Clinical trial NCT02624700
Conditions: Breast Cancer Metastatic Breast Cancer Recurrent Breast Cancer
Keywords: ER-negative PgR-negative Human epidermal growth factor receptor 2 (HER2-negative) Triple Negative Breast Cancer HER2-negative
Sponsor: Virginia Commonwealth University
Start date: 2016-01-28; Completion date: 2019-07-10
Enrollment: 13 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
This phase 2 clinical trial will evaluate the efficacy of the combination of pemetrexed and sorafenib in patients with recurrent or metastatic Triple Negative Breast Cancer (TNBC). Candidate pharmacodynamic and predictive biomarkers will also be evaluated.

Detailed description:
This study is a single-arm, open-label, phase 2 study of a regimen of dose-dense pemetrexed and sorafenib to determine the objective response rate in patients with recurrent or metastatic TNBC. Eligible patients will be those who have had disease progression during or after treatment for recurrent or metastatic disease with one previous cytotoxic chemotherapy regimen. Additionally, patients with disease progression or recurrence during or within 6 months of completion of adjuvant or neoadjuvant therapy are also eligible. Correlative studies will be conducted using blood samples and archived tumor samples.

Simon's two-stage design will be utilized in this study. In the first stage, if there are ≤ 3 patients of the first 18 efficacy-evaluable patients who have a partial or complete response, then the trial will end for futility. If ≥ 4 patients have a partial or complete response, patient accrual will continue in the second stage to add 10 more efficacy-evaluable patients.

The total sample size for the Simon's two-stage design is 35 patients. Based on enrollment of 2-3 patients per month, the expected enrollment period will be about 12-18 months.

Patients were enrolled in 2 sequential groups, referred to as "arms" for the purposes of reporting results by group. The initial group of patients were enrolled in what is referred to here as Arm A. After a study amendment patients were enrolled in what is referred to here as Arm B.

Arms: arm 1: Pemetrexed 500 mg/m2 IV Day 1 + Sorafenib 400mg PO twice each day on Days 1-5 of each 14-day cycle arm 2: Pemetrexed 375mg/m2 intravenously (IV) Day 1 + Sorafenib 200mg by mouth twice daily on days 1-5, every 21 days of each cycle.
Interventions: intervention 1: Experimental Arm A: Pemetrexed intervention 2: Experimental Arm A: Sorafenib intervention 3: Experimental Arm B: Pemetrexed intervention 4: Experimental Arm B: Sorafenib
Intervention descriptions: intervention 1: Treatment schedule is administered on day 1 of each 14-day cycle by Intravenous infusion over 10 minutes with a dose of 500 mg/m2. If necessary, the duration of the pemetrexed infusion may be extended to a maximum of 20 minutes. intervention 2: Treatment schedule is administered twice daily by mouth on an empty stomach on days 1-5 of each 14-day cycle with a dose of 400 mg. intervention 3: Treatment schedule is administered on day 1 of each 21-day cycle by Intravenous infusion over 10 minutes with a dose of 375 mg/m2. If necessary, the duration of the pemetrexed infusion may be extended to a maximum of 20 minutes. intervention 4: Treatment schedule is administered twice daily by mouth on an empty stomach on days 1-5 of each 21-day cycle with a dose of 200 mg.

Protocol documents:
Prot_SAP_000.pdf: 
Phase 2 Study of Pemetrexed and Sorafenib for Treatment of Recurrent or Metastatic Triple Negative Breast 
Cancer
NCT02624700
Version Date:  11/22/2017


Virginia Commonwealth University Massey Cancer Center 
Protocol MCC-14-10790 
Phase 2 Study of Pemetrexed and Sorafenib for Treatment of Recurrent or Metastatic 
Triple Negative Breast Cancer 
Principal Investigator 
Andrew Poklepovic, MD 
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TABLE OF CONTENTS 
REVISION HISTORY ................................................................................................................. 2 
LIST OF FIGURES ...................................................................................................................10 
LIST OF TABLES .....................................................................................................................10 
LIST OF ABBREVIATIONS ......................................................................................................11 
SCHEMA ..................................................................................................................................12 
1 
BACKGROUND .........................................................................................................13 
1.1 
AUTOPHAGY .................................................................................................................13 
1.2 
SORAFENIB ..................................................................................................................14 
1.3 
PEMETREXED ...............................................................................................................14 
1.4 
PRECLINICAL CONSIDERATIONS OF THE PEMETREXED AND SORAFENIB COMBINATION ......14 
1.5 
PHASE 1 RESULTS ........................................................................................................16 
1.6 
CLINICAL CONSIDERATIONS ...........................................................................................17 
1.7 
CORRELATIVE STUDIES .................................................................................................20 
2 
OBJECTIVES .............................................................................................................21 
2.1 
PRIMARY OBJECTIVE ....................................................................................................21 
2.2 
SECONDARY OBJECTIVES .............................................................................................21 
2.3 
EXPLORATORY OBJECTIVES ..........................................................................................21 
3 
STUDY DESIGN .........................................................................................................21 
3.1 
GENERAL DESCRIPTION ................................................................................................21 
3.2 
PRIMARY ENDPOINT ......................................................................................................22 
3.3 
SECONDARY ENDPOINTS ...............................................................................................22 
3.4 
EXPLORATORY ENDPOINTS ...........................................................................................22 
4 
PATIENT SELECTION ...............................................................................................23 
4.1 
INCLUSION CRITERIA .....................................................................................................23 
4.2 
EXCLUSION CRITERIA ...................................................................................................25 
5 
STUDY ENTRY AND WITHDRAWAL PROCEDURES ..............................................27 
5.1 
STUDY ENTRY PROCEDURES.........................................................................................27 
5.2 
STUDY WITHDRAWAL ....................................................................................................28 
6 
STUDY TREATMENT ................................................................................................28 
6.1 
BASELINE TESTS AND PROCEDURES ..............................................................................28 
6.2 
ADMINISTRATION OF STUDY TREATMENT ........................................................................28 
6.3 
MISSED SORAFENIB DOSES ..........................................................................................30 
6.4 
MONITORING PATIENT ADHERENCE WITH ORAL MEDICATIONS .........................................30 
6.5 
DURATION OF THERAPY ................................................................................................30 
6.6 
QT PROLONGATION CONSIDERATIONS ...........................................................................30 
6.7 
GENERAL CONCOMITANT MEDICATION AND SUPPORTIVE CARE GUIDELINES ....................31 
6.8 
STUDY POCKET CARD FOR PATIENTS ............................................................................35 
6.9 
FOLLOW-UP PERIOD .....................................................................................................35 
7 
DOSING DELAYS/DOSING MODIFICATIONS ..........................................................36 
7.1 
RECORDING DOSE MODIFICATIONS ................................................................................36 


 
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7.2 
TOXICITY ASSESSMENT .................................................................................................36 
7.3 
TOXICITY GRADING .......................................................................................................36 
7.4 
GENERAL INSTRUCTIONS AND GUIDELINES .....................................................................36 
7.5 
DOSE REDUCTION STEPS FOR PEMETREXED ..................................................................38 
7.6 
DOSE MODIFICATION INSTRUCTIONS FOR PEMETREXED ..................................................38 
7.7 
DOSE REDUCTION STEPS FOR SORAFENIB .....................................................................40 
7.8 
DOSE MODIFICATION INSTRUCTIONS FOR SORAFENIB .....................................................40 
8 
ADVERSE EVENT: DEFINITIONS AND REPORTING REQUIREMENTS .................45 
8.1 
DEFINITIONS .................................................................................................................45 
8.2 
KNOWN AES ................................................................................................................46 
8.3 
SECONDARY MALIGNANCY ............................................................................................47 
8.4 
TIME PERIOD AND GRADE OF AE CAPTURE ....................................................................47 
8.5 
PROCEDURES FOR RECORDING AES, SAES, AND UPS ...................................................47 
8.6 
EXPEDITED REPORTING PROCEDURES FOR SAES AND UPS ...........................................47 
8.7 
REQUIREMENTS FOR EXPEDITED REPORTING TO ELI LILLY AND COMPANY .......................48 
8.8 
REQUIREMENTS FOR EXPEDITED REPORTING TO BAYER HEALTHCARE PHARMACEUTICALS, 
INC ..............................................................................................................................49 
9 
PHARMACEUTICAL INFORMATION ........................................................................50 
9.1 
PEMETREXED (ALIMTA) .................................................................................................50 
9.2 
SORAFENIB ..................................................................................................................55 
10 
MEASUREMENT OF EFFECT ...................................................................................62 
10.1 
CRITERIA FOR TUMOR RESPONSE .................................................................................62 
10.2 
TUMOR RESPONSE REQUIREMENTS ...............................................................................62 
10.3 
CONFIRMATION OF RESPONSE ......................................................................................62 
10.4 
CENTRAL REVIEW FOR IMAGING INTERPRETATION ..........................................................62 
11 
CORRELATIVE STUDIES .........................................................................................63 
11.1 
PARTICIPATION IN CORRELATIVE STUDIES ......................................................................63 
11.2 
COLLECTION, PROCESSING, AND DISTRIBUTION OF SAMPLES ..........................................63 
11.3 
ARCHIVED TUMOR SAMPLES .........................................................................................63 
11.4 
CORRELATIVE BLOOD SAMPLES FOR MULTIPLEX ASSAYS ...............................................64 
11.5 
CORRELATIVE BLOOD SAMPLES FOR CTC ANALYSIS ......................................................65 
11.6 
BLOOD SAMPLE LABELING .............................................................................................66 
11.7 
TRACKING FOR ALL SAMPLES ........................................................................................66 
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STUDY CALENDAR ..................................................................................................67 
13 
STATISTICAL CONSIDERATIONS ...........................................................................72 
13.1 
STUDY DESIGN .............................................................................................................72 
13.2 
SAMPLE SIZE AND ACCRUAL RATE .................................................................................72 
13.3 
ANALYSIS POPULATIONS ...............................................................................................72 
13.4 
STATISTICAL ANALYSIS PLAN.........................................................................................73 
13.5 
DEFINITIONS FOR RESPONDERS AND NON-RESPONDERS ................................................73 
13.6 
STATISTICAL ANALYSIS FOR CORRELATIVE STUDIES .......................................................74 
14 
DATA AND SAFETY MONITORING ..........................................................................74 
14.1 
STUDY TEAM ................................................................................................................74 
14.2 
MONITORING AND AUDITING ..........................................................................................74 


 
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REGULATORY COMPLIANCE AND ETHICS ...........................................................74 
15.1 
ETHICAL STANDARD ......................................................................................................74 
15.2 
REGULATORY COMPLIANCE ...........................................................................................75 
15.3 
INSTITUTIONAL REVIEW BOARD .....................................................................................75 
15.4 
INFORMED CONSENT PROCESS .....................................................................................75 
15.5 
PATIENT CONFIDENTIALITY ............................................................................................75 
16 
DATA COLLECTION AND MANAGEMENT ..............................................................76 
16.1 
CRFS AND DATA COLLECTION .......................................................................................76 
16.2 
STUDY RECORD RETENTION .........................................................................................76 
17 
REFERENCES ...........................................................................................................77 
APPENDIX 1. PERFORMANCE STATUS CRITERIA ..............................................................80 
APPENDIX 2. COCKCROFT-GAULT FORMULA ....................................................................81 
APPENDIX 3. NEW YORK HEART ASSOCIATION CLASSIFICATION ..................................82 
APPENDIX 4. HEMATOLOGIC ADVERSE EVENTS ...............................................................83 
 
LIST OF FIGURES 
Figure 1. Additive Effect of Sorafenib and Pemetrexed in Increasing Number of Autophagic 
Vesicles in Tumor Cells ..............................................................................................15 
Figure 2. Reduction in Tumor Growth in HER2-positive BT474 Human Mammary Carcinoma 
Tumors Following Exposure to Sorafenib, Pemetrexed, and the Combination. ...........16 
 
LIST OF TABLES 
Table 1. Study Treatment Regimen ...........................................................................................29 
Table 2. Dose Reduction Steps for Pemetrexed ........................................................................38 
Table 3. Dose Modification Instructions for Pemetrexed ............................................................39 
Table 4. Dose Reduction Steps for Sorafenib ...........................................................................40 
Table 5. Sorafenib Dose Modification Guidelines ......................................................................41 
Table 6. Sorafenib Dose Reduction Guidelines for PPE ............................................................44 
Table 7. Expedited Reporting Requirements .............................................................................48 
Table 8. Adverse Reactions in Patients Receiving Pemetrexed versus Placebo in NSCLC.......54 
Table 9. Treatment-Emergent AEs Reported in at Least 10% of Sorafenib-Treated Patients – 
Phase 3 Advanced RCC Study ...................................................................................59 
Table 10. Study Calendar – Screening/Pretreatment Requirements .........................................68 
Table 11. Study Calendar – During Treatment and Follow-Up ..................................................70 


 
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LIST OF ABBREVIATIONS 
AE 
adverse event 
AICART 
aminoimidazolecarboxamide ribonucleotide formyltransferase 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
AST 
aspartate aminotransferase 
BID 
twice a day 
CBC 
complete blood count 
CR 
complete response 
CrCL 
creatinine clearance 
CRF 
case report form 
CTC 
circulating tumor cell 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTRL 
Clinical and Translational Research Laboratory 
DEPfff 
dielectrophoretic field flow fractionation 
DSMC 
Data and Safety Monitoring Committee 
EE 
efficacy-evaluable 
ER 
estrogen receptor 
FDA 
Food and Drug Administration 
HR 
hormone receptor 
IHC 
immunohistochemistry 
IM 
intramuscular 
INR 
international normalized ratio 
ITT 
intent-to-treat 
IV 
intravenous 
HER2 
human epidermal growth factor receptor 2 
IRB 
Institutional Review Board 
LLN 
lower limit of normal 
MCC 
Massey Cancer Center 
MMA 
methylmalonic acid 
MTD 
maximum tolerated dose 
NSAID 
non-steroidal anti-inflammatory drug 
NSCLC 
non-small cell lung cancer 
ORR 
objective response rate 
PDGFR 
platelet-derived growth factor receptor 
PO 
by mouth 
PgR 
progesterone receptor 
PR 
partial response 
PRMC 
Protocol Review and Monitoring Committee 
QTc 
QT interval, corrected 
QTcF 
QT interval with correction using Fridericia’s formula 
RCC 
renal cell carcinoma 
RECIST 
Response Evaluation Criteria in Solid Tumors 
SAE 
serious adverse event 
SIIT 
solid tumor investigator-initiated trial 
TNBC 
triple negative breast cancer 
TS 
thymidylate synthase 
UP 
unanticipated problem 
VCU 
Virginia Commonwealth University 
WCBP 
woman of child-bearing potential 


 
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SCHEMA 
 
 
Eligibility Screening & Study Registration 
Recurrent or Metastatic Triple Negative Breast Cancer 
Follow-Up After Discontinuation of Study Treatment  
30-day adverse event assessment;  
follow-up for disease progression until 2 years after initiation of study treatment 
or until new treatment is initiated, whichever occurs first; and 
 follow-up for survival until 2 years after initiation of study treatment  
Correlative Samples 
Submission of Archived Tumor Samples;  
Collection of Blood Samples 
Study Treatment Regimen 
During Each 21-Day Cycle 
Pemetrexed 375 mg/m2 IV on Day 1 
+ 
Sorafenib 200 mg BID PO on Days 1-5 
Correlative  
Blood Samples  
In Cycles 1 and 2; 
at time of response 
assessment;  
at time of disease 
progression 
Stage 2 
If ≥ 3 patients have 
PR or CR,  
an additional 13 
efficacy-evaluable 
patients will be 
enrolled  
Study Closure 
If ≤ 2 patients have 
PR or CR, no 
additional patients 
will be enrolled 
Stage 1 
Hold accrual, if needed, 
after the first 15  
efficacy-evaluable 
patients have been 
enrolled  


 
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1 BACKGROUND 
Most highly active cancer chemotherapy regimens combine agents with complementary 
activity. A treatment combination currently being studied in the phase 1 setting is 
pemetrexed, a folate analog metabolic inhibitor, and sorafenib, a tyrosine kinase inhibitor. 
Pemetrexed is approved by the Food and Drug Administration (FDA) for the treatment of 
non-squamous, non-small cell carcinoma of the lung and mesothelioma. Sorafenib is an  
FDA-approved agent for the treatment of differentiated thyroid cancer refractory to 
radioactive iodine treatment, renal cell carcinoma, and hepatocellular carcinoma. 
Preclinical studies in both tumor cell lines and animal tumor models have shown promising 
anticancer effects of the combination of pemetrexed and sorafenib in diverse solid tumor 
types. These studies also suggest that the observed promising anticancer effects may be 
related to modulation of tumor cell autophagy. The results of the preclinical studies 
prompted evaluation of the combination in a phase 1 clinical trial which has identified an 
encouraging response pattern in patients with heavily pretreated breast cancer. The clinical 
responses seen in the breast cancer population of the phase 1 trial, coupled with the 
preclinical data, provide justification for further study of this therapeutic concept as a phase 
2 clinical trial in breast cancer. 
Patients with HER2-positive breast cancer generally remain on HER2-directed therapy as 
they advance through lines of therapy, and the combination of HER2-directed therapy with 
pemetrexed and sorafenib is beyond the scope of this trial. Therefore, patients with  
HER2-positive breast cancer will not be included. Recent advances in the treatment of 
hormone receptor (HR)-positive tumors have led to increasing differences in the way that 
clinicians treat HR-positive metastatic breast cancer, compared to triple negative breast 
cancer (TNBC). As such, inclusion of both HR-positive and HR-negative tumors could make 
it more difficult to determine clinical utility in each subgroup in a study of this size. Therefore, 
only patients with HR-negative breast cancer will be included in this study. 
In summary, this phase 2 clinical trial will evaluate the efficacy of the combination of 
pemetrexed and sorafenib in patients with recurrent or metastatic TNBC. Candidate 
pharmacodynamic and predictive biomarkers will also be evaluated. 
1.1 Autophagy 
There are 2 main types of programmed cell death: Type I, also called apoptosis, refers 
specifically to an ATP energy-dependent process involving transcription of specific proteins 
and leading eventually to a cell’s demise. Type II programmed cell death is known as 
autophagy, and is a ubiquitous process that occurs in all eukaryocytes (1, 2). Autophagy is 
a non-selective process in which cytoplasm and organelles are assorted into the 
autophagosome. After autophagosome formation, this structure fuses with an acidic 
endosome, where the contents are degraded. Based on the cell system and the 
drugs/stimulus being studied, autophagy can either act to protect cells from a toxic stress 
or can augment the toxicity of the stress. There is published evidence for both “protective” 
and “toxic” forms of autophagy based on the stimulus and cell type being examined (3-9). 
Macroautophagy is one of the 3 main types of autophagy, and is regulated by 2  
ubiquitin-like conjugation systems, ATG12-ATG5 and ATG8 (LC3A) (10-14). Apoptosis 
pathways have also been linked with autophagy, for example, knockdown of caspase 8 
which can induce autophagic death (14). Beclin1 (autophagy-related gene 6 [ATG6]) 


 
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contains a BH3 domain that binds to BCL-2/BCL-XL/MCL-1; release of Beclin1 from these 
proteins permits induction of autophagy (10-14). 
The ser-thr kinase mTOR acts as one gatekeeper in the autophagy process, exerting an 
inhibitory effect. mTOR acts 1) in a signal transduction cascade that activates  
anti-autophagic transcription and translation and 2) by inhibiting the ATG proteins directly 
via their phosphorylation (15, 16). The PI3K class I/AKT pathway is involved in the  
down-regulation of autophagy by activation of mTOR, whereas Beclin1 and the class III 
type PI3K complex are positive regulators of autophagy (17). 
1.2 Sorafenib 
Sorafenib is a multitargeted protein kinase inhibitor that was originally developed as an 
inhibitor of RAF-1, a component of the ERK1/2 pathway, but which was subsequently 
found to inhibit multiple other kinases, including class III tyrosine kinase receptors such as 
platelet-derived growth factor receptor (PDGFR), vascular endothelial growth factor 
receptor (VEGFR), c-Kit, and FLT3 (3-7). Virginia Commonwealth University (VCU) 
investigator Paul Dent, PhD and collaborators have shown in vitro that sorafenib kills 
human leukemia cells through a mechanism involving down-regulation of MCL-1. In these 
studies, sorafenib-mediated down-regulation of MCL-1 occurred through a translational 
process that was mediated by endoplasmic reticulum stress signaling and the regulation of 
autophagy (18). More recently, his group has shown that sorafenib-mediated inhibition of 
PDGFR plays a key role in the ability of this agent to promote autophagy in tumor cells 
(7). 
1.3 Pemetrexed 
Pemetrexed, the first anti-folate cancer drug to be approved by the FDA in 20 years, is 
currently used for first-line therapy of mesothelioma and non-small cell lung cancer 
(NSCLC). It was originally developed as an inhibitor of thymidylate synthase (TS) (19-22). 
Pemetrexed also has at least one other target that becomes apparent from a continued 
antiproliferative effect of drug treatment in cell cultures exposed to exogenous thymidine, 
which prevents the cytotoxic effects of TS inhibition (19, 20). A secondary target is the 
downstream folate-dependent enzyme in de novo purine synthesis, 
aminoimidazolecarboxamide ribonucleotide formyltransferase (AICART). ZMP, the 
substrate of the AICART reaction, accumulates in intact pemetrexed-inhibited tumor cells, 
identifying AICART as the step in purine synthesis that becomes rate-limiting after drug 
treatment (19). The accumulating ZMP causes an activation of AMP-activated protein 
kinase with subsequent inhibition of the mammalian target of rapamycin (mTOR) and 
induction of autophagy. Inhibition of autophagy protects tumor cells from pemetrexed 
toxicity. 
1.4 Preclinical Considerations of the Pemetrexed and Sorafenib Combination 
In preclinical in vitro and in vivo models, sorafenib enhanced autophagy levels, and 
interacted in a greater than additive fashion with pemetrexed to kill tumor cells. Inhibition of 
autophagy blocked the toxic interaction between sorafenib and pemetrexed. Sorafenib and 
pemetrexed interacted in a greater than additive fashion to increase the number of 
autophagic vesicles in tumor cells, which was inhibited by knockdown of Beclin1, as shown 
in Figure 1. 


 
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Figure 1. Additive Effect of Sorafenib and Pemetrexed in Increasing Number of Autophagic Vesicles 
in Tumor Cells 
BT474, HuH7 and 4T1breast cancer cells indicated are transfected with siRNAs (si-scramble, siSCR; 
siBeclin1; 20 nM) and with a plasmid to express LC3-GFP (fluorescent protein tagged form of LC3). 
Twenty-four hours after transfection, cells were treated with vehicle (PBS) or pemetrexed (0.03-3.0 
μM) and/or vehicle (DMSO) or sorafenib. Twelve hours after drug exposure cells were examined 
under a fluorescent microscope (40x) at the indicated times after drug exposure and the mean 
number of vesicles in 40 random cells calculated per experiment (n=2, 80 cells sampled, +/- SEM; 
 * p < 0.05 less than corresponding siSCR value). 
 
Additionally, evaluations were performed examining the relative phosphorylation and 
expression levels of signal transduction proteins whose expression and activity may 
correlate to pemetrexed + sorafenib sensitivity. Tumor cell types that displayed high levels 
of cell killing after pemetrexed + sorafenib exposure tended to exhibit elevated levels of 
ERK1/2, along with elevated expression levels of class III receptor tyrosine kinases such 
as PDGFRβ, FGFR1, and VEGFR1. Knockdown of PDGFRβ, p70S6K, or mTOR 
enhanced pemetrexed + sorafenib lethality. 
Pemetrexed and sorafenib were also evaluated in murine tumor models. In orthotopic-
established human mammary carcinoma tumors, sorafenib significantly reduced tumor 
growth, whereas pemetrexed had little impact on tumor mass (Figure 2). 


 
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Figure 2. Reduction in Tumor Growth in HER2-positive BT474 Human Mammary Carcinoma 
Tumors Following Exposure to Sorafenib, Pemetrexed, and the Combination. 
For studies with human mammary carcinoma cells, athymic Nu/Nu mice (8-week old, female) were 
injected, into the 4th mammary fat pad, with 1.0 x 107 BT474cells. Tumors of ~75 mm3 grew over the 
following month. The animals were administered vehicle diluent (cremophore), sorafenib (25 mg/kg), 
pemetrexed (50 mg/kg), or the drug combination by oral gavage once every day for 5 days. Animals 
were treated for 5 days with drugs and tumor volumes measured every 2-3 days as indicated, and 
mean tumor volumes plotted (n=2 studies; 8 animals per group total +/- SEM; * p < 0.05 less than 
corresponding vehicle control value; % p < 0.05 less than corresponding sorafenib value). 
 
Collectively, these data lead us to conclude that sustained inhibition of the  
p70S6k/mTOR-signaling module following pemetrexed and sorafenib exposure plays a 
central role in drug combination lethality through toxic forms of autophagy. 
1.5 Phase 1 Results 
In the phase 1 dose escalation study designed to find the maximum tolerated doses of 
pemetrexed and sorafenib, pemetrexed was administered every 2 weeks (ie, dose-dense 
schedule) with oral sorafenib on a continuous basis. While dose escalation continued 
through the initial cohorts based on lack of dose-limiting toxicities in the first cycle, it was 
difficult for patients to remain on continuous sorafenib when combined with dose-dense 
pemetrexed for more than a few cycles. Fatigue, hand-foot syndrome, and enhancement of 
pemetrexed-induced mucositis and cytopenias were problematic in subsequent cycles 
requiring dose delays and reductions. 
However, in spite of the delayed toxicity issue, the combination demonstrated promising 
activity. Five out of 11 breast cancer patients in the phase 1 study, including 3 out of 5 
patients with TNBC, demonstrated an objective response, with 4 partial responses (PRs) 
and one complete response (CR). In the TNBC population, there were one CR, 2 PRs,  
one stable disease, and one progressive disease as best response. One PR and the CR 
each had 10-month duration of response. All responding patients were heavily pretreated, 
Vehicle 
Sorafenib 
Pemetrexed 
Sor + Ptx 


 
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with a median of 6 previous lines of therapy and a mean of 6.6 previous lines. Cutaneous, 
nodal, and visceral metastases were all observed to respond to treatment (23). In the 
TNBC population, responses occurred after 2, 7, and 4 previous lines of cytotoxic therapy 
for metastatic disease. These tumor responses suggest that TNBC, even in heavily 
pretreated patients, can respond to pemetrexed and sorafenib treatment, supporting 
further development of this combination in pretreated patients with TNBC. 
Based on the activity of the combination, the decision was made to move to an intermittent 
sorafenib dosing schedule for subsequent cohorts to allow continued dose escalation and 
dose maintenance. Intermittent dosing of sorafenib with dose-dense pemetrexed has been 
well tolerated, and tumor responses have continued to be observed, including in breast 
cancer. 
The treatment doses initially selected for this phase 2 clinical trial were pemetrexed 500 
mg/m2 IV administered on day 1 with sorafenib 400 mg taken orally twice each day on 
days 1-5 of each 14-day cycle. This treatment regimen was well tolerated and below the 
highest tolerable dose of 750 mg/m2 of pemetrexed with 400 mg PO BID of intermittent 
sorafenib tested in the phase 1 study. The lower dose of 500 mg/m2 was selected for 
phase 2 study in breast cancer, because 4 of the 5 responding patients with breast cancer 
were treated at this dose during the phase 1 study. Additionally, intensification of dosing to 
higher doses was studied in lung cancer and high dose pemetrexed was not associated 
with improvements in response rate or median overall survival (24). The doses of both 
agents have been reduced effective with version 4 of the protocol. The new doses are 
pemetrexed 375 mg/m2 IV administered on day 1 with sorafenib 200 mg taken orally twice 
each day on days 1-5 of each 21-day cycle.  
1.6 Clinical Considerations 
1.6.1 Vitamin Supplementation 
Original dose-finding studies with pemetrexed were performed without folate and 
B12 supplementation. The maximum tolerated dose (MTD), without 
supplementation, was found to be 600 mg/m2 dosed once every 3 weeks (25). 
Subsequently, it was determined that B12 and folate supplementation are required to 
mitigate pemetrexed-related hematologic toxicity. Therefore, pemetrexed will be 
supplemented with B12 and folate throughout study treatment. 
1.6.2 Pemetrexed Dose-Dense Schedule 
With vitamin supplementation, pemetrexed has been evaluated in multiple settings 
with various dosing schedules, and a variety of MTDs have been found. In a 3-week 
dosing schedule, single-agent pemetrexed has been reported to have a MTD of 
1050 mg/m2 (26). The MTD of pemetrexed has also been reported to be as high as 
1800 mg/m2 in combination with cyclophosphamide (27). 
Pemetrexed has been studied in a dose-dense fashion, and, as a single agent,  
1000 mg/m2 was tolerated well on an every-2-week schedule (28). Much lower 
doses of pemetrexed demonstrated clinical activity when pemetrexed was given 
with sorafenib in the phase 1 study. A proposed mechanism of action of the 
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pemetrexed exposure. Shortening the interval between dosing will increase the 
duration of AICART inhibition, which may be useful in defining the therapeutic index.  
Pemetrexed was initially evaluated in the dose-dense setting for this study, but 
eligibility requirements were amended such that the extended (3-week) dosing 
schedule was thought to be more appropriate. These changes are explained further 
in Section 1.6.6. 
1.6.3 Sorafenib Treatment Schedule 
Pharmacokinetic data have demonstrated that once-daily dosing results in 
extremely low systemic concentrations compared to twice-daily dosing, eg, 800 mg 
once daily has significantly lower serum concentrations than 100 mg twice daily 
(29). Therefore, sorafenib will be taken by the patient on a twice-daily schedule in 
this phase 2 trial. 
In the phase 1 study, Pemetrexed Disodium and Sorafenib Tosylate in Treating 
Patients With Advanced Solid Tumors (NCT01450384), it was identified during 
treatment of the initial cohort that it was difficult for patients to tolerate sorafenib on 
a continuous dosing schedule when combined with pemetrexed. Fatigue, hand-foot 
syndrome, and enhancement of pemetrexed-induced mucositis and cytopenias 
were observed. It is commonly recognized that single-agent sorafenib is difficult to 
tolerate when taken continuously at full dose. In the registration trial for sorafenib in 
hepatocellular carcinoma (SHARP Trial), dose reductions due to adverse events 
occurred in 26% of patients; dose interruptions due to adverse events occurred in 
44% (30). In the phase 3 trial of sorafenib as a single agent in renal cell carcinoma, 
13% of patients required dose reductions; 21% required dose omissions (31). Many 
patients in the continuously-dosed sorafenib cohort required both dose reductions 
and interruptions when combined with pemetrexed. As such, the treatment regimen 
in the phase 1 study was modified to implement an intermittent dosing strategy. 
Additionally, regorafenib, an analog of sorafenib which is FDA-approved for 
colorectal carcinoma and gastrointestinal stromal tumors (GIST), employs an 
intermittent dosing schedule, demonstrating that kinase inhibitors can be effective 
with intermittent dosing. 
As the preclinical data suggest, combination therapy is the most effective approach 
for the induction of toxic autophagy. It was determined that 5 days of sorafenib 
dosing with each dose of pemetrexed will result in drug combination effects, and the 
days without therapy will allow continued dose intensity with repeated cycles. As 
anticipated, the intermittent dosing cohort of sorafenib has been observed to have 
significantly less toxicity than the continuous dosing cohort, and antitumor effects 
have been seen. 
1.6.4 Assessment of ER, PgR, and HER2 Status in Recurrent or Metastatic Tumor 
It is well known that breast cancers can undergo phenotypic shift altering expression 
of ER, PgR, and/or HER2 (32). Additionally, progressive cancers can acquire 
resistance to systemic treatment as a result of clonal evolution and selection. 
Therefore, eligibility will be based on the HER2, ER, and PgR reported following a 
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was not biopsied, the HER2, ER, and PgR status reported at the time of the initial 
diagnosis or resection will be used for eligibility screening. 
1.6.5 Rationale for Modifying Eligibility Related to Previous Chemotherapy 
Based on clinical experience with the initial patients referred for participation in this 
study, a treatment history that includes multiple previous lines of cytotoxic 
chemotherapy has been identified as a potential risk factor for increased 
hematologic toxicity related to study treatment. The decision was made to narrow 
eligibility to include only those who have had only one prior line of cytotoxic 
chemotherapy for metastatic disease and, if the patient had disease progression 
during or within 6 months following completion of adjuvant therapy, for first-line 
therapy. The related inclusion criterion was revised at the time of the first protocol 
amendment to reflect this decision (Section 4.1.4). 
1.6.6 Rationale for Modifying Eligibility, Dose, Schedule, and Sample Size 
Patients with TNBC are regularly treated with cytotoxic chemotherapy, as either 
single agents or doublet therapy. It was identified from the phase 1 study that 
patients previously treated with multiple lines of cytotoxic chemotherapy had an 
association with enhanced toxicity from this treatment regimen, as noted in Section 
1.6.5. Accrual has been more difficult with restriction to the second line only setting, 
so the decision was made to re-expand to allow for patients to be more heavily pre-
treated and remain eligible for study enrollment. As such, we determined that 
lowering the doses of both agents and treating on a 21-day cycle would be 
appropriate. The new dose and schedule fit with current patients on the protocol, 
who have found good tolerability at this dose and schedule, and with prior 
experience from the phase 1 study in which patients with breast cancer derived 
clinical benefit at doses below the recommended phase 2 dose. 
Effective with version 4 of the protocol, patients with at least one prior regimen of 
treatment for recurrent or metastatic disease may be eligible. The dose has been 
reduced as described in Section 1.5 and Section 6 to accommodate the potential for 
hematologic toxicity in patients who have received more than one previous 
treatment regimen. The change in cycle length from a dose-dense (every 14 days) 
schedule to a 21-day schedule changes the frequency at which patients are seen in 
later cycles. The schedules for physical exams, tumor response assessments, 
Vitamin B12 administration, and correlative sample collection have been adjusted to 
better fit the new patient visit intervals. 
In order to accurately evaluate the efficacy of pemetrexed and sorafenib in 
combination at the new lower dose, it was determined that stage 1 of the two-stage 
design should include only patients treated at that lower dose. If that cohort meets 
the efficacy criteria to continue, patients previously treated at the higher dose will be 
included in the second stage for overall evaluation of efficacy. The percent non-
evaluable estimate was adjusted based on the evaluability of patients who have 
already enrolled to the trial. The necessary sample sizes for stage 1 and 2 of the 
Simon’s two-stage design were re-calculated. The new sample sizes and study 
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1.7 Correlative Studies 
1.7.1 Archived Tumor Samples 
Serial analysis can identify potential new targets for therapy. This concept is being 
formally explored in trials such as the NCI Molecular Analysis for Therapy Choice 
(NCI MATCH) Trial, and several such potential pathways will be investigated in the 
MCC-14-10790 clinical trial. 
Based on results reported for the phase 1 trial that evaluated the pemetrexed and 
sorafenib combination, the targets to be explored in this phase 2 study were revised 
at the time of the first protocol amendment. Expression of Beclin1 and other 
biomarkers evaluated in the phase 1 study that did not prove to be useful targets 
have been removed from the planned correlative studies for MCC-14-10790. 
Correlative data from the phase 1 study did suggest that the level of PTEN 
expression may be predictive of response to the pemetrexed/sorafenib combination, 
and evaluation of PTEN activity has been added to the plans for this phase 2 trial 
(33). 
TS expression will also be evaluated. TS has previously been shown to be 
predictive of response to pemetrexed. The autophagy pathway will continue to be 
explored. 
Because the expression of biomarkers can change during disease progression or in 
response to treatment, these biomarkers will be assessed using tumor samples from 
diagnostic specimens obtained at the time of initial diagnosis and tumor samples 
archived at the time of a diagnostic core biopsy or surgical resection of recurrent or 
metastatic tumor. 
1.7.2 Blood Samples for Multiplex Assays 
Blood samples will be collected on days 1 and 2 of cycle 1, day 1 of cycle 2, and at 
the time of each tumor response assessment (about every 9 weeks). Additionally, a 
blood sample will be collected, if possible, at time of disease progression (prior to 
starting new cancer therapy). 
The plasma is isolated and stored for subsequent multiplex assays. Plasma from 
each patient will be subjected to multiplex assays to determine the expression of 
about 80 cytokines/growth factors. 
1.7.3 Blood Samples for Collection and Analysis of Circulating Tumor Cells 
The presence in the blood of circulating tumor cells (CTCs) derived from breast 
cancer provides an opportunity to study the in vivo response of tumor cells to drug 
treatment, with the advantage that samples can be obtained by a simple blood draw 
rather than by tumor biopsy. 
LC3A (microtubule-associated protein 1 light chain 3) is a protein used in the 
detection of autophagic vesicles (34). Increases in autophagic vesicles were 
detected in tumor cell lines treated with the combination of pemetrexed and 
sorafenib (Figure 1). Immunohistochemical (IHC) analysis of autophagy in CTCs 


 
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has not been performed to date. The feasibility of testing for autophagic vesicle 
formation will be determined in CTCs using blood samples collected at baseline, 
about 24 hours after the first pemetrexed dose, and at the time of the first tumor 
response assessment. 
2 OBJECTIVES 
2.1 Primary Objective 
To determine the objective response rate (ORR) in patients with recurrent or metastatic 
TNBC who have received the combination of pemetrexed and sorafenib 
2.2 Secondary Objectives 
In patients with recurrent or metastatic TNBC who have received a combination of 
pemetrexed and sorafenib: 
2.2.1 To evaluate progression-free survival (PFS) 
2.2.2 To determine the 2-year survival rate 
2.2.3 To further characterize the safety and side effect profile of the combination 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
3 STUDY DESIGN 
3.1 General Description 
This study is a single-arm, open-label, phase 2 study of a regimen of dose-dense 
pemetrexed and sorafenib to determine the objective response rate in patients with 
recurrent or metastatic TNBC. Eligible patients will be those who have had disease 
progression during or after treatment for recurrent or metastatic disease with at least one 
previous regimen. Additionally, patients with disease progression or recurrence during or 
within 6 months of completion of adjuvant or neoadjuvant therapy are also eligible. 
Correlative studies will be conducted using blood samples and archived tumor samples. 


 
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Simon’s two-stage design will be utilized in this study. In the first stage, if ≤ 2 patients of 
the first 15 efficacy-evaluable patients have a partial or complete response, then the trial 
will end for futility. If ≥ 3 patients have a partial or complete response, patient accrual will 
continue in the second stage. The patients enrolled and treated at the initial higher dose 
will count toward the second stage, and patients will continue to be enrolled and treated 
until the second stage contains 13 efficacy-evaluable patients. 
The total sample size for the Simon’s two-stage design is 37 patients. Based on enrollment 
of 2-3 patients per month, the expected enrollment period will be about 18-24 months. 
3.2 Primary Endpoint 
The proportion of patients with objective response defined as a complete response (CR) or 
partial response (PR) based on Response Evaluation Criteria in Solid Tumors Version 1.1 
(RECIST v1.1) 
3.3 Secondary Endpoints 
3.3.1 PFS defined as the time from initiation of study treatment until documented disease 
progression or death, whichever occurs first 
3.3.2 Proportion of patients who are alive at 2 years following initiation of study treatment 
3.3.3 Adverse events (AEs) reported using criteria in the National Cancer Institute 
Common Terminology Criteria for Adverse Events Version 4.0 (CTCAE v4.0) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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4 PATIENT SELECTION 
4.1 Inclusion Criteria 
A patient must meet all of the following inclusion criteria to be eligible for this study. 
4.1.1 Unresectable adenocarcinoma of the breast involving chest wall, regional nodes, or 
distant site 
4.1.2 Breast cancer determined to be ER-negative and PgR-negative defined for this 
study as < 10% tumor staining by IHC 
Note: Eligibility should be based on the ER and PgR status reported at the time of 
the most recent biopsy or resection. 
4.1.3 Breast cancer determined to be HER2-negative per current American Society of 
Clinical Oncology/College of American Pathologists (ASCO/CAP) HER2 Guidelines 
Note: Eligibility should be based on the HER2 status reported at the time of the most 
recent biopsy or resection. 
4.1.4 At least one prior regimen for treatment of recurrent or metastatic disease 
Note: Prior regimen for recurrent or metastatic disease is not required if the patient 
had disease progression or recurrence during or within the first 6 months following 
completion of adjuvant or neoadjuvant chemotherapy. 
4.1.5 Measurable disease per RECIST v1.1 
4.1.6 Age ≥ 18 years 
4.1.7 Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1  
(see Appendix 1) 
4.1.8 Ability to swallow oral medications 
4.1.9 Adequate bone marrow function as defined below: 
 
Absolute neutrophil count (ANC) ≥ 1,200/mm3 
 
Platelet count ≥ 100,000/mm3 
 
Hemoglobin ≥ 9.0 g/dL, which must be stable in the opinion of the investigator 
without a history of transfusion dependence 
4.1.10 Adequate renal function as defined below: 
Calculated creatinine clearance ≥ 45 mL/min (see Appendix 2 for the Cockcroft-
Gault formula for calculating creatinine clearance) 


 
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4.1.11 Adequate hepatic function as defined below: 
 
Total bilirubin ≤ 1.5 x upper limit of normal (ULN) for the laboratory 
 
Aspartate aminotransferase (AST) ≤ 3 x ULN for the laboratory, except in the 
presence of known hepatic metastasis, wherein the AST may be ≤ 5 x ULN 
 
Alanine aminotransferase (ALT) ≤ 3 x ULN for the laboratory, except in the 
presence of known hepatic metastasis, wherein the ALT may be ≤ 5 x ULN 
4.1.12 Serum B12 and folate levels ≥ lower limit of normal (LLN) for the laboratory 
Note: Patients may begin B12 and folic acid supplementation and be reconsidered 
for participation in the study when levels are ≥ LLN for the laboratory. 
4.1.13 Ability to take folic acid, vitamin B12, and dexamethasone according to the protocol 
instructions in Table 1 (Section 6.2) 
4.1.14 Ability to interrupt chronic non-steroidal anti-inflammatory drugs (NSAIDs) beginning 
2 days before (5 days before for long-acting NSAIDs) and continuing for 2 days 
following administration of each pemetrexed dose 
4.1.15 Toxicities from previous cancer therapies resolved to ≤ grade 1 unless specified 
otherwise in the inclusion or exclusion criteria (Exceptions: Chronic residual 
toxicities that in the opinion of the investigator are not clinically relevant given the 
known safety/toxicity profiles of pemetrexed and sorafenib, such as alopecia, 
changes in pigmentation, stable endocrinopathies. Neuropathy related to previous 
chemotherapy must be resolved to ≤ grade 2.) 
4.1.16 Women who are not postmenopausal or have not undergone hysterectomy must 
have a documented negative serum pregnancy test within 7 days prior to initiating 
study treatment. Note: Postmenopausal is defined as one or more of the following: 
 
Age ≥ 60 years 
 
Age < 60 years and amenorrheic for at least 1 year with follicle-stimulating 
hormone (FSH) and plasma estradiol levels in the postmenopausal range 
 
Bilateral oophorectomy 
4.1.17 A woman of child-bearing potential (WCBP) and a male patient with partner who is a 
WCBP must agree to use a medically accepted method for preventing pregnancy for 
the duration of study treatment and for 2 months following completion of study 
treatment. 
4.1.18 Ability to understand and willingness to sign the consent form written in English 


 
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4.2 Exclusion Criteria 
4.2.1 Any investigational agent within 4 weeks prior to initiating study treatment 
4.2.2 Anticancer therapy within 2 weeks prior to initiating study treatment 
4.2.3 Plans for concurrent anticancer therapy except as permitted in Section 6.7.11 
4.2.4 Known or presumed intolerance of pemetrexed or sorafenib 
4.2.5 Known or suspected malabsorption condition or obstruction 
4.2.6 Brain metastases meeting either of the following exclusion criteria: 
 
Untreated brain metastases 
 
After completion of brain-directed therapy, the patient has not been able to 
tolerate discontinuation of steroids or a decrease in steroid dose 
4.2.7 Leptomeningeal metastasis 
4.2.8 Any documented history of clinically identifiable thrombotic, embolic, venous, or 
arterial events such as cerebrovascular accident, transient ischemic attack, deep 
vein thrombosis, or pulmonary embolism within 6 months prior to initiating study 
treatment 
Note: Patients with an asymptomatic catheter-related thrombus or a tumor-
associated thrombus of locally-involved vessels or with incidental asymptomatic 
filling defects identified on imaging are not excluded. 
4.2.9 Contraindication to antiangiogenic agents, including: 
 
Serious non-healing wound, non-healing ulcer, or bone fracture 
 
Major surgical procedure or significant traumatic injury within 4 weeks prior to 
initiating study treatment 
 
Pulmonary hemorrhage/bleeding event  grade 2 (CTCAE v4.0) within 12 weeks 
prior to initiating study treatment 
 
Any other hemorrhage/bleeding event  grade 3 (CTCAE v4.0) within 12 weeks 
prior to initiating study treatment 
4.2.10 Systolic blood pressure (BP) > 160 mmHg or diastolic BP > 100 mmHg despite 
optimal medical management 
4.2.11 QTc interval > 480 ms (≥ grade 2) on a 12-lead electrocardiogram (ECG) 
 
If baseline QTc on screening ECG is ≥ grade 2: 
- 
Check potassium and magnesium serum levels 
- 
Correct any identified hypokalemia and/or hypomagnesemia and repeat 
ECG to confirm exclusion of patient due to QTc 


 
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 
For patients with heart rate < 60 bpm or > 100 bpm, manual read of the QT 
interval by a cardiologist is required, with Fridericia correction applied to 
determine QTcF which must be used to determine eligibility. 
Note: If heart rate is 60-100 bpm, manual read of the QT interval and correction 
to QTcF is not required. 
4.2.12 Active or clinically significant cardiac disease including any of the following: 
 
Unstable angina (eg, anginal symptoms at rest) or onset of angina within  
3 months prior to initiating study treatment 
 
Myocardial infarction within 6 months prior to initiating study treatment 
 
Ventricular arrhythmias requiring anti-arrhythmic therapy other than beta 
blockers 
 
New York Heart Association (NYHA) class III or IV congestive heart failure (see 
Appendix 3) 
4.2.13 Serious (ie, ≥ grade 3) uncontrolled infection 
4.2.14 Uncontrolled effusion eg, presence of third space fluid that, in the opinion of the 
investigator, cannot be successfully controlled by drainage 
Note: Patients with small effusions remaining after pleurodesis are eligible. 
Determination of eligibility based on pleural size will be determined by the principal 
investigator. 
4.2.15 Known human immunodeficiency virus (HIV) seropositivity 
Note: HIV testing is not required. 
4.2.16 Chronic or active hepatitis B or C infection requiring treatment with antiviral therapy 
4.2.17 Seizure disorder requiring enzyme-inducing anti-epileptic drugs (EIAEDs) 
Note: If the seizure disorder can be managed with agents that are not EIAEDs  
(eg, levetiracetam or valproate), the patient should not be excluded. 
4.2.18 Planned ongoing treatment with other drugs thought to potentially have adverse 
interactions with either of the study drugs; if such drugs have been used, patients 
must have discontinued these agents at least 2 weeks (or as noted below) prior to 
initiating study treatment. Examples include: 
 
STRONG CYP3A4 inducers (see Section 6.7.12) 
Note: Examples of clinical inducers for cytochrome P450 (CYP) isozymes and 
classification of strong, moderate, and weak interactions are available through 
the FDA website (Table 3-3 of website): 
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResource
s/DrugInteractionsLabeling/ucm093664.htm 


 
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 
Immunosuppressants (eg, tacrolimus, leflunomide, tofacitinib, roflumilast, 
pimecrolimus) (see Section 6.7.12) 
 
NSAIDs 
Note: NSAIDs must be discontinued within 5 days prior to initiating study 
treatment (see Section 6.7.10). 
4.2.19 Pregnancy or breastfeeding 
4.2.20 Previous malignancy with the following exceptions: adequately treated basal cell 
carcinoma or squamous cell carcinoma of the skin; any in situ malignancy; 
adequately treated Stage 1 or Stage 2 cancer from which the patient is currently in 
remission; any other cancer from which the patient has been disease-free for 3 
years  
4.2.21 Medical, psychological, or social condition that, in the opinion of the investigator, 
may increase the patient’s risk or limit the patient’s adherence with study 
requirements 
5 STUDY ENTRY AND WITHDRAWAL PROCEDURES 
5.1 Study Entry Procedures 
5.1.1 Required Pre-Registration Screening Tests and Procedures 
5.1.2 Refer to the study calendars in Section 12 (Table 10) for the screening tests and 
procedures that are required prior to registration and/or treatment and for the timing 
of these events relative to the start of treatment. 
5.1.3 Registration Process 
To register a patient, the following documents must be provided to the registrar at 
VCU Massey Cancer Center 
 
 
Registration cover sheet 
 
Completed eligibility checklist 
 
Signed and dated informed consent form 
The registrar will complete the registration process by assigning a study 
identification (ID) number and forwarding the “Confirmation of Registration” form to 
the registering study team. 
No patient may begin study treatment until the Confirmation of Registration 
assigning a study ID number has been received from the registrar. The registering 
study team will enter the patient’s initial enrollment data (eg, demographics, 
consent, eligibility, on study) into the OnCore database within 24 hours following 
study registration and before treatment begins. 


 
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5.2 Study Withdrawal 
A patient may decide to withdraw from study participation at any time. Patients must be 
withdrawn from the study when any of the following occurs: 
 
Consent withdrawal for study treatment and study procedures 
 
If, in the investigator's opinion, continuation of the study requirements would be harmful 
to the patient's well-being 
 
Patient is lost to follow-up 
The reason for and date associated with study withdrawal or removal from the study must 
be documented in the source documents and OnCore database. 
6 STUDY TREATMENT 
6.1 Baseline Tests and Procedures 
Patients who are eligible and enrolled in the study but do not immediately initiate study 
treatment are expected to meet eligibility criteria until the time when treatment is initiated. 
For example, if an enrolled patient’s post-enrollment (pretreatment) liver function tests no 
longer meet eligibility criteria, treatment should be held until the investigator can provide 
guidance to the study team. 
6.2  Administration of Study Treatment 
Pharmaceutical information and instructions for pemetrexed and sorafenib are included in 
Sections 9.1 and 9.2, respectively. The study treatment regimen is outlined on Table 1. 


 
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Table 1. Study Treatment Regimen 
Study Medication 
Dose 
Route of 
Administration 
Treatment Schedule  
Study Treatment 
Pemetrexed  
375 mg/m2 
Intravenous 
infusion over  
10 minutesA 
Administered on day 1 of each  
21-day cycleB 
Sorafenib  
200 mg 
Oral 
Taken twice daily on an empty stomach 
on days 1-5 of each 21-day cycleC 
Supplementation and Premedication RegimenD 
Folic acid 
1 mg 
Oral 
Taken once daily as follows: 
 On at least 5 days during the 7-day 
period preceding the first dose of 
pemetrexed 
 Throughout treatment with pemetrexed 
 Continued for 21 days after the last 
dose of pemetrexed 
Vitamin B12 
1000 mcg 
Intramuscular 
Administered once at each time point as 
follows: 
 1-2 weeks prior to the first dose of 
pemetrexedE 
 Approximately every 9 weeks during 
pemetrexed treatmentF 
 Continuing through approximately 8 
weeks following the last dose of 
pemetrexed 
DexamethasoneG 
4 mg 
Oral 
Taken twice daily on the: 
 Day before pemetrexed treatment 
 Day of pemetrexed treatment 
 Day after pemetrexed treatment  
A. If necessary, the duration of the pemetrexed infusion may be extended to a maximum of  
20 minutes. 
B. The following criteria must be met for each pemetrexed treatment: ANC must be  
≥ 1,200/mm3; platelet count must be ≥ 100,000/mm3; and calculated creatinine clearance must be ≥ 45 
mL/min (see Appendix 2 for Cockcroft-Gault equation). 
C. Instruct patient to take sorafenib on an empty stomach (ie, at least 1 hour before or 2 hours after eating) 
starting the morning of each pemetrexed dose. 
D. Refer to Section 9.1.6 for supplementation rationale. 
E. The time period required for the initial B12 injection may be extended to 15 days prior to initiating 
pemetrexed. If the B12 level prior to study registration was < LLN for the lab, a second B12 injection should 
be administered, preferably prior to initiation of pemetrexed but no later than prior to the third dose of 
pemetrexed. 
F. After the initial dose (given prior to initiation of pemetrexed therapy), vitamin B12 injections may be 
administered on the same day as the pemetrexed treatment. 
G. At the investigator’s discretion, patients who do not develop pemetrexed-associated drug rash and who 
have difficulty tolerating dexamethasone may omit or reduce the dexamethasone dose.  
 


 
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6.3 Missed Sorafenib Doses 
If a sorafenib dose is missed, the patient will be instructed to omit the dose and to not take 
more than 2 doses of sorafenib on the same day to make up for doses that were missed 
on the previous day. 
6.4 Monitoring Patient Adherence with Oral Medications 
Patients will be instructed to record the doses of sorafenib they have taken in the study 
medication diary that will be provided. Also, concurrent medication assessments will be 
used to capture B12 and folic acid supplementation, dexamethasone, and supportive care 
medications. 
Patients will be instructed to bring their diary and any unused sorafenib to each visit with 
their study team. The diary will be reviewed by the study team periodically (see study 
calendar [Table 11]). Patient reports of self-administration, review of medication diary, and 
pill counts will be used to assess patient adherence with the sorafenib regimen. 
6.5 Duration of Therapy 
Study treatment will continue until one of the following occurs (also see Study Withdrawal, 
Section 5.2): 
 
More than 3 consecutive weeks of treatment delay due to unresolved toxicity 
 
AE that requires discontinuation of study treatment (see Section 7) 
 
Pregnancy 
 
Determination by the investigator that discontinuation is in the patient’s best medical 
interest 
 
Disease progression 
 
Patient decision to discontinue study treatment 
 
Withdrawal of study sponsor support 
The reason for discontinuation of study treatment must be documented in the source 
documents and in the OnCore database. 
6.6 QT Prolongation Considerations 
6.6.1 Any time the QT interval is evaluated, follow the guidelines listed below: 
 
When HR < 60 bpm or >100 bpm, manual read of the QT interval by a 
cardiologist using Fridericia correction is required. 
 
When HR is within the range of 60 bpm -100 bpm, a manual read of the QT 
interval is not required. 
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6.6.2 To the extent possible, concurrent use of sorafenib with drugs known to cause 
clinically significant QT prolongation should be avoided. Such drugs may be 
identified at the Credible Meds website (http://crediblemeds.org/login). 
Note: The Credible Meds website requires free user registration to view the list of 
clinically relevant QT-prolonging drugs, eg, those known to carry a risk of causing 
Torsade de Pointes (TdP). QT-prolonging drugs to be avoided during this trial are 
shown in the Credible Meds list of “drugs with known TdP risk.” 
6.6.3 When concurrent use of sorafenib with any drug on the Credible Meds list of “drugs 
with known TdP risk” cannot be avoided, review the QTc prior to concurrent use. If 
the pre-concurrent use QTc is: 
 
Grade 0 (< 450 ms), a follow-up 12-lead ECG with QTc evaluation should be 
done at the next scheduled visit. 
 
Grade 1 (450-480 ms), a follow-up 12-lead ECG with QTc evaluation should be 
done within 8 days after concurrent use starts. 
 
Grade 2 (481-500 ms), withhold study treatment until a follow-up 12-lead ECG at 
the next possible opportunity shows QTc ≤ grade 1 (≤ 480 ms); evaluate QTc 
within 8 days after reintroduction of study treatment. 
6.6.4 Any new onset of dysrhythmia on ECG during treatment will be reviewed and 
managed with input from cardiology. 
6.6.5 Refer to Table 5 (Section 7.8) for instructions regarding any episode of syncope 
(grade 3) or near-syncope (pre-syncope grade 2) and for prolonged QTc interval 
grade 3 or 4. 
6.7 General Concomitant Medication and Supportive Care Guidelines 
6.7.1 Hypertension 
Hypertension is commonly encountered; rarely, dangerous levels of hypertension 
are associated with sorafenib therapy. BP will be monitored on day 1 of each 
treatment cycle and as clinically indicated throughout study treatment. Clinically 
significant hypertension should be managed aggressively by the investigator to 
prevent complications. 
6.7.2 Nausea/Vomiting 
Anti-emetics should be prescribed, per the investigator’s discretion, as clinically 
indicated. 
6.7.3 Diarrhea 
Clinically significant diarrhea should be managed aggressively to prevent electrolyte 
abnormalities and dehydration. Diarrhea can be managed with loperamide. The 
recommended dose of loperamide is 4 mg at first onset, followed by 2 mg every  
2-4 hours until diarrhea-free for 12 hours. 


 
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6.7.4 Management of Dyspepsia/Gastrointestinal Reflux 
Consider the addition of proton pump inhibitors for prophylaxis or treatment of 
dyspepsia/GI reflux, especially in those who have known history of either condition. 
6.7.5 Fluid and Electrolyte Abnormalities 
 
Patients who develop diarrhea, mucositis, anorexia, or other toxicity that can 
contribute to fluid loss or inadequate fluid intake should be carefully monitored 
and rehydrated, as clinically necessary, to minimize the risk of postural 
hypotension and renal failure. 
 
Fluids should be administered, as indicated, to prevent and/or treat dehydration. 
Maintain appropriate electrolyte balance including correction of hypokalemia, 
hypophosphatemia, and hypomagnesemia, if possible, prior to and during study 
treatment. Oral supplementation of magnesium, potassium, and phosphorus 
should be considered to be standard supportive measures in those patients who 
demonstrate electrolyte abnormalities. 
6.7.6 Palmar-Plantar Erythrodysesthesia 
Palmar-plantar erythrodysesthesia (PPE), also known as hand-foot skin reaction, is 
a common adverse reaction associated with sorafenib. Biopsy specimens of 
patients with PPE secondary to tyrosine kinase inhibition show hyperkeratosis, 
keratinocyte necrosis, and dermal inflammation. Sorafenib dose modification 
instructions are provided on Table 6 in Section 7.8; recommended management 
strategies for skin toxicities consistent with PPE are summarized in this section of 
the protocol. 
PPE Prevention 
 
Before initiating sorafenib treatment, check the condition of the patient’s hands 
and feet. Suggest a manicure/pedicure, when indicated. Recommend use of a 
pumice stone for callus or rough spot removal. During sorafenib treatment, 
instruct patients to avoid pressure points and items that rub, pinch, or create 
friction. 
 
Instruct the patient to apply moisturizing lotions to their hands and feet twice 
each day throughout treatment. 
PPE Treatment 
PPE treatment may begin at the first clinical signs of PPE. At first occurrence, 
independent of grade, supportive measures should be promptly initiated. 
 
Instruct the patient to protect tender areas as follows: 
- 
Use socks/gloves to cover moisturizing creams 
- 
Wear well-padded footwear; use insole cushions or inserts. 
- 
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 
Creams may be used as follows: 
- 
Non-urea-based creams may be applied liberally. 
- 
Keratolytic creams (eg, urea-based creams 10%, salicylic acid 6%) may be 
used on affected (hyperkeratotic) areas 3 times per day. 
- 
Alpha hydroxyl acids (AHA)-based creams may be applied liberally twice 
each day. Approximately 5% to 8% strength provides gentle chemical 
exfoliation. 
- 
Topical analgesics (eg, lidocaine 2%) may be used for pain control. 
- 
Topical corticosteroids (eg, clobetasol 0.05%) should be considered for 
patients with grade 2 or 3 PPE. 
 
Systemic steroids (except the dexamethasone doses on the day before, the day 
of, and the day after each pemetrexed dose) should be avoided. 
6.7.7 Third Space Fluid 
For patients who develop clinically significant pleural or peritoneal effusions (on the 
basis of symptoms or clinical examination) before or during initiation of pemetrexed 
therapy, consideration should be given to draining the effusion prior to dosing. 
However, if in the investigator’s opinion, the effusion represents progression of 
disease, study treatment will be discontinued. 
6.7.8 Blood Product Support and Growth Factors 
Transfusions and hematopoietic growth factors are permitted at the investigator’s 
discretion. 
6.7.9 Leucovorin for Management of Severe Neutropenia, Thrombocytopenia, and 
Mucositis 
Because folic acid and vitamin B12 supplementation has significantly reduced the 
number of episodes of grade 4 hematologic and grades 3 and 4  
non-hematologic toxicities associated with pemetrexed therapy, the need for 
leucovorin as a rescue agent is not anticipated. 
However, if necessary, leucovorin is permitted, but not required, for any of the 
following: 
 
Grade 4 neutropenia lasting > 3 days 
 
Grade 4 leukopenia lasting > 3 days 
 
Grade 4 thrombocytopenia (leucovorin should be administered immediately) 
 
Grade 3 thrombocytopenia associated with bleeding 
 
Grade 3 or 4 mucositis 
The recommended doses and schedule for leucovorin rescue are as follows: 
Leucovorin 100 mg/m2 IV once, followed by leucovorin 50 mg/m2 IV every 6 hours 
for up to 8 days. 


 
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6.7.10  Use of NSAIDs 
Use of NSAIDs during study treatment should be avoided. However, if the 
investigator determines that NSAID use is required, the guidelines below should be 
followed: 
 
Patients with normal renal function (ie, creatinine clearance ≥ 80 mL/min) 
Although ibuprofen can decrease the clearance of pemetrexed, up to 400 mg  
4 times a day can be administered with pemetrexed in patients with normal renal 
function. 
 
Patients with mild to moderate renal insufficiency (creatinine clearance from  
45 mL/min to 79 mL/min) 
Caution should be used when administering ibuprofen concurrently with 
pemetrexed to patients with mild to moderate renal insufficiency. Patients with 
mild to moderate renal insufficiency, should avoid taking NSAIDs with short 
elimination half-lives beginning 2 days before and continuing until 2 days 
following administration of pemetrexed. 
 
All patients 
In the absence of data regarding potential interaction between pemetrexed and 
NSAIDs with longer half-lives, all patients taking these NSAIDs should 
interrupt dosing beginning 5 days before and continuing until 2 days following 
pemetrexed administration. If concomitant administration of an NSAID is 
necessary, patients should be monitored closely for toxicity, especially 
myelosuppression, renal toxicity, and gastrointestinal toxicity. 
6.7.11 Other Cancer Therapy 
Cancer treatment, other than the treatment specified in the protocol, is not permitted 
with the following exceptions: 
 
Palliative radiation therapy as long as the target lesion(s) is not included in the 
treatment field and no more than 10% of bone marrow is irradiated 
 
Bisphosphonates 
 
Receptor activator of nuclear factor-kappa B ligand (RANKL)-inhibitors  
(eg, denosumab) 
6.7.12 Prohibited/Discouraged Medications 
 
Non-prescription nutritional and dietary supplements are discouraged but not 
prohibited unless known to have drug interactions or modulation of drug 
metabolism pathways. If nutritional and/or dietary supplements are used, dose 
and schedule of the supplements should be documented. 
 
Hepatotoxicity from sorafenib is a known toxicity, and acetaminophen may 
confound interpretation of toxicity. Therefore, acetaminophen should be avoided, 
if possible, in patients with ≥ grade 2 elevation of AST, ALT, or total bilirubin. 


 
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 
Patients may not receive medications in the following classes during study 
treatment. If such medications have been used, the patient must have 
discontinued these agents ≥ 2 weeks before starting/resuming study treatment. 
- 
Immunosuppressants such as tacrolimus, leflunomide or tofacitinib, 
roflumilast, pimecrolimus 
- 
Strong CYP3A4 inducers (refer to Section 4.2.18). 
6.8 Study Pocket Card for Patients 
A pocket card identifying the name of the study, the names of the study medications, and 
contact information including the study team and a 24-hour on-call study physician will be 
provided to each patient. The purpose of this card is to facilitate communication between 
the study team and the patient’s health care providers not involved with the study. Patients 
will be encouraged to carry the card with them at all times and to show it to their health 
care providers so that potential interactions with the study medications can be identified 
before initiating new medications. 
6.9 Follow-Up Period 
6.9.1 Required Monitoring of Vitamin B12 and Folate Supplementation 
All patients who have received pemetrexed will be monitored to ensure that vitamin 
B12 and folic acid supplementation continue after the last pemetrexed dose as 
described in Table 1 (Section 6.2). 
6.9.2 30-Day Evaluation of AEs 
Patients who discontinue treatment for any reason other than consent withdrawal 
remain on study in follow-up status for a 30-day evaluation period following the last 
dose of study treatment. During this 30-day post-treatment period, resolution or 
stabilization of ongoing treatment-related AEs, and evolution of new treatment-
related AEs will be reported. 
6.9.3 Disease Progression and Survival Follow-Up Requirements 
 
All patients who have discontinued study treatment due to toxicity or reason 
other than disease progression will continue to have assessments for tumor 
response until 2 years after initiation of study therapy or until new cancer 
therapy is initiated or until disease progression, whichever occurs first. 
 
All patients will be followed for survival following discontinuation of study therapy 
until 2 years after initiation of study therapy or death, whichever occurs first. 
The patient’s follow-up status will be recorded in the source documents and the 
CRFs. 


 
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7 DOSING DELAYS/DOSING MODIFICATIONS 
7.1 Recording Dose Modifications 
All dosing interruptions and modifications will be recorded in the source documents and 
captured in the OnCore database. 
7.2 Toxicity Assessment 
Dose reduction should be limited to management of toxicity related to study treatment and 
not for management of adverse effects determined by the investigator to be related to 
underlying disease or other medical condition or concomitant treatment. 
If a patient experiences more than one toxicity: 
 
Dose reduction should be according to the instructions for the clinically significant 
toxicity with the higher grade. 
 
In the case of 2 or more toxicities of the same grade, the investigator may dose reduce 
according to the toxicity determined to be the most likely to be related to study 
treatment. 
7.3 Toxicity Grading 
AEs will be characterized and graded according to NCI CTCAE v4.0. 
7.4 General Instructions and Guidelines 
7.4.1 Cycle Delays 
 
The following criteria must be met before administration of pemetrexed on day 
1 of each cycle: 
- 
ANC must be ≥ 1,200/mm3 
- 
platelet count must be ≥ 100,000/mm3 
- 
calculated creatinine clearance must be ≥ 45 mL/min (see Appendix 2 for 
Cockcroft-Gault equation) 
 
If treatment has been held due to toxicity, all toxicity must have recovered to 
meet the criteria outlined in the dose modification tables and other instructions 
outlined in Section 7 before resuming study treatment. 
 
If pemetrexed must be held on cycle day 1, sorafenib must also be held until 
pemetrexed can be administered. 
 
If sorafenib must be held for sorafenib-related toxicity, administration of 
pemetrexed should also be delayed for up to 1 week. If sorafenib treatment 
cannot be resumed after 1 week of treatment delay, pemetrexed should be 
resumed. 
 
With permission from the principal investigator, a treatment cycle may be 
delayed for up to 2 weeks for scheduling purposes. 


 
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7.4.2 Dose Escalation 
If the dose of either of the study medications has been reduced, the dose may be 
re-escalated at the investigator’s discretion to no higher than the starting dose, 
unless the patient has had a grade 4 AE related to the agent being considered for 
re-escalation. 
7.4.3 Required Discontinuation of Study Treatment 
 
If treatment has been held due to toxicity and recovery has not been sufficient to 
resume treatment after 3 weeks of treatment delay, study treatment must be 
discontinued. 
7.4.4 Dose Modification Guidelines 
 
Unless specified otherwise in the dose modification protocol instructions, the 
sorafenib dose should only be reduced for sorafenib-related toxicity and the 
pemetrexed dose should only be reduced for pemetrexed-related toxicity. 
 
If a toxicity requiring interruption of sorafenib occurs early during the treatment 
cycle, the remaining sorafenib dose(s) in the cycle will be omitted (ie, these 
doses will not be made up). 
 
Study treatment should be modified in response to clinically significant toxicities 
attributed to study treatment. If a specific toxicity is not covered in the dose 
modification tables in Sections 7.6 and 7.8, follow the instructions listed below. 
(Refer to Appendix 4 for a list of hematologic toxicities using CTCAE v4.0 
terminology.) 
 
Grade 1 non-hematologic toxicity: Maintain dose 
 
Grade 2 non-hematologic toxicity: Option to modify dose 
 
Grade 3 non-hematologic toxicity: Requirement to modify dose 
Exceptions: Dose reduction is not required for alopecia, non-refractory 
nausea/vomiting, non-refractory hypersensitivity, and laboratory 
abnormalities that are asymptomatic and/or not clinically significant in the 
opinion of the investigator. 
 
Grade 4 non-hematologic toxicity: Discontinue study treatment 
 
Grade 4 hematologic toxicity: Requirement to modify the pemetrexed dose; 
recommendation to modify the sorafenib dose 
Exception: Dose reduction is not required for grade 4 decrease in 
lymphocyte count. 


 
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7.5 Dose Reduction Steps for Pemetrexed 
The dose reduction steps to be used for pemetrexed are listed in the table below. (Dose 
reduction steps for sorafenib are listed in Table 4.) 
Table 2. Dose Reduction Steps for Pemetrexed 
Dose Reduction Step 
Pemetrexed 
Full Dose 
375 mg/m2 on day 1 of each 21-day cycle 
 If reduction from previous 
step  is indicated: 
275 mg/m2 on day 1 of each 21-day cycle 
If reduction from previous 
step  is indicated: 
200 mg/m2 on day 1 of each 21-day cycle 
If reduction from previous 
step  is indicated: 
Discontinue study treatment 
7.6 Dose Modification Instructions for Pemetrexed 
In addition to the dose modification instructions in Section 7.4, instructions for specific 
pemetrexed-related toxicities are listed in Table 3. 


 
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Table 3. Dose Modification Instructions for Pemetrexed 
Toxicity 
Pemetrexed Dose Modifications 
(Refer to Table 2 for pemetrexed dose reduction steps) 
Investigations (Hematologic) 
Nadir ANC < 500/mm3 and 
nadir platelets ≥ 50,000/mm3 
 
Hold study treatment until criteria for treatment are met.* 
 
When resuming treatment, decrease pemetrexed dose by  
one dose reduction step. 
Nadir platelets < 50,000/mm3 
without bleeding regardless 
of nadir ANC 
Nadir platelets < 50,000/mm3 
with bleeding regardless of 
nadir ANC 
 
Hold study treatment until criteria for treatment are met.* 
 
When resuming treatment, decrease pemetrexed dose by  
one dose reduction step. 
Gastrointestinal Disorders 
Grade 3 or 4 mucositis 
 
Hold study treatment until resolution to ≤ grade 1. 
 
When restarting study treatment, decrease the dose of 
pemetrexed by one dose reduction step. 
Other Pemetrexed-Related Non-Hematologic Toxicities 
Grade 2 non-hematologic 
toxicity that is persistent, 
intolerable, or unresponsive 
to optimal management  
At the investigator’s discretion, reduce the dose of pemetrexed 
by one dose reduction step.  
Grade 3  
Hold study treatment until resolution to ≤ grade 1, tolerable 
grade 2, or baseline. 
 
When resuming study treatment, decrease the pemetrexed 
dose by one dose reduction step. 
Exceptions: Pemetrexed dose reduction is not required for 
alopecia, non-refractory nausea/vomiting, non-refractory 
hypersensitivity, and laboratory abnormalities that are 
asymptomatic and/or not clinically significant in the opinion 
of the investigator. 
 
If toxicity persists for more than 3 weeks of delay, 
discontinue study treatment. 
 
For bleeding that requires more than minor medical 
intervention, consider discontinuing study treatment. 
Grade 4 
Discontinue study treatment. 
*Laboratory criteria that must be met before each pemetrexed dose are: 
- ANC must be ≥ 1,200/mm3 
- platelet count must be ≥ 100,000/mm3 
- calculated creatinine clearance must be ≥ 45 mL/min (see Appendix 2 for Cockcroft-Gault 
equation) 


 
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7.7 Dose Reduction Steps for Sorafenib 
The dose reduction steps to be used for sorafenib are listed in Table 4. (Dose reduction 
steps for pemetrexed are listed in Table 2.) 
Table 4. Dose Reduction Steps for Sorafenib  
Dose Reduction Step 
Sorafenib 
(In Each Cycle) 
Full Dose  
200 mg BID on days 1-5 
If reduction from previous 
step  is indicated: 
200 mg BID on days 1-3 
If reduction from previous 
step  is indicated: 
200 mg BID on day 1 only 
If reduction from previous 
step  is indicated: 
Discontinue Sorafenib 
 
7.8 Dose Modification Instructions for Sorafenib 
In addition to the dose modification instructions in Section 7.4, dose modification 
instructions for specific sorafenib-related toxicities are listed in Table 5 and Table 6. 


 
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Table 5. Sorafenib Dose Modification Guidelines  
Toxicity 
Sorafenib Modification 
(Refer to Table 4 for sorafenib dose reduction steps) 
Cardiac 
Grade 3 or 4 myocardial 
infarction 
Discontinue sorafenib 
Gastrointestinal Disorders 
Perforation (esophageal, 
gastric, colonic, duodenal, 
ileal, jejunal, rectal, or small 
intestine) 
Discontinue sorafenib 
Investigations 
Grade 3 or 4 
AST or ALT increased 
Hold sorafenib: 
 If ≤ grade 1 elevation in AST and/or ALT at baseline: 
- If no alternative explanation for transaminitis can be 
determined (such as viral hepatitis, progressive underlying 
hepatic metastasis), discontinue sorafenib 
- Otherwise, upon resolution to ≤ grade 1, resume sorafenib 
with a decrease in sorafenib dose of one  
dose reduction step 
 If grade 2 elevation in AST and/or ALT secondary to hepatic 
metastasis at baseline: 
- If ≥ 50% increase from baseline and no alternative 
explanation for transaminitis can be determined (such as 
viral hepatitis, progressive underlying hepatic metastasis), 
discontinue sorafenib 
- If < 50% increase from baseline, upon resolution to  
≤ grade 2, resume sorafenib with a decrease in sorafenib 
dose of one dose reduction step 
Grade 3 ECG QTc interval 
prolonged 
 
See Section 6.6 for 
additional instructions 
Hold sorafenib: 
 Check and immediately administer potassium and/or 
magnesium to achieve potassium level of ≥ 4 mEq and 
magnesium level of ≥ 2 mEq 
 Consider chronic oral potassium and/or magnesium 
supplementation 
 Review with investigator prior to patient’s next scheduled 
treatment, considering the following options: 
- Hold sorafenib until QTc recovers to pre-study treatment 
baseline (≤ grade 1 [≤ 480ms]) 
- When QTc returns to baseline, resume sorafenib cautiously 
with additional QTc monitoring at earliest opportunity within 
8 days after resuming sorafenib 
- If QTc prolongation is thought to be related to sorafenib, 
decrease sorafenib dose by one dose reduction step when 
resuming sorafenib 
- For recurrent grade 3 QTc thought to be related to 
sorafenib despite dose reduction, consider discontinuation 
of sorafenib 
Grade 4 ECG QTc interval 
prolonged 
Discontinue sorafenib 
Table 5 continued on the next 2 pages 


 
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Table 5. Sorafenib Dose Modification Guidelines  
Toxicity 
Sorafenib Modification 
(Refer to Table 4 for sorafenib dose reduction steps) 
Nervous System Disorders  
Grade 2 pre-syncope or 
grade 3 syncope 
(potentially reflecting 
cardiotoxicity) 
 
 
 
Obtain 12-lead ECG for cardiology review/consultation 
 
Check magnesium and/or potassium levels; promptly 
administer potassium and magnesium to achieve a 
potassium level of  
≥ 4 mEq and magnesium level ≥ 2 mEq 
 
IF ECG shows new dysrhythmia or QTc ≥ grade 2  
(> 480ms), hospitalize for monitoring with cardiology 
consultation 
 
Hold sorafenib until any potassium and magnesium 
abnormalities are corrected, symptoms resolved, and QTc 
improved to ≤ grade 1 (≤ 480ms) 
 
Reintroduce sorafenib cautiously, with input from cardiology 
and with additional QTc evaluation, either concurrent with 
reintroduction or at earliest possible opportunity within 8 days 
from reintroduction 
 
If event is thought to be related to sorafenib, consider 
reducing the sorafenib dose by one dose reduction step 
when resuming sorafenib 
 
Consider chronic oral supplementation of potassium and/or 
magnesium 
 
For recurrent syncope or near-syncope thought to be related 
to sorafenib, consider discontinuation of sorafenib 
Skin and Subcutaneous Disorders 
PPE (hand-foot syndrome) 
See Table 6 for instructions related to PPE  
Grade 3 or 4 
rash acneiform 
Hold sorafenib: 
 Re-evaluate at least weekly until resolution to ≤ grade 1 or 
tolerable grade 2 
 When resuming sorafenib, decrease sorafenib dose by one 
dose reduction step 
 If rash persists for more than 3 weeks of treatment delay, 
discontinue sorafenib 
 If grade 4 acneiform rash (related to sorafenib), sorafenib may 
be discontinued at investigator’s discretion 
Stevens-Johnson 
syndrome or toxic 
epidermal necrolysis 
Discontinue sorafenib if Stevens-Johnson Syndrome or toxic 
epidermal necrolysis are suspected 
Vascular Disorders 
Hypertension defined as  
systolic BP > 160 mmHg 
and  
diastolic BP > 100 mm/Hg 
 
Hold sorafenib until resolution to ≤ grade 2 
When resuming sorafenib, decrease sorafenib dose by one dose 
reduction step; monitor BP weekly for 4 weeks 
Grade 4 hypertension 
Discontinue sorafenib 
Table 5 continued on the next page 
 


 
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Table 5. Sorafenib Dose Modification Guidelines 
Toxicity 
Sorafenib Modification 
(Refer to Table 4 for sorafenib dose reduction steps) 
Other Sorafenib-Related Non-Hematologic Toxicities 
Any grade 2  
non-hematologic toxicity 
that is persistent, 
intolerable, or unresponsive 
to optimal management  
At the investigator’s discretion, reduce by one dose reduction 
step  
Grade 3  
Hold sorafenib until resolution to ≤ grade 1, tolerable grade 2, or 
baseline: 
 
When resuming sorafenib, decrease the sorafenib dose by 
one dose reduction step 
Exceptions: Sorafenib dose reduction is not required for 
alopecia, non-refractory nausea/vomiting, non-refractory 
hypersensitivity, and laboratory abnormalities that are 
asymptomatic and/or not clinically significant in the opinion of 
the investigator 
 
If toxicity persists for more than 3 weeks of treatment delay, 
discontinue sorafenib 
 
For bleeding that requires more than minor medical 
intervention, consider discontinuing sorafenib 
Grade 4 
Discontinue sorafenib 


 
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Table 6. Sorafenib Dose Reduction Guidelines for PPE 
Grade 
Occurrence 
Action 
(Refer to Table 4 for sorafenib 
dose reduction steps) 
Grade 1 
1st occurrence or 
recurrence 
Continue sorafenib and institute 
supportive measures for 
symptomatic relief.* 
Grade 2 
Moderate and painful skin 
changes of hands and/or feet 
such as peeling, blisters, 
bleeding, hyperkeratosis, 
erythema, swelling; and/or any 
such changes that are limiting 
instrumental activities of daily 
living (preparing meals, 
shopping for groceries, using 
the telephone, managing 
money, etc) 
1st or 2nd occurrence 
 Continue sorafenib and 
institute supportive measures 
for symptomatic relief.* 
 If no improvement during the 
remainder of the cycle, see 
below. 
3rd occurrence or 
persistence of 
grade 2 toxicity through 
the remainder of the 
cycle  
 Stop sorafenib treatment 
until toxicity resolves to ≤ 
grade 1. 
 When resuming treatment 
(next cycle), decrease 
sorafenib dose by one dose 
reduction step. 
 Institute or continue 
supportive measures for 
symptomatic relief.* 
Grade 3 
Severe and painful skin 
changes of the hands and/or 
feet, such as moist 
desquamation, ulceration, 
blistering, bleeding, 
hyperkeratosis, erythema, 
swelling; and/or any such 
severe changes or pain that 
are limiting self-care activities 
of daily living (bathing, 
dressing, feeding self, using 
toilet, taking medications or 
becoming bedridden) 
1st or 2nd occurrence 
 Stop sorafenib treatment 
until toxicity resolves to ≤ 
grade 1. 
 When resuming treatment, 
decrease sorafenib by one 
dose reduction step. 
 Institute or continue 
supportive measures for 
symptomatic relief.* 
3rd occurrence or 
persistence of grade 3 
toxicity through the 
remainder of the cycle 
Discontinue sorafenib. 
* See Section 6.7.6 for prevention and management guidelines for PPE.  
 
 


 
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8 ADVERSE EVENT: DEFINITIONS AND REPORTING 
REQUIREMENTS 
8.1 Definitions 
8.1.1 Adverse Event (AE) 
AE means any untoward medical occurrence associated with the use of a drug in 
humans, whether or not considered drug related. 
8.1.2  Serious AE (SAE) 
An AE is considered “serious” if, in the view of the investigator, it results in any of 
the following outcomes: 
 
death, 
 
a life-threatening AE (An AE is consider “life-threatening” if, in the view of the 
investigator, its occurrence places the patient or patient at immediate risk of 
death. It does not include an AE that, had it occurred in a more severe form, 
might have caused death.), 
 
inpatient hospitalization or prolongation of existing hospitalization, 
Planned inpatient hospitalizations, eg, for planned surgery, or those that occur 
for logistical reasons, eg, to complete a therapy that cannot be completed due to 
outpatient clinic business hours, are exempt from SAE reporting. Events that 
prolong such hospitalizations and otherwise meet reporting criteria are, 
however, still subject to SAE reporting requirements. 
 
a persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions, or 
 
a congenital anomaly/birth defect. 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical 
judgment, they may jeopardize the patient or patient and may require medical or 
surgical intervention to prevent one of the outcomes listed in this definition. 
8.1.3 Unanticipated Problem (UP) 
Unanticipated problems include any incident, experience, or outcome that meets all 
of the following criteria: 
 
unexpected (in terms of nature, severity, frequency) given (a) the research 
procedures that are described in the protocol-related documents, such as the 
research protocol and informed consent document approved by the institutional 
review board (IRB); and (b) the characteristics of the patient population being 
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 
related or possibly related to participation in the research (possibly related 
means there is a reasonable possibility that the incident, experience, or outcome 
may have been caused by the procedures involved in the research); and 
 
suggests that the research places patients or others at a greater risk of harm 
(including physical, psychological, economic, or social harm) than was 
previously known or recognized. 
8.1.4 AE Description and Grade 
The descriptions and grading scales found in the revised CTCAE v4.0 will be utilized 
for AE reporting. 
8.1.5 AE Expectedness 
AEs can be ‘Unexpected’ or ‘Expected’. Expected AEs are those AEs, the specificity 
and severity of which are consistent with the listings for pemetrexed and sorafenib 
found in protocol Sections 9.1 and 9.2, respectively, or in the most current version of 
the FDA-approved prescribing information for each drug. 
Unexpected AEs are those AEs occurring in one or more patients participating in the 
study, the nature, severity, or frequency of which is not consistent with either: 
 
The known or foreseeable risk of AEs associated with the procedures involved 
in the research that are described in (a) the protocol-related document, such as 
the IRB-approved research protocol, any applicable investigator brochure, and 
the current IRB-approved informed consent document, and (b) other relevant 
sources of information, such as product labeling and package inserts; or 
 
The expected natural progression of any underlying disease, disorder, or 
condition of the patient(s) experiencing the AE and the patient’s predisposing 
risk factor profile for the AE. 
8.1.6 AE Attribution 
 
Definite – The AE is clearly related to the study treatment. 
 
Probable – The AE is likely related to the study treatment. 
 
Possible – The AE may be related to the study treatment. 
 
Unlikely – The AE is doubtfully related to the study treatment. 
 
Unrelated – The AE is clearly NOT related to the study treatment. 
8.2 Known AEs 
The expected AEs for pemetrexed can be found in protocol Section 9.1 and in the 
pemetrexed (Alimta) prescribing information. The known AEs for sorafenib can be found in 
protocol Section 9.2 and in the sorafenib (Nexavar) prescribing information. 


 
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8.3 Secondary Malignancy 
A secondary malignancy is a cancer caused by previous treatment for a malignancy  
(eg, treatment with investigational agent/intervention, radiation therapy, or chemotherapy). 
A secondary malignancy is not considered a metastasis of the initial neoplasm. Any 
secondary malignancy should be reported via expedited reporting mechanisms. 
8.4 Time Period and Grade of AE Capture 
All AEs regardless of grade will be recorded from the beginning of the study procedures 
through 30 days following the end of the study treatment. 
8.5 Procedures for Recording AEs, SAEs, and UPs 
All AEs, SAEs, and UPs will be recorded in MCC’s OnCore Clinical Trials Management 
System. In most cases, it is acceptable to record in OnCore only the highest grade of a 
toxicity occurring during a particular study segment when an event has serial fluctuations in 
grade over time. 
SAE’s will be entered into the OnCore SAE domain. UPs will be entered into the OnCore 
Deviations domain. An SAE that is both an SAE and a UP will be entered in both domains. 
For all SAEs, a corresponding entry should be made in the routine AE record to match the 
event entries in the SAE domain. 
8.6 Expedited Reporting Procedures for SAEs and UPs 
Refer to Table 7 for expedited reporting requirements and instructions. Also, refer to 
Section 8.7 for requirements and instructions for expedited reporting to Eli Lilly and 
Company and to Section 8.8 for requirements and instructions for expedited reporting to 
Bayer HealthCare Pharmaceuticals, Inc. 


 
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Table 7. Expedited Reporting Requirements  
SAEs 
UPs 
Principal InvestigatorA 
Andrew Poklepovic 
 
 
Principal InvestigatorA 
Andrew Poklepovic 
 
 
Study TeamA 
 
 
Study TeamA 
 
 
Eli Lilly and CompanyB 
DSMCC 
 
Bayer HealthCare Pharmaceuticals, IncD 
IRBE 
 
Eli Lilly and CompanyB 
 
Bayer HealthCare Pharmaceuticals, IncD 
A. Report event within 1 business day of becoming aware of the occurrence. A PDF of a  
de-identified OnCore SAE or Deviation record may be used for expedited event reporting 
purposes. 
B. Refer to Section 8.7 for requirements and instructions for expedited reporting to Lilly. 
C. Report each UP within 24 hours of becoming aware of the occurrence. A PDF of a  
de-identified OnCore SAE or Deviation record may be used for expedited event reporting 
purposes. 
D. Refer to Section 8.8 for requirements and instructions for expedited reporting to Bayer. 
E. Report each UP to the VCU IRB within 24 hours of becoming aware of the occurrence.  
8.7 Requirements for Expedited Reporting to Eli Lilly and Company 
8.7.1 SAEs 
 
All SAEs possibly, probably, or definitely related to pemetrexed must be 
reported to Lilly within 24 hours of the principal investigator’s awareness. 
 
The written SAE report should be completed using a Council for International 
Organization for Medical Sciences (CIOMS) Suspect Adverse Reaction Report 
Form. This form is available on the CIOMS website 
8.7.2 Other Events Requiring Expedited Reporting to Lilly 
In addition to an event determined to be an UP, any event that the principal 
investigator determines is new and important and possibly, probably, or definitely 
related to pemetrexed will be reported to Lilly within 24 hours of the investigator’s 
awareness. 


 
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8.7.3 Reporting Method 
Fax completed forms and reports to Lilly using either of the following numbers: 
 
8.8 Requirements for Expedited Reporting to Bayer HealthCare Pharmaceuticals, Inc 
8.8.1 SAEs 
All SAEs must be reported to Bayer within 24 hours of the principal investigator’s 
awareness and must include the following minimum information: 
 
Name and contact information of the reporter 
 
Name of the study drug(s) 
 
Description of the reported SAE 
 
Patient identified by one or more of the following: 
 
Patient initials 
 
Patient identification number for the study 
 
Knowledge that a patient who experienced the AE exists 
 
Age 
 
Sex 
 
Investigator assessment of study drug causality; a separate causality 
assessment should be provided for each study drug. 
Additional data that would aid the review and causality assessment of the case 
include but are not limited to: 
 
Date of onset 
 
Severity 
 
Time from administration of study drug(s) to start of the event 
 
Duration and outcome of the event 
 
Any possible etiology for the event 
 
Final diagnosis or syndrome, if known 
 
Actions taken, if any 
8.8.2 Other Events Requiring Expedited Reporting to Bayer 
The investigator will report to Bayer within 24 hours of the investigator’s awareness 
of other events such as: 
 
UPs or any other new and important event related to treatment with the study 
medications 
 
Any pregnancy during which a female patient was exposed to sorafenib 


 
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8.8.3 Form to be Used for Expedited Reporting of SAEs to Bayer 
The written SAE report should be completed using a CIOMS form. This form is 
available on the CIOMS website. 
8.8.4 Reporting Methods 
All reports will be sent to Bayer by either of the following methods: 
 
 
 
 
9 PHARMACEUTICAL INFORMATION 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 


 
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10 MEASUREMENT OF EFFECT 
10.1 Criteria for Tumor Response 
Tumor response will be evaluated and recorded using RECIST v1.1 (35). 
10.2 Tumor Response Requirements 
10.2.1 Time Points for Assessment of Tumor Response 
Tumor response will be assessed at the following time points: 
 
At baseline 
 
At the end of cycle 3 and then every 9 weeks (+/- 1 week) 
At the investigator’s discretion, additional assessments may be performed when 
clinically indicated. 
10.2.2 Imaging 
Only imaging of the initial sites of disease is required at subsequent time points to 
provide tumor measurements for assessment of antitumor effect. The same type of 
imaging used at baseline should be used at each scheduled assessment. 
10.2.3 Clinical Examination 
 
Per RECIST v1.1 criteria (35), imaging-based evaluation should always be done 
rather than clinical examination unless the lesion(s) being followed cannot be 
imaged but can be assessed by clinical exam. 
 
Clinical lesions will only be considered measurable when they are superficial 
and ≥ 10 mm in diameter as assessed using calipers (eg, skin nodules). 
10.3 Confirmation of Response 
In the event of a PR or CR, the method used when the response was first documented 
must be repeated at the time of the next scheduled evaluation (ie, in about 10 weeks) to 
confirm the tumor response. (At the investigator’s discretion, confirmatory assessments 
can be performed sooner, but no less than 4 weeks following the assessment [imaging or 
clinical examination] indicating the PR or CR.) 
10.4 Central Review for Imaging Interpretation 
Centralized radiologic review for evaluation of tumor response will be conducted. 


 
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11 CORRELATIVE STUDIES 
11.1 Participation in Correlative Studies 
Section 1.7 outlines the plans and rationale for the correlative studies. 
Participation in the correlative studies using collected blood samples and samples from 
archived tumor tissue, if available, is mandatory. 
11.2 Collection, Processing, and Distribution of Samples 
 
The study team will coordinate collection of all correlative samples. 
 
Tumor and blood samples will be de-identified prior to distribution to the laboratories 
performing the correlative studies. 
 
Massey Cancer Center Clinical and Translational Research Lab (CTRL) will receive, 
process, store, and/or distribute all correlative blood samples to the laboratories that 
will be performing the correlative studies. 
 
Questions regarding study requirements should be directed to the study team. The 
principal investigator should be contacted in the event that a correlative sample must 
be missed or is found to be inadequate for submission. 
11.3 Archived Tumor Samples 
Expression of PTEN, TS, and additional cellular proteins (see Section 1.7.1) will be 
analyzed by IHC methods using samples from tumor archived at the time of: 1) the initial 
breast cancer diagnosis, and 2) disease progression, ie, biopsy of recurrent or metastatic 
tumor performed prior to study registration. 
11.3.1 Archived Diagnostic Tumor Samples 
 
A tumor block or a total of 20 unstained slides (as tissue quantity permits), each 
with specimen 5 microns thick, should be requested from the archived initial 
diagnostic samples. 
 
A tumor block or a total of up to 20 unstained slides (as tissue quantity permits), 
each with specimen 5 microns thick, should be requested from samples 
archived following a biopsy of recurrent or metastatic tumor. 
11.3.2  Requesting Tumor Samples from Outside Hospitals 
To obtain an archived biopsy specimen from an outside hospital: 
 
Request that a tissue block be sent to the study team; the study team will 
coordinate with VCU Anatomic Pathology for slide preparation and for return of 
the block to the outside hospital. 
 
If the outside hospital does not transfer blocks of tissue, request delivery of 20 
unstained slides (if from the initial diagnostic biopsy) or up to 20 unstained slides 


 
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(if from a biopsy of recurrent or metastatic tumor), each with specimen 5 microns 
thick. 
11.3.3 Tumor Sample Slide Labeling 
The tumor sample slides should be labeled with the following information before 
transfer to the CTRL: 
 
Study number 
 
Patient study identification number 
 
Date of tumor sample collection 
11.3.4 Immunostaining of Unstained Slides 
All unstained slides will be de-identified by labeling as in Section 11.3.3 and 
delivered to the CTRL where immunostains for expression of PTEN, TS, and other 
proteins of interest will be performed. 
11.3.5 Interpretation of Immunostaining Results 
After staining, slides stained with validated antibodies for standard IHC will be 
returned to the VCU Anatomic Pathology for interpretation by a clinical pathologist. 
Results will be communicated to the CTRL and the study team. 
11.4 Correlative Blood Samples for Multiplex Assays 
11.4.1 Time Points for Blood Sample Collection for Multiplex Assays 
A blood sample to be used for the multiplex assays will be collected at the following 
time points: 
 
Prior to initiation of study treatment (after study registration) 
 
Approximately 24 hours after the first dose of pemetrexed (cycle 1, day 2) 
Note: If collection is not possible on day 2, this sample may be collected on day 
3 or day 4. 
 
Cycle 2, day 1 
 
At approximately the time of each tumor response assessment prior to disease 
progression 
 
If possible, at time of disease progression 
11.4.2 Instructions for Blood Sample Collection for Multiplex Assays 
 
At each time point for the multiplex assays: 
 
Collect 5 mL of blood in a purple top EDTA blood collection tube. 
 
Invert 8-10 times after collection and deliver at ambient temperature within 2 
hours of collection to the Massey CTRL. 


 
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 
The CTRL will: 
 
Spin sample for 10 minutes at 1200 ×g. 
 
Collect 0.25 mL aliquots of supernatant into approximately fifteen (15) 1.0 
mL cryovials. 
 
Collect the “buffy coat” into a 1.0 mL cryovial using care to not contaminate 
with red blood cells (RBCs). 
 
Freeze the vials at - 80°C. 
 
Resuspend the RBC/WBC pellet in 1.0 mL ice cold phosphate buffered 
saline (PBS). 
 
Place 0.1 mL of the resuspension onto 10 glass microscope slides. 
 
Using another slide, streak the blood across each slide to create a film. 
 
Permit the slides to air dry. 
 
Label the slides “RBC”; refer to Section 11.6 for additional information to be 
included. 
 
Store the slides at 4°C. 
 
Email Dr. Paul Dent that the slides are ready for pick-up. 
11.4.3 Testing and Analysis 
Multiplex assay testing and analysis using blood samples will be performed by  
Paul Dent, PhD. Frozen plasma samples from each time point for each patient will 
be stored at - 80°C until the trial is completed. Using commercially-available 
characterized multiplex beads of the same lot purchased from Bio-Rad, the levels of 
approximately 100 cytokines and growth factors in the plasma will be determined. 
Changes during study treatment will be assessed. Refer to Section 1.7.2 for a 
description of the planned research. 
11.5 Correlative Blood Samples for CTC Analysis 
11.5.1 Time Points for Blood Sample Collection for CTCs 
A blood sample to be used for CTC analysis will be collected at the following time 
points: 
 
Prior to initiation of study treatment (after study registration) 
 
Approximately 24 hours after the first dose of pemetrexed (cycle 1, day 2) 
Note: If collection is not possible on day 2, this sample may be collected on day 
3 or day 4. 
 
At approximately the time of the first tumor response assessment 


 
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11.5.2 Blood Sample Collection Instructions for CTC 
 
For all patients: 
At each time point, collect at least 9 mL of blood in each of two 10-mL green top 
heparin blood collection tubes. 
 
For a subset of 17 patients: 
Collect at least 9 mL of blood in a 10-mL purple top EDTA blood collection tube 
for provision to ApoCell (a molecular diagnostics and profiling company) at the 
following 2 time points: 
 
Prior to initiation of study treatment (after study registration) 
 
About 24 hours after the first dose of pemetrexed (cycle 1, day 2) 
Note: If collection is not possible on day 2, this sample may be collected on day 
3 or day 4. 
 
Each tube collected will be inverted 8-10 times after collection and then 
delivered at ambient temperature within 2 hours of collection to the CTRL for 
further processing, labeling, and storage. 
11.5.3 CTC Processing and Analysis 
The Massey CTRL staff will: 
 
Receive, process, and analyze samples per standard CTRL procedures for CTC 
isolation. 
Note: Specimens cannot be analyzed unless, at a minimum, the pretreatment 
sample AND at least one post-treatment sample have been collected. 
 
For the subset of patients who have a second blood sample collected for CTC 
analysis (see Section 11.5.2), coordinate the provision of samples to ApoCell for 
CTC isolation using the ApoStream DEPff device and analysis. 
Refer to Section 1.7.3 for a description of the planned research 
11.6 Blood Sample Labeling 
Each collected blood sample and processed end product should be labeled as follows: 
 
Study number 
 
Patient study identification number 
 
Date of sample collection 
 
Time of sample collection 
 
Study time point 
11.7 Tracking for All Samples 
Collection and distribution of all samples will be logged by the study team in OnCore on the 
appropriate eCRF(s). 


 
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12 STUDY CALENDAR 
The schedule of tests, exams, disease assessments, collection of samples for correlative 
studies, and administration of study medications are listed on 2 tables: requirements during 
screening and after registration (before treatment begins) on Table 10; requirements during 
treatment and study follow-up on Table 11.


 
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Table 10. Study Calendar – Screening/Pretreatment Requirements 
Tests, Exams, Procedures, and  
Other Requirements  
Prior to Initiation of Study Treatment 
Informed Consent 
Prior to study-specific procedures 
ImagingA 
Within 28 days 
Disease AssessmentB 
Medical/Surgical History  
Demographics 
Height 
12-Lead ECGC 
Concurrent MedicationsD 
Within 14 days 
Baseline Conditions and Symptoms 
Physical Exam 
Weight 
Vital Signs 
Blood Pressure 
Performance StatusE 
CBC with Differential 
Serum ChemistryF 
Serum B12, Folate, MMA, 
Homocysteine 
INR  
Serum Pregnancy TestG 
Within 7 days 
Correlative Blood Sample Collection 
After study registrationH 
Folic AcidI 
On at least 5 out of the 7 days before  
the 1st dose of pemetrexed 
Vitamin B12I 
7-14 days before  
the 1st dose of pemetrexed 
DexamethasoneI 
One day before the 1st dose of pemetrexed 


 
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Table 10 Footnotes: 
A. Baseline imaging must be contrast-enhanced and include the following: 
 Chest CT, CT or MRI of abdomen and pelvis, and all other suspected sites of 
disease within 28 days prior to initiation of study treatment (pemetrexed or 
sorafenib); for patients with a CT contrast allergy, the chest CT may be 
performed without contrast or, if the chest is not a known site of disease, a 
chest x-ray may be used. 
 Brain (CT or MRI) within 8 weeks prior to initiation of study treatment to 
screen for brain metastasis. 
The imaging used at baseline will be used at each subsequent imaging time point. 
B. Disease assessment by imaging or clinical examination; see Section 10. 
C. 12-Lead ECG with rhythm strip and determination of QTc interval; see Section 
4.2.11 for related exclusion criteria. 
D. Include over-the-counter medications. 
E. Refer to Appendix 1 for ECOG criteria. 
F. Chemistry includes the following panels and tests: basic metabolic panel (sodium, 
potassium, carbonate, chloride, glucose, calcium, BUN, and creatinine); hepatic 
panel (ALT, AST, ALP, total bilirubin, direct bilirubin, albumin, and total protein); 
magnesium; and phosphorous. 
G. Only required for WCBP; see Section 4.1.16 for the definition of WCBP. (Note: 
FSH and plasma estradiol levels may be required to determine if a patient is 
postmenopausal which may be needed to determine if the patient is a WCBP.) 
H. Baseline blood samples for multiplex assays and samples for CTC analysis can 
be collected any time following study registration (including on cycle 1, day 1) but 
must be collected prior to initiation of study treatment; see Sections 11.1, 11.4, 
and 11.5. 
I. Refer to Table 1 (Section 6.2) for instructions regarding the required supplementation and 
premedication regimen which begins prior to cycle 1, day 1. 
 


 
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Table 11. Study Calendar – During Treatment and Follow-Up 
 
Cycle 1 and Cycle 2A 
(21 days) 
Cycle 3 and OngoingA 
(21 Days)  
Every  
9 Weeks 
(+/- 1 week) 
End of 
Treatment 
Follow-UpB 
Day 1 
Day 2 
Days 
3-5 
Day 
1 
Day 
2 
Days  
3-5 
30-
Day 
Ongoing 
Weight 
X 
 
 
X 
 
 
 
X 
 
 
Vital Signs 
X 
 
 
X 
 
 
 
X 
 
 
Blood Pressure 
X 
 
 
X 
 
 
 
X 
 
 
Performance StatusC 
X 
 
 
X 
 
 
 
X 
 
 
Adverse EventsD 
X 
 
 
X 
 
 
 
X 
X 
 
Concurrent MedicationsE 
X 
 
 
X 
 
 
 
X 
 
 
Physical Exam 
X 
 
 
XF 
 
 
 
X 
 
 
CBC with Differential 
X 
 
 
X 
 
 
 
X 
 
 
Serum ChemistryG 
X 
 
 
X 
 
 
 
X 
 
 
INR 
XH 
 
 
XH 
 
 
 
 
 
 
Imaging/Clinical Examination 
and Disease AssessmentI 
 
 
 
 
 
 
XI 
XJ 
Correlative Blood Samples  
(Multiplex Assays) 
XK 
(cycles 
1, 2) 
XK 
(only 
cycle1) 
 
 
 
 
XK 
XK 
Correlative Blood Samples  
 for CTCs 
XL 
(only 
cycle1) 
XL 
(only 
cycle1) 
 
 
 
 
XL 
(at 1st tumor 
assessment) 
 
 
 
Submission of Archived 
Tumor  
X (request samples by  
end of cycle 2)M  
 
 
 
 
 
Folic Acid PON 
Daily doses for the duration of treatment and for 21 days after the last pemetrexed dose 
 
Vitamin B12 IMN 
 
 
 
 
 
 
X 
XO 
Dexamethasone PON 
On days -1, 1, 2 
 
On days -1, 1, 
2  
 
 
  
 
 
Pemetrexed IV N 
X 
 
 
X 
 
 
 
 
 
 
Sorafenib PO BID N 
X 
X 
X 
X 
X 
X 
 
 
 
 
Diary Review/Pill Count 
X  
 
 
X 
 
 
 
X 
 
 
Survival Status 
 
 
 
 
 
 
 
 
 
XP 


 
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Table 11 Footnotes: 
A. Cycle 1, day 1 assessments do not need to be repeated if done within 7 days prior to initiation of study treatment. Subsequent day 1 
assessments may be done up to 3 days prior to day 1 of each cycle. 
B. See Section 6.9 for information regarding the duration of follow-up. 
C. See Appendix 1 for ECOG criteria. 
D. Assessment and reporting of AEs based on the NCI CTCAE v4.0. 
E. Include over-the-counter medications. 
F. Physical exam is required on day 1 of each of the first 3 cycles. Beginning with cycle 4, physical exam is required on day 1 of every other 
cycle, ie, cycles 4, 6, 8, etc. 
G. Chemistry includes the following panels and tests: basic metabolic panel (sodium, potassium, carbonate, chloride, glucose, calcium, BUN, and 
creatinine); the hepatic panel (ALT, AST, ALP, total bilirubin, direct bilirubin, albumin, and total protein); magnesium; and phosphorous. 
H. If the patient is taking warfarin. 
I. 
Only imaging of initial sites of disease is required at each scheduled time point (ie, at the end of cycle 3 and then every 9 weeks [+/- 1 week]). 
The same method used at baseline should be used at each subsequent time point. (Refer to Section 10 regarding centralized radiologic 
review, the timing of confirmatory scans, and assessments by clinical examination.) 
J. For patients who discontinued study treatment in the absence of disease progression, assessment of tumor response every  
10 weeks (+/- 1 week) continues to be required for 2 years following initiation of study treatment or until disease progression or initiation of 
new cancer treatment, whichever occurs first. 
K. Blood samples for the multiplex assays will be collected in cycle 1 on day 1 before initiation of treatment (if not collected previously), on day 2 
(if day 2 is not possible, collect samples on day 3 or 4), on day 1 of cycle 2, at approximately the time of each tumor response assessment, 
and, if possible, at the time of disease progression (before initiation of new cancer therapy); see Section 11.4. 
L. Blood samples for CTC analysis will be in cycle 1 on day 1 before initiation of treatment (if not collected previously), on day 2 (about 24 hours 
after initiation of treatment; if 24 hours is not possible, collect samples on day 3 or 4), and at the time of the first tumor response assessment; 
see Section 11.5. 
M. Samples from recurrent or metastatic tumor (archived following a biopsy or surgical resection performed prior to study registration) 
and samples from tumor archived at time of initial breast cancer diagnosis (see Section 11.3). 
N. Refer to Table 1 in Section 6.2 for a summary of the treatment regimen. 
O. Continuing approximately every 9 weeks until approximately 8 weeks following the last dose of pemetrexed. 
P. All patients will be followed for survival about every 2 months after discontinuation of study therapy until 2 years after the initiation of study 
therapy or until death, whichever occurs first. If the patient is unable to return for a study visit, the study team may contact the patient, family 
member, and/or other members of the patient’s health care team to determine the patient’s vital status. 


 
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13 STATISTICAL CONSIDERATIONS 
13.1 Study Design 
This is a single-arm phase 2 study of pemetrexed and sorafenib in the treatment of 
patients with recurrent or metastatic TNBC. The primary objective is to determine the 
efficacy of the combination therapy in terms of the objective response rate. 
13.2 Sample Size and Accrual Rate 
The sample size and power are calculated based on Simon’s two-stage minimax design 
which minimizes the expected maximum sample size under the alternative hypothesis. The 
primary endpoint will be determined by objective radiologic criteria (RECIST v1.1). In the 
phase 1 trial of pemetrexed and sorafenib, 5 of 11 patients with breast cancer had a 
clinical response (CR or PR). We assume that the null hypothesis, the proportion of 
patients who have responses, is ≤ 15%, ie, p0 ≤ 0.15, which is unacceptably low, and the 
promising response rate is p1 ≥ 0.35. 
With a one-sided type I error of 5% and power of at least 80%, by Simon’s two-stage 
minimax method, the first stage needs to enroll 15 efficacy-evaluable patients at the lower 
doses of pemetrexed and sorafenib effective with version 4 of the protocol. If there are ≤ 2 
patients who have a response, then the trial will end for futility. If 3 or more patients have a 
response, then the trial will move into the second stage. Efficacy-evaluable patients 
enrolled at the previous higher dose level will be counted toward the second stage. 
Patients will continue to be enrolled until there are 13 efficacy-evaluable patients in the 
second stage. If 8 or more out of the total of 28 efficacy-evaluable patients have a CR or 
PR, the intervention meets efficacy criteria and further study can be pursued.  
To account for about 25% of patients not being evaluable for response, the total sample 
size for the Simon’s two-stage design is 37 patients. Based on previous recruiting history, 
we anticipate that 2-3 patients will be enrolled per month and the expected enrollment 
period will be about 18-24 months. 
13.3 Analysis Populations 
There will be 2 efficacy populations and 1 safety population used for statistical analysis of 
the primary and secondary endpoints. 
13.3.1 Intent-to-treat (ITT) Population 
The ITT population includes all patients who have received at least one dose of 
pemetrexed and one dose of sorafenib. 
13.3.2 Efficacy-Evaluable (EE) Population 
The EE population includes all patients who initiated a minimum of 2 cycles of study 
treatment and have undergone at least one assessment of response after receiving 
study treatment. 
13.3.3 Safety Population 


 
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The safety population includes all patients who have received at least one dose of 
pemetrexed and one dose of sorafenib. 
13.4 Statistical Analysis Plan 
All efficacy analyses will be conducted both the EE population and the ITT population. Only 
the EE population analyses will be used to determine if the number of responses met the 
criteria for the study to proceed from Stage 1 to Stage 2 and if the study meets  
pre-specified criteria for activity of interest. 
13.4.1 Analysis of the Primary Endpoint 
The primary endpoint is the percentage of patients with HER2-negative metastatic 
breast cancer achieving an objective response (either PR or CR). In the first stage 
(n=15), if ≤ 2 EE patients have a response, then the trial will end for futility. If 3 or 
more patients have a response, an additional 13 patients (including those enrolled 
at the previous higher dose) will be enrolled in the second stage. If 8 or more of the 
total of 28 EE patients have a response, the intervention meets efficacy criteria, 
shows promising evidence, and allows further study to be pursued. The proportion 
of patients who have a response will be calculated along with its 95% confidence 
interval by the biased-reduced estimation method by Chang et al (36), 
recommended by Porcher and Desseaux (37). 
13.4.2 Analysis of Secondary Endpoints 
Patients’ demographics, AEs and SAEs, disease status, treatment status, clinical  
response, time-to-event intervals, etc will be listed and summary descriptive 
statistics will be calculated. 
The Kaplan-Meier method will be used to describe the time to death or disease 
progression; the median time to death or progression will be estimated, along with 
95% confidence intervals. A Cox regression model may be used to model the time 
to death or progression, adjusting for any effects of potential covariates (such as 
tumor size, tumor stage, biomarker, and age). 
13.5 Definitions for Responders and Non-Responders 
Response status will be reported in OnCore at the time of each scheduled response 
evaluation. The OnCore entry, in the Follow-up tab, supported by source documents and 
related CRFs, will capture the “best response” experienced by a patient for the duration of 
study participation. 
The coding of patients as responders or non-responders will be made by the principal 
investigator with the concurrence of the biostatistician. 
 
Responders are defined as patients whose best response is PR or CR. 
 
Non-Responders are defined as patients whose best response is stable disease or 
progressive disease. Non-responders will also include patients who were not evaluable 
for response for the ITT analyses. 


 
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14 DATA AND SAFETY MONITORING 
14.1 Study Team 
The study team minimally consists of the principal investigator, the research nurse, the 
clinical research associate, and the study biostatistician. While patients are on treatment, 
the principal investigator, the research nurse, and the clinical research associate will meet 
at least monthly to review study status; quarterly meetings will be held with the study 
biostatistician. This review will include, but not be limited to, reportable AEs and UPs and 
an update of the ongoing study summary that describes study progress in terms of the 
study schema. All meetings, including attendance, are documented. 
14.2  Monitoring and Auditing 
14.2.1 MCC Compliance Office 
Compliance specialists in the MCC Compliance Office will provide ongoing 
monitoring and auditing for this study. 
14.2.2 Data Safety and Monitoring Committee 
The study will be reviewed by the MCC Data Safety and Monitoring Committee 
(DSMC) initially according to the risk level specified by the MCC Protocol Review 
and Monitoring Committee (PRMC) and then according to a schedule based on 
study status and quality indicators. The DSMC reviews reports provided by the 
principal investigator/study team and the MCC Compliance Office focusing on data 
integrity and patient safety. 
15 REGULATORY COMPLIANCE AND ETHICS 
15.1 Ethical Standard 
This study will be conducted in conformance with the principles set forth in The Belmont 
Report: Ethical Principles and Guidelines for the Protection of Human Patients of Research 
(US National Commission for the Protection of Human Patients of Biomedical and 
Behavioral Research, April 18, 1979). 


 
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15.2 Regulatory Compliance 
This study will be conducted in compliance with the clinical trial protocol and with federal 
regulations, as applicable, including: 21 CFR 50 (Protection of Human Patients/Informed 
Consent); 21 CFR 56 (Institutional Review Boards); 21 CFR 312 (IND Application); and 45 
CFR 46 Subparts A (Common Rule), B (Pregnant Women, Human Fetuses and 
Neonates), C (Prisoners), and D (Children). 
15.3 Institutional Review Board 
Each participating institution must provide for the review and approval of this protocol and 
the associated informed consent documents and recruitment material by an appropriate 
IRB registered with the Office for Human Research Protections (OHRP). Any amendments 
to the protocol or consent materials must also be approved. Only institutions holding a 
current US Federalwide Assurance issued by OHRP may participate. 
15.4 Informed Consent Process 
Informed consent is a process that is initiated prior to the individual’s agreeing to 
participate in the study and continues throughout the individual’s study participation. 
Extensive discussion of risks and possible benefits of this therapy will be provided to 
patients and their families. Consent forms describing in detail the study interventions/, 
study procedures, and risks are given to the patient and written documentation of informed 
consent is required prior to starting intervention/administering study product. 
Consent forms will be IRB-approved and the patient will be asked to read and review the 
document. Upon reviewing the document, the investigator will explain the research study to 
the patient and answer any questions that may arise. The patient will sign the informed 
consent document prior to any procedures being done specifically for the study. Patients 
should have the opportunity to discuss the study with their surrogates or think about it prior 
to agreeing to participate. Patients may withdraw consent at any time throughout the 
course of the trial. A copy of the informed consent document will be given to patients for 
their records; the original consent form will be maintained in the research records. The 
rights and welfare of patients will be protected by emphasizing to them that the quality of 
their medical care will not be adversely affected if they decline to participate in this study. 
15.5 Patient Confidentiality 
Patient confidentiality is strictly held in trust by the participating investigators and their staff. 
This confidentiality includes the clinical information relating to participating patients, as well 
as any genetic or biological testing. 
The study protocol, documentation, data, and all other information generated will be held in 
strict confidence. No information concerning the study or the data will be released to any 
unauthorized third party without prior written approval of the principal investigator. 
The study monitor or other authorized representatives of the principal investigator may 
inspect all documents and records required to be maintained by the investigator, including 
but not limited to, medical records (office, clinic, or hospital) and pharmacy records for the 
patients in this study. The clinical study site will permit access to such records. 


 
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16 DATA COLLECTION AND MANAGEMENT 
16.1 CRFs and Data Collection 
MCC OnCore data management will provide standard electronic CRFs (eCRFs) and create 
study-specific eCRFs to be able to capture all information required by the protocol. The 
eCRFs will be approved by the study team to ensure the most effective data acquisition. 
The investigator(s) and study coordinator(s) must maintain source documents for each 
patient in the study. All information on eCRFs will be traceable to these source documents, 
which are generally maintained in the patient’s file. 
All eCRFs should be completed and available for collection within a timely manner, 
preferably no more than 14 days after the patient’s visit. 
16.2 Study Record Retention 
As applicable, study records will be maintained a minimum of 5 years beyond the 
publication of any abstract or manuscript reporting the results of the protocol or submission 
of a final report to clinicaltrials.gov. 


 
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Res Methodol 12: 117 


 
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 APPENDIX 1. PERFORMANCE STATUS CRITERIA 
 
ECOG Performance Status Scale 
 
Karnofsky Performance Scale 
 
Grade 
Description 
Percent 
Description 
0 
Normal activity. Fully active, 
able to carry on all pre-disease 
performance without restriction. 
100 
Normal, no complaints, no evidence 
of disease. 
90 
Able to carry on normal activity; minor 
signs or symptoms of disease. 
1 
Symptoms, but ambulatory. 
Restricted in physically 
strenuous activity, but 
ambulatory and able to carry 
out work of a light or sedentary 
nature (eg, light housework, 
office work). 
80 
Normal activity with effort; some signs 
or symptoms of disease. 
70 
Cares for self; unable to carry on 
normal activity or to do active 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 > 50% of waking hours. 
60 
Requires occasional assistance, but is 
able to care for most of his/her needs. 
50 
Requires considerable assistance and 
frequent medical care. 
3 
In bed > 50% of the time. 
Capable of only limited self-
care, confined to bed or chair  
> 50% of waking hours. 
40 
Disabled; requires special care and 
assistance. 
30 
Severely disabled; hospitalization 
indicated. Death not imminent. 
4 
100% bedridden. Completely 
disabled. Cannot carry on any 
self-care. Totally confined to 
bed or chair. 
20 
Very sick, hospitalization indicated. 
Death not imminent. 
10 
Moribund, fatal processes progressing 
rapidly. 
5 
Dead. 
0 
Dead. 


 
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APPENDIX 2. COCKCROFT-GAULT FORMULA 
 
 
Calculated Creatinine Clearance (Cockcroft-Gault) 
 
Creatinine clearance (mL/min) = [(140 - Age) × Weight in kg ×G] / (Creatinine × 72) 
 G=1 (males); G=0.85 (females) 


 
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APPENDIX 3. NEW YORK HEART ASSOCIATION CLASSIFICATION 
 
New York Heart Association Classification of Heart Failure 
Class I 
No symptoms. Ordinary physical activity such as walking and climbing 
stairs does not cause fatigue or dyspnea. 
Class II 
Symptoms with ordinary physical activity. Walking or climbing stairs 
rapidly, walking uphill, walking or stair climbing after meals, in cold 
weather, in wind or when under emotional stress causes undue fatigue or 
dyspnea. 
Class III 
Symptoms with less than ordinary physical activity. Walking one to two 
blocks on the level and climbing more than one flight of stairs in normal 
conditions causes undue fatigue or dyspnea. 
Class IV 
Symptoms at rest. Inability to carry on any physical activity without fatigue 
or dyspnea. 


 
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APPENDIX 4. HEMATOLOGIC ADVERSE EVENTS 
For the purposes of this study, the following CTCAE v4.0 AE terms qualify as “Hematologic” 
AEs. 
From the Blood and Lymphatic system disorders category: 
 
Anemia 
 
Febrile neutropenia 
 
Leukocytosis 
From the Investigations category: 
 
Hemoglobin increased 
 
Lymphocyte count decreased 
 
Lymphocyte count increased 
 
Neutrophil count decreased 
 
White blood cell decreased