Clinical trial NCT02384850
Conditions: Colorectal Neoplasm
Keywords: metastatic
Sponsor: GSO Global Clinical Research BV
Start date: 2015-03-01; Completion date: 2017-03-09
Enrollment: 10 participants; Allocation: NA; Intervention model: SEQUENTIAL

Brief summary:
This trial will evaluate the combination treatment of established chemotherapy regimen mFOLFOX6 with Selinexor, an oral Selective Inhibitor Of Nuclear Export, in patients with metastatic Colorectal Cancer. The purpose is to determine the maximum tolerated dose (MTD) of selinexor in combination with mFOLFOX6.

Detailed description:
This was a multi center, open-label, non-randomized phase I trial study to determine the MTD of a combination of mFOLFOX6 (Folinic Acid (Leucovorin)-Fluorouracil-Oxaliplatin) and selinexor in patients with metastatic colorectal cancer.

After screening and registration in the study, all enrolled patients were to be treated with oxaliplatin (85 mg/m² IV over 2 hours, Day 1), 5-FU (5-Fluorouracil 400 mg/m2 IV bolus, Day 1), leukovorin (400 mg/m2 IV over 2 hours, Day 1), and 5-FU (2,400 mg/m² continuous infusion, Days 1-3) every 2 weeks and escalating doses of selinexor as follows:

Patients in Dose Level 1 were to receive oral selinexor 40 mg on day 1, 3, and 8.

Patients in Dose Level 2 were to receive oral selinexor 60 mg on day 1, 3, and 8.

Patients in Dose Level 3 were to receive oral selinexor 80 mg on day 1, 3, and 8.

Patients in Dose Level -1 were to receive oral selinexor 20 mg on day 1, 3, and 8.

The MTD was defined as the highest dose level at which six patients had been treated with no toxicity and tolerance of the dose escalation of Selinexor with mFOLFOX6 was evaluated.

Six patients were to be initially treated in a cohort. Safety data were monitored in real time. As soon as last patient of the cohort (either 6th or 9th) reached day 28, safety data of all patients within that cohort were reviewed for decision about opening up a new cohort by moving to the next dose level or expand the cohort or discontinue dose escalation.

Arms: arm 1: Different Dose Levels of Selinexor will be evaluated in combination with mFOLFOX6 (see interventions)
Interventions: intervention 1: Selinexor intervention 2: Oxaliplatin intervention 3: 5-FU intervention 4: Folinic Acid
Intervention descriptions: intervention 1: Dose Level 1: 40 mg on day 1, 3 and 8 in a two-weeks cycle. Dose Level 2: 60 mg on day 1, 3 and 8 in a two-weeks cycle. Dose Level 3: 80 mg on day 1, 3 and 8 in a two-weeks cycle. Dose Level -1: 20 mg on day 1, 3 and 8 in a two-weeks cycle. intervention 2: 85 mg/m² IV over 2 hours, Day 1 of a two-weeks cycle intervention 3: 400 mg/m² IV bolus, Day 1 of a two-weeks cycle 2,400 mg/m² continuous infusion IV, Days 1-3 intervention 4: 400 mg/m2 IV over 2 hours, Day 1 of a two-weeks cycle

Protocol documents:
Prot_SAP_000.pdf: 
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Current version: Version 1.1, 2015.01.22 
SENTINEL 
 
An Investigator Initiated Phase 1 Trial To Evaluate mFOLFOX6 With 
Selinexor (KPT-330), An Oral Selective Inhibitor Of Nuclear Export 
(SINE), In Patients With Metastatic Colorectal Cancer 
 
Study Code:  
 
Sentinel 
 
Sponsor: 
 
 
GSO Global Clinical Research B.V. 
 
Coordinating investigator  Prof. Dr. Carsten Bokemeyer, Hamburg 
 
Coordinating CRO:  
GSO mbH 
 
 
 
EudraCT Number:   
2014-003526-40 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Confidentiality 
The contents of the protocol are confidential and may neither be communicated verbally nor 
in writing without the agreement of the study sponsor. 


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Current version: Version 1.1, 2015.01.22 
Contact Addresses 
 
 
Sponsor 
GSO Global Clinical Research B.V. 
Keizersgracht 62-64 
1015 CS Amsterdam, The Netherlands  
 
Coordinating Investigator Prof. Dr. Carsten Bokemeyer 
 
 
Coordinating CRO 
GSO mbH 
Harvestehuder Weg 21 
20148 Hamburg 
Germany 
Phone +494044195460 
Fax +494044195478 
e-mail: kranich@gso-hamburg.com 
 
Drug Supply 
Karyopharm Therapeutics 
85 Wells Ave  
Newton MA 02459 
USA 
 
Protocol Committee  
Prof. Dr. Carsten Bokemeyer 
Anders Jakobsen, Professor, MD, DMSc 
Dr. Anne L. Kranich 
Prof. Dr. Christian Rolfo  
Karen-Lise Garm Spindler, MD PhD 
Dr. Alexander Stein 
Prof. Dr. Henk Verheul 
 
 
 
 




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Investigator’s Agreement 
 
I have read the attached protocol entitled 
 
“An Investigator Initiated Phase 1 Trial To Evaluate mFOLFOX6 With Selinexor 
(KPT-330), An Oral Selective Inhibitor Of Nuclear Export (SINE), In Patients 
With Metastatic Colorectal Cancer”, dated 22.01.2015,  
 
and agree to abide by all provisions set forth therein. 
 
I agree to comply with the International Conference on Harmonization Tripartite Guideline on 
Good Clinical Practice, all applicable national regulations as well as the requirements of the 
appropriate Institutional Review Board/Independent Ethics Committee and any other 
institutional requirements. 
 
I agree to ensure that the confidential information contained in this document will not be used 
for any purpose other than the evaluation or conduct of the clinical investigation without the 
prior written consent of the study sponsor. 
 
 
 
 
 
 
Signature  
  
Date (DD Month YYYY)  
Investigator  
  
  
Investigator’s Institution 
  
  
 


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Synopsis 
 
Protocol no. 
SENTINEL 
Protocol version 
(Date) 
Version 1.1, 2015.01.22 
Abbreviated Title 
 
Detailed title 
An Investigator Initiated Phase 1 Trial To Evaluate Combination 
Treatment mFOLFOX6 With Selinexor (KPT-330) In Patients 
With Metastatic Colorectal Cancer 
EudraCT no. 
2014-003526-40 
Coordinating 
investigator 
Professor Dr. Carsten Bokemeyer, Hamburg 
Sponsor 
GSO Global Clinical Research B.V. 
Keizersgracht 62-64 
1015 CS Amsterdam, The Netherlands 
Study design 
· 
Multi center, open-label, non-randomized phase I trial 
· 
Patients with metastatic colorectal cancer will receive 
FOLFOX6: Oxaliplatin 85mg/m² day 1, 5-FU 400 mg/m2 iv 
bolus day 1, leucovorin 400 mg/m2 day 1 and 5-FU 2400 
mg/m² days 1-3 every 2 weeks; combined with Selinexor 40, 
60 or 80 mg on day 1, 3 and 8 of each two-week cycle.   
Treatment will be continued until disease progression or 
significant toxicities occur or patient withdraws consent.  
Anticipated start 
date 
January 2015 
Duration of study 
With an estimated accrual rate of 2-3 patients per month, and a 
total number of 27 patients planned, the anticipated enrollment 
period will last about 12 months.  
Total number of 
sites 
4-8 
 
Study population 
Patients with metastatic colorectal cancer according to the 
inclusion and exclusion criteria below will be enrolled in this study 
trial. 
Objectives 
 
Primary objective 
 
Primary objective is the determination of the maximum tolerated 
dose (MTD) of selinexor in combination with mFOLFOX6 in 
patients with metastatic colorectal cancer.  
Secondary 
objectives 
Secondary objectives are efficacy parameters and tolerability. 
Exploratory 
objectives 
NA 
Planned sample 
size 
A sample size of 27 patients is planned and all patients receive 
mFOLFOX6 and Selinexor.  
Inclusion criteria 
1. Patients with histologically confirmed diagnosis of colorectal 
cancer presenting with unresectable stage IV (UICC) disease 
(primary tumor may be present)  
2. Patients who are feasible for treatment with FOLFOX (prior 
adjuvant or palliative treatment is allowed) 
3. ECOG Performance status ≤ 1 
4. Life expectancy > 3 months 
5. Age ≥18 years  


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6. Haematologic function as follows (5% deviation allowed):  
· 
ANC ³ 1.5 x 109/L 
· 
platelets ³ 125 x109/L 
· 
hemoglobin ³ 9 g/dl or 5.59 mmol/l 
7. Adequate liver function as follows (10% deviation allowed) 
· 
serum alanine transaminase (ALT) £ 2.5 x ULN (in 
case of liver metastases < 5 x ULN) 
· 
total bilirubin £ 1.5 x ULN (patients with Gilbert’s 
syndrome total bilirubin ≤2.5 x ULN) 
8. Adequate renal function as follows (10% deviation allowed) 
· 
creatinine £ 1.5 x ULN 
9. Signed written informed consent 
10. Women of child-bearing potential must have a negative 
pregnancy test 
 
Exclusion criteria 
Patients with any of the following will not be eligible for 
participation: 
1. Patients with significant medical illness that in the 
investigator’s opinion cannot be adequately controlled 
with appropriate therapy or would compromise the 
patient’s ability to tolerate this therapy; 
2. Treatment with any systemic anticancer therapy ≤ 3 
weeks prior to cycle 1 day 1 
3. Uncontrolled active infection (Hepatitis B and C infection 
are NOT exclusion criteria) and/or known HIV infection; 
4. Renal failure requiring haemodialysis or peritoneal 
dialysis; 
5. Patients who are pregnant or breast-feeding; 
6. Patients 
with 
significantly 
diseased 
or 
obstructed 
gastrointestinal tract, malabsorption, uncontrolled vomiting 
or diarrhea resulting in inability to swallow oral 
medications; 
7. Presence of symptomatic CNS metastasis 
8. Unresolved toxicity from previous anti-cancer therapy or 
incomplete recovery from surgery, in particular oxaliplatin-
induced peripheral neuropathy > grade 1. 
9. Any of the following within the 12 months prior to study 
drug 
administration: 
myocardial 
infarction, 
severe/unstable angina, coronary/peripheral artery bypass 
graft, 
symptomatic 
congestive 
heart 
failure, 
cerebrovascular accident or transient ischemic attack, 
pulmonary embolism, deep vein thrombosis, or other 
thromboembolic event. 
 
Treatment scheme 
 
All enrolled patients will be treated with mFOLFOX6 every two 
weeks and escalating doses of Selinexor (according to the 
mentioned dose levels)  
mFOLFOX 6 
Oxaliplatin at a dose of 85 mg/m2 iv over two hours (day 1) 
5-FU 400 mg/m2  iv bolus (day 1) 
LV at a dose of 400 mg/m2 iv over two hours (day 1) 


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5-FU at a dose of 2400 mg/m2 iv over 46 hours (day 1-3) 
 
Selinexor will be given orally on days 1, 3 and 8 of each two-
week cycle.  
Dose-level 1 
Selinexor will be administered at a dose of 40 mg. 
Dose-level 2 
Selinexor will be administered at a dose of 60 mg. 
Dose-level 3 
Selinexor will be administered at a dose of 80 mg. 
 
Dose-level -1 
Selinexor will be administered at a dose of 20 mg 
Treatment will be continued until disease progression or 
significant toxicities occur. 
Primary parameter 
· 
Determination of the maximum tolerated dose (MTD) 
Secondary 
parameters 
· 
Overall response rate (RR) (acc. to RECIST v1.1) 
· 
Progression free survival (PFS) (acc. to RECIST v1.1) 
· 
Overall survival (OS) 
· 
Toxicity (acc. to NCI CTC AE v4.03) 
 
Dose-limiting 
toxicities (DLT) 
Toxicity and tolerance of the dose escalation of Selinexor with 
mFOLFOX6 will be evaluated. 
Six patients will be initially treated in a cohort. Safety data will be 
monitored in real time. As soon as last patient of the cohort 
(either 6th or 9th) reaches day 28, safety data of all patients 
within that cohort will be reviewed for decision about opening up 
a new cohort by moving to the next dose level or expand the 
cohort or discontinue dose escalation. 
Dose escalation: 
If 0-1/6 patients experience a DLT, dose will be moved to the next 
level. 
If 2-3/6 patients experience a DLT, 3 more patients will be treated 
on that dose level. 
If 4-6/6 patients experience a DLT, dose will be regarded as toxic 
and dose escalation will be stopped. 
 
In case the dose escalation will be stopped at dose level 1, dose 
level -1 will be included in the study and evaluated by the same 
design. 
Dose limiting toxicity should be at least possibly related to study 
drug Selinexor combinational therapy.  Dose-Limiting Toxicity 
(DLT) is defined as any of the following occurring in the first 28 
days (cycle 1 +Cycle2) of study participation that are considered 
at least possibly related to selinexor administration. 
·         2 missed doses (out of 3 doses) of selinexor per 


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cycle due to study drug related toxicity 
·         Delay of more than 14 days in initiating cycle 2 or 
3 on the scheduled date due to study drug related 
toxicity 
·         Discontinuation of a patient due to study drug 
related toxicity before completing cycle 2 
Haematological toxicities  
1. febrile neutropenia  
2. leukopenia or neutropenia Grade 4 > 7 days 
3. thrombopenia Grade 4 or Grade 3 with clinically significant 
bleeding, petechiae or purpura  thrombopenia 
Non-haematological toxicities  
4. Grade 3 nausea/vomiting, diarrhea for >3 days while taking 
optimal supportive medications 
5. Grade 3 fatigue lasting for ≥5 days while taking optimal 
supportive care and with correction of dehydration, anorexia, 
anemia, endocrine, or electrolyte abnormalities. 
6. Grade  3 dehydration lasting for ≥5 days while taking optimal 
supportive care  
7. Grade 4 vomiting, dehydration and diarrhea 
8. Any other Grade ≥3 non-hematological toxicity except 
Electrolyte abnormalities that are reversible and 
asymptomatic, hair loss, ALT, AST or alkaline phosphatase in 
the setting of baseline grade 2 elevations from disease 
9. Any other grade 4 non-hematologic toxicity 
10. For the purposes of DLT assessment, asymptomatic 
hyponatremia will be “graded” not by CTCAEv4 but rather by 
clinically meaningful criterion of <125mmol/L. Sodium 
<125mmol/L will be graded as DLT with the exception of 
asymptomatic translational hyponatremia due to 
hyperglycemia (see footnote below for calculation).  
11. *In marked hyperglycemia, ECF osmolality rises and exceeds 
that of ICF, since glucose penetrates cell membranes slowly 
in the absence of insulin, resulting in movement of water out 
of cells into the ECF. Serum Na concentration falls in 
proportion to the dilution of the ECF, declining 1.6 mEq/ L for 
every 100 mg/dL (5.55 mmol/L) increment in the plasma 
glucose level above normal. This condition has been called 
translational hyponatremia because no net change in total 
body water (TBW) has occurred. No specific therapy is 
indicated, because Na concentration will return to normal 
once the plasma glucose concentration is lowered. Corrected 
Sodium (Hillier, 1999) = Measured sodium + 0.024 * (Serum 
glucose - 100)32.  
12. Mucositis Grade 4 persistent for >7 days 
13. Heart-insufficiency Grade ≥3  
14. Interstitial lung disease Grade ≥3 


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15. Skin toxicity Grade 4 
16. Hepatic toxicity Grade 3 (in case of hepatic metastasis  
Grade 4) 
17. Any toxicity causing a delay of therapy continuation of more 
than 2 weeks more than one case of or 9 patients have been 
treated with no more than 3 cases of DLT. 
IMP Definition 
Selinexor will be supplied by Karyopharm Therapeutics and 
defined as IMP. 
Assessments 
Screening 
· 
Review of inclusion and exclusion criteria 
· 
Medical and medication history, physical examination      
including height, weight, vital signs (blood pressure, heart 
rate, respiratory rate, body temperature), ECOG-performance 
status 
· 
Laboratory Tests: 
o 
Hematology panel: hemoglobin, hematocrit, red blood cell 
(RBC) count, platelets, white blood cell (WBC) count and 
WBC differential (neutrophils, lymphocytes).  
o 
Chemistry panel: sodium, potassium, calcium, creatinine, 
total bilirubin, alkaline phosphatase, alanine 
aminotransferase (ALT), aspartate aminotransferase 
(AST), total protein, albumin, LDH, amylase, lipase 
o 
Coagulation: INR, aPTT, PT 
o 
CEA, (CA 19-9 if appropriate) 
o 
Pregnancy test for women of childbearing potential within 
7 days prior to start of the treatment 
o 
ECG 
o 
Radiological imaging of the chest, abdomen and all other 
sites of disease (CT/MRI-scan of the thoracic and 
abdominal region) (within 4 weeks before start of 
treatment). 
o 
Ophthalmological examination: required at screening and 
if clinically indicated. Prior to dilation:  best corrected 
visual acuity, and slit lamp examination including 
tonometry; following dilation, fundoscopy and slit lamp 
exam to document lens clarity - if a cataract is seen during 
the exam, the cataract will be graded according to the 
Lens Opacities Classification System (LOCS III) 
(Appendix 7). 
Treatment phase 
Day 1 of every 2 week cycle (+/-2 days allowed)  
· 
Vital signs including weight, ECOG-performance status, 
assessment of toxicity, concomitant medication, physical 


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Examination (as clinically indicated) 
· 
Laboratory Tests:  
o 
Hematology panel: hemoglobin, platelets, white blood cell, 
neutrophils, lymphocytes,  
o 
Chemistry panel: sodium, potassium, calcium, creatinine, 
total bilirubin, alkaline phosphatase, alanine 
aminotransferase (ALT), aspartate aminotransferase 
(AST), total protein, albumin, LDH, amylase, lipase 
o 
Coagulation: INR, aPTT, PT  
 
Day 8 during first two cycles 
· Vital signs including weight, ECOG-performance status, 
assessment of toxicity, concomitant medication, physical 
Examination (as clinically indicated) 
· Laboratory Tests:  
o Hematology panel: hemoglobin, platelets, white blood cell, 
neutrophils, lymphocytes,  
 
Additional assessments every 8 weeks (+/- 7 days allowed) 
· 
Radiological imaging of the chest, abdomen and all other sites 
of disease (CT or MRI scan of the thoracic and abdominal 
region)  
· 
CEA, (CA 19-9) 
End of treatment (30 days after last dose +/-7 days) 
When any subject discontinues dosing of all study treatment, the 
following assessments should be made. 
· 
Physical examination, vital signs including weight, ECOG-
performance status, assessment of toxicity, concomitant 
medication  
· 
Laboratory Tests: hemoglobin, platelets, white blood cell, 
neutrophils, lymphocytes, sodium, potassium, calcium, 
creatinine, total bilirubin, alkaline phosphatase, alanine 
aminotransferase (ALT), aspartate aminotransferase (AST), 
total protein, amylase, lipase 
· 
ECG 
· 
Tumor response assessment (in case discontinuation is not 
due to progressive disease) 
Follow-up 
All subjects will be contacted every 3 months ± 28 days after EOT 
(for overall 2 years from study inclusion).  
Tumor Response Assessment 
During study treatment tumor response will be assessed by the 


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investigator according to RECIST v1.1 (CT and/or MRI) at 
baseline (within 4 weeks before first study treatment) and every  
8 weeks thereafter (during study treatment). 
CT and/or MRI scans will be retrospectively reviewed.  
Safety 
assessment 
All adverse events occurring during the course of the trial and for 
up to 30 days after the last dose of study medication will be 
captured, documented and reported.  
 
Safety blood samples include complete blood count, clinical 
chemistry, including liver function test, coagulation, and 12-lead 
electrocardiogram. 
Timelines 
Recruitment period: 12 months 
Follow up for survival 24 months.  
 


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Information to be provided regarding SAEs/Pregnancy 
 
In the case of a serious adverse event (SAE) or pregnancy, the following person 
must be contacted by fax within 24 hours of knowledge: 
Clinical Trial Manager 
Dr. Anne L. Kranich 
Address: 
GSO mbH 
Harvestehuder Weg 21 
20148 Hamburg 
Germany 
 
Phone: 
0049-40-44 19 54 60  
Fax: 
0049-40-44 19 54 78 
 
 
 


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Dose escalation scheme 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dose levels: 
Dose level 1:  Oxaliplatin at a dose of 85 mg/m2 IV over two hours (Day 1) 
5-FU 400 mg/m2 IV bolus (Day 1) 
Leucovorin 400 mg/m2 IV over two hours (Day 1) 
5-FU 2400 mg/m2 IV over 46 hours (Day 1-3) 
Selinexor 40 mg, PO (Day 1, 3 and 8) 
Dose level 2: Oxaliplatin at a dose of 85 mg/m2 IV over two hours (Day 1) 
5-FU 400 mg/m2 IV bolus (Day 1) 
Leucovorin 400 mg/m2 IV over two hours (Day 1) 
5-FU 2400 mg/m2 iv over 46 hours (Day 1-3) 
Selinexor 60 mg, PO (Day 1, 3 and 8) 
Dose level 3:  Oxaliplatin at a dose of 85 mg/m2 iv over two hours (Day 1) 
5-FU 400 mg/m2 iv bolus (Day 1) 
Leucovorin 400 mg/m2 iv over two hours (Day 1) 
5-FU 2400 mg/m2 iv over 46 hours (Day 1-3) 
Selinexor 80 mg, PO (Day 1, 3 and 8) 
Dose level -1:  Oxaliplatin at a dose of 85 mg/m2 IV over two hours (Day 1) 
5-FU 400 mg/m2 IV bolus (Day 1) 
Leucovorin 400 mg/m2 IV over two hours (Day 1) 
5-FU 2400 mg/m2 IV over 46 hours (Day 1-3) 
Selinexor 20 mg, PO (Day 1, 3 and 8) 
 
Initially, 6 patients will be enrolled into each cohort. After enrollment of the sixth patient of a 
cohort, further recruitment will be temporarily stopped and dose-limiting toxicities will be 
3 additional patients at the 
same dose level 
Next Dose level 
6 Patients  
If 0 or 1 DLT then ... 
If 2 or 3 DLT then ... 
If 4 or 6 DLT 
then... 
Dose escalation will be 
stopped 
If additional 
DLT 
Dose escalation will be 
stopped 
If no 
additional 
DLT 
Dose level 1 
In case of dose level 1, 
dose level -1 will be 
explored.


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assessed. When the last patient of a given cohort has completed the first 4 weeks of 
treatment, all adverse events and other relevant safety data available up to that date will be 
reviewed by the coordinating investigator and the principal investigators and a decision will 
be made regarding dose escalation, expansion of cohort or end of escalation. To ensure that 
the assessment of a DLT is consistent between the sites, the Investigators from the sites will 
have a TC to discuss the DLT information at each dose escalation meeting. Before the TC all 
documentation of AEs and SAEs will be provided in writing. A new cohort may only be 
opened after a favourable decision has been made. The decision will be documented in 
writing and sent out to all sites on the same day.  
 
If MTD was exceeded, another three patients will be treated at the previous dose level if 
there were only six patients treated at that level.  
The MTD is defined as the highest dose level at which six patients have been treated with 
no more than one case of DLT or 9 patients have been treated with no more than 3 cases of 
DLT. 


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Flow Chart: Schedule of Assessments during the study 
 
 
Screening/ Baseline 
Treatment phase 
End of 
treatment 
Follow-up 
 
Within 14 days 
prior to registration 
Day 1 of each 
cycle (-2 days) 
Day 8 of cycle 
1 and 2  
(+/-1 day)s 
Additionally 
every 8 weeks 
(+/-7 days) 
30-days after 
last dose 
(+/- 7 days) 
Every 3 months 
± 28 days 
Informed consent 1 
X 
 
 
 
 
 
Inclusion and exclusion 
criteria 
X 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
Medical history 2 
X 
 
 
 
 
 
Pregnancy test (if applicable) 3
X 
 
 
 
 
 
Physical examination and 
ECOG4 
X 
X 
X 
 
X 
 
Body height and weight 5 
X 
X 
X 
 
X 
 
BSA 
X 
 
 
 
 
 
Vital signs 6 
X 
X 
X 
 
X 
 
Standard clinical neurologic 
examination 
X 
 
 
 
X 
 
Ophthalmological exam7 
X 
 
 
 
 
 
12-lead ECG 
X 
 
 
 
X 
 
Hematology 8 
X 
X 
X 
 
X 
X 
Calculation 9 (or 
measurement) of GFR 
X 
 
 
 
X 
 
Clinical Chemistry10 
X 
X 
 
 
X 
 
Urine dipstick  
X 
X 
 
 
X 
 
CEA (CA19-9) 
X 
 
 
X 
 
 
Coagulation test 11 
X 
X 
 
 
X 
 
Assessment of signs and 
symptoms, AE 
X 
X 
 
 
X 
 
Concomitant medication 
X 
X 
 
 
X 
 


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Screening/ Baseline 
Treatment phase 
End of 
treatment 
Follow-up 
 
Within 14 days 
prior to registration 
Day 1 of each 
cycle (-2 days) 
Day 8 of cycle 
1 and 2  
(+/-1 day)s 
Additionally 
every 8 weeks 
(+/-7 days) 
30-days after 
last dose 
(+/- 7 days) 
Every 3 months 
± 28 days 
CT/ MRI chest and abdomen12
X 
 
 
X 
X 
X13 
Survival 
 
 
 
 
 
X 
 
Notes 
 
1  Prior to the first study-specific measures 
2  Medical history includes baseline symptoms as well as a detailed history of prior cancer therapies including start and stop dates, disease progression during or after 
therapy, as well as discontinuations due to intolerability or any other serious illness. 
3   Applicable for women of childbearing potential. Serum b-HCG test within 7 days before the first dose of study drug. To be repeated by urine test, if date of first result 
exceeds the 7-day window 
4  Full physical examination for baseline and end of study visit. Physical examinations during the study should be symptom directed. 
5  
Body height will be measured at screening only. 
6  
Vital signs: blood pressure, heart rate, respiratory rate and temperature 
7  
Ophthalmologic exam: required at screening and if clinically indicated. Prior to dilation:  best corrected visual acuity, and slit lamp examination including tonometry; 
following dilation, fundoscopy and slit lamp exam to document lens clarity - if a cataract is seen during the exam, the cataract will be graded according to the Lens 
Opacities Classification System (LOCS III) Appendix 7. 
8  
Hematology: hemoglobin, red blood cell (RBC) count, hematocrit, platelets, white blood cell (WBC) count and WBC differential (neutrophils, lymphocytes),. 
9  Calculated GFR according to the formula of Cockroft and Gault . 
10  Clinical chemistry: Sodium, Potassium, Calcium, Creatinine, Total Bilirubin, Alkaline Phosphatase, alanine aminotransferase (ALT), aspartate aminotransferase (AST), 
Total Protein, Albumin, LDH 
11  Coagulation test include prothrombin time (PT), activated partial thromboplastin time (aPTT) and INR 
12   CT/MRI abdomen must include pelvis. PET/CT is allowed, but ultrasound of the abdomen and x-ray of thorax is not allowed. Within 4 weeks of treatment start and every 
8 weeks thereafter during treatment phase.  
13  Patients who discontinued for reasons other than progression of disease should be encouraged to continue visit the clinic for evaluation of their disease as per local 
hospital policy until progression of disease is determined.. 
 
 


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Glossary of Abbreviations  
 
b-HCG 
Beta human chorionic gonadotropin 
5-FU 
5-Fluoruracil 
ADR 
Adverse drug reaction 
AE 
Adverse event 
ALT (SGPT) 
Alanine aminotransferase 
ANC 
Absolute Neutrophile Count 
aPTT 
Activated partial thromboplastin time 
AST (SGOT) 
Aspartate aminotransferase 
BID 
Twice a  day 
BSA 
Body surface area 
CA 19-9 
Carbohydrate-Antigen 19-9 
CEA 
Carcinoembryonales Antigen 
CI 
Confidence interval 
CNS 
Central nervous system 
CR 
Complete response 
CRC 
Colorectal cancer 
CRF 
Case report form 
CRM1 
Chromosome region maintenance protein 1 
CRO 
Contract research organisation 
CT 
Computer tomography 
CTCAE 
Common terminology criteria for adverse events 
DLT 
Dose-limiting toxicity 
DNA 
Desoxyribonucleic acid 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EOT 
End of treatment 
ESMO 
European Society for Medical Oncology 
GCP 
Good Clinical Practice 
GFR 
Glomerular filtration rate 
GI 
Gastrointestinal 
GLP 
Good Laboratory Practice 
GRP 
Growth regulatory protein 
h 
Hour 
HIV 
Human immunodeficiency virus 
HR 
Hazard ratio 
HUS 
Hemolytic-uremic syndrome 
ICH 
International Conference on Harmonization 
IEC 
Independent ethics committee 
IMP 
Investigational medicinal product 
INR 
International normalization ratio 
IRB 
Institutional review board 
ITT 
Intent to treat 
IV 
Intravenous 
LDH 
Lactate dehydrogenase 
LOCS 
Lens Opacities Classification System 
LV 
Leucovorin 
m² 
Square metre (body surface area) 
mg 
Milligram 
min 
Minute 
mL 
Millilitre 
MRI 
Magnetic resonance imaging 
MTD 
Maximum tolerated dose 
NCCN 
National Comprehensive Cancer Network 


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NCI 
National Cancer Institute  
OS 
Overall survival 
PD 
Progressive disease 
PET 
Positron emission tomography 
PFS 
Progression-free survival 
PO 
Per os 
PPS 
Per protocol set 
PR 
Partial response 
PRN 
As needed (Pro re nata) 
PT 
Prothrombin time 
RECIST 
Response Evaluation Criteria In Solid Tumors 
RR 
Response rate 
RBC 
Red blood cell 
SAE 
Serious adverse event 
SD 
Stable disease 
SINE 
Selective inhibitor of nuclear export 
SmPC 
Summary of product characteristics 
SADR 
Serious adverse drug reaction 
SUSAR 
Suspected unexpected serious adverse reaction 
TEAE 
Treatment emergent adverse event 
TID 
Three times a day 
TSP 
Tumor suppressor protein 
UICC 
Union for International Cancer Control 
ULN 
Upper limit of normal 
WBC 
White blood cell 
WHO 
World Health Organization 
XPO1 
Exportin 1 
 


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Current version: Version 1.1, 2015.01.22 
 
Table of Contents 
 
1 
BACKGROUND AND RATIONALE 
23 
1.1 
BACKGROUND 
23 
1.1.1 
COLORECTAL CANCER 
23 
1.1.2 
SELINEXOR 
24 
1.2 
STUDY RATIONALE 
30 
2 
OBJECTIVES OF THE STUDY 
30 
2.1 
PRIMARY OBJECTIVE 
30 
2.2 
SECONDARY OBJECTIVES 
30 
2.3 
EXPLORATORY OBJECTIVES 
30 
3 
STUDY DESIGN 
31 
3.1 
OVERVIEW OF STUDY DESIGN AND DOSING REGIMEN 
31 
3.1.1 
DEFINITION OF DLT 
32 
3.1.2 
DEFINITION OF TREATMENT CYCLE 
33 
3.1.3 
TREATMENT DURATION 
33 
3.1.4 
END OF TREATMENT VISIT 
33 
3.1.5 
FOLLOW-UP PHASE 
33 
3.2 
STUDY TIMELINES 
34 
4 
SELECTION OF THE STUDY POPULATION 
34 
4.1 
TARGET POPULATION 
34 
4.2 
INCLUSION CRITERIA 
34 
4.3 
EXCLUSION CRITERIA 
35 
4.4 
REGISTRATION OF PATIENTS 
35 
5 
SCHEDULE OF ASSESSMENT AND PROCEDURES 
36 
5.1 
STUDY ASSESSMENTS 
36 
5.1.1 
RESPONSE ASSESSMENTS 
36 
5.1.2 
TRANSLATIONAL ANALYSES 
37 
5.1.3 
SAFETY ASSESSMENTS 
37 
5.1.4 
LABORATORY ASSESSMENTS 
38 
5.2 
STUDY PROCEDURES 
38 
5.2.1 
SUPPORTIVE CARE 
38 


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a. 
Required Supportive Care Medication 
38 
b. 
Supportive Care Recommendations for Selinexor-Related Adverse Events 
38 
5.2.2 
SCREENING PROCEDURES 
39 
5.2.3 
TREATMENT PHASE 
40 
5.2.4 
END OF TREATMENT 
40 
5.2.5 
FOLLOW-UP 
41 
5.2.6 
END OF STUDY 
41 
5.3 
PLANNED TREATMENT OF THE PATIENT AFTER END OF TREATMENT PHASE 
41 
5.4 
REMOVAL OF PATIENTS FROM TREATMENT 
41 
5.5 
STUDY DISCONTINUATION 
42 
6 
TREATMENT 
43 
6.1 
INVESTIGATIONAL MEDICINAL PRODUCT (IMP) 
43 
6.2 
PREPARATION AND ADMINISTRATION OF SELINEXOR 
43 
6.2.1 
DRUG NAME, FORMULATION AND STORAGE 
44 
6.2.2 
ROUTE OF ADMINISTRATION 
44 
6.2.3 
COMPLIANCE 
44 
6.3 
DOSE MODIFICATION OF SELINEXOR 
45 
6.3.1 
DOSE ADJUSTMENT GUIDELINES FOR SELINEXOR RELATED TOXICITIES 
46 
6.3.2 
SELINEXOR DOSE REDUCTION IN THE SETTING OF INFECTION 
51 
6.4 
GENERAL DOSE MODIFICATIONS: MFOLFOX6 
52 
6.4.1 
MODIFICATIONS FOR FIRST TWO CYCLES 
52 
6.4.2 
IMPLICATIONS OF DOSE REDUCTIONS FOR SUBSEQUENT CYCLES 
52 
6.4.3 
CONTINUATION OF THERAPY ON-STUDY IN THE SETTING OF DISCONTINUATION OF 
ONE COMPONENT OF STUDY THERAPY 
52 
6.4.4 
OXALIPLATIN DOSE MODIFICATIONS FOR NEUROLOGIC ADVERSE EVENTS 
55 
6.5 
CONCOMITANT MEDICATION AND TREATMENT 
56 
6.5.1 
PERMITTED CONCOMITANT MEDICATION 
56 
6.5.2 
PREVENTION OF PREGNANCY 
56 
6.5.3 
USE OF BLOOD PRODUCTS 
56 
6.5.4 
GLUCOCORTICOID THERAPY 
57 
6.5.5 
PROHIBITED MEDICATIONS 
57 
6.6 
SUPPORTIVE CARE GUIDELINES 
57 
6.6.1 
ANOREXIA 
58 


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6.6.2 
FATIGUE 
58 
6.6.3 
EMESIS 
58 
6.6.4 
ACUTE EMESIS 
59 
6.6.5 
DELAYED EMESIS - > 24H AFTER TREATMENT 
59 
6.6.6 
DIARRHEA 
60 
6.6.7 
HYPONATREMIA 
60 
7 
SAFETY REPORTING 
61 
7.1 
ADVERSE EVENTS AND LABORATORY ABNORMALITIES REPORTING 
61 
7.1.1 
ADVERSE EVENT 
61 
7.1.2 
ADVERSE DRUG REACTION 
61 
7.1.3 
SERIOUS ADVERSE EVENT 
61 
7.1.4 
NOT TO BE REPORTED AS SAES 
62 
7.1.5 
SUSAR/ UNEXPECTED SERIOUS ADR 
63 
7.2 
REPORTING OF SAES 
63 
7.3 
REPORTING OF SUSARS/ EXPEDITED REPORTING OF UNEXPECTED SERIOUS ADRS64 
7.4 
RECORDING OF ADVERSE EVENTS 
65 
7.5 
LABORATORY TEST ABNORMALITIES 
66 
7.6 
PREGNANCY 
66 
7.7 
ADVERSE DRUG REACTIONS WITH CONCOMITANT MEDICATION 
66 
8 
BIOSTATISTICAL ASPECTS 
66 
8.1 
SAMPLE SIZE ESTIMATION 
67 
8.2 
ANALYSIS POPULATION 
67 
8.3 
STATISTICAL ANALYSIS 
67 
8.3.1 
GENERAL STATISTICAL CONSIDERATIONS 
67 
8.3.2 
DEMOGRAPHICS AND BASELINE CHARACTERISTICS 
68 
8.3.3 
PRIMARY VARIABLE 
68 
8.3.4 
SECONDARY VARIABLES 
68 
8.4 
INTERIM AND FINAL ANALYSIS 
70 
9 
DATA QUALITY ASSURANCE 
71 
10 
ETHICAL ASPECTS 
72 
10.1 
DECLARATION OF HELSINKI / GOOD CLINICAL PRACTICE 
72 
10.2 
PATIENT INFORMATION AND INFORMED CONSENT 
72 


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10.3 
INDEPENDENT ETHICS COMMITTEES AND REGULATORY AUTHORITIES 
73 
10.3.1 
APPROVAL OF THE STUDY BY THE REGULATORY AUTHORITY AND INDEPENDENT 
ETHICS COMMITTEES 
73 
10.3.2 
NOTIFICATION OF THE STUDY 
73 
10.3.3 
OBLIGATION TO REPORT AND DOCUMENT 
73 
11 
CONDITIONS FOR MODIFYING THE PROTOCOL 
74 
12 
STUDY DOCUMENTATION, CRFS AND RECORD-KEEPING 
75 
12.1 
INVESTIGATOR’S FILES / RETENTION OF DOCUMENTS 
75 
12.2 
SOURCE DOCUMENTS AND BACKGROUND DATA 
76 
12.3 
AUDITS AND INSPECTIONS 
76 
12.4 
CASE REPORT FORMS 
76 
13 
MONITORING THE STUDY 
77 
14 
CONFIDENTIALITY OF TRIAL DOCUMENTS AND PATIENT RECORDS 
78 
15 
STUDY REPORT AND PUBLICATION POLICY 
79 
16 
APPENDICES 
80 
16.1 
APPENDIX 1 – OVERVIEW OF CRC STUDIES 
81 
16.2 
APPENDIX 2 – DEFINITIONS ACCORDING TO ICH TOPIC E2A CLINICAL SAFETY DATA 
MANAGEMENT, DEFINITIONS AND STANDARDS FOR EXPEDITED REPORTING, 
(CPMP/ICH/377/95) 
84 
16.3 
APPENDIX 3 – ECOG PERFORMANCE STATUS 
86 
16.4 
APPENDIX 4 – COCKROFT-GAULT FORMULA 
87 
16.5 
APPENDIX 5 – NCCN PRACTICE GUIDELINES IN ONCOLOGY: NAUSEA/VOMITING 
88 
16.6 
APPENDIX 6- RESPONSE CRITERIA 
92 
16.7 
APPENDIX 7- LENS OPACITIES CLASSIFICATION SYSTEM III (LOCS III) 
93 
REFERENCES 
94 
 
 


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1 BACKGROUND AND RATIONALE 
1.1 BACKGROUND 
1.1.1 COLORECTAL CANCER 
Colorectal cancer (CRC) represents the third most commonly diagnosed cancer worldwide1. 
Despite a decrease in incidence and mortality colorectal cancer (CRC) with nearly 1.25 
million patients diagnosed per year still represents the second leading cause of cancer 
death. Consequently, CRC is considered a prominent global health problem. 
Approximately 25 percent of patients with CRC will have metastatic disease at the time of 
diagnosis and further 25% will develop metastatic disease after curative resection of 
localised CRC. Over the last two decades, the development of treatment options has 
significantly improved the prognosis for metastatic CRC patients. 
Traditionally, systemic chemotherapy in this setting has been based on fluoropyrimidines 
regimens. By the introduction of cytotoxic agents, such as irinotecan and oxaliplatin the 
response rate (RR), time to progression, and OS has improved from 15-20%, 5-6 and 10-12 
months to 30-40%, 8 and 20-24 months, respectively 2 3) 
Multiagent regimens, including a combination of 5-fluorouracil (5-FU) plus leucovorin (LV) 
with oxaliplatin or irinotecan, are superior to 5-FU plus LV alone29,30 and achieve a median 
survival of around 20 months4,5,6. Both, oxaliplatin combined with bolus and continuous 
infusion 5-FU plus LV (FOLFOX) and irinotecan combined with bolus and continuous infusion 
5-FU plus LV (FOLFIRI) are recognized as standard first-line therapies for mCRC.  
More recent studies have shown that survival outcomes can further be improved by adding 
biologic agents to combination chemotherapy regimens in first and second line therapy or 
use these agents as monotherapy in more advanced treatment situations. In particular 
angiogenesis inhibitors (bevacizumab, aflibercept), the epidermal growth factor receptor 
(EGFR) antibodies (cetuximab, panitumumab) and the multitarget tyrosine kinase inhibitor 
regorafenib have shown to improve the efficacy and extend overall survival7 for a summary of 
efficacy in recent trials see appendix 1). Despite the inclusion of molecular agents, the 
median survival of mCRC does not exceed 30 months and therefore new treatment options 
are urgently needed. 
 


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1.1.2 SELINEXOR 
 
More than 10 major tumor suppressor pathways have evolved in order to prevent the 
development and progression of neoplasia. Because the vast majority of tumor suppressor 
(TSP) and growth regulatory (GRP) proteins require nuclear localization in order to carry out 
their antineoplastic activities, enhancing their nuclear export leads to their functional 
inactivation.  
The major TSP/GRP are exported exclusively by the protein CRM1 (also called XPO1), and 
tumors showing elevated CRM1 levels with cytoplasmic mislocalization of TSP/GRP. 
Further detailed information is provided in the Investigator’s Brochure.  
Selinexor is an orally available, slowly reversible, potent and Selective Inhibitor of Nuclear 
Export (SINE) that specifically blocks XPO1. It is selectively cytotoxic for cells with genomic 
damage, i.e., for tumor cells, both in vitro and in vivo.  Normal cells, with minimal or no DNA 
damage, remain in transient, reversible cell cycle arrest until the export block is relieved. 
Selinexor and other SINE compounds are not intrinsically cytotoxic; rather, they can restore 
the highly effective tumor suppressing pathways that lead to selective elimination of 
genomically damaged (i.e., neoplastic) cells. Tumors of hematopoietic lineage are 
particularly susceptible to induction of apoptosis by XPO1 inhibition; normal hematopoietic 
cells and their functions are largely spared.   
 
 


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Current version: Version 1.1, 2015.01.22 
1.1.2.1 Preclinical Efficacy and Safety 
 
Preclinical Efficacy 
In a xenograft efficacy model of colorectal cancer (HCT-116 cell line with genetic mutation 
status of:  p53wt, K-ras G13D, MLH–, PIK3CAmut, p14ink4adel, CTNNB1mut, APCwt) SINE was 
administered at 10-75mg/kg QDx5 each week, and the positive control 5-fluorouracil (5-FU) 
was injected intraperitoneally at 50 mg/kg on Days 1 and 3; as shown in Figure 1. 
SINE slowed down tumor growth at all doses in a statistically significant manner when 
compared to vehicle and 5-FU.  In this model, all vehicle animals were euthanized due to 
tumor burden by Day 17.  Animals treated with 5-FU survived up to Day 30 and tumor growth 
was statistically significantly reduced when compared to vehicle treated animals. SINE 
administered orally at 10, 25 and 75 mg/kg slowed down tumor growth when compared to 
vehicle and 5-FU. And there was a significant improvement on survival benefit associated 
with SINE treatment.    
 
Figure 1 
 
 
 
Data showing that when combined with CPT-11, oxaliplatin or 5FU, SINE displays a 
synergistic cytotoxic effect was previously generated in vitro.  In vivo synergistic effects of 
SINE to three conventional colon cancer therapeutic regimens were assessed using a LoVo 
colon cancer xenograft model (Figure 2). Mice were treated with vehicle or 75 mg/kg of SINE 
twice a week via oral route with or without CPT-11 (33mg/kg, i.v., twice a week), or 
oxaliplatin (10 mg/kg, i.p., one time), or 5-FU (33 mg/kg, i.p., twice a week). All treatments 
were continued until 4 weeks. In oxaliplatin-treated or 5- FU-treated groups, tumor inhibition 
effects were slightly enhanced by addition of SINE p=0.09 (oxaliplatin) and p=0.07 (5-FU), 
0 
200 
400 
600 
800 
1000 
1200 
1400 
1 
2 
3 
4 
5 
6 
7 
8 
9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 
Mean Tumor Volume  (mm3) 
Days 
Vehicle 
5FU 
75 mg/kg 
25 mg/kg 
10 mg/kg 


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whereas inhibition effects were definitively enhanced by addition of SINE in CPT-11- treated 
group (p < 0.001). 
 
Figure 2 
 
 
In conclusion, XPO1 blockade by the orally bioavailable SINEs show significant single agent 
anti-tumor activity on colon cells in vitro and in vivo, and striking synergy in combination with 
the major clinically relevant colon cancer treatments irinotecan (CPT-11), oxaliplatin, and 5-
FU. These results support the further development of SINEs for the single agent and 
combination treatment of colorectal cancer for advanced stage colorectal cancer. 
 
Preclinical Safety 
In the Selinexor non-clinical safety program in Sprague-Dawley rats and cynomolgus 
monkeys, the primary effects of oral Selinexor were dose-dependent reductions in food 
intake and body weight (or reductions in body weight gain), with minimal clinical symptoms 
(no or mild non-bloody diarrhea), associated primarily with gastrointestinal atrophy.  Similar 
effects are observed in mice and dogs.  At high repeated doses of Selinexor associated with 
marked weight loss, there were changes in cerebellar granular layer neurons in both rats 
(≥300 mg/m²) and monkeys (≥72 mg/m²), but only monkeys showed any CNS symptoms.  No 
central nervous system (CNS)-related adverse side effects were observed in the GLP, rat 
and monkey 4-cycle toxicity studies. A GLP, rat neurofunctional study (Irwin test) has also 
been performed at dose levels of 12, 60, or 300 mg/m² (2, 10, and 50 mg/kg).  No behavioral 
changes were observed at all doses tested.   
In the pivotal, GLP, 4-week monkey study, there was no evidence of a direct or indirect effect 
of Selinexor on the morphology and intervals of the ECG at up to 36 mg/m² (3 mg/kg).  
Based on these results, QT prolongation or other cardiac effect does not appear to be a 
safety concern for Selinexor.  
In summary, dose limiting toxicity (DLT)/mortality in both rats and monkeys is related 
primarily to marked weight loss with atrophy of the gastrointestinal (GI) tract and noncritical 
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Further detailed information is provided in the Investigator’s Brochure 
1.1.2.2 Clinical Efficacy and Safety 
 
Clinical Evidence of Anti-Cancer Activity 
Karyopharm Therapeutics  is currently conducting three open label Phase 1 clinical trials to 
assess the safety, tolerability and anti-tumor activity of of selinexor given orally 2-3 times per 
week. The first study (KCP-330-001) is in patients with advanced hematological 
malignancies, the second (KCP-330-002) is in patients with advanced or metastatic solid 
tumor malignancies and the third (KCP-330-003), a food effect study, is in patients who have 
metastatic, locally advanced or locally recurrent soft tissue or bone sarcomas. All patients 
entering these single-agent phase 1 studies have relapsed after available therapies and have 
objectively progressing tumors at time of study drug initiation. To date, selinexor has been 
administered to over 400 patients.   
 
Efficacy in KCP-330-002 (selinexor in patients with advanced solid tumors) 
Data was generated across a variety of heavily pretreated, progressing solid tumors 
including melanoma, head & neck, ovarian, cervical, colorectal, and chemotherapy refractory 
prostate cancers. Enrolled patients had a mean of 3.7 prior therapies and were progressing 
at study entry. Patients received doses of selinexor ranging from 3 - 85 mg/m2. The disease 
control rate was 49% (stable disease or better). Partial responses were observed in 4 
patients: colorectal cancer (KRAS mutant), melanoma (BRAFwt), ovarian adenocarcinoma, 
and cervical. Stable disease was noted in 47 patients, with 17 patients (16%) experiencing 
stable disease for six months or longer.  Seven of eight evaluable patients with hormone and 
chemotherapy refractory prostate cancer achieved stable disease and remained on study for 
70 to 317+ days. Among 14 evaluable patients with head and neck cancer, nine achieved 
stable disease with eight on study for 75 - 401+ days.  
Table 1 Best Responses in Solid Tumor Patients as of 13-May-2014 
Cancer Type 
N 
PRs and SD (%) 
PR (%) 
SD (%) 
PD (%) 
Colorectal 
39 
14 (36%) 
1 (3%) 
13 (33%) 
25 (64%) 
Head & Neck 
14 
9 (64%) 
-- 
9 (64%) 
5 (36%) 
Prostate 
8 
7 (88%) 
-- 
7 (88%) 
1 (12%) 
Cervical 
5 
4 (80%) 
1 (20%) 
3 (60%) 
1 (20%) 
Ovarian 
5 
3 (60%) 
1 (20%) 
2 (40%) 
2 (40%) 
GBM 
5 
-- 
-- 
-- 
5 (100%) 
Melanoma 
3 
2 (67%) 
1 (33%) 
1 (33%) 
1 (33%) 
Sarcoma 
8 
7 (88%) 
-- 
7 (88%) 
1 (12%) 
Other 
19 
6 (32%) 
-- 
6 (32%) 
13 (68%) 
Total 
106
52 (49%) 
4 (4%) 
48 (45%) 
54 (51%) 


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PR=Partial Response, SD=Stable Disease, PD=Progressive Disease 
 
 
Side effects were generally low grade and typically gastrointestinal in nature, or 
fatigue. These common side effects decreased over time, in part due to prophylactic use of 
standard supportive care. Major organ dysfunction or clinically significant cumulative 
toxicities have not been observed. The recommended single agent dose for Phases 2 and 3 
is 65 mg/m2 twice weekly. 
In the Phase I study, KCP-330-003, tumor shrinkage and disease stabilization were observed 
in patients with advanced sarcomas including Liposarcoma and Leiomyosarcoma. Among 19 
patients evaluable for response, stable disease was observed in 52% of patients. Five 
patients remain on study (61-211+ days).  
 
Table 2. 
Cancer Type 
N 
SD (%) 
PD (%) 
NE (%) 
Sarcoma Type 
  
  
  
  
Leiomyosarcoma 
6 
3 (50%) 
2 (33%) 
1 (17%) 
Liposarcoma 
4 
4 (100%) 
-- 
-- 
Synovial Sarcoma 
3 
-- 
3 (100%) 
-- 
Chondrosarcoma 
2 
1 (50%) 
1 (50%) 
-- 
Others 
6 
3 (50%) 
2 (33%) 
1 (17%) 
Total 
21 
11 (52%) 
8 (38%) 
2 (10%) 
SD=Stable Disease, PD=Progressive Disease, NE=Non-Evaluable 
 
 
Clinical Safety 
In patients with solid tumors, the most common AEs suspected to be related to selinexor are 
anorexia, fatigue, nausea, vomiting, diarrhea, and thrombocytopenia.  Virtually all of these 
side effects can be managed effectively with dose modification and/or supportive care 
initiated prior to first dosing.  Overall, the most frequently observed laboratory abnormalities 
include thrombocytopenia, hyponatremia, and a decrease in red blood cells.  The majority of 
these have been mild to moderate.  Please refer to the KPT-330 (selinexor) Investigator’s 
Brochure for the most current information.   
One patient, heavily pre-treated for recurrent pancreatic cancer, developed acute cerebellar 
syndrome following 4 doses of selinexor at 85 mg/m2 BSA twice weekly.  The patient 
experienced abnormal speech, loss of coordination, and was unable to walk.  Since the time 
of the initial reported event, this patient is recovering both her speech and mobility.  No other 
patients have reported such symptoms to date. 
 
Reproductive Risks 
Patients should not become pregnant or father a child while on this study because the drugs 
in this study can affect an unborn baby.  Women should not breastfeed a baby while on this 


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study.  It is important for patients to understand the need to use birth control while on this 
study.  Female patients of child bearing potential must agree to use dual methods of 
contraception and have a negative serum pregnancy test at screening, and male patients 
must use an effective barrier method of contraception if sexually active with a female of child 
bearing potential.  Acceptable methods of contraception are condoms with contraceptive 
foam; oral, implantable or injectable contraceptives; contraceptive patch; intrauterine device; 
diaphragm with spermicidal gel; or a sexual partner who is surgically sterilized or post-
menopausal.  For both male and female patients, effective methods of contraception must be 
used throughout the study and for three months following the last dose. 
 
 
 
 


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1.2 STUDY RATIONALE 
Current guidelines recommend an intensive first line three-drug regimen (chemodoublet and 
biological agent) for patients with either potentially resectable or symptomatic disease 
(ESMO group 1 and 210) However, the large majority of patients are either asymptomatic or 
definitely unresectable due to spread of disease or co-morbidity (ESMO group 3). For these 
patients a sequential approach with a two-drug combination (e.g. FOLFOX) is recommended. 
Moreover, a certain group of patients might not be amenable for VEGF or EGFR inhibition in 
combination with chemotherapy and might thus be treated with FOLFOX regimen in second 
line. To further enhance the efficacy of the mFOLFOX6 combination regimen while 
maintaining an acceptable tolerability is worth to be explored. Selective inhibition of nuclear 
export (SINE) is a novel therapeutic strategy that could potentially be applicable to many 
cancers. In the phase I solid tumor study 35 heavily pretreated patients with CRC have been 
included and showed promising results. Moreover, preclinical studies has shown a strong 
synergistic effect of Selinexor and 5FU and oxaliplatin.   
2 OBJECTIVES OF THE STUDY 
2.1 PRIMARY OBJECTIVE 
The primary objective is to determine the maximum tolerated dose (MTD) of selinexor in 
combination with mFOLFOX6 in patients with metastatic colorectal cancer. 
2.2 SECONDARY OBJECTIVES  
Secondary objectives of the study are:  
· 
To determine the efficacy and tolerability of selinexor in combination with mFOLFOX6 
in patients with metastatic colorectal cancer by  
o Overall response rate (RR) (acc. to RECIST v1.1) 
o Progression free survival (PFS) (acc. to RECIST v1.1) 
o Time to progression (acc. To RECIST v1.1) 
o Overall survival (OS) 
o Toxicity (acc. to NCI CTC AE v4.03) 
2.3 EXPLORATORY OBJECTIVES 
Not applicable within the study.  
 
 


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3 STUDY DESIGN 
3.1 OVERVIEW OF STUDY DESIGN AND DOSING REGIMEN 
This is a multi center, open-label, non-randomized phase I trial study to determine the MTD 
of a combination of mFOLFOX6 and selinexor in patients with metastatic colorectal cancer. 
After screening and registration in the study, all enrolled patients will be treated with 
oxaliplatin (85 mg/m² IV over 2 hours, Day 1), 5-FU (400 mg/m2 IV bolus, Day 1), leukovorin 
(400 mg/m2 IV over 2 hours, Day 1) and 5-FU (2,400 mg/m² continuous infusion, Days 1-3) 
every 2 weeks and escalating doses of selinexor as follows:  
 
Patients in Dose Level 1 will receive oral selinexor 40 mg on day 1, 3, and 8.  
Patients in Dose Level 2 will receive oral selinexor 60 mg on day 1, 3, and 8. 
Patients in Dose Level 3 will receive oral selinexor 80 mg on day 1, 3, and 8.  
Patients in Dose Level -1 will receive oral selinexor 20 mg on day 1, 3, and 8.   
 
Figure 3: Dose escalation scheme 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
The MTD is defined as the highest dose level at which six patients have been treated with no 
Toxicity and tolerance of the dose escalation of Selinexor with mFOLFOX6 will be evaluated. 
 
3 additional patients at the 
same dose level 
Next Dose level 
6 Patients  
If 0 or 1 DLT then ... 
If 2 or 3 DLT then ... 
If 4 or 6 DLT 
then... 
Dose escalation will be 
stopped 
If additional 
DLT 
Dose escalation will be 
stopped 
If no 
additional 
DLT 
Dose level 1 
In case of dose level 1, 
dose level -1 will be 
explored.


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Six patients will be initially treated in a cohort. Safety data will be monitored in real time. As 
soon as last patient of the cohort (either 6th or 9th) reaches day 28, safety data of all patients 
within that cohort will be reviewed for decision about opening up a new cohort by moving to 
the next dose level or expand the cohort or discontinue dose escalation. 
Dose escalation: 
If 0-1/6 patients experience a DLT, dose will be moved to the next level. 
If 2-3/6 patients experience a DLT, 3 more patients will be treated on that dose level. 
If 4-6/6 patients experience a DLT, dose will be regarded as toxic and dose escalation will be 
stopped. 
 
In case the dose escalation will be stopped at dose level 1, dose level -1 will be included in 
the study and evaluated by the same design. 
 
3.1.1 DEFINITION OF DLT 
 
Dose limiting toxicity should be at least possibly related to study drug Selinexor 
combinational therapy.  Dose-Limiting Toxicity (DLT) is defined as any of the following 
occurring in the first 28 days (cycle 1 +Cycle2) of study participation that are considered at 
least possibly related to selinexor administration. 
·2 missed doses (out of 3 doses) of selinexor per cycle due to study drug related 
toxicity 
·Delay of more than 14 days in initiating cycle 2 or 3 on the scheduled date due to 
study drug related toxicity 
·Discontinuation of a patient due to study drug related toxicity before completing 
cycle 2 
Haematological toxicities  
1. febrile neutropenia  
2. leukopenia or neutropenia Grade 4 > 7 days 
3. thrombopenia Grade 4 or Grade 3 with clinically significant bleeding, petechiae or 
purpura  thrombopenia 
Non-haematological toxicities  
4. Grade 3 nausea/vomiting, diarrhea for >3 days while taking optimal supportive 
medications 
5. Grade 3 fatigue lasting for ≥5 days while taking optimal supportive care and with 
correction of dehydration, anorexia, anemia, endocrine, or electrolyte abnormalities. 
6. Grade  3 dehydration lasting for ≥5 days while taking optimal supportive care  
7. Grade 4 vomiting, dehydration and diarrhea 
8. Any other Grade ≥3 non-hematological toxicity except Electrolyte abnormalities that are 
reversible and asymptomatic, hair loss, ALT, AST or alkaline phosphatase in the setting 
of baseline grade 2 elevations from disease 
9. Any other grade 4 non-hematologic toxicity 
10. For the purposes of DLT assessment, asymptomatic hyponatremia will be “graded” not 
by CTCAEv4 but rather by clinically meaningful criterion of <125mmol/L. Sodium 
<125mmol/L will be graded as DLT with the exception of asymptomatic translational 
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11. *In marked hyperglycemia, ECF osmolality rises and exceeds that of ICF, since glucose 
penetrates cell membranes slowly in the absence of insulin, resulting in movement of 
water out of cells into the ECF. Serum Na concentration falls in proportion to the dilution 
of the ECF, declining 1.6 mEq/ L for every 100 mg/dL (5.55 mmol/L) increment in the 
plasma glucose level above normal. This condition has been called translational 
hyponatremia because no net change in total body water (TBW) has occurred. No 
specific therapy is indicated, because Na concentration will return to normal once the 
plasma glucose concentration is lowered. Corrected Sodium (Hillier, 1999) = Measured 
sodium + 0.024 * (Serum glucose - 100)32.  
12. Mucositis Grade 4 persistent for >7 days 
13. Heart-insufficiency Grade ≥3  
14. Interstitial lung disease Grade ≥3 
15. Skin toxicity Grade 4 
16. Hepatic 
toxicity 
Grade 
3 
(in 
case 
of 
hepatic 
metastasis  
Grade 4) 
17. Any toxicity causing a delay of therapy continuation of more than 2 weeks more than one 
case of or 9 patients have been treated with no more than 3 cases of DLT. 
3.1.2 DEFINITION OF TREATMENT CYCLE 
A treatment cycle in this study consists of application of mFOLFOX6 chemotherapy regimen 
and Selinexor given twice weekly. Cycles will be repeated on Day 15.  
3.1.3 TREATMENT DURATION 
 
Patients will be treated until progression of disease, intolerable toxicity, or secondary 
resection. Treatment with oxaliplatin should not exceed 6 months and patients may continue 
with 5FU/LV and Selinexor afterwards.  
3.1.4 END OF TREATMENT VISIT 
Patients that discontinue from treatment will undergo an end of treatment visit, regardless of 
the reason of discontinuation, approximately 30 days (±7 days) after the last dose of study 
medication 
3.1.5 FOLLOW-UP PHASE 
Patients who discontinued for reasons other than withdrawal of consent for participation in 
the trial will be followed every 3 months ± 28 days for overall survival for 2 years from study 
inclusion. Patients who discontinued for reasons other than progression of disease should be 
encouraged to continue visit the clinic for evaluation of their disease as per local hospital 
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Of note, a patient may decide to discontinue study treatment. This is not the same as fully 
withdrawal of consent to participate in the trial and these patients should be encouraged to 
continue to be followed up as for other patients for event free and overall survival. If a patient 
chooses to have no further interaction regarding the study (fully withdrawal of consent), the 
investigator must provide written documentation of the patient’s decision to fully withdraw 
from the study. 
3.2 STUDY TIMELINES 
Patients will be recruited within 12 months. Analysis of primary endpoint and preliminary 
analysis of secondary endpoints RR and toxicities will be done after 8 weeks of therapy of 
the last patient included. Additional analysis for PFS and OS as well as follow-up analysis of 
secondary endpoints RR and toxicities will be performed up to 2 years after registration of 
last patient.  
4 SELECTION OF THE STUDY POPULATION 
4.1 TARGET POPULATION 
Patients with metastatic colorectal cancer according to the inclusion and exclusion criteria 
below will be enrolled in this study trial. Both male and female patients are enrolled. 
The baseline assessment must have taken place within 2 weeks (4 weeks for radiographic 
evaluation) prior to start of treatment. Under no circumstances are patients, who were once 
enrolled in this study, permitted to be re-enrolled into the same study. 
4.2 INCLUSION CRITERIA 
To be eligible for this trial, patients must fulfil the following criteria: 
1. Patients with histologically confirmed diagnosis of colorectal cancer presenting with 
unresectable stage IV (UICC) disease (primary tumor may be present)  
2. Patients who are feasible for treatment with FOLFOX (prior adjuvant or palliative 
treatment is allowed) 
3. ECOG Performance status ≤ 1 
4. Life expectancy > 3 months 
5. Age ≥18 years  
6. Haematologic function as follows (5% deviation allowed):  
· 
ANC ≥ 1.5 x 109/L 
· 
platelets ≥ 100 x109/L 


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· 
hemoglobin ≥ 9 g/dl or 5.59 mmol/l 
7. Adequate liver function as follows (10% deviation allowed) 
· 
serum alanine transaminase (ALT) ≤ 2.5 x ULN (in case of liver metastases < 
5 x ULN) 
· 
total bilirubin ≤ 1.5 x ULN (patients with Gilbert’s syndrome total bilirubin ≤2.5 
x ULN) 
8. Adequate renal function as follows (10% deviation allowed) 
· 
creatinine ≤ 1.5 x ULN 
9. Signed written informed consent 
10. Women of child-bearing potential must have a negative pregnancy test 
4.3 EXCLUSION CRITERIA 
Patients with any of the following will not be eligible for participation: 
1. Patients with significant medical illness that in the investigator’s opinion cannot be 
adequately controlled with appropriate therapy or would compromise the patient’s 
ability to tolerate this therapy; 
2. Treatment with any systemic anticancer therapy ≤ 3 weeks prior to cycle 1 day 1 
3. Uncontrolled active infection (Hepatitis B and C infection are NOT exclusion criteria) 
and/or known HIV infection; 
4. Renal failure requiring haemodialysis or peritoneal dialysis; 
5. Patients who are pregnant or breast-feeding; 
6. Patients with significantly diseased or obstructed gastrointestinal tract, malabsorption, 
uncontrolled vomiting or diarrhea resulting in inability to swallow oral medications; 
7. Presence of symptomatic CNS metastasis 
8. Unresolved toxicity from previous anti-cancer therapy or incomplete recovery from 
surgery, in particular oxaliplatin-induced peripheral neuropathy > grade 1. 
9. Any of the following within the 12 months prior to study drug administration: 
myocardial infarction, severe/unstable angina, coronary/peripheral artery bypass 
graft, symptomatic congestive heart failure, cerebrovascular accident or transient 
ischemic 
attack, 
pulmonary 
embolism, 
deep 
vein 
thrombosis, 
or 
other 
thromboembolic event. 
4.4 REGISTRATION OF PATIENTS  
 
Patients will be screened for eligibility and eligibility check form/Patient Registration Form will 
be sent to GSO.  
Patient eligibility will be reviewed by GSO for all patients participating in the study prior to 
receiving study treatment. 
 
PROTOCOL SPECIFIC QUESTIONS: 
 
· 
all eligibility criteria will be checked one by one 
· 
date of written informed consent (day/month/year) 


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Patient eligibility will be checked by GSO once all screening procedures are completed. 
There will be no exceptions. Any questions should be addressed GSO prior to registration. 
The eligibility check form/Patient Registration Form will be sent from the site to GSO either 
by fax or email for evaluation. Upon confirmation of eligibility, GSO will assign a patient 
number and return the signed eligibility check form/Patient Registration Form via fax or email 
to the site. The Patient Registration Form will confirm the treatment arm the patient will 
participate in. 
 
GSO mbH 
Fax: 0049-40-44 19 54 78   
 
If slots within one cohort have been filled, i.e. after enrollment of 6th patient or 9th patient in 
case of expanded cohort further recruitment will be temporarily stopped and dose-limiting 
toxicities will be assessed. GSO will send a notification to investigational sites concerning 
hold of accrual. The decision of the cohort review, i.e. opening new cohort at next dose level, 
expansion of cohort or stop of dose escalation will be documented in writing and sent out to 
all sites.  
5 SCHEDULE OF ASSESSMENT AND PROCEDURES 
5.1 STUDY ASSESSMENTS 
5.1.1 RESPONSE ASSESSMENTS 
 
Objective response will be evaluated based on RECIST criteria Version 1.1 (see Appendix 7) 
using CT scan or MRI scan. For patients with multiple measurable lesions, up to 5 lesions in 
total and 2 lesions per organ should be identified. 
The exact technique used for measurement of lesions (i.e., either CT or MRI scan) will be left 
to the discretion of the investigator, however, for each patient the same technique must be 
used throughout the study, assessed whenever possible by the same individual. The CT/ 
MRI abdomen must include the pelvis. A PET/CT is allowed, but ultrasound and x-ray of 
thorax is not allowed. 
All lesions identified at screening have to be assessed at each scheduled tumor 
measurement. Patients with measurable lesions will be eligible for inclusion. Measurable 
lesions must have at least one diameter of 10 mm by CT scan (CT slice thickness no greater 
than 5 mm. When CT scans have slice thickness greater than 5 mm, the minimum size for 
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assessment is based on the sum of the longest diameters of the individual target lesions. 
Lymph nodes with a short axis of > 15 mm are considered measurable and assessable a 
target lesions. The short axis measurement should be included in the sum of lesions in 
calculation of tumor response. Nodes that shrink to < 10 mm short axis are considered 
normal. All other pathological nodes (those with short axis > 10 mm but < 15 mm) should be 
considered non-target lesions. In cases where there is suspicion of progression before the 
next scheduled assessment, an unscheduled tumor assessment should be performed. 
In case a detected increase in tumor size is below the resolution limit of the CT/ MRI 
scanner, it is accepted to continue with treatment until a second assessment at a later time 
point unequivocally confirms progressive disease.  
The following are defined as non-target lesions: bone lesions, leptomeningeal disease, 
pleural/pericardial effusion, ascites, inflammatory breast disease, lymphangitis, cystic lesions 
and lesions not measurable by computed tomography (CT) or magnetic resonance imaging 
(MRI). All non-target lesions are described over time and need not be measured. 
The tumor assessment for inclusion must be recorded and measured within 28 days prior to 
treatment start. 
Thereafter, tumor assessments by CT/MRI will be performed every 8 weeks during 
treatment, independent of cycle delays. 
Patients will also be eligible for the study if their disease is evaluable outside irradiated field 
on CT/ MRI. In case palliative radiation becomes necessary during the treatment within the 
study, there must be at least two target lesions left outside the irradiated filed for continuous 
assessment for response. 
5.1.2 TRANSLATIONAL ANALYSES 
 
Not applicable in this study. 
 
5.1.3 SAFETY ASSESSMENTS 
Throughout the treatment period until the EOT visit, patients will be assessed for all adverse 
events. Common terminology criteria for adverse events (CTCAE v4.03) will be used for 
grading. If necessary, the patient may be withdrawn from the study treatment.  
· 
Medical history including concurrent illnesses and information on dates and description 
of initial diagnosis of colorectal cancer and prior cancer treatment history will be 
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· 
Concomitant medications will be documented during screening and throughout the 
treatment phase until the EOT visit.  
· 
Adverse events (see also section 7): All patients will be closely monitored for adverse 
events from the date of informed consent through the end of treatment visit. Adverse 
events should be followed up until they have returned to baseline status or stabilized.  
· 
Pregnancy test a serum β-HCG test within 7 days before the first dose of study drug will 
be performed for women with childbearing potential. A urine test will be done if the date 
of the first result exceeds the 7 day window. 
5.1.4 LABORATORY ASSESSMENTS 
Blood samples will be taken for hematological and serum chemistry monitoring at screening, 
during the treatment phase before start of each treatment cycle and at the end of treatment 
visit. The local laboratory will perform the analyses and provide reference ranges.  
5.2 STUDY PROCEDURES 
5.2.1 SUPPORTIVE CARE 
a. Required Supportive Care Medication 
 
5-HT3 Antagonists 
In order to minimize nausea, unless contraindicated, all patients must receive 5-HT3 
antagonists (ondansetron 8 mg or equivalent) starting before the first dose of selinexor and 
continued twice daily (bid) – three times a day(tid) as needed (prn). 
b. Supportive Care Recommendations for Selinexor-Related Adverse 
Events 
 
Supportive measures for optimal medical care should be provided during participation in this 
clinical trial.  Based on clinical observations in over 400 adult patients treated with selinexor 
as of 01 October 2014, the main side effects are primarily related to anorexia with poor 
caloric and fluid intake, fatigue, and nausea.  Thrombocytopenia also occurs, although it is 
rarely associated with bleeding.   
Besides the required 5-HT3, supportive care including anti-nausea / anti-emetic therapy, acid 
suppression (proton pump inhibitors and/or H2-blockers) and other treatments may be 
administered as described below: 
1. Glucocorticoids: dexamethasone (4-12 mg) or equivalent glucocorticoid (e.g., 
prednisone 10-20 mg) on days of, and 1 day after, selinexor dosing may improve 
appetite, reduce nausea or vomiting, and minimize fatigue.  A maximum of 40 mg 
dexamethasone or equivalent may be given per week. 
2. Appetite stimulants: megesterol acetate at a dose of 80-400 mg daily. 
3. Centrally acting agents: per National Comprehensive Cancer Network® [NCCN] 
Clinical Practice Guidelines® for antiemesis and anorexia/cachexia [palliative care] 


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see Appendix 5. 
4. NK1R antagonist:  aprepitant or equivalent should be considered and will be covered 
for selected patients who have severe nausea and vomiting. 
Additional information on supportive care and dose modifications for specific adverse events 
can be found in Table 4. 
5.2.2 SCREENING PROCEDURES  
All patients will be screened and screening procedures performed within 14 days prior to the 
start of treatment unless specified otherwise below. These include the following:  
Signed written informed 
consent 
Obtained prior to any study specific assessments 
Demographics and medical 
history 
Age, gender, ethnic background 
Tumor diagnosis including dates and description of 
initial diagnosis of colorectal cancer 
Details on prior therapy, including start and stop 
dates, disease progression during or after therapy, as 
well as discontinuation due to toxicities 
Previous and concurrent relevant diseases 
Current symptoms and/ or residual toxicities from 
prior therapies 
Pregnancy test (if applicable) 
A serum pregnancy test will be performed in pre-
menopausal women and women who are post-
menopausal for < 2 years. In case the sampling date 
for the serum pregnancy test exceeds 7 days before 
treatment start, a urine test is required for 
confirmation 
Physical examination and vital 
signs  
Body height and weight 
BSA 
Blood pressure, heart rate, respiratory rate , 
temperature 
Physical examination 
ECOG performance status  
Please refer to Appendix 4 
Standard clinical neurological 
examination  
A neurological exam will be performed to assess 
motor, sensory and balance functions 
Cardiac evaluation  
12-lead ECG 
Ophthalmological examination  
Required at screening and if clinically indicated. Prior 
to dilation:  best corrected visual acuity, and slit lamp 
examination including tonometry; following dilation, 
fundoscopy and slit lamp exam to document lens 
clarity - if a cataract is seen during the exam, the 
cataract will be graded according to the Lens 
Opacities Classification System (LOCS III). See 
Appendix 7. 
Calculation (or measurement) 
of GFR 
Please refer to Appendix 6 
Urine dipstick 
Urine bilirubin, glucose, hemoglobin, ketones, pH, 
protein 
Hematology  
Hemoglobin, red blood cell (RBC) count, platelets, 
white blood cell (WBC) count, WBC differential 
(neutrophils, lymphocytes) 
Clinical chemistry  
Sodium, Potassium, Calcium, Creatinine, Total 


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Bilirubin, Alkaline Phosphatase, alanine 
aminotransferase (ALT), aspartate aminotransferase 
(AST), Total Protein, Albumin, LDH 
Coagulation tests 
prothrombin time (PT), activated partial 
thromboplastin time (aPTT) and INR 
Tumor marker 
CEA, CA19-9 
Assessment of disease status 
(Day -28 to 0)  
The disease status will be measured by CT/MRI and 
evaluated according to RECIST 1.1 criteria 
Concomitant medication 
Concomitant medication currently used 
 
5.2.3 TREATMENT PHASE 
During the treatment phase the following assessments are to be performed according to the 
study flow chart within the allowed visit windows (page14-15): 
Physical examination and vital 
signs 
Body weight 
BSA 
Blood pressure, heart rate, respiratory rate, 
temperature 
Physical examination (symptom directed) 
ECOG performance status  
Please refer to Appendix 4 
Urine dipstick 
Urine bilirubin, glucose, hemoglobin, ketones, pH, 
protein 
Hematology  
Hemoglobin, white blood cell (WBC) count, 
neutrophils, lymphocytes, platelets,  
Clinical chemistry  
 
Sodium, Potassium, Calcium, Creatinine, Total 
Bilirubin, Alkaline Phosphatase, alanine 
aminotransferase (ALT), aspartate aminotransferase 
(AST), Total Protein, Albumin, LDH 
Tumor marker (every 8 weeks) 
CEA, CA19-9 
Assessment of disease status 
(every 8 weeks) 
The disease status will be measured by CT/MRI and 
evaluated according to RECIST 1.1 criteria 
Adverse events and 
concomitant medication 
Assessed on an ongoing basis.  
 
5.2.4 END OF TREATMENT 
Patients who discontinue therapy for any reason must have and end of treatment (EOT) visit 
completed 30 days (± 7 days) after the last application of study drug. At the EOT visit, the 
patients will undergo the following assessments: 
Physical examination and vital 
signs 
Body weight 
Blood pressure, heart rate, respiratory rate, 
temperature 
Physical examination 
ECOG performance status  
Please refer to Appendix 4 
Standard clinical neurological 
examination  
A neurological exam will be performed to assess 
motor, sensory and balance functions 
Hematology  
Hemoglobin, white blood cell (WBC) count, 
neutrophils, lymphocytes, platelets, leukemic blasts 
Clinical chemistry  
Sodium, Potassium, Calcium, Creatinine, Total 
Bilirubin, Alkaline Phosphatase, alanine 


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aminotransferase (ALT), aspartate aminotransferase 
(AST), Total Protein, Albumin, LDH 
Urine dipstick 
Urine bilirubin, glucose, hemoglobin, ketones, pH, 
protein 
Cardiac evaluation  
12-lead ECG 
Tumor marker (if reason for 
EOT is not PD) 
CEA, CA19-9 
Assessment of disease status (if 
reason for EOT is not PD) 
The disease status will be measured by CT/MRI and 
evaluated according to RECIST 1.1 criteria 
Adverse events and 
concomitant medication 
Assessed on an ongoing basis 
5.2.5 FOLLOW-UP  
Patients who discontinued for reasons other withdrawal of consent for participation in the trial 
will be followed every 3 months ± 28 days to assess the following:  
· 
Overall survival  
· 
Progression-free survival for patients discontinued for other reason than disease 
progression  
Follow-Up will be continued for maximum of 24 months per patient or end of study as defined 
below, whichever is first. 
5.2.6 END OF STUDY 
The primary statistical analysis (i.e. primary endpoint and secondary endpoints RR and 
toxicity) will be performed when all patients have received treatment with study medication 
for 4 cycles i.e. after first in study tumor assessment of last patient.  End of study will be 
defined 2 years after registration of last patient. 
5.3 PLANNED TREATMENT OF THE PATIENT AFTER END OF TREATMENT PHASE 
After completion of the study at routine follow-up (EOT), patients will generally be treated at 
the discretion of the investigator according to medical routine. 
5.4 REMOVAL OF PATIENTS FROM TREATMENT 
Subjects will be free to discontinue treatment or withdraw from the study at any time, for any 
reason, or they may be withdrawn/ removed if necessary in order to protect their health (see 
reasons for withdrawal below). It is understood by all concerned that an excessive rate of 
withdrawals can render the study uninterpretable; therefore, unnecessary withdrawal of 
subjects should be avoided. Patients who are withdrawn from the study and not evaluable for 
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Patients may be removed from further treatment for the following reasons: 
· 
Disease progression 
· 
Non-compliance 
· 
Need of treatment with medications not allowed by the study protocol 
· 
Patient no longer consents to participate in the study 
· 
Intercurrent illness that interferes with study assessments 
· 
Incidence or severity of AEs in this study indicates a potential health hazard to the 
patient 
· 
Investigator discretion 
· 
Pregnancy 
· 
Termination of the study by the sponsor 
 
If there is a medical reason for withdrawal of treatment, the patient will remain under the 
supervision of the investigator until the AEs have been resolved or declined to baseline 
values. 
 
If a patient has failed to attend scheduled assessments in the study, the investigator must 
determine the reasons and circumstances as completely and accurately as possible.  
 
In case of premature discontinuation of the study treatment, the investigations scheduled for 
the EOT and the follow-up visits should be performed, if possible. The CRF section entitled 
“End of Treatment” must be completed in all cases. Should a patient decide to withdraw, 
every effort will be made to complete and report the observations as thoroughly as possible. 
The investigator should contact the patient to determine as completely as possible the 
reason for the withdrawal. A complete final evaluation at the time of the patient’s withdrawal 
should be made, with an explanation of why the patient is withdrawing from the study. If the 
reason for removal of a patient from the study is an adverse event or an abnormal laboratory 
test result, the principal specific event or test will be recorded on the CRF. 
 
If a patient withdraws consent for further study treatment, the patient should still be followed 
for disease progression and overall survival. If a patient withdraws consent for further 
participation in the study, follow-up assessments will be discontinued. 
5.5 STUDY DISCONTINUATION 
The whole study may be discontinued at the discretion of the sponsor in the event of any of 
the following: 
· 
Medical or ethical reasons affecting the continued performance of the study 


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· 
Difficulties in the recruitment of patients 
6 TREATMENT 
6.1 INVESTIGATIONAL MEDICINAL PRODUCT (IMP) 
An investigational medicinal product is a pharmaceutical form of an active substance or 
placebo being tested or used as a reference in a clinical trial, including products already with 
a marketing authorisation but used or assembled (formulated or packaged) in a way different 
from the authorised form, or when used for an unauthorised indication, or when used to gain 
further information about the authorised form. 
The IMP in this study is Selinexor. Oxaliplatin, 5-FU and LV are not considered IMP as the 
treatment is according to the standard of care.  
The investigator or other appropriate individual, who is designated by the local principal 
investigator, should maintain records of the inventory at the site, the use for each patient and 
delivery, storage and destruction. Investigators should maintain records that adequately 
document that patients were provided the doses specified in the protocol and reconcile all 
investigational product(s) received from the drug provider. 
6.2 PREPARATION AND ADMINISTRATION OF SELINEXOR 
The investigator or responsible site personnel must instruct the patient or caregiver to take 
the study drug as per protocol. Study drug will be dispensed to the patient by authorized site 
personnel only. All dosages prescribed to the patient and all dose changes during the study 
must be recorded on the Dosage Administration Record CRF. 
Tablets, including instructions for administration, are dispensed by study personnel on an 
outpatient or inpatient basis. 
Patients will be provided with an adequate supply of study drug for self-administration at 
home until at least their next scheduled study visit. 


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6.2.1 DRUG NAME, FORMULATION AND STORAGE 
INN 
 Selinexor 
Company´s Drug ID
 
 
KPT-330 
Chemical name 
(Z)-3-(3-(3,5 bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)-N'-
(pyrazin-2-yl)acrylohydrazide 
Classification 
Cell biological modifier Apoptosis inducing agent 
Mechanism of action
Selinexor is a Selective Inhibitor of Nuclear Export (SINE) that 
specifically blocks nuclear export by binding irreversibly to 
XPO1 protein.  
Molecular formula: 
C17H11F6N7O 
Molecular weight: 
443.31 
Approx. Solubility: 
 <0.03 mg/mL in water (pH 2-8) 
 
>10 mg/mL in dimethylsulfoxide 
 
<2 mg/mL in 40% v/v PEG-400/H2O 
 
<2 mg/mL in 15% v/v EtOH/H2O 
 
Tablets: Selinexor (KPT-330) for oral administration will be supplied in tablet with strengths: 
of 10 mg. 
 
Labelling: Each bottle of Selinexor tablets will be labelled in accordance with current ICH 
GCP and specific national requirements. 
 
Storage: Selinexor tablets will be stored at ambient temperatures between 5 –30 °C in a 
locked and secured area with restricted access to study staff. The tablets should not be 
stored at freezer temperatures or allowed to freeze. Tablets will be supplied in white high 
density polyethylene (HDPE) bottles.  
6.2.2 ROUTE OF ADMINISTRATION 
Selinexor tablets will be taken on Day 1, 3 and 8 of each two–week cycle. 
Selinexor is to be taken within approximately 30-minutes of solid food consumption together 
with >120 mL (8 ounces) of water. 
6.2.3 COMPLIANCE 
The investigator should ensure that the investigational product is used only in accordance 
with the protocol. All doses given are to be documented in the CRF, including exact dose, 
number of tablets, time and date administered. The principal investigator or the designee will 
account for the number of tablets dispensed against those stored at the site. Any deviations 
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with the reasons for missed doses. The investigator/ designee will try to ensure complete 
compliance with the dosing schedule by providing timely instructions to the patients. It will be 
requested from patients to document intake of Selinexor in a patient diary. 
The investigational product should be stored as specified by the drug provider and in 
accordance with applicable regulatory requirements. 
6.3 DOSE MODIFICATION OF SELINEXOR 
Based on observations from the ongoing Phase 1 studies in patients with advanced 
hematological and solid tumors, Selinexor (KPT-330) shows a wide therapeutic range, with 
documented anti-cancer activity from ~12mg/m² to ≥50mg/m² orally twice weekly. At the 
present time, we cannot predict which patient's CRC will respond to lower doses, nor can 
tolerability be predicted. Therefore, in order to individualize and optimize safety and 
therapeutic benefit, study therapy will be initiated with 30mg/m² twice weekly by mouth of 
Selinexor. This dose is below the MTD of oral Selinexor when used as monotherapy and is 
associated with clinical benefit.   
Toxicity will be graded according to NCI CTCAE, version 4.03; the therapy modifications 
described below are applied according to this severity grading. 
If more than one different type of toxicity occurs concurrently, the most severe grade will 
determine the modification. 
Study medication cycles will be repeated every 2 weeks provided that on Day 1 of each cycle 
the laboratory parameters are deemed adequate and study medication-related toxicities have 
resolved to Grade < 2 or baseline. Dose modifications for Selinexor are permitted in the 
setting of non-life-threatening, reversible Grade 3-4 AEs that resolve to Grade ≤ 1 within one 
treatment cycle (approximately 2 weeks).  
Flexible dose reductions and/or schedule modifications will be permitted. In patients with 
tolerability issues on Selinexor, it is recommended either: (1) reducing Selinexor dose by 
30% or (2) reducing Selinexor dosing frequency to once weekly. Specific criteria for dose 
reductions or delays in the setting of various AEs are presented in Table 10. 
Re-escalation of the study drug is allowed as outlined in the sections that apply for the 
specific toxicity. If toxicity requires a treatment delay of more than 4 weeks the patient is 
taken off protocol treatment.  
Each dose modification or treatment delay has to be documented in the CRF, including the 
respective reason. 
 
 


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6.3.1 DOSE ADJUSTMENT GUIDELINES FOR SELINEXOR RELATED TOXICITIES 
 
Table 3 Dose level   
Dose Level 3 
selinexor 80 mg on day 1, 3, and 8 
Dose Level 2 
selinexor 60 mg on day 1, 3, and 8 
Dose Level 1 
selinexor 40 mg on day 1, 3, and 8 
Dose Level -1 
selinexor 20 mg on day 1, 3, and 8 
 
 
Dose adjustments should be made based on specific toxicities as shown in Table 10. 
 
Table 4 Criteria for dose adjustments of Selinexor related toxicities 
Toxicity and Intensity 
Supportive treatment 
Selinexor Dose Modification 
Fatigue (common) 
Grade 1 
Rule out other causes of fatigue. 
Insure adequate caloric intake 
and assess volume status. 
Consider addition of 4-12 mg 
dexamethasone or equivalent 
with each dose of selinexor +/- 
the day after selinexor. 
Maintain dose.  
Grade 2 
Rule out other causes of fatigue. 
Insure adequate caloric intake 
and assess volume status. 
Consider addition of 4-12 mg 
dexamethasone or equivalent 
with each dose of selinexor +/- 
the day after selinexor.  
For additional support see NCCN 
guidelines a (appendix. 
Maintain dose. 
Consult medical monitor for 
additional option such as 
temporary dose reduction or 
short dose interruptions. 
Grade 3 
See guidelines for Grade 2 
fatigue. 
Interrupt selinexor dosing until 
resolved to Grade ≤ 2, For first 
occurrence of Grade 3, if 
adequate supportive care 
resulted in fatigue improving to 
Grade ≤1 within 7 days, restart 
selinexor at current dose.  
Otherwise, restart selinexor at 
one dose level below (Table 3). 
 
Anorexia or Weight loss 
Grade 1 
Rule out other causes of 
anorexia. 
Assess dietary options (e.g., try a 
variety of other foods).  
Add high-calorie supplements 
(e.g., Ensure®).  
Consider addition of 4-12 mg 
dexamethasone or equivalent 
with each dose of selinexor +/- 
the day after selinexor. 
Maintain dose. 


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Toxicity and Intensity 
Supportive treatment 
Selinexor Dose Modification 
Grade 2 
Rule out other causes of 
anorexia. 
Assess dietary options (e.g., try a 
variety of other foods).  
Add high-calorie supplements 
(e.g., Ensure®).  
Consider addition of 4-12 mg 
dexamethasone or equivalent 
with each dose of selinexor +/- 
the day after selinexor.  
Consider megesterol acetate 80-
400 mg daily. 
Consider anabolic steroids such 
as oxandrolone, or dronabinol 
(Marinol®) or other cannabinoid, 
mainly for patients who can’t 
tolerate steroids or at high risk to 
progress. 
For additional supportive care see 
NCCN guidelinesb(Appendix 6). 
Selinexor may be skipped 
intermittently while supportive 
medications are instituted, 
usually for <1 week.  
 
Grade 3  
See guidelines for Grade 2 
anorexia. 
Interrupt dosing with selinexor.   
Restart selinexor at 1 dose level 
reduction (Table 3) once 
anorexia resolves to Grade ≤ 2 
and patient is clinically stable.   
Grade 4 (anorexia only) 
See guidelines for Grade 2 
anorexia. 
Stop dosing of selinexor.   
Restart selinexor at 1 dose level 
reduction (Table 3) only if 
anorexia resolves to Grade ≤ 2, 
patient is clinically stable other 
contributing factors have been 
addressed.   
Nausea/ - acute  (common) 
Grade 1 
Insure adequate caloric intake 
and assess volume status. 
Consider alternate 5-HT3 
antagonists and/or D2 
antagonists as needed. Consider 
addition of NK1 antagonists. 
 
Consider addition of 4-12 mg 
dexamethasone or equivalent 
with each dose of selinexor +/- 
the day after selinexor.  
 
Maintain dose. 
Grade 2 
See guidelines for Grade 1 
nausea 
 
For additional options see NCCN 
guidelines for antiemesisc 
(Appendix 6) 
Selinexor may be skipped 
intermittently while supportive 
medications are instituted, 
usually for <1 week.  
 


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Toxicity and Intensity 
Supportive treatment 
Selinexor Dose Modification 
Grade 3 
See guidelines for Grade 1 
nausea 
 
For additional options see NCCN 
guidelines for antiemesisc 
(Appendix 6) 
Interrupt selinexor dosing until 
resolved to Grade ≤ 2, For first 
occurrence of Grade 3, if 
adequate supportive care 
resulted in nausea improving to 
Grade ≤1 within 3 days, restart 
selinexor at current dose.  
Otherwise, restart selinexor at 
one dose level below (Table 3).  
If nausea stabilizes for at least 4 
weeks at Grade ≤1, then original 
dose of selinexor may be 
resumed. 
Hyponatremia (common) 
Grade 1 (sodium levels <Normal 
to 130 nM) 
  
Be certain sodium level is 
corrected for hyperglycemia 
(serum glucose >150mmol/L).   
Rule out other causes of low 
sodium (e.g., cardiac, hepatic, 
adrenal, renal and thyroid 
diseases, SIADH, Fanconi 
Syndrome, hyperglycemia, 
diuretic use). 
Consider salt supplementation 
one – two times per day. 
Maintain dose. 
 
Grade 3 (sodium levels 126-
129nM) without Symptoms  
Be certain sodium level is 
corrected for hyperglycemia 
(serum glucose >150mmol/L).   
Rule out other causes of low 
sodium (e.g., cardiac, hepatic, 
adrenal, renal and thyroid 
diseases, SIADH, Fanconi 
Syndrome, hyperglycemia, 
diuretic use). 
Initiate salt supplementation two-
three times per day. 
Hold selinexor until Grade ≤1 
(≥130 nM), restart on the same 
dose level.  
Grade 3 (120-125 nM) or Grade 4 
or any Grade 3 with Symptoms 
Correct sodium as per 
institutional guideline 
Initiate salt supplementation two-
three times per day. 
Hold selinexor until resolved to 
Grade ≤ 1 (≥130nM) then reduce 
selinexor dose by 1 level (Table 
3). 
For Grade 3 hyponatremia, if 
serum sodium stabilizes to grade 
≤1 for at least 4 weeks, then 
original dose of selinexor may be 
resumed. 
Diarrhea (common) 
Grade 1+2  
  
Diet recommendation as per 
guidelines (Benson, 2004)d. 
Institute standard anti-diarrheal 
therapy 
After the first occurrence of 
diarrhea, loperamide 2 mg should 
be considered prophylactically 
approximately 1-2 hours before 
the administration of selinexor 
and repeated every 4 hours for 
the first 12 hours. 
For Grade 2 only, reduce 
selinexor one dose level (Table 
3) until resolved to ≤ Grade 1, 
then re-start at the current dose 
level. 
 


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Toxicity and Intensity 
Supportive treatment 
Selinexor Dose Modification 
Grade 3   
  
Institute IV fluids  
Diet recommendation as per 
guidelines (Benson, 2004)d.  
 
Institute standard anti-diarrheal 
therapy. 
 
Once the symptoms resolve to 
≤Grade 1, loperamide 2 mg 
should be considered 
prophylactically approximately 1-2 
hours before the administration of 
selinexor and repeated every 4 
hours for the first 12 hours. 
Delay selinexor until resolved to 
≤ Grade 1, then reduce selinexor 
dose by one dose level (Table 3). 
If diarrhea stabilizes for at least 4 
weeks at Grade ≤1, then original 
dose of selinexor may be 
resumed. 
Grade 4 
Rule out other causes of diarrhea, 
including infectious agents. In 
case of opportunistic infection, 
withdraw all steroids (with 
tapering if medically appropriate) 
until culture is negative. Follow 
institutional guidelines for Grade 
4 diarrhea. 
Delay selinexor until resolved to 
≤ Grade 1, then reduce selinexor 
dose by one dose level (Table 3). 
 
Thrombocytopenia 
Grade 1  
In cases of marked reduction in 
platelet numbers from baseline, 
consider implementing platelet 
growth factors (eltrombopag or 
romiplostim +/- oprelvekin  [IL-
11]). 
Maintain dose. 
Grade 2  
Strongly consider implementing 
platelet growth factors 
(eltrombopag or romiplostim +/- 
oprelvekin  [IL-11]). 
Monitor platelet counts weekly. 
If Grade 2 thrombocytopenia 
persist > 14 days, hold selinexor 
dosing until platelet count returns 
to Grade 1 or baseline values, 
then re-start at the current dose 
level. 
Grade 3 Thrombocytopenia 
Without bleeding 
 
Initiate platelet growth factors 
(eltrombopag or romiplostim +/- 
oprelvekin  [IL-11]). 
Monitor platelet counts at least 
weekly. 
Consider holding anti-platelet 
agents. 
Hold selinexor dosing until the 
patient’s platelet count returns to 
Grade ≤2 or baseline.  
For Grade 2, restart selinexor at 
same dose level taken once 
weekly only until platelet counts 
resolve to Grade ≤1 or baseline., 
then resume twice weekly dosing 
at current dose. 
 
Second occurrence: hold 
selinexor dosing until platelet 
counts return to Grade ≤2 or 
baseline.  For Grade 2, restart 
selinexor at same dose level 
taken once weekly only until 
platelet counts resolve to Grade 
≤1 or baseline, then resume 
twice weekly dosing at one dose 
level below (Table 3). 
 
If platelet counts stabilize at 
Grade ≤1 or baseline for at least 
4 weeks, then original dose of 
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Toxicity and Intensity 
Supportive treatment 
Selinexor Dose Modification 
Grade 4 Thrombocytopenia 
Without bleeding 
 
Follow guidelines for Grade 3 
thrombocytopenia without 
bleeding. 
Transfuse as per institutional 
guidelines. 
Hold selinexor dosing until 
platelet counts return to Grade 
≤2 or baseline.  For Grade 2, 
restart selinexor at same dose 
level taken once weekly only until 
platelet counts resolve to Grade 
≤1 or baseline, then resume 
twice weekly dosing at one dose 
level belowv(Table 3). 
 
If platelet counts stabilize at 
Grade ≤1 or baseline for at least 
4 weeks, then original dose of 
selinexor may be resumed. 
≥ Grade 3 Thrombocytopenia 
associated with bleeding 
 
Transfuse as per institutional 
guidelines. 
 
Follow guidelines for Grade 3 
thrombocytopenia without 
bleeding. 
 
 
Hold selinexor dosing until 
platelet counts return to Grade 
≤1 or baseline, then resume 
selinexor dosing at one dose 
level below (Table 3). 
Neutropenia 
Grade 3 neutropenia without 
fever 
Implement growth factors per 
institutional guidelines. 
Hold dosing with selinexor until 
the patient’s ANC returns to 
Grade ≤2 or baseline values. 
Resume dosing with selinexor at 
current dose. 
Grade 4 neutropenia without 
fever 
Implement growth factors per 
institutional guidelines. 
Hold dosing with selinexor until 
the patient’s ANC returns to 
Grade ≤2 or baseline values. 
Resume dosing with selinexor at 
current dose. 
 
Second occurrence: hold dosing 
with selinexor until the patient’s 
ANC returns to Grade ≤2 or 
baseline values then reduce 
selinexor dose by one dose level 
(Table 3). 
Grade 3 or 4 neutropenia with 
fever (febrile neutropenia) 
Implement growth factors per 
institutional guidelines. 
 
Implement broad anti-microbial 
coverage per institutional 
guidelines. 
 
Please note that selinexor has not 
been associated to date with any 
opportunistic infections 
Hold dosing with selinexor until 
the patient’s ANC returns to 
Grade 1 or baseline values, 
fever has resolved and patient is 
stable, then reduce selinexor 
dose by one dose level (Table 
3). 
 
Other selinexor-related adverse events* 
Grade 1 or 2 
Initiate standard supportive care 
and follow institutional guidelines. 
Maintain dose. 
Grade 3 
Initiate standard supportive care 
and follow institutional guidelines. 
Delay dose until resolved to 
Grade ≤  1 or baseline, then 
reduce by one dose level (Table 
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Toxicity and Intensity 
Supportive treatment 
Selinexor Dose Modification 
Grade 4 
Initiate standard supportive care 
and follow institutional guidelines. 
Delay dose until resolved to 
Grade ≤  1 or baseline, then 
reduce by two dose levels (Table 
3). 
All dose modifications should be based on the worst preceding toxicity. 
* Isolated values of ≥ Grade 3 alkaline phosphatase values will NOT require dose 
interruption.  Determination of liver vs. bone etiology should be made, and evaluation of gamma-glutamyl 
transferase (GGT), 5'-nucleotidase (5’NT), or other liver enzymes should be performed. 
aNational Comprehensive Cancer Network®.  NCCN Clinical Practice Guidelines in Oncology (NCCN 
Guidelines®): Fatigue. Available at http://www.nccn.org/professionals/physician_gls/pdf/fatigue.pdf 
bNational Comprehensive Cancer Network®.  NCCN Clinical Practice Guidelines in Oncology (NCCN 
Guidelines®): Palliative Care, version 1.2014. Fort Washington, NY.  April 2014.  Available at: 
http://www.lls.org/content/nationalcontent/resourcecenter/freeeducationmaterials/generalcancer/p
df/facts.pdf. 
cNational Comprehensive Cancer Network®.  NCCN Clinical Practice Guidelines in Oncology (NCCN 
Guidelines®): Antiemesis, version 2.2014. Fort Washington, NY.  April 2014.  Available at: 
http://www.nccn.org/professionals/physician_gls/PDF/antiemesis.pdf. 
dBenson AB, Ajani JA, Catalano RB, et al. Recommended guidelines for the treatment of cancer 
treatment-induced diarrhea. J Clin Onc 2004; 22:2918. 
 
6.3.2 SELINEXOR DOSE REDUCTION IN THE SETTING OF INFECTION 
Patients with active uncontrolled infections should have Selinexor treatment withheld until the 
infection has resolved or the patient is clinically stable. After the infection has stabilized 
clinically or resolved, Selinexor treatment may continue at the original dose. Missed doses 
will not be replaced. Patients may continue on antibiotics for prolonged periods while re-
initiating their Selinexor regimen at the discretion of the investigator. Prophylactic antibiotics 
are permitted concurrently with Selinexor treatment, but are not required. Opportunistic 
infections related to Selinexor therapy have not been reported in >170 patients treated as of 
15 October 2013. 
6.3.2.1 Missed or Vomited Doses 
Missed doses 
A maximum of two doses may be given per week. If the dose was missed for more than 24 
hours, the dose will be skipped and the next dose will be taken as per schedule. If the dose 
was missed within 24 hours, then it will be replaced. Doses should not be administered in 
less than 36 hours apart and all missed doses should be documented in the patient diary and 
the CRF. 
Vomited doses 
If a dose is vomited within one hour of ingestion, it will be replaced. If vomiting occurs more 
than 1 hour after dosing, it will still be considered a complete dose. 
 


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6.4 GENERAL DOSE MODIFICATIONS: MFOLFOX6 
Table 5 
Drug 
Dose Level 
Starting Dose 
-1 
-2 a 
Oxaliplatin 
85 mg/m2 
65 mg/m2 
50 mg/m2,a 
5-FU bolus 
400 mg/m2 
OMIT 
OMIT 
5-FU continuous 
infusion over 46-48 
hours 
2400 mg/m2 
1900 mg/m2 
1500 mg/m2,a 
Leucovorinb 
400 mg/m2 
100% 
100% 
Abbreviations:  5-FU = 5-fluorouracil; DP = drug product; mFOLFOX6 = 5-FU), leucovorin, and 
oxaliplatin. 
a. 
For 5-FU or oxaliplatin infusions, further dose levels (-3, -4, etc.) will be 20% dose 
reductions from the previous level for oxaliplatin and 5-FU continuous infusion. In addition, 
the bolus dose of 5-FU will continue to be omitted, and the leucovorin dose will remain 
unadjusted (100%). 
b. 
Dosing of leucovorin will remain fixed at 100% of recommended dose. 
 
6.4.1 MODIFICATIONS FOR FIRST TWO CYCLES 
Strictly follow the modifications in the following tables for the first two cycles, until individual 
treatment tolerance can be ascertained. Thereafter, these modifications should be regarded 
as guidelines to prevent side effects from exceeding a mild-to-moderate level, and minimize 
the incidence and duration of debilitating side effects. 
If multiple adverse events are seen, administer dose based on greatest reduction required for 
any single adverse event observed. 
6.4.2 IMPLICATIONS OF DOSE REDUCTIONS FOR SUBSEQUENT CYCLES 
If the patient experiences a significant adverse event requiring a dose reduction at the start 
of the next cycle, then the dose will remain lowered for all subsequent cycles. 
6.4.3 CONTINUATION OF THERAPY ON-STUDY IN THE SETTING OF DISCONTINUATION OF 
ONE COMPONENT OF STUDY THERAPY 
If one therapeutic agent is permanently discontinued secondary to toxicity (for example, 
oxaliplatin discontinued secondary to neurotoxicity), then therapy with the other study agents 
should continue and the patient should remain on-study with full adherence to all protocol 
related requirements. 
Omit: 
 Treatment is not given for this cycle 
Hold/Delay: 
 Treatment can be made up as part of this cycle 
Discontinue: 
 Treatment is totally stopped 
Recommended Dose Modifications for Oxaliplatin+5-Fluorouracil/Leucovorina 
 


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Table 6 
CTCAE v. 4.03 
System Organ 
Classb 
Adverse Event 
Dose Level 
for 
Subsequent 
Cycles 
Based on 
Interval 
Adverse 
Events 
 
At Time of Retreatment 
All Adverse Events <1 
Maintain dose 
level 
Maintain dose level 
Blood and 
lymphatic 
system 
disorders 
Hemolytic 
uremic 
syndrome 
(HUS)c 
>Grade 3 
 
 
Discontinue 
oxaliplatin 
 
 
Discontinue oxaliplatin 
Investigations: 
 
 
Neutrophil 
count 
decreased 
 
Grade 1 
(ANC <LLN-
1500/mm3) 
 
Grade 2 
(ANC <1500-
1000/mm3) 
 
Grade 3 
(ANC <1000 - 
500/mm3) 
 
 
Grade 4 (ANC 
<500/mm3)  
 
 
Maintain dose 
level 
 
 
Maintain dose 
level 
 
 
¯ 1 oxaliplatin 
dose level 
 
 
 
¯ 1 5-FU dose 
level 
¯ 1 oxaliplatin 
dose level 
If ANC <1500 at start of 
cycle, hold and check 
weekly then treat based 
on interval adverse 
event.  If ANC <1500 
after 4 weeks, 
discontinue therapy. 
Platelet count 
decreased 
 
Grade 1 
(PLT<LLN-
75,000/mm3) 
 
Grade 2 
(PLT<75,000-
50,000/mm3) 
 
Grade 3 
(PLT <50,000-
25,000/mm3) 
 
Grade 4 
(PLT 
<25,000/mm3) 
 
 
Maintain dose 
level 
 
 
Maintain dose 
level 
 
 
¯ 1 oxaliplatin 
dose level 
 
¯ 2 oxaliplatin 
dose levels 
If PLT <75,000 at start of 
cycle, hold and check 
weekly then treat based 
on interval adverse 
event.  If PLT <75,000 
after 4 weeks, 
discontinue therapy. 
 


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Gastrointestinal 
disorders:  
Diarrhea 
 
Grade 1, 2 
 
Grade 3 
 
 
Grade 4 
 
 
 
Mucositis oral  
Grade 1, 2 
 
Grade 3 
 
 
Grade 4 
 
Vomiting 
Grades 1, 2 
 
Grade 3 
 
 
Grade 4 
 
 
Maintain 
dose 
level 
 
¯ 
One 
5-FU 
dose level 
 
¯ 
Both 
5-FU 
and oxaliplatin 
1 dose level 
 
 
 
 
Maintain 
dose 
level 
 
¯ 
One 
5-FU 
dose level 
 
 
¯ 
One 
5-FU 
dose level 
 
 
Maintain 
dose 
level 
 
¯ 1 oxaliplatin 
dose level 
 
¯ 
Both 
5-FU 
and oxaliplatin 
1 dose level 
If Grade ³2 at 
start 
of 
cycle, 
hold and check 
weekly then treat 
based on interval 
adverse event.  If 
Grade ³2 after 
4 weeks, 
discontinue 
therapy. 
Neurology 
Do not use CTCAE. 
See xxx for adverse event scale and 
oxaliplatin dose modifications. 
Respiratory, 
thoracic, 
and 
mediastinal 
disorders 
 
Cough ³Grade 3 
Dyspnea ³Grade 3 
Hypoxia ³Grade 3 
Pneumonitis ³Grade 3 
Hold oxaliplatin until interstitial lung 
disease is ruled out.  If interstitial lung 
disease, 
oxaliplatin 
should 
be 
permanently discontinued. 
Other 
nonhematologic 
adverse eventsd, e 
 
Grades 1, 2 
 
Grades 3, 4 
Maintain dose level 
 
¯1 5-FU dose level  
a. 
The dose of leucovorin will not be adjusted due to adverse event.  It should remain at 400 mg/m2 for all 
courses.  Leucovorin will be given immediately prior to each 5-FU dose; thus, if 5-FU is delayed, 
leucovorin will be delayed. 
b. 
For £ NCI CTCAE v. 4.03 Grade 2 toxicity not described, maintain dose level of agent. 
c. 
Recommended evaluation of suspected HUS:  Evaluation should include CBC differential, platelets, PT, 
PTT, fibrinogen, FDP, Anti thrombin III, Von Willebrand factor, anti-nuclear antibody, rheumatoid factor, 
Compliment Cascade C3, C4, and CH50, anti-platelet antibodies, platelet-associated IgG, and circulating 
immune complexes.  Renal evaluation should include creatinine, BUN, and urinalysis with microscopic 
examination.  Other laboratory and hematological evaluations as appropriate should also be obtained, 
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d. 
Exceptions:  alopecia, fatigue, anorexia, nausea/vomiting if can be controlled by antiemetics, and viral 
infections. 
e. 
Dose modifications for other nonhematologic adverse events at the start of subsequent courses of therapy, 
and at time of retreatment are also based on NCI CTCAE v. 4.03 criteria. 
 
6.4.4 OXALIPLATIN DOSE MODIFICATIONS FOR NEUROLOGIC ADVERSE EVENTS 
Adverse Events 
Duration of Adverse Event 
Persistentb 
Between 
Cycles 
1 - 7 Days 
>7 Days 
Paresthesias/Dysesthesias 
Paresthesias/dysesthesiasc 
of short duration that 
resolve and do not 
interfere with function 
(Grade 1) 
No change 
No change 
No change 
Paresthesias/dysesthesiasc 
interfering with function, 
but not activities of daily 
living (ADL) 
(Grade 2) 
No change 
No change 
¯1 oxaliplatin 
dose level 
Paresthesias/dysesthesiasc 
with pain or with functional 
impairment that also 
interfere with ADL 
(Grade 3) 
1st time: ¯1 
oxaliplatin dose 
level 
 
2nd time: ¯1 
oxaliplatin dose 
level 
1st time: ¯1 
oxaliplatin dose level 
 
2nd time: ¯1 
oxaliplatin dose level 
Discontinue 
Persistent 
paresthesias/dysesthesias 
that are disabling or life-
threatening 
(Grade 4) 
Discontinue 
Discontinue 
Discontinue 
Laryngeal Dysesthesias 
(investigator discretion used for grading): 
Grade 1 = mild 
No change 
- duration of infusion 
to 6 hours 
- duration of 
infusion 
to 6 hours 
Grade 2 = moderate.  (Also 
recommended is 
administration of 
benzodiazepine and 
patient education.  
Management of patient if 
³Grade 2 laryngeal 
dysesthesias occurs while 
treatment is being 
administered.) 
Stop oxaliplatin infusion. 
Administer benzodiazepine and give patient reassurance. 
At the discretion of the investigator, the infusion can be restarted 
at 1/3 the original rate of infusion. 
Grade 3 = severe 
Abbreviations:  ADL = activities of daily living; CTCAE = Common Terminology Criteria for Adverse Events. 
a 
If oxaliplatin is discontinued, continue other study agents unless adverse events preclude their 
continuation. 
b 
Not resolved by the beginning of the next cycle. 
c 
May be cold-induced. 
 
 


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6.5 CONCOMITANT MEDICATION AND TREATMENT 
Concomitant medication is defined as any prescription or over-the-counter preparation, 
including vitamins and supplements. Patients may continue their baseline medication(s). All 
concomitant medication(s) must be reported in the case report form (CRF). Any diagnostic, 
therapeutic or surgical procedure performed during the study period should be recorded, 
including the dates, description of the procedure(s) and any clinical findings. Patients should 
minimize the use of products containing acetaminophen, which can interfere with the 
metabolism of Selinexor. For combination painkillers containing acetaminophen it is 
recommended that single agent opiates or aspirin combinations (when clinically acceptable) 
be substituted. 
6.5.1 PERMITTED CONCOMITANT MEDICATION 
Patients will receive concomitant medications to treat symptoms, adverse events and 
intercurrent illnesses that are medically necessary as standard care. Medications to treat 
concomitant diseases like diabetes, hypertension, etc. are allowed. 
6.5.2 PREVENTION OF PREGNANCY 
Female patients of child-bearing potential must agree to use dual methods of contraception 
and have a negative serum pregnancy test at screening, and male patients must use an 
effective barrier method of contraception if sexually active with a female of child-bearing 
potential. Acceptable methods of contraception are condoms with contraceptive foam, oral, 
implantable or injectable contraceptives, contraceptive patch, intrauterine device, diaphragm 
with spermicidal gel, or a sexual partner who is surgically sterilized or post-menopausal. For 
both, male and female patients, effective methods of contraception must be used throughout 
the study and for three-months following the last dose. 
6.5.3 USE OF BLOOD PRODUCTS 
During the administration of Selinexor, patients may receive red blood cell (RBC) or platelet 
transfusions, if clinically indicated, per institutional guidelines. Appropriate anti-coagulation is 
allowed during the study (eg: LMW heparin, direct factor Xa inhibitors, etc).  
 
 


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6.5.4 GLUCOCORTICOID THERAPY 
Glucocorticoids ≤ 10 mg oral prednisone (or equivalent) per day are permitted at baseline 
and during the study for non-malignant conditions (i.e., asthma, IBD, etc.) as needed.   
As part of supportive care (e.g. for nausea or anorexia), oral dexamethasone, up to 40 
mg/week, may be given to patients, in consultation with the Medical Monitor. 
Dexamethasone (4-10mg) or prednisone (10-20mg) on days of (±1 day after) Selinexor 
dosing may improve appetite, reduce nausea or vomiting, and minimize fatigue. 
6.5.5 PROHIBITED MEDICATIONS 
Patients should minimize the use of products containing acetaminophen. For combination 
painkillers containing acetaminophen it is recommended that single agent opiates or aspirin 
combinations (when clinically acceptable) be substituted, particularly on the days of 
Selinexor dosing. 
Concurrent therapy with an approved or investigational anticancer therapeutic, other than 
Oxaliplatin, 5-fU and Levamisol as specified herein, is not allowed.  
Use of any immunosuppressive agents during the study must be confirmed by the medical 
monitor.  Other investigational agents should not be used during the study. 
Inactivation of Selinexor by glutathione conjugation is a significant metabolic pathway in vitro 
and in vivo, including in humans. This process can be mediated in the absence of proteins, 
indicating that it is thermodynamically favorable. In vitro studies using human liver 
microsomes confirm in vivo findings that Selinexor undergoes minimal CYP450 metabolism. 
Therefore, administration of Selinexor with drugs which undergo substantial glutathione 
conjugation should be minimized or avoided. These drugs include acetaminophen 
(paracetamol) and ethyl alcohol. It should be noted that studies of Selinexor in combination 
with acetaminophen are currently on-going and therefore that these recommendations are 
empirical. It should also be noted that recreational ethanol ingestion is associated with 
glutathione depletion; therefore, the use of products containing ethanol should be minimized 
or avoided on Selinexor dosing days. 
6.6 SUPPORTIVE CARE GUIDELINES 
Supportive measures for optimal medical care shall be provided during participation in this 
clinical trial. Supportive care including anti-nausea / anti-emetic therapy, acid suppression 
(proton pump inhibitors and/or H2-blockers), glucocorticoids, and other standard treatments 
may be administered as per institutional guidelines for symptomatic patients. As needed and 
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antifungals, and antibiotics, may be administered to ameliorate risks associated with non-
malignant disorders or of immune system compromise. 
6.6.1 ANOREXIA 
Based on clinical observations on Schedules 1-3 with over 200 patients treated with 
Selinexor across phase 1 clinical trials (KCP-330-001 and KCP-330-002), the dose limiting 
toxicities (DLTs) are primarily related to anorexia with poor caloric and fluid intake leading to 
weight loss, fatigue and nausea. Therefore, it is strongly recommended that patients at risk 
for anorexia, weight loss, and/or fatigue receive strong nutritional counseling, high caloric 
beverages with adequate electrolyte levels (e.g., Ensure®), prophylaxis with appetite-
stimulating agent(s), and anti-emetic agents. Patients with proper nutritional support and 
counseling have remained on Selinexor for >11 months. There is no correlation between 
initial BMI or weight and the development of anorexia. 
In patients with problematic food/liquid/caloric intake, a patient log of food and drink should 
be considered and monitored by the treatment team. 
Fresh juices, simple carbohydrates, as well as ginger can improve appetite before the meal; 
ginger may also improve dysgeusia. 
Since the duration of treatment is short and most of the patients are hospitalized during 
induction treatment patients with anorexia nutrition is usually provided by infusion directly into 
the circulatory system  
If constipation occurs, then laxatives should be given as constipation can contribute to 
anorexia and loss of appetite. 
6.6.2 FATIGUE    
Fatigue may be related to underlying malignancy, Selinexor side effects, side effects of other 
agents or concurrent morbidities. Fatigue may also be related to anorexia and/or 
dehydration, so caloric and fluid intake should be optimized in all patients (please see above 
aggressive guidelines for maintenance of food and fluid intake). Acid suppression (proton 
pump inhibitors and/or H2-blockers) may be beneficial in some patients with fatigue. 
6.6.3 EMESIS    
Supportive care for nausea and vomiting should be given promptly. The site can consider 
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cancer therapy. The treatment should start with the first sign of nausea. Standard anti-
emetics are allowed and strongly recommended. 
6.6.4 ACUTE EMESIS 
Acute emesis is not a major observation with Selinexor but has been reported. Selinexor 
associated nausea/emesis generally responds to D2-antagonists, 5-HT3 antagonists, or 
combinations of agents. 
5-HT3 receptor antagonists (Zofran® 8 mg od on days of dosing) — First-generation 5-HT3 
receptor antagonists all appear equally effective at preventing nausea/emesis at the 
recommended doses. A single dose of a 5-HT3 receptor antagonist prior to therapy is 
equivalent to a multiple dose schedule. The efficacy of 5-HT3 receptor antagonists is 
significantly improved when they are combined with glucocorticoids.  As QTc prolongation is 
the main side effect, magnesium and potassium should be corrected prior to use. If first-
generation 5-HT3 receptor antagonists+dexamethasone do not adequately control emesis, 
second generation 5-HT3 receptor antagonists (e.g., palonosetron) should be considered. 
Second generation 5-HT3 receptor antagonists also improve delayed nausea/emetic 
response. 
Neurokinin-1 receptor antagonists (e.g., aprepitant or fosaprepitant, Emend®) – should be 
considered in case of uncontrolled emesis with standard treatments as described above. 
Neurokinin-1 receptor antagonists should be given with combination of dexamethasone and 
first or second generation 5-HT3 receptor antagonists. 
Additional treatment: Metoclopramide Hydrochloride 10mg, 30 min before meal (up to 4 time 
a day) or prochlorperazine (standard doses) have been effective in many patients.  
Dronabinol (Marinol) has shown some activity in both nauea/emesis and anorexia in patients 
treated with Selinexor. Lorazapeam can be added to the combination treatment of 5-HT3 
receptor antagonists +dexamethasone, e.g., at night, but has been less effective in Selinexor 
associated nausea/emesis. 
6.6.5 DELAYED EMESIS - > 24H AFTER TREATMENT 
Management — Selinexor is infrequently associated with delayed, resistant emesis. Many of 
the regimens associated with delayed emesis are classified as high-emetic risk, and 
professional guidelines recommend the use of an NK1 receptor antagonist (either NK-1 
blockers e.g., aprepitant on days 1 to 3 or fosaprepitant on day 1 only), plus a glucocorticoids 
on days 1 to 4, along with a 5-HT3 receptor antagonist (particularly second generation 


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agents) on day 1. This regimen is effective against both acute and delayed emesis. The data 
supporting the individual components of this regimen are reviewed below. 
Olanzapine — Conventional antiemetics are more successful at preventing emesis than in 
preventing nausea, particularly delayed nausea. Olanzapine 10 mg once daily (typically 
given at night to mitigate sedative effects) was proven effective in both anti emesis and 
nausea control. It may also be useful for management of breakthrough emesis, and to 
improve food intake in patients with anorexia. 
Glucocorticoids are also consistently useful and should be administered as described above. 
Granisetron transdermal patch — A transdermal preparation of granisetron should be 
consider in patients that have uncontrolled emesis/nausea >grade 2 under best supportive 
treatment 
Ginger — Supplemental ginger added to foods or at doses of 0.5, 1.0gm powder daily total 
dose, usually in divided doses. Ginger may also improve dysgeusia. 
Additional agents can be added, including lorazepam or alprazolam, olanzapine, a 
dopaminergic D2-antagonist (eg, prochlorperazine, thiethylperazine, haloperidol), or 
substituting high-dose intravenous metoclopramide for the 5-HT3 antagonist. 
6.6.6 DIARRHEA    
Diarrhea is common at up to 32% (mostly Grade 1), which responds to standard anti-
diarrheal agents. Fluid replacement is important to prevent dehydration, fatigue and 
electrolyte abnormalities (e.g., hyponatremia). 
6.6.7 HYPONATREMIA   
Hyponatremia (Grade 3) has been reported in about 9% of patients. One of these cases was 
pseudohyponatremia due to hyperglycemia (not associated with Selinexor).  None of these 
cases have been symptomatic. Most of the patients had anorexia, nausea, vomiting and/or 
diarrhea. Two of the patients with Grade 3 hyponatremia had third-space fluid accumulation 
or resolution (e.g., ascites, edema). Adequate fluid and caloric intake, including electrolyte 
rich beverages rather than free water, has led to reversal of the hyponatremia. 
 
 
 


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7 SAFETY REPORTING 
 
The Investigator’s Brochure will be used as reference document for KPT-330 (selinexor) and 
will be provided to the investigators in the investigator’s file. 
7.1 ADVERSE EVENTS AND LABORATORY ABNORMALITIES REPORTING 
7.1.1 ADVERSE EVENT 
An adverse event is defined in the International Conference on Harmonization (ICH) 
Guideline for Good Clinical Practice as “any untoward medical occurrence in a patient or 
clinical investigation subject administered a pharmaceutical product and that does not 
necessarily have a causal relationship with this treatment” (ICH E6:1.2). 
An adverse event can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding, for example), symptom or disease temporally associated with 
the use of a medicinal product, whether or not it is considered related to the medicinal 
product. 
7.1.2 ADVERSE DRUG REACTION 
All untoward and unintended responses to a medicinal product related to any dose 
administered. 
The phrase “responses to a medicinal product” means that a causal relationship between the 
medicinal product and the adverse event is at least a reasonable possibility, i.e. the 
relationship cannot be ruled out. 
A serious ADR (SADR) is an ADR that meets the definition of serious (provided below). 
7.1.3 SERIOUS ADVERSE EVENT 
A serious adverse event (SAE) is defined as an adverse event that meets one or more of the 
following: 
· 
is fatal 
· 
is life threatening (places the subject at immediate risk of death) 
· 
requires in-patient hospitalization or prolongation of existing hospitalization 
· 
results in persistent or significant disability/incapacity 
· 
is a congenital anomaly/birth defect 
· 
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A hospitalization meeting the regulatory definition for “serious” is any inpatient hospital 
admission that includes a minimum of an overnight stay in a healthcare facility. Any adverse 
event that does not meet one of the definitions of serious (e.g. visit to A&E, outpatient 
surgery, or requires urgent investigation) may be considered by the investigator to meet the 
“other significant medical hazard” criterion for classification as a serious adverse event. 
Examples include allergic bronchospasm, convulsions, and blood dyscrasias. 
Important medical events are defined as those occurrences that may not be immediately life 
threatening or result in death, hospitalization, or disability, but may jeopardize the subject or 
require medical or surgical intervention to prevent one of the other outcomes listed above. 
Medical judgment should be exercised in deciding whether such an AE should be considered 
serious. 
7.1.4 NOT TO BE REPORTED AS SAES 
For this study, the following is not classified as serious adverse event: 
· 
Progression or deterioration of the malignancy under study (including new metastatic 
lesions) or death due to progression. 
· 
Hospitalization for the performance of protocol-required procedures or administration 
of study treatment. However, hospitalization or a prolonged hospitalization for a 
complication of therapy administration will be reported as an SAE. 
· 
Hospitalization or procedures planned prior to study start. A pre-planned procedure 
must be documented in the source documents. However, hospitalization or prolonged 
hospitalization for a complication remains to be reported as an SAE. 
· 
An elective hospitalization for a pre-existing condition unrelated to the studied 
indication. 
· 
Hospital admission that is not associated with an adverse event (e.g. social 
hospitalization for purpose of respite care). 
· 
Routine treatment or monitoring of the studied indication not associated with any 
deterioration in condition. 
· 
The administration of blood or platelet transfusion as routine treatment of studied 
indication. However, hospitalization or prolonged hospitalization for a complication of 
such transfusions remains to be reported as an SAE. 
· 
Emergency outpatient treatment or observation that does not result in admission, 
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7.1.5 SUSAR/ UNEXPECTED SERIOUS ADR 
A SUSAR/ Unexpected Serious ADR is a suspected unexpected serious adverse reaction. A 
suspected adverse reaction is an adverse event for which there is a reasonable possibility 
that the drug caused the event. An unexpected adverse reaction is any adverse reaction with 
a reasonable possibility that the study drug caused the event and the specificity or severity is 
not consistent with the current investigator’s brochure for Selinexor. Also, reports that provide 
significant information on the specificity or severity of a known, already documented adverse 
event constitute unexpected adverse events. An event more specific or more severe than 
described in the investigator’s brochure would be considered “unexpected”. All suspected 
adverse reactions related to Selinexor which occur in the trial and that are both unexpected 
and serious (SUSARs/ Unexpected Serious ADR ) are subject to expedited reporting. 
7.2 REPORTING OF SAES 
Any clinical adverse event or abnormal laboratory test value that is serious occurring during 
the course of the study from the date of signing the informed consent, irrespective of the 
treatment received by the patient, must be reported to the sponsor and the drug provider   
within 24 hours of knowledge (expedited reporting). For each patient, all serious adverse 
events must be reported up to 30 days after the last dose of investigational product. Serious 
adverse events occurring more than 30 days after a patient is discontinued from the study 
treatment may be reported at the discretion of the investigator. 
The completed SAE form must be faxed to: 
SAE reporting forms will be completed within 24 hours of the event and faxed to: 
  
Clinical Trial Manager 
Dr. Anne L. Kranich 
Address: 
GSO mbH 
Harvestehuder Weg 21 
20148 Hamburg 
Germany 
 
Phone: 
0049-40-44 19 54 60  
Fax: 
0049-40-44 19 54 78 
 
The drug provider will medically review all SAEs.  
The following detailed information must be recorded for each serious adverse event in the 
SAE report form: 
· 
A description of the AE in medical terms  


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· 
The severity grade as assessed by the investigator according to the definitions in 
NCI-CTC Version 4.03 
· 
The date of becoming serious and the date of becoming known (if different) 
· 
The reason for seriousness 
· 
The outcome of the SAE at the time of the report 
· 
Information on administration of the study drug and chemotherapy and any action 
taken 
· 
Information on any treatment procedures necessary for the SAE, concomitant 
medications, relevant lab tests and relevant medical history 
If in any one subject the same SAE occurs on several occasions, then the SAE in question 
must be documented and assessed anew each time. 
The investigator is required to submit SAE Follow-up reports until the SAE has resolved or 
stabilized and all queries have been answered. 
7.3 REPORTING OF SUSARS/ EXPEDITED REPORTING OF UNEXPECTED SERIOUS ADRS 
The sponsor will via coordinating CRO ensure the notification of the appropriate ethics 
committees, competent authorities and participating investigators of all SUSARs events 
occurring at the sites in accordance with local legal requirements, statutes and the European 
Clinical Trial Directive as follows: 
· 
Reporting of the SUSAR to the Competent Authorities and Ethics Committees within 
15 days (or within 7 days for fatal and life-threatening events) 
· 
Sending the event to all participating Investigators for information (with confirmation 
of receipt). 
In addition, all events that require a new assessment of the risk-benefit ratio will be reported 
to the Ethics Committee and the Competent Authority of each concerned Member State 
within 15 days. This includes: 
· 
Single reports of expected serious adverse reactions with unexpected outcome.  
· 
An increase in the rate of occurrence of expected serious adverse reactions which is 
judged to be clinically relevant 
· 
Post-study SUSARs that occur after the patient has completed a clinical trial 
· 
New events related to the conduct of the trial or the development of the 
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The sponsor is responsible to ensure that the latest investigator's brochure is used as the 
source document for determining the expectedness of an SAE. 
7.4 RECORDING OF ADVERSE EVENTS 
The investigator is responsible for ensuring that all adverse events observed by the 
investigator or reported by subjects are properly recorded in the subjects’ medical records 
and the electronic case report form.  
The following adverse event attributes must be assigned by the investigator:  
· 
Adverse event term according to the NCI-CTC criteria Version 4.03 and verbatim 
term 
· 
Severity grade according to the NCI-CTC criteria Version 4.03 
· 
Start date and stop date (or date of last assessment) 
· 
Outcome 
· 
Causality to study drug and chemotherapy (to be assessed as either related or 
unrelated) 
· 
Any action taken 
Adverse events will be followed until they resolve to baseline or considered stable. It will be 
left to the investigator’s clinical judgment to determine whether an adverse event is related 
and of sufficient severity to require the subject’s removal from treatment or from the study. A 
subject may also voluntarily withdraw from treatment due to what he or she perceives as an 
intolerable adverse event. If either of these situations arises, the subject should be strongly 
encouraged to undergo an end-of-study assessment and be under medical supervision until 
symptoms cease or the condition becomes stable. 
Pre-existing diseases, when worsening during study therapy, have to be considered as 
adverse events. They can lead to serious adverse events, if the meet the criteria described in 
section 7.1.3. 
Intensity of adverse events will be graded using the National Cancer Institute Common 
Terminology Criteria for Adverse Events (CTCAE), version 4.03. If an adverse event occurs 
which is not described in the CTCAE version 4.03, the four-point scale below will be used. 
Pre-existing diseases, when worsening during study therapy, have to be considered as 
adverse events. They can lead to serious adverse events, if the meet the criteria described in 
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Intensity of adverse events will be graded using the National Cancer Institute Common 
Terminology Criteria for Adverse Events (CTCAE), version 4.03 . If an adverse event occurs 
which is not described in the CTCAE version 4.03, the four-point scale below will be used. 
Mild: 
Discomfort noticed but no disruption of normal daily activity 
Moderate: 
Discomfort sufficient to reduce or affect daily activity 
Severe: 
Inability to work or perform normal daily activity 
Life-threatening:
Represents an immediate threat to life 
 
7.5 LABORATORY TEST ABNORMALITIES 
Laboratory test results will be recorded on the laboratory results pages of the CRF. In the 
event of unexplained abnormal laboratory test values, the tests should be repeated 
immediately and followed up until they have returned to the normal range and/or an ade-
quate explanation of the abnormality is found. Laboratory test value abnormalities as such 
should not be reported on the AE page of the CRF as adverse events unless they are judged 
clinical significant by the investigator. 
7.6 PREGNANCY 
Female patients must be instructed to immediately inform the investigator if they become 
pregnant during the study. The study treatment must immediately be stopped and the patient 
must be withdrawn from the study. Pregnancies occurring up to 3 months after the 
completion of the last treatment cycle must also be reported to the investigator. The 
investigator must report all pregnancies within 24 hours to GSO. The investigator should 
counsel the patient; discuss the risks of continuing the pregnancy and the possible effects on 
the fetus. The patient should be monitored until the conclusion of the pregnancy. 
Pregnancy occurring in the partner of a patient participating in the study should also be 
reported to the investigator, the sponsor and the CRO. The partner should be counseled and 
followed as described above. 
7.7 ADVERSE DRUG REACTIONS WITH CONCOMITANT MEDICATION 
The investigators must be aware that for all concomitant medications the regulations of post-
marketing reporting for suspected adverse drug reactions apply, i.e. reporting to the 
marketing authorization holder or the local regulatory bodies. 
 
8 BIOSTATISTICAL ASPECTS 
 


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Based on the phase I design no sample size calculation will be performed, as sample size 
will be determined by the respective dose escalations.  
However, secondary endpoints will be analyzed. Overall response rate, and secondary 
resection rate will be summarized using frequency tables. For the time-to-event variables 
PFS and OS, the Kaplan-Meier method will be used to estimate the event free survival. 
Toxicity will be documented in a descriptive way.  
All secondary efficacy analyses will be based on the ITT population and the corresponding 
statistical testing results will be interpreted in the exploratory sense. 
 
8.1 SAMPLE SIZE ESTIMATION 
Due to the sequential nature of the traditional 6+3-design described in section 3.1, the exact 
number of patients in the trial is unknown. The number of evaluable patients that will be 
needed depends on the number of times the dose is escalated or possibly de-escalated and 
consequently varies between 6 and 27. 
8.2 ANALYSIS POPULATION 
Within this phase I trial all patients enrolled who started study treatment with Selinexor and 
mFOLFOX6 will be evaluable for statistical analysis. 
8.3 STATISTICAL ANALYSIS 
8.3.1 GENERAL STATISTICAL CONSIDERATIONS 
 
Statistical analysis is based on the International Conference on Harmonization (ICH) 
Guidelines “Statistical Principles for Clinical Trials”. 
 
Standard descriptive methods will be used to present all relevant data. All data recorded in 
the case report forms describing the sample, the efficacy and the safety will first be analyzed 
descriptively. Categorical data will be presented in contingency tables with frequencies and 
percentages. 
Continuous data will be summarized with at least the following: frequency (n), median, 
quartiles, mean, standard deviation (standard error), minimum and maximum. Summary 
tabulations will be provided. Time-to-event data will be analyzed by Kaplan-Meier methods.  
 
Number of patients with protocol deviations during the study and listings describing the 
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Safety analysis will be presented stratified by dose level. Since no other covariates of 
prognostic relevance are pre-specified within this protocol, an adjustment for co-variables will 
not be performed. Due to the small sample size, no site-specific analyses will be performed.  
 
In case that the trial is prematurely stopped after enrollment of merely six evaluable patients, 
no aggregated tables and figures will be presented and statistical analysis is restricted to 
data listings only.   
8.3.2 DEMOGRAPHICS AND BASELINE CHARACTERISTICS 
 
All demographic and clinical characteristics recorded at baseline will be submitted to 
descriptive analyses using descriptive statistics by means of listing, tables and figures, if 
applicable.  
8.3.3 PRIMARY VARIABLE 
 
The primary study endpoint is defined as the maximally tolerated dose of Selinexor in 
combination with a dose of mFOLFOX6 defined by means of the rate of patients 
experiencing dose-limiting toxicity. A patient is considered to have experienced a DLT if at 
least one of the toxicity listed in section 3.1.1 has occurred within 28 days from start of 
treatment. For descriptive purposes, each individual adverse event fulfilling the definition of a 
DLT will be listed by dose level and patient. 
The statistical decision strategy for dose (de-)escalation is outlined in section 3.1. 
8.3.4 SECONDARY VARIABLES 
 
Overall safety profile:  
The incidence of patients experiencing adverse events will be analyzed as follows:  
· 
All information recorded such as onset date, stop date, duration, maximum intensity, 
seriousness, relationship to study drug will be listed. 
· 
Adverse event tables will be produced presenting the total number of patients reporting 
at least one specific event and the maximum toxicity grade. Thus, patients reporting 
more than one episode of the same event are counted only once by the worst grade per 
patient. Tabulations consist of the number and percentages of patients involved per CTC 
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· 
Special tables will be displayed for severe and life threatening adverse events and for 
adverse events resulting in discontinuation of the trial or reduction of the study 
medication or death.  
· 
Additionally, analysis will be restricted to adverse events judged to be at least possibly 
related to study drug.  
· 
Furthermore, summary tables with patient identification will be presented. These tables 
provide the number and percentage of patients with adverse events and also includes the 
subject identification in the table. 
· 
Subset-tables will be provided for toxicity of special interest, i.e. ophthalmological events, 
thromboembolic events and bleeding.  
 
The above mentioned analyses will be presented for all (pooled) evaluable patients together 
and stratified by dose level. Furthermore, subset-tables will be presented for those adverse 
events occurring within 4 weeks after start of treatment in order to be consistent with the time 
span defined for DLT-evaluation. 
 
Safety laboratory parameters will be evaluated stratified by visit. For each parameter, the 
distribution over time as well as the mean values at baseline and changes from baseline will 
be computed and reported with descriptive statistics. Values outside normal ranges will be 
displayed and tabulated. In addition, for applicable laboratory parameters, NCI-CTCAE 
version 4.03 grades will be provided and incorporated in the patient laboratory listings. 
 
Response rate:  
Best response is defined as the best clinical response, as per RECIST version 1.1, 
documented during treatment phase. Patients without any documented tumor assessments 
are considered to have experienced a progressive disease, in case of therapy 
discontinuation due to progressive disease or early death (defined as death prior to first 
scheduled tumor assessment after start of treatment). The frequency distribution of response 
categories will be presented.  
In addition the response rate, i.e. the percentage of patients experiencing partial or complete 
response during study, will be presented.  
 
Progression-free survival:  
Progression-free survival is defined as the time from start of therapy to the first observation 
of disease progression or death due to any cause. If a patient has not progressed or died, 
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of progression-free survival will be estimated by Kaplan-Meier methods. 90% confidence 
limits for specific time points will be extracted together with their 90% confidence intervals.  
 
Due to sparse data, progression-free survival will merely presented on all evaluable patients; 
no dose level stratifications are planned.  
8.4 INTERIM AND FINAL ANALYSIS 
No formal interim analyses are planned. A continuous monitoring of both safety and efficacy 
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9 DATA QUALITY ASSURANCE 
 
Accurate and reliable data collection will be assured by verification and cross–check of the 
CRFs against the investigator’s records by the study monitor (source document verification), 
and the maintenance of a drug–dispensing log by the investigator. Data for this study will be 
recorded via CRF. It will be transcribed by the site from the source documents onto the CRF. 
Data are reviewed and checked for omissions, apparent errors, and values requiring further 
clarifications using computerized and manual procedures. Data queries requiring clarification 
are communicated to the site for resolution. Only authorized personnel will make corrections 
to the clinical database and an audit trail will document all corrections. 
 
 
 
 


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10 ETHICAL ASPECTS 
10.1 DECLARATION OF HELSINKI / GOOD CLINICAL PRACTICE 
The Declaration of Helsinki is the accepted basis for clinical study ethics, and must be fully 
followed and respected by all those engaged in research on human beings. Any exceptions 
must be justified and stated in the protocol. The latest version of the Declaration of Helsinki is 
available at www.wma.net. 
Additionally it is the responsibility of all those engaged in research on human beings to 
ensure that the study is performed in accordance with the international standards of Good 
Clinical Practice and according to all local laws and regulations concerning clinical studies. 
10.2 PATIENT INFORMATION AND INFORMED CONSENT 
It is the responsibility of the investigator to obtain written informed consent from each patient 
participating in this study, after an adequate explanation of the aims, importance, anticipated 
benefits, potential hazards and consequences of the study according to applicable local laws. 
Written informed consent must be obtained before any study-specific procedures are 
performed. It must be also explained to the patient that they are completely free to refuse to 
enter the study or to withdraw from it at any time, for any reason, without incurring any 
penalty or withholding of treatment on the part of the investigator.  
With the declaration of consent, the patient agrees to data about his/ her disease being 
recorded within the context of the clinical trial and that it may be transferred to the sponsor in 
pseudonymized form. 
The subject/ patient also agrees to allow the monitor/ auditor/ health authorities to verify the 
patient data collected against the subject’s/ patient’s original medical records for the purpose 
of source data verification.  
The informed consent form personally signed and dated by the patient must be kept on file 
by the investigator(s) and documented in the CRF and the subject’s medical records. The 
investigator must confirm with the sponsor/coordinating CRO that he/ she has obtained 
written informed consent. 
If new safety information results in significant changes to the risk/ benefit assessment, the 
consent form should be reviewed and updated if necessary. All patients (including those 
already being treated) should be informed of the new information and must give their written 
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If family doctors are to be informed of their patients’ participation in the clinical study, this 
should be mentioned in the consent form. 
 
10.3 INDEPENDENT ETHICS COMMITTEES AND REGULATORY AUTHORITIES 
10.3.1 APPROVAL OF THE STUDY BY THE REGULATORY AUTHORITY AND INDEPENDENT ETHICS 
COMMITTEES 
It is the responsibility of the sponsor to obtain and maintain independent approval from the 
applicable regulatory authority and a positive opinion from the competent ethics committees 
to conduct the study in accordance with local legal requirements and statutes.  
Indemnity insurance will be arranged for the trial subjects in accordance with the applicable 
local law. The sponsor provides appropriate insurance. 
10.3.2 NOTIFICATION OF THE STUDY 
The sponsor is responsible for notifying the competent regional authority about the study and 
all principal investigators at the participating investigational sites, if applicable by local law. 
10.3.3 OBLIGATION TO REPORT AND DOCUMENT 
The sponsor and the investigator are responsible for complying with the requirements for 
reporting and documentation in accordance with local legal requirements and statutes. 


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11 CONDITIONS FOR MODIFYING THE PROTOCOL 
 
Protocol modifications to ongoing studies must be made via amendment. The sponsor is 
responsible for obtaining independent approval for substantial amendments from the 
applicable regulatory authority and a positive opinion from the competent ethics committees 
in accordance with local legal requirements, statutes and the European Clinical Trial 
Directive. Approval must be obtained before any changes can be implemented, except for 
changes necessary in order to eliminate an immediate hazard to trial subjects or when the 
changes are non-substantial and involve only logistical or administrative aspects of the trial 
(e.g. change of telephone numbers). 


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12 STUDY DOCUMENTATION, CRFS AND RECORD-KEEPING 
12.1 INVESTIGATOR’S FILES / RETENTION OF DOCUMENTS 
The investigator must maintain adequate and accurate records to enable the conduct of the 
study to be fully documented and the study data to be subsequently verified. These docu-
ments should be classified into two separate categories: investigator’s study file and subject/ 
patient data. 
The investigator’s study file will contain all essential documents such as the protocol/ 
amendments, case report and query forms, patient information and informed consent form, 
ethics committee and regulatory authority approval, notification of the federal regulatory 
authority and competent regional authorities (if applicable), drug records, staff curriculum 
vitae and authorisation forms, and other appropriate documents/correspondence, etc. 
Patient data includes patient hospital/clinic records (e.g. medical reports, surgery reports 
appointment book, medical records, pathology and laboratory reports, ECG, EEG, X-ray, 
etc.), signed informed consent forms and patient screening and eligibility screening forms.  
The investigator must keep these two categories of documents on file for at least 15 years 
(or longer, as legally required, e.g. 20 years in Belgium) after completion or discontinuation of 
the study. The documents must be archived in a secure place and treated as confidential 
material.  
Should the investigator wish to assign the study records to another party or move them to 
another location, the sponsor must be notified in advance. 
If the investigator cannot guarantee this archiving requirement at the investigational site for 
any or all of the documents, special arrangements must be made between the investigator 
and the sponsor to store these in sealed containers outside of the site so that they can be 
returned sealed to the investigator in the event of a regulatory audit. Where source 
documents are required for the continued care of the patient, appropriate copies should be 
made for storing outside of the site. 
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12.2 SOURCE DOCUMENTS AND BACKGROUND DATA 
The investigator shall supply the sponsor on request with any required background data from 
the study documentation or clinic records. This is particularly important when case report 
forms are illegible or when errors in data transcription are suspected. In the event of special 
problems and/or governmental queries or requests for audit inspections, it is also necessary 
to have access to the complete study records, provided that patient confidentiality is 
protected. According to the standards of the data protection law, all data obtained in the 
course of a clinical study must be treated with discretion in order to guarantee the rights of 
the patient’s privacy. 
12.3 AUDITS AND INSPECTIONS 
This study may be audited by the sponsor, any person authorised by the sponsor, or the 
competent health authority in order to determine the authenticity of the recorded data and 
compliance with the study protocol.  
The investigator must be aware that source documents for this trial should be made available 
to appropriately qualified personnel working on behalf of the sponsor/monitor/auditor/health 
authority inspectors after appropriate notification for the purposes of source data verification 
and proper review of the study progress. The verification of the case report form data must 
be done via direct inspection of the source documents. The investigator agrees to comply 
with the sponsor and regulatory authority requirements regarding the auditing of the study. 
All materials used in clinical studies are subjected to quality control. 
12.4 CASE REPORT FORMS 
For each patient enrolled, an electronic case report form must be completed and signed by 
the principal investigator or an authorised delegate from the study team. This also applies to 
records for those patients who fail to complete the study. If a patient withdraws from the 
study, the reason must be noted in the CRF. If a patient is withdrawn from the study because 
of a treatment-limiting adverse event, thorough efforts should be made to document the 
outcome clearly. 
 


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13 MONITORING THE STUDY 
 
The monitor is responsible for familiarising the investigator(s) and the entire centre staff 
involved in the study with all study procedures, including the administration of the study drug. 
The monitor will visit the clinical study centre before the first patient has been enrolled 
(initiation visit). During the study, the monitor will visit the site regularly to check the 
completeness of patient records, the accuracy of entries on the CRFs (source data 
verification), the adherence to the protocol to Good Clinical Practice, the progress of 
enrollment, and to ensure that study drug is being stored, dispensed, and accounted for 
according to specifications.  
Key study personnel must be available to assist the monitor during these visits. The 
investigator (or his/her deputy) agrees to cooperate with the monitor to ensure that any 
problems detected in the course of these monitoring visits are resolved. 


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14 CONFIDENTIALITY OF TRIAL DOCUMENTS AND PATIENT RECORDS 
 
The investigator and the sponsor (or designated person) must ensure that all data obtained 
in the course of a clinical study is treated with discretion in order to guarantee the rights of 
the patient’s privacy, according to the standards of the data protection law. CRFs or other 
documents should be submitted to the sponsor in pseudonymised form. The investigator 
should keep a patient identification log showing codes and names. The investigator should 
maintain documents not intended for submission to the sponsor, e.g. patients’ written 
consent forms, in the strictest confidence. 


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15 STUDY REPORT AND PUBLICATION POLICY  
 
This study will be entered into a clinical trial protocol registry and clinical results database. 
The sponsor is responsible for the timely reporting of study data. An integrated clinical study 
report (CSR) has to be completed one year after the end of the study (whether completed or 
prematurely terminated). The report has to be approved by the responsible specialist chosen 
by the sponsor, the project manager of the CRO, the statistician and the coordinating 
investigator by provision of their signatures. In this multi-center study, the main publication 
will be a full publication of all data from all sites. Any publication of the results, either in part 
or in whole (abstracts in journals, oral presentations, etc.) by investigators or their 
representatives will require a pre-submission review by the sponsor and the coordinating 
investigator. The coordinating investigator will be the first author. The senior author of the 
study will be the last author. The remaining positions will be based on recruitment, good data 
quality and scientific input to the study. The final author list will be a joint agreement between 
the coordinating investigator and the sponsor. For all other publications, the order of the 
authors will be determined according to recruitment, data quality and significant scientific 
input to the study, after consulting the coordinating investigator. 
 


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16 APPENDICES 
 
Appendix 1: 
Overview of current CRC studies 
Appendix 2:  Definitions According to ICH Topic E2A Clinical Safety Data Management, 
Definitions and Standards for Expedited Reporting, (CPMP/ICH/377/95) 
Appendix 3: 
ECOG Performance Status 
Appendix 4: 
Cockroft-Gault Formula  
Appendix 5:  National Cancer Institute Common Terminology Criteria for Adverse Events 
(CTCAE) version 4.0


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16.1 APPENDIX 1 – OVERVIEW OF CRC STUDIES 
Authors 
Indication 
Treatment 
line 
Number of 
patients 
enrolled 
(evaluable) 
Drug 
ORR (CR 
/ PR) 
SD 
PFS 
(months) 
OS 
(months) 
Saltz et al.11 
 metastatic CRC 
first-line 
699 
FOLFOX4 or XELOX plus 
bevacizumab 
38% 
(-) 
9,4 
21,3 
701 
FOLFOX4 or XELOX plus 
placebo 
38% 
(-) 
8 
19,9 
Hurwitz et al.12 
mCRC 
first line 
411 (-) 
placebo plus bolus- IFL  
34,80% 
(-) 
6,2 
15,6 
402 (-) 
bevacizumab plus bolus- IFL  
44,80% 
(-) 
10,6 
20,3 
Bennouna et 
al.13 
metastatic CRC 
second-line 
53 (-) 
bevacizumab plus FOLFIRI, 
FOLFOX, irinotecan or XELIRI  
32% 
55% 
6,5 
19,3 
Bennouna et 
al.14 
mCRC 
second-line 
409 (-) 
bevacizumab + Oxaliplatin-or 
Irinotecan-based chemotherapy 
(-) 
(-) 
5,7 
11,2 
411 (-) 
Oxaliplatin-or Irinotecan-based 
chemotherapy alone 
(-) 
(-) 
4,1 
9,8 
Van Cutsem et 
al.15 
unresectable mCRC 
first-line 
1965 (1914) 
bevacizumab plus 5-
FU/LV+oxaliplatin or 
irinotecan+5-FU/LV or 
capecitabine+oxaliplatin or 
monotherapy 
44,80% 
(-) 
10,8 
22,7 
van Cutsem et 
al.16 
mCRC 
first-line 
599 (533 
KRAS 
population) 
FOLFIRI 
38,5% 
(39,7% 
WT-
KRAS) 
46,2% 
(46,3% 
WT-
KRAS) 
8,1 (9,1 
WT-KRAS) 
18,7 (20,0 
WT-KRAS) 
599 (530 
KRAS 
population) 
Cetuximab plus FOLFIRI 
46,8% 
(57,3% 
WT-
KRAS) 
37,9% 
(31,6% 
WT-
KRAS) 
8,4 (9,9 
WT-KRAS) 
20,2 (23,5 
WT-KRAS) 
Bokemeyer et 
al.17 
mCRC 
first-line 
169 (113 
KRAS 
population) 
cetuximab plus FOLFOX4 
48% (61% 
WT-
KRAS) 
41% 
(31% 
WT-
KRAS) 
7,3 (7,7 
WT-KRAS) 
(-) 
168 (120 
KRAS 
population) 
FOLFOX4 alone 
42% (37%  
WT-
KRAS) 
39% 
(41% 
WT-
KRAS) 
7,2 (7,2 
WT-KRAS) 
(-) 


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Authors 
Indication 
Treatment 
line 
Number of 
patients 
enrolled 
(evaluable) 
Drug 
ORR (CR 
/ PR) 
SD 
PFS 
(months) 
OS 
(months) 
Authors 
Indication 
Treatment 
line 
Number of 
patients 
enrolled 
(evaluable) 
Drug 
ORR (CR 
/ PR) 
SD 
PFS 
(months) 
OS 
(months) 
Carrato et al.18 
wild-type KRAS 
mCRC 
second-line 
53 (-) 
panitumumab plus irinotecan 
 23% (PR 
12) 
41% 
4,5 
15,1 
Douillard et 
al.19 
mCRC 
first-line 
1183 (-) 
panitumumab-FOLFOX4 
55% (WT-
KRAS) 
 40% 
(mutant) 
(-) 
9,6 (WT-
KRAS) 
23,9 (WT-
KRAS) 15,5 
(mutant) 
FOLFOX4 alone 
48% (WT-
KRAS)  
40% 
(mutant) 
(-) 
8 (WT-
KRAS) 
19,7 (WT-
KRAS) 19,3 
(mutant) 
Peeters et al.20 
mCRC 
second line  
1186 (-) 
panitumumab-FOLFIRI 
36% (WT-
KRAS) 
(-) 
6,7 (WT-
KRAS) 
14,5 (WT-
KRAS)  
FOLFIRI 
10% (WT-
KRAS)  
(-) 
4,9 (WT-
KRAS) 
12,5 (WT-
KRAS)  
Saltz et al.21 
 metastatic CRC 
first-line 
124 (118) 
mFOLFOX6 plus bevacizumab 
52% 
35% 
(12-
months 
PFS 45%) 
21 
123 (121) 
5-FU, leucovorin, bevacizumab, 
cetuximab (FOLF-CB) 
41% 
42% 
(12-
months 
PFS 32%) 
19,5 
Tol et al.22 
 metastatic CRC 
first-line 
124 (118) 
XELOX plus bevacizumab 
50% 
44% 
10,7 
20,3 
123 (121) 
XELOX plus bevacizumab and 
cetuximab 
53% 
42% 
9,4 
19,4 
Grothey et 
al.23 
Metastatic CRC 
(progressed after all 
standard therapy) 
  
505 (-) 
Regorafenib +BSC 
1% (0+5 
patients)  
(-) 
59 days 
6,4 
255 (-) 
Placebo  +BSC 
0.4% (0+1 
pt)  
(-) 
52 days 
5 


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Authors 
Indication 
Treatment 
line 
Number of 
patients 
enrolled 
(evaluable) 
Drug 
ORR (CR 
/ PR) 
SD 
PFS 
(months) 
OS 
(months) 
Schultheis et 
al.24 
metastatic CRC 
first- or 
second-line 
45 (38) 
FOLFOX or FOLFIRI plus 
regorafenib 
18,40% 
71% 
4,0 (119 
days)  
(-) 
Tabernero et 
al.25 
mCRC 
first-line 
198 (-) 
sorafenib plus mFOLFOX6 
45% 
(-) 
9,1 
17,8 (535 
days) 
placebo plus mFOLFOX6 
61% 
(-) 
8,7 
18,4 (552 
days) 
Van Cutsem et 
al. 26 
previously treated 
metastatic colorectal 
adenocarcinoma 
second line  
855 (-) 
PTK787/ZK 222584 plus 
FOLFOX4 
(-) 
(-) 
5,6 
13,1 
placebo plus FOLFOX4 
(-) 
(-) 
4,2 
11,9 
Schmoll et 
al.27 
advanced mCRC 
first-line 
709 (-) 
mFOLFOX6 plus cediranib 
46% 
(-) 
9,9 
22,8 
713 (-) 
mFOLFOX6 plus bevacizumab 
47% 
(-) 
10,3 
21,3 
Van Cutsem et 
al. (J Clin 
Oncol. 2012 
28) 
mCRC, previously 
treated with 
oxaliplatin 
second line  
612 (-) 
aflibercept plus FOLFIRI 
19,80% 
(-) 
6,9 
13,5 
614 (-) 
placebo plus FOLFIRI 
11% 
(-) 
4,7 
12,1 
(-) 
not assessed 
 
 
 
 
 
 
 


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16.2 APPENDIX 2 – DEFINITIONS ACCORDING TO ICH TOPIC E2A CLINICAL SAFETY DATA 
MANAGEMENT, DEFINITIONS AND STANDARDS FOR EXPEDITED REPORTING, 
(CPMP/ICH/377/95) 
An adverse event is any untoward medical occurrence in a patient or clinical investigation 
subject who has been administered a pharmaceutical product, and which does not 
necessarily have to have a causal relationship with this treatment. 
Adverse reactions are defined as all untoward and unintended responses to an 
investigational medicinal product related to any dose administered. The phrase "responses to 
a medicinal products" means that a causal relationship between a medicinal product and an 
adverse event is at least a reasonable possibility, i.e., the relationship cannot be ruled out. 
A serious adverse event or serious adverse reaction is any experience that suggests a signi-
ficant hazard, contraindication, side effect or precaution. It is any adverse event that at any 
dose fulfils at least one of the following criteria: 
· 
is fatal (results in death) (NOTE: Death is an outcome, not an event) 
· 
is life-threatening (NOTE: The term “life-threatening” refers to an event in which the 
patient was at immediate risk of death at the time of the event; it does not refer to an 
event which could hypothetically have caused a death had it been more severe) 
· 
required in-patient hospitalisation or prolongation of existing hospitalisation 
· 
results in persistent or significant disability/incapacity 
· 
is a congenital anomaly/birth defect 
· 
is medically significant or requires intervention to prevent one or other of the outcomes 
listed above 
Medical and scientific judgement should be exercised in deciding whether expedited 
reporting to the sponsor is appropriate in other situations, such as important medical events 
that may not be immediately life-threatening or result in death or hospitalisation but may 
jeopardise the patient or may require intervention to prevent one of the outcomes listed in the 
definitions above. These situations should also usually be considered serious. 
Examples of such events are intensive treatment in A&E or at home for allergic bronchospasm; 
blood dyscrasias or convulsions that do not result in hospitalisation, or development of drug 
dependency or drug abuse. 
An unexpected adverse event, the nature or severity of which is not consistent with the 
applicable product information (e.g., Investigator's Brochure for an unapproved investigational 
medicinal product) 


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Causality is initially assessed by the investigator. With respect to the obligation to report and 
document (regulatory authorities, ethics committees and other investigators) serious adverse 
events, causality can be one of two possibilities: 
· 
No (unrelated; equals not drug-related) 
· 
Yes (remotely, possibly or probably drug-related) 
All adverse events not assessed as definitively “not drug-related” by the investigator will be 
considered as adverse drug reactions. 
A suspected unexpected serious adverse reaction (SUSAR) is a serious adverse reaction 
whose nature or severity is not consistent with the applicable product information. 
It is important that the severity of an adverse event is not confused with the seriousness of 
the event. For example, vomiting which persists for many hours may be severe, but is not 
necessarily a serious adverse event. On the other hand, stroke which results in only a limited 
degree of disability may be considered a mild stroke, but would be a serious adverse event. 
A serious adverse event occurring during the study or which comes to the attention of the 
investigator within three weeks of stopping the treatment or during the protocol-defined 
follow-up period, if this is longer, must be reported, whether considered treatment-related or 
not. In addition, serious adverse events occurring after this time should be reported if 
considered related to test “drug”. 
Such preliminary reports will be followed by detailed descriptions later that will include copies 
of hospital case reports, autopsy reports and other documents. 
For serious adverse events, the following must be assessed and recorded on the adverse 
events page of the case report form: intensity, relationship to test substance, action taken, 
and outcome to date. 
The obligation to document and report must be adhered to according to the national and 
international laws and regulations.  
For contact details and fax no. for SAE and pregnancy reporting, please refer to page 11. 
 
 
 
 
 
 
 


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16.3 APPENDIX 3 – ECOG PERFORMANCE STATUS 
GRADE 
SCALE 
0 
Fully active, able to carry out all pre-disease performance without restriction  
1 
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature, e.g., light housework, office work 
2 
Ambulatory and capable of all self-care, but unable to carry out work activities. 
Up and about more than 50% of waking hours.  
3 
Capable of only limited self-care, confined to bed or chair more than 50% of 
waking hours 
4 
Completely disabled. Cannot carry out any self-care. Totally confined to bed or 
chair. 
5 
Dead  
 


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16.4 APPENDIX 4 – COCKROFT-GAULT FORMULA 
 
 
 
Calculated CLCR (ml/min) = [(140 – subject’s age in years) x subject’s actual body weight in kilograms] * 
 
 
 
 
 
 
72 x subject’s serum creatinine (in mg/dL) 
 
*: x 0.85 for females 
 
 
 
 
Calculated CLCR (ml/min) = [(140 – subject’s age in years) x subject’s actual body weight in kilograms] x K* 
 
 
 
 
 
 
subject’s serum creatinine (in µmol/L) 
 
K*: 1.23 for males, 1.05 for females 
 
 
 
 


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16.5 APPENDIX 5 – NCCN PRACTICE GUIDELINES IN ONCOLOGY: NAUSEA/VOMITING 
 
 
 
Reproduced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Antiemesis V.2.2014. © 2014 
National Comprehensive Cancer Network, Inc. All rights reserved. The NCCN Guidelines® and illustrations herein may not be reproduced in any 
form for any purpose without the express written permission of the NCCN. To view the most recent and complete version of the NCCN Guidelines
go online to www.nccn.org. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, NCCN GUIDELINES®, and all other NCCN Content 
are trademarks owned by the National Comprehensive Cancer Network, Inc. 


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Reproduced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Antiemesis V.2.2014. © 2014 
National Comprehensive Cancer Network, Inc. All rights reserved. The NCCN Guidelines® and illustrations herein may not be reproduced in any 
form for any purpose without the express written permission of the NCCN. To view the most recent and complete version of the NCCN Guidelines, 
go online to www.nccn.org. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, NCCN GUIDELINES®, and all other NCCN Content 
are trademarks owned by the National Comprehensive Cancer Network, Inc. 


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Reproduced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Antiemesis V.2.2014. © 2014 
National Comprehensive Cancer Network, Inc. All rights reserved. The NCCN Guidelines® and illustrations herein may not be reproduced in any 
form for any purpose without the express written permission of the NCCN. To view the most recent and complete version of the NCCN Guidelines
go online to www.nccn.org. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, NCCN GUIDELINES®, and all other NCCN Content 
are trademarks owned by the National Comprehensive Cancer Network, Inc. 


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Current version: Version 1.1, 2015.01.22 
 
 
 
Reproduced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Antiemesis V.2.2014. © 2014 
National Comprehensive Cancer Network, Inc. All rights reserved. The NCCN Guidelines® and illustrations herein may not be reproduced in any 
form for any purpose without the express written permission of the NCCN. To view the most recent and complete version of the NCCN Guideline
go online to www.nccn.org. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, NCCN GUIDELINES®, and all other NCCN Content
are trademarks owned by the National Comprehensive Cancer Network, Inc. 


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16.6 APPENDIX 6- RESPONSE CRITERIA  
 
 
 
 


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16.7 APPENDIX 7- LENS OPACITIES CLASSIFICATION SYSTEM III (LOCS III) 
If a cataract is seen during the slit lamp examination to document lens clarity, the cataract 
will be graded according to the LOCS III. 


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REFERENCES 
 
1 
Siegel, R., Ward, E., Brawley, O. & Jemal, A. Cancer statistics, 2011: the impact of 
eliminating socioeconomic and racial disparities on premature cancer deaths. CA: a 
cancer journal for clinicians 61, 212-236, doi:10.3322/caac.20121 (2011). 
2 
Tournigand, C. et al. FOLFIRI followed by FOLFOX6 or the reverse sequence in 
advanced colorectal cancer: a randomized GERCOR study. Journal of clinical 
oncology : official journal of the American Society of Clinical Oncology 22, 229-237, 
doi:10.1200/JCO.2004.05.113 (2004). 
3 
Colucci, G. et al. Phase III randomized trial of FOLFIRI versus FOLFOX4 in the 
treatment of advanced colorectal cancer: a multicenter study of the Gruppo 
Oncologico Dell'Italia Meridionale. Journal of clinical oncology : official journal of the 
American Society of Clinical Oncology 23, 4866-4875, doi:10.1200/JCO.2005.07.113 
(2005). 
4 
Saltz, L. B. et al. Irinotecan plus fluorouracil and leucovorin for metastatic colorectal 
cancer. Irinotecan Study Group. The New England journal of medicine 343, 905-914, 
doi:10.1056/NEJM200009283431302 (2000). 
5 
Douillard, J. Y. et al. Irinotecan combined with fluorouracil compared with fluorouracil 
alone as first-line treatment for metastatic colorectal cancer: a multicentre 
randomised trial. Lancet 355, 1041-1047 (2000). 
6 
de Gramont, A. et al. Leucovorin and fluorouracil with or without oxaliplatin as first-
line treatment in advanced colorectal cancer. Journal of clinical oncology : official 
journal of the American Society of Clinical Oncology 18, 2938-2947 (2000). 
7 
Prenen, H., Vecchione, L. & Van Cutsem, E. Role of targeted agents in metastatic 
colorectal cancer. Targeted oncology 8, 83-96, doi:10.1007/s11523-013-0281-x 
(2013). 
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