Section 9  
10.3 Exploratory Endpoint 
10.3.1 To correlate KRAS circulating tumor DNA (ctDNA) using CAPP-Seq1 
pre-treatment and throughout treatment with clinical outcome measures, including 
response rate and progression-free survival 
• Relevant Subset: All patients treated with at least one dose of regorafenib and 
methotrexate, have at least one evaluable ctDNA measurement, and at least one 
follow-up imaging.   
• Measurement Definition  
o ctDNA measured as percentage of total circulating free DNA and/or as ctDNA titer 
(continuous variable in units pg/mL) 
• Measurement Methods 
o ctDNA levels measured using CAncer Personalized Profiling by deep Sequencing 
(CAPP-Seq)  
o Radiographic tumor assessments using RECIST v1.1 criteria (Appendix B)121 
o See primary outcome and secondary outcome definitions of objective response rate 
and progression-free survival  
• Measurement Timepoints 
o Refer to Study Calendar Section 9 
11. 
REGULATORY CONSIDERATIONS 
This protocol was submitted to FDA as IND 136973, and determined to be IND-exempt.  FDA 
noted that an eligibility criteria specifying the use of non-approved diagnostic tests, eg, the 
KRAS-mutation test, without an IDE submission to the FDA requires the investigator’s judgment 
that the use is non-significance risk (NSR), and the IRB’s agreement as indicated by 
IRB approval of the protocol.  
Patients with non-squamous non-small cell lung cancer undergo molecular testing of their tumor 
tissue and/or circulating tumor DNA at the time of diagnosis and/or at variable times throughout 
their disease and treatment course as part of their routine clinical care.  This testing generally 
include testing of the KRAS gene.  There are many platforms available for molecular testing.  At 


 
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this time, none of these are formally approved by the FDA to make treatment determinations for 
KRAS-mutated lung cancer patients.  KRAS mutation testing on tissue includes but is 
not limited to the following CLIA certified assays:  Stanford in-house assay STAMP (Solid 
Tumor Actionable Mutation Panel) and Foundation Medicine.  KRAS mutation testing on blood 
(ie, circulating tumor DNA) includes but is not limited to the following CLIA certified assays:  
Foundation Medicine, Guardant 360, Biodesix.  Patients will enroll in the study if they have a 
known KRAS mutation as by detected by one of the aforementioned assays and/or similar assays 
that were performed as part of their routine clinical care.  This study usage is considered by the 
investigators to be of non-significant risk.  
11.1 
Institutional Review of Protocol 
The protocol, the proposed informed consent and all forms of participant information related to 
the study (e.g., advertisements used to recruit participants) will be reviewed and approved by the 
Stanford IRB and Stanford Cancer Institute Scientific Review Committee (SRC).  Any changes 
made to the protocol will be submitted as a modification and will be approved by the IRB prior 
to implementation.  When necessary, an extension, amendment or renewal of the IRB approval 
should be obtained and also forwarded to Bayer.  The Protocol Director will disseminate the 
protocol amendment information to all participating investigators.  Modifications to the study 
protocol should be discussed and agreed on by Bayer when possible unless a modification is 
required to eliminate an immediate hazard(s) to the trial patient .   
11.2 
Data and Safety Monitoring Plan 
The Stanford Cancer Institute Data and Safety Monitoring Committee (DSMC) will be the 
monitoring entity for this study.  The DSMC will meet after the first 5 patients have 
completed the DLT period, and again after 10 patients have completed the DLT period.  
The DSMC will audit study-related activities to determine whether the study has been conducted 
in accordance with the protocol, local standard operating procedures, FDA regulations, and Good 
Clinical Practice (GCP).  This may include review of the following types of documents 
participating in the study: regulatory binders, case report forms, eligibility checklists, and source 
documents.  In addition, the DSMC will regularly review serious adverse events and protocol 
deviations associated with the research to ensure the protection of human subjects.  Results of the 
DSMC audit will be communicated to the IRB and the appropriate regulatory authorities at the 
time of continuing review, or in an expedited fashion, as needed. 
11.3 
Data Management Plan 
The Protocol Director, or his/her designee, will prepare and maintain adequate and accurate 
participant case histories with observations and data pertinent to the study.  Study specific Case 
Report Forms (CRFs) will document treatment outcomes for data analysis.  Case report forms 
will be developed using the  OnCore  database system and will be maintained by the research 
team.  CRFs will be kept in a locked office, only accessible to the research team. 


 
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12. 
STATISTICAL CONSIDERATIONS 
12.1 
Statistical Design 
This is a prospective open-label non-randomized single-arm phase II study of oral regorafenib in 
combination with oral methotrexate in metastatic KRAS mutated non-squamous NSCLC patients 
who have received at least 1 systemic therapy, with a primary endpoint of progression free 
survival (PFS).   
12.1.1 Randomization 
This is a single arm study and randomization will not be performed.   
12.2 
Interim Analyses - “safety stopping rule” 
Given the combination of oral regorafenib and oral methotrexate has never been studied together 
but each individual compound has been studied extensively, we will monitor the number of 
patients with dose limiting toxicity (DLT), defined in Section 6.1, based on repeated 
significance testing, to ensure there is not excessive toxicity.  If 2 or more of the first 6 
patients have a DLT, or if 3 or more out of the first 12 patients have a DLT, we will suspend 
enrollment to the trial and reconsider the dosing strategy (including dose and schedule of 
regorafenib and/or methotrexate).  Finally, if at the final analysis, 3 or more patients have DLT, 
we will take this as an indication that the regimen may be too toxic and additional dose and 
schedule may be considered for future development of the combination.  The table below shows 
the probability of stopping early (pstop) and the probability of declaring the regimen too toxic at 
an interim look or at the final analysis (pcross), for various value of the probability of DLT 
(ptox); the expected sample size under each scenario is also shown (ess). 
ptox pcross  pstop   ess 
0.05  0.012  0.004  18.0 
0.10  0.102  0.033  17.7 
0.14  0.243  0.089  17.2 
0.18  0.417  0.175  16.5 
0.22  0.588  0.284  15.5 
0.26  0.731  0.406  14.5 
0.30  0.838  0.530  13.3 
 
12.3 
Descriptive Statistics and Exploratory Data Analysis 
Demographic variables (such as age) and baseline tumor and treatment characteristics will be 
summarized by descriptive statistics (i.e., proportions for binary or categorical variables; mean, 
standard deviation and range for symmetrically distributed continuous characteristics; medians, 
quartiles and ranges for characteristics with skewed distributions).  The correlation of 
dichotomies will be assessed using Fisher's exact test.  The correlation of continuous or ordinal 
variables with a dichotomy will be made using Wilcoxon rank sum test.  The correlations of two 
continuous variables will be performed using Kendall correlation.  Time-to-event categories will 


 
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be calculated with Kaplan-Meier method.  Correlation involving a time-to-event variable with a 
dichotomy will be made using the log-rank test and displayed using Kaplan-Meier.  All analyses 
will use a two-sided significance level of 5%.  No adjustment for multiplicity will be carried out. 
12.4 
Primary Analysis  
The primary analysis is to determine the progression-free survival (PFS) of the oral combination 
of regorafenib and methotrexate for patients with pre-treated metastatic KRAS mutated 
non-squamous NSCLC.  Progression-free survival is measured from the time of first study 
treatment until objective tumor progression as determined by RECIST 1.1 criteria or death from 
any cause, whichever comes earlier.  The primary analysis population will include all patients 
treated with at least one dose of regorafenib and methotrexate.  Progression-free survival will be 
calculated using the Kaplan-Meier method along with 95% confidence interval.   
For analysis purposes: 
• 1) Recorded progression date is the date of the protocol-scheduled clinic visit closest 
after all protocol-scheduled radiological assessments and/or physical exam assessments 
(which collectively document progression) have been done.   
• 2) Recorded censoring date is defined in patients with no documented progression 
before data cutoff or dropout as the last date on which progression status was adequately 
assessed (i.e., date of the protocol-scheduled clinic visit corresponding to the last 
adequate radiological assessments and/or physical exam assessment that showed no 
documented progression).  For instance, patients going off-study for undocumented 
clinical progression, treatment toxicity or other reason, change of cancer treatment, or 
decreasing performance status will be censored at the last adequate tumor assessment.    
For the primary analysis, progression events and censoring events are detailed below.   


 
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Situation 
Date of Progression or Censoring 
Outcome 
No baseline tumor assessment 
First day of study treatment 
Censored 
Progression documented between 
protocol scheduled 
visits/radiological assessments  
Date of next scheduled protocol-visit 
Progressed 
No progression 
Date of last visit with adequate assessment  
Censored 
Treatment discontinuation for 
undocumented progression  
Date of last visit with adequate assessment  
Censored 
Treatment discontinuation for 
toxicity or other reason  
Date of last visit with adequate assessment  
Censored 
New anticancer treatment started  
Date of last visit with adequate assessment  
Censored 
Death before first PD assessment 
Date of death 
Progressed 
Death between adequate assessment 
visits 
Date of death 
Progressed 
Death or progression after more than 
one missed visit 
Date of last visit with adequate assessment  
Censored 
Sensitivity analyses for primary endpoint of PFS may be performed: 
• 1) PFS may be calculated with the investigator’s claim of clinical progression, noted as a 
progression event, with date of progression at the protocol-scheduled visit (or next 
protocol-scheduled visit if in between visits). 
• 2) PFS may be calculated with “dropouts” (i.e., clinical progression, treatment 
discontinuation for toxicity or other event,  change of cancer treatment, or decreasing 
performance status) as progression events, with date of progression at the 
protocol-scheduled visit (or next protocol-scheduled visit if in between visits). 
12.5 
Secondary Analysis 
• Objective response rate (ORR): The ORR will be assessed using RECIST v1.1 criteria.  
This analysis will include all patients treated with at least one dose of regorafenib and 
methotrexate.  Percent responding will be tabulated by response category (complete 
response, partial response, stable disease, and progressive disease) and summarized as 
responding  (CR+PR) or not, with exact 95% confidence intervals based on a binomial 
distribution.  Both confirmed and unconfirmed ORR will be reported per RECIST v1.1 
criteria. 
• Disease control rate at 8 weeks (DCR@8 weeks): The DCR@8 weeks will be assessed 
using RECIST v1.1 criteria.  This analysis will include all patients treated with at least 
one dose of regorafenib and methotrexate.  Percent responding will be tabulated by 
response category (complete response, partial response, stable disease, and progressive 


 
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disease) and summarized as having disease control (CR+PR+SD) or not at the week 8 
(+1 week) follow-up scan, with exact 95% confidence intervals.   
• Safety: Safety will be assessed using Common Terminology Criteria for Adverse Events 
(CTCAE v4.03).  This analysis will include all patients treated with at least one dose of 
regorafenib and methotrexate.  Adverse events will be tabulated by category and severity.  
Dose limiting toxicities will also be tabulated. 
• Pharmacokinetic parameters of methotrexate when combined with regorafenib (i.e., 
trough and Cmax).  PK for methotrexate will be assessed by a fluorescent polarization 
immunoassay.  For analysis of methotrexate trough levels, patients with at least one 
evaluable baseline pharmacokinetic sample and one follow-up trough pharmacokinetic 
sample treated with at least one dose of regorafenib and methotrexate will be included.  
For analysis of methotrexate Cmax levels, all patients with at least one evaluable Cmax 
pharmacokinetic sample treated with at least one dose of regorafenib and methotrexate 
will be included.  Descriptive statistics will be used. 
12.5.1  Secondary Analysis Population 
In general, except where noted elsewhere in statistical plan: 
• Efficacy population: All patients enrolled on study treated with at least one dose of study 
treatment. 
• Safety Population: All patients treated with at least one dose of study treatment. 
12.6  Sample Size 
Sample size is 22 patients, with at least 18 evaluable for PFS. 
12.6.1  Accrual Estimates 
We estimate accrual of 2-3 patients per month based on prior accrual to KRAS specific NSCLC 
trials in the second line setting and beyond.  If accrual falls short of expectations, we will 
enhance our efforts to discuss the trial with our patients and will consider advertising to local 
community oncologists. 
12.6.2  Sample Size Justification 
Our null hypothesis is that the median PFS is 2 months. We wish to have 80% power at the 
alternative hypothesis of a median PFS of 8 months. Assuming a horizon for PFS of 2.0 months 
and exponential PFS, the probability of being PFS-free at that time is 50.0% under the null 
hypothesis and 8% under the alternative hypothesis. With 18 informative patients, we would 
have approximately 80% power to reject the null hypothesis at a one-sided significance level of 
5%. 


 
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12.6.3  Effect Size Justification 
The null hypothesis for this study is based on two major references: 1) Median PFS with 
regorafenib alone in pre-treated metastatic NSCLC (KRAS mutation not specified) was 84 days 
(approximately 2-3 months), and 2) Median PFS with a similar agent to regorafenib, sorafenib, 
in pre-treated metastatic KRAS mutated NSCLC was 2.3 months (95% CI 1.6-3.0)2. A clinically 
meaningful alternative hypothesis would be 8 months. 
12.7 
 Criteria for Future Studies 
If the study meets its primary endpoint with acceptable toxicity profile, future studies with the 
combination of oral regorafenib and methotrexate may be pursued in KRAS driven cancers, 
including but not limited to lung cancer. 
12.8  Exploratory Objective 
The exploratory objective is to correlate KRAS circulating tumor DNA (ctDNA) using 
CAPP-Seq1 pre-treatment and throughout treatment with clinical outcome measures such as 
objective response rate and progression-free survival.  ctDNA levels will be measured using 
CAncer Personalized Profiling by deep Sequencing (CAPP-Seq).  This exploratory analysis will 
be identified retrospectively in terms of patients and timepoints selected.  The analysis may 
include  patients treated with at least one dose of regorafenib and methotrexate, have at least one 
evaluable ctDNA measurement, and at least one follow-up imaging.  ctDNA may be measured as 
percentage of total circulating free DNA and/or  as ctDNA titer (continuous variable in units 
pg/mL).  Suggested analyses are outlined below.  Changes in ctDNA may be analyzed by 
transforming absolute value of ctDNA (pg/ml) using base-2 logarithm base-2.  The distribution 
of change will be summarized as percent change from baseline in a waterfall plot (cumulative 
distribution function).  The correlation of percent ctDNA (and/or DNA titer) with sum of 
longest diameter of tumor target lesions (continuous variable in mm or cm, RECIST 1.1) will be 
calculated using Kendall correlation.  The correlation of ctDNA (and/or DNA titer) with overall 
response category (RECIST v1.1) will be calculated using the Wilcoxon rank sum test.  
Significance of the change in the biomarker (ctDNA) will be assessed using a paired t-test; 
however, if normal quantile plots indicate a departure from normality, the assessment will be 
made using the Wilcoxon signed-rank test.  Baseline ctDNA will be correlated with PFS by 
means of a Cox regression model (ctDNA on log scale).  Changes in ctDNA will be correlated 
with PFS by means of a Cox model with ctDNA as a time-varying covariate and baseline ctDNA 
as an adjustment variable.  P-values will be reported without correction for multiple testing, 
however the number of statistical tests planned and/or performed will be included in reports of 
this study.   


 
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emerging role of interleukin-1 receptor antagonist as a novel therapeutic agent in cancer 
treatment. J Transl Med 4:48, 2006 
 
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Waters JP, Pober JS, Bradley JR: Tumour necrosis factor and cancer. J Pathol 
230:241-8, 2013 
 
111. 
Newman AM, Bratman SV, To J, et al: An ultrasensitive method for quantitating 
circulating tumor DNA with broad patient coverage. 20:548-54, 2014 
 
112. 
Chabon JJ, Simmons AD, Lovejoy AF, et al: Circulating tumour DNA profiling 
reveals heterogeneity of EGFR inhibitor resistance mechanisms in lung cancer patients. Nat 
Commun 7:11815, 2016 
 
113. 
Stewart JS, Cohen EE, Licitra L, et al: Phase III study of gefitinib compared with 
intravenous methotrexate for recurrent squamous cell carcinoma of the head and neck 
[corrected]. J Clin Oncol 27:1864-71, 2009 
 
114. 
Forastiere AA, Metch B, Schuller DE, et al: Randomized comparison of cisplatin 
plus fluorouracil and carboplatin plus fluorouracil versus methotrexate in advanced squamous-
cell carcinoma of the head and neck: a Southwest Oncology Group study. J Clin Oncol 10:1245-
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Colebatch AN, Marks JL, Edwards CJ: Safety of non-steroidal anti-inflammatory 
drugs, including aspirin and paracetamol (acetaminophen) in people receiving methotrexate for 
inflammatory arthritis (rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, other 
spondyloarthritis). Cochrane Database Syst Rev:CD008872, 2011 


 
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116. 
Carroll GJ, Thomas R, Phatouros CC, et al: Incidence, prevalence and possible 
risk factors for pneumonitis in patients with rheumatoid arthritis receiving methotrexate. J 
Rheumatol 21:51-4, 1994 
 
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Carson CW, Cannon GW, Egger MJ, et al: Pulmonary disease during the 
treatment of rheumatoid arthritis with low dose pulse methotrexate. Semin Arthritis Rheum 
16:186-95, 1987 
 
118. 
McKendry RJ, Cyr M: Toxicity of methotrexate compared with azathioprine in 
the treatment of rheumatoid arthritis. A case-control study of 131 patients. Arch Intern Med 
149:685-9, 1989 
 
119. 
McKendry RJ, Dale P: Adverse effects of low dose methotrexate therapy in 
rheumatoid arthritis. J Rheumatol 20:1850-6, 1993 
 
120. 
Stewart CF, Fleming RA, Germain BF, et al: Aspirin alters methotrexate 
disposition in rheumatoid arthritis patients. Arthritis Rheum 34:1514-20, 1991 
 
121. 
Eisenhauer EA, Therasse P, Bogaerts J, et al: New response evaluation criteria in 
solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 45:228-47, 2009 


 
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APPENDICES 
 
Appendix A: ECOG Performance Status 
Grade 
Description 
0 
Normal activity.  Fully active, able to carry on all pre-disease 
performance without restriction. 
1 
Symptoms, but ambulatory.  Restricted in physically strenuous 
activity, but ambulatory and able to carry out work of a light or 
sedentary nature (e.g., light housework, office work). 
2 
In bed < 50% of the time.  Ambulatory and capable of all self-care, 
but unable to carry out any work activities.  Up and about more than 
50% of waking hours. 
3 
In bed > 50% of the time.  Capable of only limited self-care, 
confined to bed or chair more than 50% of waking hours. 
4 
100% bedridden.  Completely disabled.  Cannot carry on any 
self-care.  Totally confined to bed or chair. 
5 
Dead. 
* As published in Am.  J Clin Oncol.:  Oken, M.M., Creech, R.H., Tormey, D.C., 
Horton, J., Davis, T.E., McFadden, E.T., Carbone, P.P.: Toxicity And Response 
Criteria Of The Eastern Cooperative Oncology Group.  Am J Clin Oncol 5:649-655, 
1982.  The Eastern Cooperative Oncology Group, Robert Comis M.D., Group Chair.   


 
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Appendix B: RECIST Version 1.1 Criteria  
Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 for Evaluating 
Response in Solid Tumors 
RECIST version 1.1* will be used in this study for assessment of tumor response.  While either 
CT or MRI may be utilized, as per RECIST 1.1, CT is the preferred imaging technique in this 
study.   
 
* As published in the European Journal of Cancer: 
E.A.  Eisenhauer, P.  Therasse, J.  Bogaerts, L.H.  Schwartz, D.  Sargent, R.  Ford, J.  Dancey, S.  
Arbuck, S.  Gwyther, M.  Mooney, L.  Rubinstein, L.  Shankar, L.  Dodd, R.  Kaplan, D.  
Lacombe, J.  Verweij.  New response evaluation criteria in solid tumors: Revised RECIST 
guideline (version 1.1).  Eur J Cancer.  2009 Jan;45(2):228-47.   
 
At baseline, tumor lesions/lymph nodes will be categorized measurable or non-measurable as 
follows: 
 
Measurable: 
• Tumor lesions: Must be accurately measured in at least one dimension (longest diameter in 
the plane of measurement is to be recorded) with a minimum size of: 
o 10 mm by CT, MRI or PET scan (slice thickness no greater than 5 mm) 
o 10 mm caliper measurement by clinical exam (lesions which cannot be accurately 
measured with calipers should be recorded as non-measurable) 
o 20 mm by chest X-ray 
• Malignant lymph nodes:  To be considered pathologically enlarged and measurable, a lymph 
node must be ≥ 15 mm in short axis when assessed by CT, MRI or PET scan (slice thickness 
recommended to be no greater than 5 mm).  At baseline and in follow-up, only the short axis 
will be measured and followed.   
 
Non-measurable: 
• All other lesions, including small lesions (longest diameter < 10 mm or pathological lymph 
nodes with ≥ 10 to < 15 mm short axis) as well as truly non-measurable lesions.  Lesions 
considered truly non-measurable include: leptomeningeal disease, ascites, pleural or 
pericardial effusion, inflammatory breast disease, lymphangitic involvement of skin or lung, 
abdominal masses/abdominal organomegaly identified by physical exam that is not 
measurable by reproducible imaging 
 
Guidance: 


 
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• The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up.  Imaging-based evaluation 
should always be done rather than clinical examination unless the lesion(s) being followed 
cannot be imaged but are assessable by clinical exam.   
• Clinical lesions: Clinical lesions will only be considered measurable when they are 
superficial and ≥ 10mm diameter as assessed using calipers (e.g., skin nodules).  For the case 
of skin lesions, documentation by color photography including a ruler to estimate the size of 
the lesion is suggested.  As noted above, when lesions can be evaluated by both clinical exam 
and imaging, imaging evaluation should be undertaken since it is more objective and may 
also be reviewed at the end of the study.   
• Chest X-ray: Chest CT is preferred over chest X-ray, particularly when progression is an 
important endpoint, since CT is more sensitive than X-ray, particularly in identifying new 
lesions.  However, lesions on chest X-ray may be considered measurable if they are clearly 
defined and surrounded by aerated lung.   
• CT, MRI: CT is the best currently available and reproducible method to measure lesions 
selected for response assessment.  This guideline has defined measurability of lesions on CT 
scan based on the assumption that CT slice thickness is 5mm or less.   
• Ultrasound: Ultrasound is not useful in assessment of lesion size and should not be used as a 
method of measurement.   
• Endoscopy, laparoscopy: The utilization of these techniques for objective tumor evaluation is 
not advised.   
• 
Tumor markers: Tumor markers alone cannot be used to assess objective tumor response.  If 
markers are initially above the upper normal limit, however, they must normalize for a 
patient to be considered in complete response.   
• Cytology, histology: These techniques can be used to differentiate between PR and CR in 
rare cases if required by protocol.   
 
Tumor Response Evaluation 
Baseline documentation of ‘target’ and ‘non-target’ lesions 
• When more than one measurable lesion is present at baseline all lesions up to a maximum of 
5 lesions total (and a maximum of 2 lesions per organ) representative of all involved organs 
should be identified as target lesions and will be recorded and measured at baseline.   
• Target lesions should be selected on the basis of their size (lesions with the longest diameter), 
be representative of all involved organs, but in addition should be those that lend themselves 
to reproducible repeated measurements.   


 
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• A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all 
target lesions will be calculated and reported as the baseline sum diameters.  If lymph nodes 
are to be included in the sum, then as noted above, only the short axis is added into the sum.  
The baseline sum diameters will be used as reference to further characterize any objective 
tumor regression in the measurable dimension of the disease.   
 
Systemic Response Criteria 
Complete Response (CR) requires ALL of the following:  
• Disappearance of all target and non-target lesions 
• All pathological lymph nodes, whether target or non-target, must have reduction in short 
axis to < 10 mm.   
• No new lesion 
 
Partial Response (PR) requires ALL of the following: 
• At least 30% decrease in the sum of diameters of target lesions, taking as reference the 
baseline sum of diameters.   
• No unequivocal progression of existing non-target lesions 
• No new lesion 
 
Progression of Disease (PD) requires ANY of the following: 
• At least 20% increase in the sum of diameters of target lesions, taking as reference the 
smallest sum on study (this includes the baseline sum if that is the smallest on study).  In 
addition to the relative increase of 20%, the sum must also demonstrate an absolute increase 
of at least 5 mm.   
• Unequivocal progression of existing non-target lesions 
• Appearance of one or more new lesions 
 
Stable Disease (SD) requires ALL of the following: 
• Not CR 
• Not PR 
 


 
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Appendix C: CYP3A4 Inhibitors/Inducers  
References: 
• Huang, S.  Drug Development and Drug Interactions.  
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugIn
teractionsLabeling/ucm093664.htm Accessed [01-22-2017]. 
o Please see this site for a comprehensive and up to date list. 
Definitions: 
Strong, moderate, and weak inhibitors are drugs that increase the AUC of sensitive index 
substrates of a given metabolic pathway ≥5-fold, ≥2 to <5-fold, and ≥1.25 to <2-fold, 
respectively.   
 
CYP3A4 INHIBITORS 
 
Enzyme 
Strong Inhibitors 
Moderate inhibitors 
Weak inhibitors 
CYP3A 
boceprevir, cobicistat, 
conivaptan, danoprevir 
and ritonavir, elvitegravir 
and ritonavir, grapefruit 
juice, indinavir and 
ritonavir, itraconazole, 
ketoconazole, lopinavir 
and ritonavir, paritaprevir 
and ritonavir and 
(ombitasvir and/or 
dasabuvir), posaconazole, 
ritonavir, saquinavir and 
ritonavir, telaprevir, 
tipranavir and ritonavir, 
troleandomycin, 
voriconazole, 
clarithromycin, diltiazem, 
idelalisib, nefazodone, 
nelfinavir, suboxone 
aprepitant, cimetidine, 
ciprofloxacin, 
clotrimazole, crizotinib, 
cyclosporine, 
dronedarone, 
erythromycin, fluconazole, 
fluvoxamine, imatinib, 
tofisopam, verapamil 
chlorzoxazone, cilostazol, 
fosaprepitant, istradefylline, 
ivacaftor, lomitapide, 
ranitidine, ranolazine, 
tacrolimus, ticagrelor 
Note, most p-GP inhibitors also inhibit CYP3A4 to some degree: amiodarone, carvedilol, 
clarithromycin, dronedarone, itraconazole, lapatinib, lopinavir and ritonavir, propafenone, 
quinidine, ranolazine, ritonavir, saquinavir and ritonavir, telaprevir, tipranavir and ritonavir, 
verapamil.   
 


 
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CYP3A4 INDUCERS 
Definitions: 
Strong, moderate, and weak inducers are drugs that decreases the AUC of sensitive index 
substrates of a given metabolic pathway by ≥80%, ≥50% to <80%, and ≥20% to <50%, 
respectively. 
CYP 
Enzymes  
Strong Inducers 
 
Moderate Inducers 
 
Weak Inducers 
 
CYP3A 
carbamazepine, 
enzalutamide, mitotane, 
phenytoin, 
phenobarbital, rifampin, 
St.  John’s Wort 
bosentan, efavirenz, 
etravirine, modafinil 
armodafinil, rufinamide 
 


 
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Appendix D: Examples of Clinical Substrates for the Cytochrome Enzymes CYP2B6, 
CYP2C8, and CYP2C9 
Please see these sites for a comprehensive and up to date list  
References: 
• Huang, S.  Drug Development and Drug Interactions.  
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugIn
teractionsLabeling/ucm093664.htm Accessed [01-22-2017]. 
• Flockhart DA.  Drug Interactions: Cytochrome P450 Drug Interaction Table.  Indiana 
University School of Medicine (2007).  
"http://medicine.iupui.edu/clinpharm/ddis/clinical-table/" Accessed [01-22-2017]. 
 
 
Cytochrome Enzyme 
Substrates 
CYP2B6 
Artemisinin, bupropion, cyclophosphamide, efavirenz, ifosfhamide, 
ketamine, meperidine, methadone, nevirapine, propafol, selegiline, 
sorafenib 
CYP2C8 
Amodiaquine, cerivastatin, montelukast, paclitaxel, pioglitazone, 
repaglinide, rosiglitazone, sorafenib, torsemide 
CYP2C9 
NSAIDS: diclofenac, ibuprofen, lornoxicam, meloxicam, 
S-naproxen, piroxicam, suprofen 
 
Oral hypoglycemic agents: glipizide, tolbutamide 
 
Angiotensin II Blockers: irbesartan, losartan 
 
Sulfonylureas: glyburide, glibenclamide, glipizide, glimepiride, 
tolbutamide 
 
Others: amitriptyline, celecoxib, fluoxetine, fluvastatin, glyburide, 
nateglinide, phenytoin, rosiglitazone, tamoxifen, torsemide, valproic 
acid, S-warfarin, zakirlukast  
  


 
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Appendix E: Participant Eligibility Checklist3.1 Inclusion Criteria 
In order to be eligible for participation in this trial, the patient must meet ALL of the following 
criteria (i.e., mark “yes” or “N/A” to all criteria): 
YES NO 
INCLUSION CRITERIA 
SUPPORTING 
DOCUMENTATION 
 
 
1. Histologic or cytologic confirmed diagnosis of non-squamous 
non-small cell lung cancer that is recurrent or metastatic. 
Adenosquamous is allowed provided the patient has confirmed 
adenocarcinoma component. 
 
 
 
2. Documentation of pathogenic KRAS mutation  
 
 
 
3. Previous receipt of at least one systemic therapy for recurrent or 
metastatic disease OR previous receipt of adjuvant systemic therapy 
within 6 months of enrollment.  There is no limit on number of prior 
therapies allowed.   
 
 
 
4. Prior systemic therapy must be completed at least 2 weeks prior to study 
treatment, with either improvement of clinically significant 
treatment-related toxicities to grade 0 to 1 OR stabilized to a new 
baseline.   
 
 
 
5. Previously treated OR asymptomatic non-progressing < 1 cm untreated 
brain metastases are allowed 
 
 
 
6. Measurable disease based on RECIST version 1.1 criteria (Appendix B) 
 
 
 
7. Ability to understand and the willingness to sign a written informed 
consent document  
 
 
 
8. Age ≥ 18 years-old 
 
 
 
9. ECOG performance status of 0 or 1 (Appendix A) 
 
 
 
10. Adequate bone marrow, liver and renal function as assessed by the 
following laboratory requirements: 
a. Absolute neutrophil count (ANC) ≥ 1500/mm3 
b. Platelet count ≥ 100,000 /mm3 
c. Hemoglobin (Hb) ≥ 9 g/dL  
d. Serum creatinine ≤ 1.5x upper limit of normal (ULN) OR 
calculated (Cockcroft-Gault formula) or measured creatinine 
clearance ≥ 50 mL/min for patients with creatinine levels > 1.5x 
ULN 
e. Total bilirubin ≤ 1.5x ULN OR Direct bilirubin ≤ ULN for patients 
with total bilirubin levels > 1.5x ULN  
f. Alanine aminotransferase (ALT) and aspartate aminotransferase 
(AST) ≤ 3x ULN (≤ 5x ULN for patients with liver involvement of 
their cancer) 
 
 
 
11. Must be able to swallow and retain oral medication. 
 


 
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12. Women patients of childbearing potential and men patients with women 
partners of childbearing potential must agree to use adequate 
contraception or agree to abstain from heterosexual activity beginning at 
the time of signing informed consent until at least 3 months after the last 
dose of study treatment.  Post-menopausal women (defined as no 
menses for at least 1 year) and surgically sterilized women are not 
considered childbearing.   
 
 
 
3.2 Exclusion Criteria 
In order to be eligible for participation in this trial, the patient must NOT meet the following 
criteria (i.e., mark “no” or “N/A” to all criteria): 
YES NO 
EXCLUSION CRITERIA 
SUPPORTING 
DOCUMENTATION 
 
 
1. Previously treated with regorafenib  
 
 
 2. Known allergy to regorafenib or methotrexate  
 
 
 3. Currently receiving another systemic standard or investigational 
anti-cancer therapy.  Prior investigational therapy must be completed 
within 4 half-lives (if known) or 2 weeks, whichever is longer.  The 
maximal washout of investigational therapy will not exceed 4 weeks 
prior to study treatment.  Bone medications such as bisphosphonates and 
RANK ligand inhibitors permitted.   
 
 
 4. Leptomeningeal disease as documented by CSF cytology. 
 
 
 5. Clinically significant cardiovascular-related disease including: 
a. Uncontrolled hypertension (systolic pressure >150 mm Hg or 
diastolic pressure > 90 mm Hg on repeated measurements that does 
not resolve prior to study treatment on C1D1 despite optimal medical 
management 
b. Congestive heart failure – New York Heart Association (NYHA) 
Class III or greater 
c. Active coronary artery disease (i.e., unstable or new onset angina 
within 3 months of study treatment; myocardial infarction within 6 
months of study treatment) 
d. Clinically significant cardiac arrhythmias other than atrial 
flutter/fibrillation  
e. Stroke, including transient ischemic attacks, within 6 months of 
study treatment  
f. Other clinically significant arterial events, except for controlled 
asymptomatic pulmonary embolism, within 6 months of study 
treatment 
 


 
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 6. Clinically significant hemorrhage or bleeding event within 1 month of 
study treatment  
 
 
 7. Uncontrolled symptomatic pleural effusion or ascites  
 
 
 8. Known active additional malignancy that is undergoing or expected to 
undergo systemic treatment during duration of study participation.   
 
 
 9. Known history of human immunodeficiency virus (HIV) infection or 
known current active hepatitis B (i.e., Hep B DNA positive in prior 
3 months) or hepatitis C infection (i.e., Hep C RNA positive in prior 
3 months, with the exception of patients who have completed curative 
therapy and are Hep C RNA negative on retest). 
 
 
 10. Major surgical procedure (e.g., involving the opening of a major body 
cavity) within 4 weeks of study treatment.  This does not apply to 
low-risk procedures (i.e., thoracentesis; paracentesis;  chest tube/PleurX 
catheter placement;  line placement;  needle biopsy of tumor;  and 
bronchoscopy).   
 
 
 11. Presence of a clinically significant non-healing wound or non-healing 
ulcer 
 
 
 12. Concomitant therapy required at time of first dose of study treatment, 
including: 
a. Strong CYP3A4 inhibitors and CYP3A4 inducers (Appendix C) 
b. Regular use of NSAIDs, proton pump inhibitors, and probenecid 
 
 
 13. Women who are pregnant or breast-feeding. 
 
 
 14. Any condition which, in the investigator’s opinion, including substance 
abuse, medical, psychological or social conditions that makes the patient 
unsuitable for trial participation or may interfere with the patient’s 
participation in the study.   
 
 
By signing this form of this trial, I verify that this patient is [
 eligible / 
 ineligible] for 
participation in the study.  This study is approved by the Stanford Cancer Institute Scientific 
Review Committee, the Stanford IRB, and has finalized financial and contractual agreements as 
required by Stanford School of Medicine’s Research Management Group.   
 
Treating Physician Signature: 
 
 
 
Date: 
Printed Name: 
 
 
 


 
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Secondary Reviewer Signature: 
 
 
Date: 
Printed Name: 
 
 
 
Study Coordinator Signature: 
 
 
Date: 
Printed Name: 
 
 
 
 


 
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Appendix F: Cellworks Modeling Overview 
 
The methodology entails predictive simulation via computational biology modeling to create 
virtual tumor models based on tumor genomics to determine disease characteristics and identify 
therapy responses.  Computational biology modeling (CBM) was previously outlined and 
published in studies of glioblastoma multiforme, multiple myeloma, myelodysplastic syndrome, 
acute myeloid leukemia and myeloproliferative neoplasm [1–4].  Based on over 10,000 
published PubMed references, this model incorporates signaling, metabolic and epigenetic 
pathway interactions important in cancer including growth factor signaling cascades, cytokines, 
chemokines, mTOR regulators, cell cycle regulators, oxidative and ER stress responses, cancer 
metabolism, autophagy and proteosomal degradation, DNA damage repair, apoptosis cascades 
and p53 signaling to predict a patient’s response to a single drug or a combination of drugs.  The 
CBM cancer network includes comprehensive coverage of the kinome, transcriptome, proteome, 
and metabolome.   
 
Virtual lung cancer models in CBM are created via genomic profiling information of KRAS 
positive NSCLC cell lines.  Genomic information of 5 NSCLC cell lines [TABLE 1] were taken 
from publicly accessible cBioPortal and COSMIC databases.  For each NSCLC cell line 
available genomic information (i.e., cytogenetic abnormalities and DNA sequencing data) was 
entered into the CBM, which utilized PubMed, STRING, HumanNet, and PathwayCommons 
online resources to determine whether the cell lines gene mutation generated an activated or 
inactivated protein.  Unique NSCLC cell line models with their individualized disease network 
maps of dysregulated activated and inactivated protein pathways were created via simulation.  
The genomic aberration information derived from cytogenetics and sequencing data was used to 
create a list of genes with mutations and CNV in the cell lines’ genome.  The genes found on the 
loci of the affected regions of the chromosomes were extracted from the human reference 
genome at ENSEMBL, and the complete list of genes is matched with the Cancer Technology 
Network to determine the subset of genes to be represented in the model.   
 
Key assumptions are made when representing the aberrations input to the model network: gain of 
function or amplification of tumor promoter genes and loss of tumor suppressor genes 
dynamically creates the neoplastic disease state upon simulation [5].  Gene variants with 
therapeutic implications are searched using public domain to determine each mutation’s 
functionality, represented as either a loss or gain of function.  However, genes with mutations of 
unknown significance are parsed through a suite of variant calling algorithms to determine if the 
mutation is deleterious.  For a deleterious mutation of unknown significance, a tumor promoter 
gene is assumed to have gain of function while a tumor suppressor gene is assumed to have loss 
of function at the protein activity level.  Frameshift and nonsense mutations are assumed to cause 
a loss of gene function [6]. 
 
For CNV interpretation, amplifications are represented as an increase of gene expression while 
deletions are represented as knockdown of gene expression.  Additionally, amplifications of 
tumor suppressor genes have lower contribution to the disease when compared to amplification 
of tumor promoter genes.  A deletion of tumor suppressor genes has a higher dominance in the 
disease network when compared to deletion of tumor promoter genes. 
 


 
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Dynamic disease models of the NSCLC cell line profiles with their individualized protein 
network maps were created for each KRAS mutant NSCLC cell line based on their mutanome 
data.  A digital drug library of 67 FDA approved drugs including Methotrexate and Regorafenib 
was created for CBM by programming each individual agent’s mechanism of action, as well as 
effects on specific protein targets and pathways determined from published literature.  Using the 
drug models, virtual applications of these drugs were applied to each cell line model 
individually, and in combination, via computer simulation, amounting to thousands of simulation 
studies for testing multiple drugs in combination and at different doses.  The efficacy of each 
therapy in the genetically varying NSCLC KRAS cell lines was measured as a function of 
relative growth inhibition score – the degree to which crucial cancer signaling pathways and 
phenotypes were repressed. 
 
Relative Growth Inhibition Score = Proliferation/Viability=Proliferation/(Survival/Apoptosis) 
 
The proliferation index is an average function of the active CDK-cyclin complexes that define 
cell cycle checkpoints: CDK4-CCND1, CDK2-CCNE, CDK2-CCNA, and CDK1-CCNB1.  A 
viability index based on survival and apoptosis is also generated for each cell line model.  The 
biomarkers constituting the survival index include AKT1, BCL2, MCL1, BIRC5, BIRC2, and 
XIAP, while the apoptosis index includes BAX, CASP3, NOXA, and CASP8.  The overall 
viability index of a cell is calculated as a ratio of survival index/apoptosis index, and the 
weightage of each biomarker is adjusted to achieve a maximum correlation with the 
experimental trends for the endpoint.  Reduction on relative growth characteristic (proliferation, 
viability, apoptosis) was monitored in the NSCLC cell lines with every drug simulation study to 
shortlist and identify the most efficacious combination of Methotrexate and Regorafenib in 
KRAS driven NSCLC profiles.   
 
TABLE 1 
5 following NSCLC Cell lines used for predicting response for Methotrexate and Regorafenib 
combination. 
 
Cell lines 
KRAS status 
H358 
mut 
H2122 
mut 
A549 
mut 
Calu3 
wt 
H1650 
wt 
 


 
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Figure 1 Scientific Rationale for Combining Methotrexate with Regorafenib 
 
 
 
In Conclusion – Why Regorafenib and Methotrexate are Synergistic and Predicted by the 
Simulation Approach 
 
This is established relevant known biological knowledge coded in the computational model 
 
• KRAS undergoes sequential post-translational modifications (PTM) which makes its 
membrane interaction more stable [7]. 
• The process involves prenylation of KRAS, proteolysis of the prenylated CAAX by 
RCE1 (Ras Converting CAAX Endopeptidase 1), followed by carboxymethylation of the 
prenylated cysteine by ICMT (Protein-S-isoprenylcysteine-O-methyltransferase) [7]. 
• KRAS interaction with membrane is important for KRAS mediated signaling.  Disruption 
of PTM events modulates KRAS functionality [7]. 
• RAF/ERK is one of the dominant pathway under KRAS mutant signaling [7]. 
 
Hence synergistic reasons –  
 


 
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• Methotrexate (MTX) interferes with the carboxymethylation step by inhibiting ICMT via 
S-adenosyl methionine (SAM) [8].  In this way MTX can show synthetic lethality in 
KRAS mutant profiles [9].   
• MTX also inhibits SAM mediated DNA CpG methylation resulting in increased 
expression of DUSP6 [10].  DUSP6 inhibits activated ERK [11]. 
• KRAS profiles have higher level of activated MYC due to up-regulation of 
KRAS/RAF/ERK/MYC pathway [12].  Regorafenib inhibits RAF/ERK pathway and will 
inhibit KRAS signaling [16].  Regorafenib indirectly inhibits MYC which makes 
Methotrexate effective and decreases DHFR.  Low DHFR will further sensitize MTX to 
have a higher impact [17].   
• Activated MYC causes resistance to MTX by transcriptional up-regulation of DHFR 
[13-15]. 
 
Of note, the predictive results were subsequently validated through wet lab experiments (see 
Figure 2 on next page).   


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Figure 2 Dose Response Curve Regorafenib (0-10 uM) with Methotrexate (0.25 uM) in (A) 
laboratory and (B) simulation model of H2122 KRAS Mutated NSCLC, and in (C) laboratory 
and (D) simulation model of CALU3 KRAS Wild Type NSCLC.  (E) Synergy confirmed with 
Regorafenib (3.3 uM) and Methotrexate (0.25 uM) with Bliss Ratio in H2122 KRAS mutated 
NSCLC but not in CALU3 KRAS Wild Type NSCLC. 
LABORATORY 
 
 
 
 
SIMULATION
A 
 
 
 
 
 
 
B 
C 
 
 
 
 
 
 
D 
E
0.00
20.00
40.00
60.00
80.00
100.00
120.00
REGO (0)
REGO(0.1)
REGO(0.4)
REGO(1.1)
REGO(3.3)
REGO(10.0)
% Relative Growth
H2122 - KRAS Mutant
MTX (0)
MTX (0.25 uM)
0.00
20.00
40.00
60.00
80.00
100.00
120.00
REGO (0)
REGO(0.1)
REGO(0.4)
REGO(1.1)
REGO(3.3)
REGO(10.0)
% Relative Growth
Calu3 - KRAS Wild-type
MTX (0)
MTX (0.25 uM)


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References
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