Clinical trial NCT02352831
Conditions: Pancreatic Cancer Cancer of Pancreas Cancer of the Pancreas Pancreas Cancer
Sponsor: Washington University School of Medicine
Start date: 2015-08-31; Completion date: 2018-10-19
Enrollment: 16 participants; Allocation: NON_RANDOMIZED; Intervention model: SINGLE_GROUP

Brief summary:
There are two parts to this study: the goal of the first part of the study is to find the best dose of tosedostat when given in combination with capecitabine. The goal of the second part of the study is to look at how participants respond to treatment with tosedostat and capecitabine.

Detailed description:

Arms: arm 1: * The phase I study will be conducted in the standard 6-patient-per-cohort dose de-escalation fashion.
* Tosedostat by mouth daily Days 1-21 of each 21-day cycle. Dose Level 0 (starting dose) = 120 mg PO daily and Dose Level -1 = 60 mg PO daily. All 6 patients in the Phase 1 received 120 mg starting dose of tosedostat.
* Capecitabine 1000 mg/m\^2 by mouth BID Days 1-14 of each 21-day cycle
* Fresh tissue biopsy: Patients who have a partial response at the end of cycle 2 will be required to undergo biopsy if deemed safe for the patient and tissue is feasible to obtain. arm 2: * Tosedostat (dose determined by Phase I portion of study) by mouth daily Days 1-21 of each 21-day cycle
* Capecitabine by mouth BID Days 1-14 of each 21-day cycle
Interventions: intervention 1: Tosedostat intervention 2: Capecitabine intervention 3: Fresh tissue biopsy
Intervention descriptions: intervention 1: None intervention 2: None intervention 3: Patients who have a partial response at the end of cycle 2 will be required to undergo biopsy if deemed safe for the patient and tissue is feasible to obtain.

Protocol documents:
Prot_SAP_000.pdf: 
Protocol Version: 07/11/17 
 
Page 1 of 57 
 
 
Phase I/II Study Combining Tosedostat with Capecitabine in Patients with Advanced or 
Metastatic Pancreatic Adenocarcinoma 
 
Washington University School of Medicine 
Division of Oncology 
660 South Euclid Avenue, Campus Box 8056 
St. Louis, MO  63110 
 
Protocol #: 201503074  
Version Date: 07/11/17 
 
Principal Investigator: 
 
Andrea Wang-Gillam, M.D., Ph.D. 
Phone:  (314) 362-5740 
E-mail:  awang-gillam@wustl.edu 
 
Sub-Investigators 
 
 
 
Modality 
Manik Amin, M.D. 
 
 
 
Medical Oncology 
Eric Knoche, M.D. 
 
 
 
Medical Oncology 
Kian-Huat Lim, M.D., Ph.D.  
            Medical Oncology 
Michael Naughton, M.D. 
 
 
Medical Oncology 
Peter Oppelt, M.D. 
 
 
 
Medical Oncology 
Haeseong Park, M.D.   
 
 
Medical Oncology 
Joel Picus, M.D. 
 
 
 
Medical Oncology 
Alex Politsmakher, M.D. 
 
 
Medical Oncology 
Caron Rigden, M.D.  
 
 
Medical Oncology 
Rama Suresh, M.D. 
 
 
 
Medical Oncology 
Benjamin R. Tan, M.D. 
 
 
Medical Oncology 
Esther Lu, Ph.D. 
 
 
 
Biostatistics  
 
Study Drug(s): 
 
Tosedostat 
 
 
 
 
Capecitabine (Xeloda) 
 
 
 
IND #: 
125615 
 
ClinicalTrials.gov #: 
NCT02352831 
 
CONFIDENTIAL 
The information contained in this document is regarded as confidential and, except to the extent necessary to 
obtain informed consent, may not be disclosed to another party unless law or regulations require such 
disclosure.  Persons to whom the information is disclosed must be informed that the information is 
confidential and may not be further disclosed by them 
 
 


Protocol Version: 07/11/17 
 
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Phase I/II Study Combining Tosedostat with Capecitabine in Patients with Advanced or 
Metastatic Pancreatic Adenocarcinoma 
 
Protocol Revision History 
 
Initial Approval Version 
 
 
 
 
 
 
03/12/2015 
Amendment #1 Version 
 
 
 
 
 
 
05/15/2015 
Amendment #2 Version 
 
 
 
 
 
 
10/07/2015 
Amendment #3 Version 
 
 
 
 
 
 
07/05/2016 
Amendment #4 Version 
 
 
 
 
 
 
09/16/2016 
Amendment #5 Version 
 
 
 
 
 
 
07/11/2017 


Protocol Version: 07/11/17 
 
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Phase I/II Study Combining Tosedostat with Capecitabine in Patients with Advanced or 
Metastatic Pancreatic Adenocarcinoma 
 
 
SCHEMA 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
     
 
 
Dose De-Escalation Schedule 
Dose Level 
Tosedostat (PO daily) 
Days 1-21 
Capecitabine (PO BID)  
Days 1-14 
Level 0 
(Starting dose) 
120 mg 
1000 mg/m2 
Level -1 
60 mg 
 
 
Treatment Plan 
 
Phase I 
Tosedostat daily(dosing schedule below) Days 1-21 
with capecitabine 1000 mg/m2 PO BID Days 1-14 of 
each 21-day cycle 
 
Phase II 
Tosedostat PO daily (dose determined during Phase 
I) Days 1-21 with capecitabine 1000 mg/m2 PO BID 
Days 1-14 of each 21-day cycle 
 
 
Patients to continue on treatment as long as the 
regimen is tolerated and the patient does not meet 
discontinuation criteria.  Patient will be assessed 
with CT scans after every 2 cycles.  
Eligible Patients 
 
 Histologically or cytologically confirmed pancreatic adenocarcinoma 
 Metastatic or inoperable pancreatic adenocarcinoma 
 Previously received a gemcitabine-based regimen  
 Radiographically measurable or evaluable disease 
 Eastern Cooperative Oncology Group (ECOG) performance status 0-2 


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Glossary of Abbreviations 
 
AE 
Adverse event 
ALT (SGPT) 
Alanine transaminase (serum glutamate pyruvic transaminase) 
AML 
Acute myeloid leukemia 
ANC 
Absolute neutrophil count 
AST (SGOT) 
Aspartate transaminase (serum glutamic oxaloacetic transaminase) 
B-HCG 
Beta human chorionic gonadotropin  
BID 
Bis in die (twice a day) 
BSC 
Best supportive care 
CBC 
Complete blood count 
CFR 
Code of Federal Regulations 
CIVI 
Continuous IV infusion 
CMP 
Complete metabolic panel 
CR 
Complete response 
CRF 
Case report form 
CRP 
C-reactive protein 
CT 
Computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTEP 
Cancer Therapy Evaluation Program 
DLTs 
Dose Limiting Toxicities 
DNA 
deoxyribonucleic acid 
DPD 
Dihydropyrimidine dehydrogenase 
DSM 
Data and Safety Monitoring  
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EDTA 
ethylenediaminetetraacetic acid 
FDA 
Food and Drug Administration 
FFPE 
Formalin-fixed paraffin-embedded 
FWA 
Federal wide assurance 
HIV 
Human Immunodeficiency Virus 
HRPO 
Human Research Protection Office (IRB) 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
IULN 
Institutional upper limit of normal 
IV 
Intravenous 
KPS 
Karnofsky performance score 
LVEF 
Left ventricular ejection fraction 
MM 
Multiple myeloma 
mOS 
Median overall survival 
MRI 
Magnetic resonance imaging 
MTD 
Maximum tolerated dose 


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MUGA 
Multi-gated acquisition scan 
NCCN 
National Cancer Center Network 
NCI 
National Cancer Institute 
NIH 
National Institutes of Health 
NSCLC 
Non-small cell lung cancer 
OHRP 
Office of Human Research Protections  
ORR 
Overall response rate 
OS 
Overall survival 
PD 
Progressive disease 
PFS 
Progression-free survival 
PI 
Principal investigator 
PK 
Pharmacokinetic 
PO 
Per os (by mouth) 
PR 
Partial response 
QASMC 
Quality Assurance and Safety Monitoring Committee 
RECIST 
Response Evaluation Criteria in Solid Tumors (Committee) 
RNA 
Ribonucleic acid 
RP2D 
Recommended phase II dose 
rt-PCR 
Reverse transcriptase polymerase chain reaction 
SAE 
Serious adverse event 
SCC 
Siteman Cancer Center 
SD 
Stable disease 
TTP 
Time to progression 
UPN 
Unique patient number 
 
 


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Table of Contents 
SCHEMA ........................................................................................................................................ 3 
1.0 
BACKGROUND AND RATIONALE ................................................................................ 8 
1.1 
Metastatic Pancreatic Adenocarcinoma ........................................................................... 8 
1.2 
First-Line Therapy for Inoperable or Metastatic Pancreatic Adenocarcinoma ................ 8 
1.3 
Second-line Therapy for Inoperable or Metastatic Pancreatic Adenocarcinoma ............. 9 
1.4 
Study Rationale .............................................................................................................. 11 
1.5 
Correlative Studies Background..................................................................................... 12 
2.0 
OBJECTIVES .................................................................................................................... 12 
2.1 
Primary Objectives ......................................................................................................... 12 
2.2 
Secondary Objectives ..................................................................................................... 12 
2.3 
Exploratory Objectives ................................................................................................... 13 
3.0 
PATIENT SELECTION .................................................................................................... 13 
3.1 
Inclusion Criteria ............................................................................................................ 13 
3.2 
Exclusion Criteria ........................................................................................................... 14 
3.3 
Inclusion of Women and Minorities ............................................................................... 15 
4.0 
REGISTRATION PROCEDURES ................................................................................... 15 
4.1 
Confirmation of Patient Eligibility ................................................................................. 15 
4.2 
Patient Registration in the Siteman Cancer Center OnCore Database ........................... 16 
4.3 
Assignment of UPN ....................................................................................................... 16 
5.0 
TREATMENT PLAN ........................................................................................................ 16 
5.1 
Premedication Administration ........................................................................................ 16 
5.2 
Agent Administration ..................................................................................................... 16 
5.3 
Dose De-Escalation Schema .......................................................................................... 17 
5.4 
Phase II Treatment Plan ................................................................................................. 17 
5.5 
Definition of RP2D, DLT, Dose De-Escalation Criteria, and Toxicity, Response, and 
DLT Evaluations ....................................................................................................................... 17 
5.6 
General Concomitant Medication and Supportive Care Guidelines .............................. 19 
5.7 
Women of Childbearing Potential .................................................................................. 19 
5.8 
Duration of Therapy ....................................................................................................... 20 
5.9 
Duration of Follow-up .................................................................................................... 20 
6.0 
DOSE DELAYS/DOSE MODIFICATIONS .................................................................... 21 
6.1 
Tosedostat Dose Reduction Table .................................................................................. 21 
6.2 
Capecitabine Dose Reduction Table .............................................................................. 23 
6.3 
Stopping Rule for Excess Toxicity ................................................................................. 24 
7.0 
REGULATORY AND REPORTING REQUIREMENTS ............................................... 24 
7.1 
Definitions ...................................................................................................................... 24 
7.2 
Reporting to the Human Research Protection Office (HRPO) at Washington University
 
………………………………………………………………………………………….26 
7.3 
Reporting to the Quality Assurance and Safety Monitoring Committee (QASMC) at 
Washington University .............................................................................................................. 26 
7.4 
Reporting to the FDA ..................................................................................................... 27 
7.5 
Reporting to CTI BioPharma, Inc. ................................................................................. 27 
7.6 
Timeframe for Reporting Required Events .................................................................... 28 
8.0 
PHARMACEUTICAL INFORMATION .......................................................................... 28 
8.1 
Tosedostat ....................................................................................................................... 28 


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8.2 
Capecitabine (Xeloda) .................................................................................................... 29 
9.0 
CORRELATIVE STUDIES .............................................................................................. 30 
9.1 
Proteomic samples .......................................................................................................... 30 
9.2 
Tumor Specimen Collection ........................................................................................... 31 
9.3 
Pharmacokinetic Studies ................................................................................................ 33 
10.0 STUDY CALENDAR ....................................................................................................... 34 
11.0 DATA SUBMISSION SCHEDULE ................................................................................. 35 
12.0 MEASUREMENT OF EFFECT........................................................................................ 35 
12.1 Antitumor Effect – Solid Tumors ................................................................................... 35 
12.2 Disease Parameters ......................................................................................................... 35 
12.3 Methods for Evaluation of Measurable Disease ............................................................ 36 
12.4 Response Criteria ........................................................................................................... 39 
13.0 DATA AND SAFETY MONITORING ............................................................................ 41 
14.0 STATISTICAL CONSIDERATIONS............................................................................... 42 
14.1 Sample Size .................................................................................................................... 42 
14.2 Data Analysis ................................................................................................................. 42 
14.3 Interim Analysis ............................................................................................................. 43 
14. 
REFERENCES .................................................................................................................. 44 
APPENDIX A: ECOG Performance Status Scale ........................................................................ 46 
APPENDIX B: PATIENT’S MEDICATION DIARY ................................................................. 47 
APPENDIX C: List of QT Prolonging Medications..................................................................... 48 
APPENDIX D: CTI SAE form ....................................................................................................... 0 
 
 


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1.0 
BACKGROUND AND RATIONALE 
 
1.1 
Metastatic Pancreatic Adenocarcinoma 
 
Metastatic pancreatic adenocarcinoma has a dismal prognosis, with a median overall 
survival of less than one year (1).  According to the American Cancer Society, there were 
an estimated 45,220 new cases of pancreatic cancer in 2013 with 38,460 deaths (1). 
Despite comprising only 3% of all new cancer diagnoses, pancreatic cancer remains the 
fourth most common cause of cancer death, and it is expected to rise to the second most 
common cause of death by 2030. Unfortunately, pancreatic cancers are typically 
diagnosed at advanced stages when the only available treatments are palliative; around 
40% of patients are found to have metastatic disease at the time of diagnosis. Recent 
advances using combination chemotherapies have extended the overall survival (OS) of 
patients with metastatic disease, but only by about 6 months (to one year) (2), still 
making pancreatic adenocarcinoma one of the most deadly solid malignancies. 
   
1.2 
First-Line Therapy for Inoperable or Metastatic Pancreatic Adenocarcinoma 
 
For over 40 years, until the approval of gemcitabine in 1997, fluorouracil-based 
chemotherapy was the mainstay of treatment for pancreatic adenocarcinoma despite mean 
survival rates of less than 6 months (3).  Gemcitabine was approved after it was shown to 
be superior to 5-FU in terms of clinical benefit. In a randomized controlled trial (4), 126 
patients with advanced pancreatic cancer were randomized to receive either gemcitabine 
at 1000 mg/m2 weekly for 7 weeks followed by one week off, then on Days 1, 8, and 15 
of a 28-day cycle, or weekly 5-FU at 600 mg/m2. The primary endpoint in this trial was 
clinical benefit, which was defined by pain score, Karnofsky performance score (KPS), 
and body weight. Not only did patients receiving gemcitabine have a better clinical 
benefit rate (23.8% vs. 4.2%; p=0.0022), but gemcitabine-treated patients had a 
statistically better median overall survival (mOS) (5.65 vs. 4.41 months; p=0.0025) and 
overall one year survival rate (18% vs. 2%; p=0.0025).  
 
Combining gemcitabine with nab-paclitaxel (nanoparticle albumin bound paclitaxel) 
improved overall survival compared to gemcitabine alone. In a phase III randomized, 
open-label, multicenter trial (MPACT), 861 untreated patients with metastatic pancreatic 
cancer were randomized to receive gemcitabine plus nab-paclitaxel or gemcitabine alone 
(5).  mOS, progression-free survival (PFS), and tumor response rates were significantly 
improved in the combination group compared to gemcitabine alone (8.5 vs. 6.7 months, 
p<0.001; 5.5 vs. 3.7 months, p<0.001; 23% vs 7%, p<0.001, respectively). 
 
In 2011, combination chemotherapy with drugs other than gemcitabine in metastatic 
pancreatic cancer also showed a meaningful survival benefit over single agent 
gemcitabine (2). The ACCORD phase II/III trial studied 342 patients with previously 
untreated metastatic pancreatic cancer who were randomized to receive FOLFIRINOX 
(14-day cycles of 5-FU at 400 mg/m2 on Day 1 followed by 2400 mg/m2 CIVI over 46 
hours, leucovorin at 400 mg/m2 on Day 1, irinotecan at 180 mg/m2 on Day 1, and 


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oxaliplatin at 85 mg/m2 on Day 1) or gemcitabine alone (1000 mg/m2 given weekly for 7 
weeks followed by one week off, then on Days 1, 8, and 15 of a 28-day cycle).  Patients 
treated with FOLFIRINOX had a significantly improved mOS of 11.1 months compared 
with 6.8 months in the gemcitabine arm (p<0.001), as well as an improved PFS of 6.4 
months compared to 3.3 months (p<0.001).  A higher tumor response rate was seen in the 
FOLFIRINOX arm as well (31.6% vs 9.4%; p<0.001).  FOLFIRINOX is now considered 
one of the standard first-line regimens for patients with metastatic pancreatic cancer and 
good performance status. 
 
1.3 
Second-line 
Therapy 
for 
Inoperable 
or 
Metastatic 
Pancreatic 
Adenocarcinoma 
 
Despite the aggressive nature of pancreatic cancer, nearly half of the patients who have 
progressed on front-line therapy are able to receive second-line therapy. A fluorouracil-
based regimen is currently recommended for patients who progress through a 
gemcitabine-based regimen.  In a phase III clinical trial, patients who had progressed on a 
gemcitabine-based chemotherapy were randomized to receive folinic acid at 200 mg/m2 
5-FU at 2000 mg/m2 as a continuous 24 hour infusion on Days 1, 8, 15, and 22, and 
oxaliplatin at 850 mg/m2 on Days 8 and 22 of a 42-day cycle (OFF regimen), or best 
supportive care (BSC) (6). The study was terminated early due to low recruitment, but 
despite this, the OFF regimen showed a median survival of 4.82 versus 2.30 months 
(p=0.008) and a mOS survival benefit of 9.09 versus 7.90 months (p=0.031) in patients 
treated with OFF compared to BSC. However, recently the results of the CONKO-003 
trial were published, which was a randomized, open-label phase III trial in which 168 
patients with advanced pancreatic cancer who had progressed on gemcitabine were 
randomized to folinic acid and fluorouracil (FF) or oxaliplatin and FF (OFF) (7). Median 
overall survival was significantly longer in the OFF group compared to FF alone (5.9 
versus 3.3 months, p=0.010).  PFS was also extended in the OFF treatment arm compared 
to the FF arm (2.9 versus 2.0 months, p=0.019).  Based on these trials, the National 
Comprehensive Cancer Network (NCCN) recommends fluoropyrimidine plus oxaliplatin 
as one of the second-line treatment options.  
 
However, for patients who performance status is poor, a fluoropyrimidine alone is often 
given, either as infusional 5-FU or capecitabine, and it is considered to be a reasonable 
second line option endorsed by the NCCN. 5-FU is a fluorinated pyrimidine that acts as 
an antimetabolite antineoplastic agent. Capecitabine is an orally administered prodrug of 
5’-deoxy-5-fluorouridine which generates 5-FU selectively in tumor cells, and so is often 
used instead of 5-FU given its ease of administration.  Both are frequently used as the 
control group in the second-line setting in clinical trials.  For example, three recent phase 
II and phase III trials have used capecitabine or 5-fluorouracil in combination with an 
investigational drug compared with capecitabine or 5-fluorouracil alone.  A phase II 
randomized, double-blind, placebo-controlled trial of ruxolitinib, a JAK1/JAK2 inhibitor, 
in combination with capecitabine in patients with recurrent or metastatic pancreatic 
cancer (RECAP trial) showed improved OS in patients with an elevated C-reactive 
protein (CRP).  The hazard ratio (HR) for OS in the intent to treat population was 0.79 
[95% CI, 0.53-1.18; P=0.25 (2-sided)] and in the pre-specified subgroup analysis in 


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patients with an elevated CRP, the HR for OS was 0.47 (95% CI: 0.26-0.85; P=0.01 (2-
sided)), with 6-month survival in the ruxolitinib arm of 42% vs. 11% in the placebo arm 
(8).  And, as mentioned above, 5-FU was used as the control arm in the CONKO-003 
trial.  Finally, in a phase III trial of MM-398 (NAPOLI-1 trial), patients were randomized 
to receive MM-398, 5-FU, or combination therapy (9).  Median OS was 6.1 months in the 
combination arm compared to 4.2 months in the 5-FU arm (HR 0.67, p=0.012).   
 
1.4 
Tosedostat 
 
Tosedostat is a metalloenzyme inhibitor with activity against a range of human cancer 
cells in vitro and in vivo (10, 11, 12) Tosedostat inhibits multiple mellatoenzymes, such 
as the puromycin-sensitive aminopeptidase, leukotriene A4 (LTA4) hydrolase, leucine 
amionopedptidase 3, and members of the M1 and M17 classes of aminopeptidases that 
includes the zinc-dependent aminopeptidases (Investigator’s brochure).  Aminopeptidases 
catalyze the hydrolysis of the terminal amino acids from peptides or polypeptides 
generated by proteasomal degradation.  These metallopeptidases have been shown to be 
frequently overexpressed in different cancers, including pancreatic adenocarcinoma (13).  
Aminopeptidases catalyze the cleavage of amino acids from the amino terminus of 
proteins and peptides downstream of proteasomal degradation (14).  Disruption of protein 
degradation, like with proteasome inhibitors, is thought to contribute to tumor cell death 
in two ways.  First, inhibition of aminopeptidases leads to an intracellular depletion of 
amino acids, impacting cells ability to make new proteins (15).  Secondly, a decrease in 
the pool of free amino acids induces a cellular stress response known as the amino acid 
deprivation response (16), which leads to apoptosis. 
 
Tosedostat, an aminopeptidase inhibitor, has been shown to have antiproliferative effects 
in solid and hematological malignancies (10, 11, 12).   To date, there have been several 
phase 1/2 studies using tosedostat as a single agent in the treatment of advanced solid 
tumors, acute myelogenous leukemia, and multiple myeloma. In a phase I study to 
evaluate the safety and tolerability of tosedostat in patients with advanced solid tumors 
(CHR-2797-001), the maximum tolerated dose (MTD) was determined to be 320 mg and 
the 240 mg dose was determined to be the maximum accepted dose (17).  Two events at 
this dose were qualified as dose-limiting toxicities (DLTs).  One patient had anemia, 
dizziness, and vision abnormalities and the second patient had thrombocytopenia, 
dizziness and vision abnormalities that resulted in treatment discontinuation. Forty 
patients were treated in this study, with a mean duration of study treatment of 75 days.  
One patient with hepatocellular carcinoma remained on treatment for 350 days and 6 
patients continued treatment for more than 6 months.  No patient achieved a CR, but one 
patient with metastatic renal cell carcinoma achieved a durable partial response.   
 
A second phase I study evaluated tosedostat in combination with a common 
chemotherapeutic agent used in solid malignancies.  Patients were enrolled in a phase Ib 
study to evaluate the safety and tolerability of the addition of tosedostat to paclitaxel in 
patients with advanced solid tumors (18).  Of the 21 patients treated with the 
combination, three patients achieved a best response of PR and time to progression was 
45, 214, and 217 days.  Twelve patients had SD as a best response, so the overall 


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response rate (SD or PR) was 71%.  No formal MTD was determined due to a high rate 
of paclitaxel infusion reactions at a dose of 240 mg.  
 
A second phase I/II trial to evaluate tosedostat in combination with erlotinib in patients 
with non-small cell lung cancer was closed early due to poor recruitment.   
 
In all, a total of 194 patients with such indications as advanced or refractory tumors, 
NSCLC, AML, and MM have been treated in single-agent phase 1/2 studies.  Two 
patients were treated with a combination of tosedostat and erlotinib and 22 were treated 
with a combination of tosedostat and paclitaxel.  The most common adverse events 
related to tosedostat treatment (≥5%) include the following: fatigue (23.7%), diarrhea 
(22.2%), thrombocytopenia (18%), nausea (17%), decreased appetite (16.5%), edema 
peripheral (11.3%), rash (10.8%), anemia (9.8%), dizziness (8.8%), vomiting (8.8%), 
increased alanine aminotransferase(6.2%), atrial fibrillation (6.2%), febrile neutropenia 
(6.2%), and neutropenia (5.7%).   
 
1.4 
Study Rationale 
 
Unresectable advanced or metastatic pancreatic adenocarcinoma is an incurable disease, 
with a mean overall survival of less than one year despite current available treatments.  
The two most common first-line chemotherapies for pancreatic adenocarcinoma are 
FOLFIRINOX (2) or gemcitabine plus nab-paclitaxel (5).  However, most patients will 
progress on these regimens.  Many patients cannot tolerate FOLFIRINOX due to 
significant adverse side effects, making gemcitabine plus nab-paclitaxel a frequent first-
line choice.  And although 5-FU and capecitabine have activity in pancreatic cancer, their 
use as a single agent generally only gives an overall survival benefit of a few months.  
Therefore, one treatment strategy is to improve the efficacy of capecitabine with an 
additional chemotherapeutic agent.   
 
APN/CD13 is a zinc metalloprotease and has been investigated in pancreatic cancer (19).  
Reverse transcriptase polymerase chain reaction (rt-PCR) was performed on 50 tumor 
samples in patients who underwent pancreatectomy between 1992 and 1999, to quantify 
the expression of this gene in pancreatic cancer.  Of the 50 tumors tested, 24 (48%) were 
positive by immunohistochemistry and 25 (50%) were positive for gene expression of 
APN/CD13 by rt-PCR.  There was a correlation between APN/CD13 expression and 
overall survival.  Patients whose tumors  were positive for APN/CD13 expression had a 
shorter overall survival than in patients whose tumors were negative, 9.5 versus 13.2 
months respectively, p=0.0009).  Multivariate analysis of the 50 patients showed that 
APN/CD13 expression was a significant independent prognostic factor (p=0.016).    
 
Given the evidence of possible upregulation of metalloproteases and their potential 
prognostic values in pancreatic cancer, the study rationale is to combine tosedostat with 
capecitabine, a standard second-line chemotherapy.  We chose tosedostat at 120 mg daily 
as the first dose level for the following reasons.  In the phase I study using tosedostat as a 
single agent, the MTD was determined to be 240 mg in patients with solid tumors (17).  
However, in patients with acute myeloid leukemia or multiple myeloma (20), the MTD 


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was determined to be 180 mg daily due to two cases of Grade 4 thrombocytopenia in 
patients who received 180 mg/day, and 130 mg was declared the maxiumum 
administered dose for phase II dosing.  However, there were a number of cardiac events 
reported across the investigator sponsored trials, including atrial fibrillation, cardiac 
dysfunction, cardiac arrest and edema. An expert cardiology review panel concluded that 
events assessed as related to tosedostat may have been dose-related, as a greater 
proportion of the cardiac events were reported at the 180 mg dose than at the 120 mg 
dose. However, the panel noted that the pattern and diversity of the reported cardiac 
events might suggest exacerbations of underlying vulnerability, rather than primary drug 
toxicity.  Because of the potential risk of cardiac toxicity, the maximum tosedostat dose 
will be 120 mg po daily.  
 
Capecitabine is typically administered in combination with other chemotherapeutic drugs 
at a dose of 2000mg/m2/day to 2500mg/m2/day, and its dose-limiting toxicity is diarrhea.  
Because there is no signfiicant overlapping toxicites,  we feel that the combination of 
tosedostat 120 mg daily and the lower dose of 1000 mg/m2 BID capecitabine is a safe 
level to start. 
 
1.5 
Correlative Studies Background 
 
Please refer to Section 9.2. 
 
 
2.0 
OBJECTIVES 
 
2.1 
Primary Objectives 
 
1. Phase I: To determine the recommended phase II dose (RP2D) and dose-limiting 
toxicities (DLTs) of tosedostat and capecitabine combination therapy in patients with 
advanced or metastatic pancreatic cancer. 
2. Phase II: To determine progression-free survival (PFS) rate at 3 months of tosedostat 
and capecitabine combination therapy in patients with advanced or metastatic 
pancreatic cancer. 
 
2.2 
Secondary Objectives 
 
1. To determine the overall response rate (ORR) of patients with advanced or metastatic 
pancreatic cancer being treated with tosedostat and capecitabine combination therapy. 
2. To determine the time-to-progression (TTP) of patients with advanced or metastatic 
pancreatic cancer being treated with tosedostat and capecitabine combination therapy. 
3. To determine overall survival (OS) of patients with advanced or metastatic pancreatic 
cancer being treated with tosedostat and capecitabine combination therapy. 
4. To determine CA19-9 response of patients with advanced or metastatic pancreatic 
cancer being treated with tosedostat and capecitabine combination therapy. 
 
 


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2.3 
Exploratory Objectives 
 
1. To explore the predictive molecular biomarkers for treatment response in patients 
with advanced or metastatic pancreatic cancer being treated with tosedostat and 
capecitabine combination therapy.  
2. To explore the prognostic biomarkers for patients with advanced or metastatic 
pancreatic cancer receiving tosedostat and capecitabine combination therapy.   
3. To correlate genetic alterations with response to treatment with combination 
tosedostat and capecitabine in patients with advanced or metastatic pancreatic cancer. 
 
 
3.0 
PATIENT SELECTION 
 
3.1 
Inclusion Criteria 
 
1. Histologically or cytologically proven metastatic or inoperable pancreatic 
adenocarcinoma.   
 
2. Measurable disease defined as lesions that can be accurately measured in at least one 
dimension (longest diameter to be recorded) as >10 mm with CT scan or MRI, as >20 
mm by chest x-ray, or >10 mm with calipers by clinical exam. 
 
3. Must have progressed on, been intolerant to, or refused gemcitabine-based therapy. 
 
4. At least 18 years of age. 
 
5. ECOG performance status ≤ 2 (see Appendix A). 
 
6. Normal bone marrow and organ function as defined below: 
a. Absolute neutrophil count ≥ 1,000/mcl 
b. Platelets ≥ 100,000/mcl 
c. Total bilirubin ≤ 2.0 mg/dL 
d. Creatinine ≤ 2.0 mg/dL 
e. AST or ALT ≤2.5 IULN  (≤5X IULN if liver metastases are present) 
 
7. Women of childbearing potential and men must agree to use adequate contraception 
(hormonal or barrier method of birth control, abstinence) prior to study entry and for 
the duration of study participation.  Should a woman become pregnant or suspect she 
is pregnant while participating in this study, she must inform her treating physician 
immediately. 
 
8. Able to understand and willing to sign an IRB approved written informed consent 
document (or that of legally authorized representative, if applicable). 
 
 


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3.2 
Exclusion Criteria 
 
1. Chemotherapy < 2 weeks prior to the first planned dose of study treatment.  
 
2. Radiotherapy < 3 weeks prior to the first planned dose of study treatment. 
 
3. A history of other malignancy ≤ 2 years previous with the exception of basal cell or 
squamous cell carcinoma of the skin which were treated with local resection only or 
carcinoma in situ of the cervix. 
 
4. Currently receiving any other investigational agents. 
 
5. Known brain metastases.  Patients with known brain metastases must be excluded 
from this clinical trial because of their poor prognosis and because they often develop 
progressive neurologic dysfunction that would confound the evaluation of neurologic 
and other adverse events. 
 
6. A history of allergic reactions attributed to compounds of similar chemical or biologic 
composition to tosedostat or capecitabine or other agents used in the study. 
 
7. Previous treatment with any aminopeptidase inhibitor. 
 
8. Previous exposure to either 5-FU or capecitabine at a systemic dose except for use in 
concurrent chemoradiation. 
 
9. Known dihydropyrimidine dehydrogenase (DPD) deficiency or severe renal 
impairment (creatinine clearance < 30 mL/min by Cockcroft-Gault formula), as this 
would preclude use of capecitabine.  
 
10. Significant cardiovascular disease defined as: 
a. Myocardial infarction within 6 months of screening.  
b. Unstable angina pectoris  
c. Uncontrolled or clinically significant arrhythmia Grade ≥ 2 
d. LVEF below institutional limits at screening 
e. Congestive heart failure NYHA class III or IV 
f. Presence of clinically significant valvular heart disease 
 
11. Baseline troponin I or T> IULN and b-type natriuretic peptide > IULN. 
 
12. Prior exposure to cardiotoxic agent, such as anthracyclines, within 3 months of 
enrollment. 
 
13. Patient must have a QTc interval on ECG ≤ 0.48 seconds by Bazett’s calculation at 
screening. 
 


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14. Patient may not be taking any drugs that prolong the QT/QTc interval (see Appendix 
C).  If patient is on any of these drugs, patient may enroll in the study if the drugs can 
be discontinued for at least 5 half-lives prior to the first dose of tosedostat and 
capecitabine. 
 
15. Uncontrolled intercurrent illness including, but not limited to, ongoing or active 
infection or psychiatric illness/social situations that would limit compliance with 
study requirements. 
 
16. Pregnant and/or breastfeeding.  Patients that are of childbearing age must have a 
negative pregnancy test at screening and agree on using contraception during the 
duration of the study. 
 
17. Known HIV-positivity on combination antiretroviral therapy because of the potential 
for pharmacokinetic interactions with tosedostat or capecitabine.  In addition, these 
patients are at increased risk of lethal infections when treated with marrow-
suppressive therapy.  Appropriate studies will be undertaken in patients receiving 
combination antiretroviral therapy when indicated. 
 
3.3 
Inclusion of Women and Minorities 
 
Both men and women and members of all races and ethnic groups are eligible for this 
trial. 
 
 
4.0 
REGISTRATION PROCEDURES 
 
Patients must not start any protocol intervention prior to registration through the Siteman 
Cancer Center. 
 
The following steps must be taken before registering patients to this study: 
 
1. Confirmation of patient eligibility 
2. Registration of patient in the Siteman Cancer Center OnCore database 
3. Assignment of unique patient number (UPN) 
 
4.1 
Confirmation of Patient Eligibility 
 
Confirm patient eligibility by collecting the information listed below: 
 
1. Registering MD’s name 
2. Patient’s race, sex, and DOB 
3. Three letters (or two letters and a dash) for the patient’s initials 
4. Copy of signed consent form  
5. Completed eligibility checklist, signed and dated by a member of the study team 
6. Copy of appropriate source documentation confirming patient eligibility 


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4.2 
Patient Registration in the Siteman Cancer Center OnCore Database 
 
All patients must be registered through the Siteman Cancer Center OnCore database. 
 
4.3 
Assignment of UPN 
 
Each patient will be identified with a unique patient number (UPN) for this study.  All 
data will be recorded with this identification number on the appropriate CRFs. 
 
 
5.0 
TREATMENT PLAN 
 
This is a single institution phase I/II study combining tosedostat, an aminopeptidase inhibitor, 
with capecitabine. The study aims to determine the recommended phase 2 dose (RP2D) of 
tosedostat when given with a standard dose of capecitabine (1000 mg/m2 BID) and to evaluate 
the preliminary efficacy of tosedostat and capecitabine combination therapy in advanced or 
metastatic pancreatic adenocarcinoma.   
 
The phase I study will be conducted in a standard 6-patient-per-cohort dose de-escalation 
fashion.  For the phase II part of the study, the primary endpoint of the study is to assess the 
progression-free survival  (PFS) of the combination therapy.  The dose of tosedostat used in 
phase II of this study will be determined during the phase I dose de-escalation portion. 
 
5.1 
Premedication Administration 
 
No premedications are required for either capecitabine or tosedostat.  Anti-nausea 
medications can be used as per the treating physician’s discretion.  
 
5.2 
Agent Administration 
 
Tosedostat is an oral drug which will be taken on an outpatient basis daily on a 21-day 
cycle.  Patients should take tosedostat at approximately the same time every day 
(preferably morning) with a glass of water after food.  If a patient misses a dose by more 
than 6 hours, the patient should be instructed not to take or make up that dose and to 
resume dosing with the next scheduled dose.  Patients will be instructed to bring all 
unused drug and their medication diary (Appendix B) to each study visit for assessment 
of compliance.  Dosing of tosedostat during phase I will be as described in Section 5.4.  
Dosing of tosedostat during phase II will be the dose determined during phase I. 
 
Capecitabine is an oral drug which will be taken on an outpatient basis at a dose of 1000 
mg/m2 twice a day on Days 1 through 14 of a 21-day cycle.  The tablets are to be 
swallowed with water and taken 30 minutes after the end of a meal.  If the patient vomits 
or misses a dose by more than 2 hours, s/he must not take the missed dose and must not 
double the next dose.  Instead, s/he should continue with the dosing as scheduled.  


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Patients will be instructed to bring all unused tablets and medication diary (Appendix B) 
to each study visit for assessment of compliance. 
 
5.3 
Dose De-Escalation Schema 
 
Dose Escalation Schedule 
Dose Level 
Tosedostat (PO daily) 
Days 1-21 
Capecitabine (PO BID) 
Days 1-14 
Level 0 (Starting dose) 
120 mg 
1000 mg/m2 
Level -1  
60 mg 
 
5.4 
Phase II Treatment Plan 
 
Once the RP2D is determined, additional patients will be enrolled for a total of 36 
evaluable patients (the patients from the RP2D level of phase I will be included in this 
group). 
 
5.5 
Definition of RP2D, DLT, Dose De-Escalation Criteria, and Toxicity, 
Response, and DLT Evaluations 
 
5.5.1 Definition of Recommended Phase 2 Dose (RP2D)  
 
The recommended phase 2 dose (RP2D) is defined as the dose level immediately 
below the dose level at which 2 patients of a cohort (of 2 to 6 patients) experience 
dose-limiting toxicity during the first cycle.  If 0 or 1 of 6 patients in Dose Level 1 
experience DLT during the first cycle, Dose Level 1 will be presumed to be the 
RP2D. 
 
5.5.2 Dose Limiting Toxicities (DLTs) 
 
Hematologic DLT is defined as any of the following that occur during the first 
cycle that are attributed as possibly, probably, or definitely related to the study 
treatment: 
 Grade 4 neutropenia > 7 day duration 
 Febrile neutropenia of any duration with temperature ≥ 38.5 °C 
 Grade 4 anemia which requires transfusion therapy on more than two 
occasions in 7 days 
 Grade 4 thrombocytopenia  
 
Non-hematologic DLT is defined as any possibly, probably, or definitely related 
grade 3 or grade 4 non-hematologic toxicity that occurs during the first cycle with 
the following specific EXCEPTIONS: 
 Grade 3 nausea, vomiting, diarrhea, or anorexia lasting no more than 72 
hours that returns to Grade 1 prior to the start of Cycle 2 
 Grade 3 hand-foot syndrome will only be considered a DLT for patients 
who have received one week of supportive care treatment with no 


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improvement 
 Grade 3 fatigue that returns to Grade 1 prior to the start of Cycle 2 
 Grade 3 flu-like symptoms lasting no more than 72 hours that returns to 
Grade 1 prior to start of Cycle 2 
 Grade 3 arthralgia or myalgias lasting no more than 72 hours that return to 
Grade 1 prior to the start of Cycle 2 
 Grade 3 potassium, phosphorus, or magnesium that is asymptomatic or of 
non-clinical significance lasting no more than 72 hours 
 Grade 3 hypoalbuminemia 
 
5.5.3 Dose De-Escalation Criteria 
 
Dose de-escalations will proceed as follows after the occurrence of dose-limiting 
toxicity (DLT): 
 
Number of 
Patients with DLT 
at a Given Dose 
Level 
De-Escalation Decision Rule 
0 or 1 out of 6 
If Dose Level 0: If 0-1 patients experience a DLT move 
to the phase II portion at Dose Level 0. 
 
If Dose Level -1: If 0-1 patients experience a DLT, move 
to the phase II portion at Dose Level -1 
≥ 2 out of 6  
Dosing at this dose level will be stopped and 6 additional 
patients will be entered at the next lowest dose level, if 
available. 
 
5.5.4 Toxicity, Response, and DLT Evaluations 
 
All patients who receive any study treatment are evaluable for toxicity.  Patients 
are evaluated from first receiving study treatment until a 30-day follow up after 
the conclusion of treatment or death. 
 
All patients are evaluable for disease response unless they come off study due to 
treatment related adverse events(s) prior to completion of Cycle 2 and have not 
had any disease assessment. 
 
A patient is evaluable for DLT assessment only if enrolled in the phase I portion 
and only during Cycle 1 of treatment.  If the patient is not able to be treated on 
Day 1 of Cycle 2, then s/he is still considered in Cycle 1 active treatment and can 
experience a DLT.  Once the patient has been treated in Cycle 2, s/he will no 
longer be evaluated for DLTs in all subsequent cycles.   
 
 


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5.6 
General Concomitant Medication and Supportive Care Guidelines 
 
Currently available in vitro data suggest that tosedostat may be a moderate inhibitor of 
selected catalytic activities of CYP3A4. Therefore, it may participate in or contribute to 
inhibitory drug-drug interactions in vivo, which are mediated by CYP3A4. Drugs that are 
known to be substrates for CYP3A4 include acetaminophen, carbamazepine, cyclosporin, 
digitoxin, diazepam, erythromycin, felodipine, fluoxetine, nifedipine, quinidine, 
saquinavir, triazolam, verapamil and warfarin. It is not expected, however, that tosedostat 
will reach sufficiently high, prolonged concentrations to significantly impact the 
metabolism of such drugs.  Concomitant use of these drugs should be done with caution.   
 
Due to the potential risk of cardiotoxicity, concomitant use of drugs that prolong the 
QT/QTc interval are prohibited (see Appendix C).  
 
Due to the thrombocytopenic effects of capecitabine, an additive risk of bleeding may be 
seen in patients receiving concomitant anticoagulants and should be avoided. The 
manufacturer labeling for capecitabine includes a black box warning regarding 
concomitant use with warfarin.   Administration of capecitabine concomitantly with 
Coumadin-derivative anticoagulants has resulted in prolonged coagulation parameters 
and/or bleeding; deaths have been reported. The interaction with warfarin is probably due 
to an inhibition of cytochrome P450 2C9 by capecitabine and/or its metabolites.  If 
capecitabine is used with warfarin, close monitoring of the INR is necessary as dose 
adjustments may be necessary.  If a patient is on enoxaparin or other anticoagulants, 
NSAIDs, or aspirin, use cautiously and discontinue with any bleeding episodes or if 
patient becomes thrombocytopenic. 
 
Caution is advised when capecitabine is combined with phenytoin or fosphenytoin. 
Increased phenytoin plasma concentrations have been reported during concomitant use of 
phenytoin and capecitabine.  Increased phenytoin plasma concentrations may be due to 
inhibition of cytochrome P450 2C9 by capecitabine and/or its metabolites. Patients taking 
phenytoin or fosphenytoin concurrently with capecitabine should be monitored for 
increased phenytoin plasma concentrations and associated clinical symptoms of 
phenytoin toxicity such as nystagmus, diplopia, ataxia, and confusion. A reduction in the 
phenytoin dosage may be required in some patients receiving concomitant capecitabine. 
 
Patients should receive full supportive care during the study, including transfusion of 
blood and blood products, treatment with antibiotics, analgesics, erythropoietin, or 
bisphosphonates as appropriate.   Anti-emetics (such as prochlorperazine, lorazepam, or 
other 5-HT3 antagonists) may be administered prophylactically in the event of nausea. 
Anti-diarrheals, such as loperamide, may be administered as needed in the event of 
diarrhea. 
 
5.7 
Women of Childbearing Potential 
 
Women of childbearing potential (defined as women with regular menses, women with 


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amenorrhea, women with irregular cycles, women using a contraceptive method that 
precludes withdrawal bleeding, and women who have had a tubal ligation) are required to 
have a negative pregnancy test within 14 days prior to the first doses of tosedostat and 
capecitabine.   
 
Female and male patients (along with their female partners) are required to use two forms 
of acceptable contraception, including one barrier method, during participation in the 
study and for 3 months following the last dose of either study drug.  
 
If a patient is suspected to be pregnant, study treatment should be immediately 
discontinued.  In addition a positive urine test must be confirmed by a serum pregnancy 
test.  If it is confirmed that the patient is not pregnant, the patient may resume dosing. 
 
If a female patient or female partner of a male patient becomes pregnant during therapy 
or within 3 months after the last dose of either study drug, the investigator must be 
notified in order to facilitate outcome follow-up. 
 
5.8 
Duration of Therapy 
 
If at any time the constraints of this protocol are considered to be detrimental to the 
patient’s health and/or the patient no longer wishes to continue protocol therapy, the 
protocol therapy should be discontinued and the reason(s) for discontinuation 
documented in the case report forms. 
 
In the absence of treatment delays due to adverse events, treatment may continue until 
one of the following criteria applies: 
 
 Documented and confirmed disease progression 
 Death 
 Adverse event(s) that, in the judgment of the investigator, may cause severe or 
permanent harm or which rule out continuation of study drug 
 General or specific changes in the patient’s condition render the patient 
unacceptable for further treatment in the judgment of the investigator 
 Suspected pregnancy 
 Serious non-compliance with the study protocol 
 Lost to follow-up 
 Patient withdraws consent 
 Investigator removes the patient from study 
 The Siteman Cancer Center decides to close the study 
 
Patients who prematurely discontinue treatment for any reason will be followed as 
indicated in the study calendar. 
 
5.9 
Duration of Follow-up 
 
Patients will be followed every 3 months for 1 year or until death, whichever occurs first.  


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Patients removed from study for unacceptable adverse events will be followed until 
resolution or stabilization of the adverse event. 
 
 
6.0 
DOSE DELAYS/DOSE MODIFICATIONS 
 
6.1 
Tosedostat Dose Reduction Table 
 
Starting Dose 
120 mg po daily 
Dose Level -1 
60 mg po daily 
  
Patients will be monitored for toxicity and the dose of tosedostat may be adjusted. Dose 
reduction by one dose level will be allowed. Patients requiring more than one dose 
reduction will be discontinued from the study.  
 
Recommended dose reductions for tosedostat are to decrease the current dose by 60 mg. 
The lowest dose available is 60 mg. Doses may be held as needed for toxicity resolution 
during a cycle. Doses omitted for toxicity are not replaced or restored within the same 
cycle (meaning that the cycle remains 21 days regardless of the number of doses of 
taken). If a patient experiences  toxicity which has not resolved to grade 2 or lower within 
two weeks, treatment with tosedostat should be permanently discontinued. 
 
6.1.1 Cardiac Toxicity 
 
Ejection Fraction 
Grade 
Occurrence  Tosedostat 
Grade 2* 
1st 
Hold Tosedostat and repeat ECHO.  
 Hold drug until LVEF is less than or 
equal to 9% points of baseline and 
resume at the current dose. 
 If LVEF is below institutional normal 
limit, please hold the study drug 
 
2nd 
Hold Tosedostat and repeat ECHO.  
 Hold drug until LVEF is less than or 
equal to 9% points of baseline and 
resume at the next lower dose. 
 If LVEF is below institutional normal 
limit, please hold the study drug 
 
3rd and beyond 
Hold Tosedostat and repeat ECHO.  
 If LVEF is above institutional normal 
limits: Hold drug until LVEF is less 
than or equal to 9% points of baseline 
and resume at the same dose. 
 If LVEF is below institutional normal 
limits: Discontinue 
Grade 3  
Any 
Discontinue 


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*Per the PI’s discretion, patients may be referred to Cardiology for a second 
opinion.   
 
 
 
6.1.2 Hematologic Toxicity 
 
ANC must be ≥ 1,000 cells/μl and platelet count must be ≥75,000 cells/μl at the 
start of each cycle.  
 
Grade  
Occurrence  Tosedostat 
Neutrophils   
Grade ≤2 
Any 
Current dose  
Grade 3  
Any 
Hold till ANC≥1,000, resume the current dose  
Grade 4 
1st  
Hold till ANC≥1,000, resume the next lower 
dose 
Grade 4  
2nd  
Discontinue  
Platelets  
Grade ≤1 
Any 
Current dose  
Grade 2  
Any 
Hold till platelets ≥75,000, resume the current  
dose level 
Grade 3 
Any  
Hold till platelets ≥75,000, resume the next 
lower dose  
Grade 4  
 
1st  
Hold till platelets ≥75,000, resume the next 
lower dose  
2nd  
Discontinue  
Febrile neutropenia 
Grade 3 
1st 
Hold till ANC≥1,000, resume the next lower 
dose 
2nd 
Discontinue 
 
The patient will be taken off the trial if more dose reductions are called for than 
are allowed.  
 
6.1.3 Other Nonhematologic Toxicities Reasonably Related to Treatment 
 
Grade  
Occurrence  Tosedostat 
Grade 1 
Any  
Current dose  
Grade 2* 
 
 
1st  
Hold until ≤ grade 1, then resume at the current dose 
2nd  
Hold until ≤ grade 1, then resume at the next lower 
dose  
3rd  
Discontinue  
Grade 3* 
 
 
1st  
Hold until ≤ grade 1, then resume the next lower dose 
2nd  
Hold until ≤ grade 1, then resume the next lower dose 
3rd  
Discontinue 
Grade 4* 
1st  
Hold until ≤ grade 1, then resume the next lower dose 


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2nd  
Discontinue  
*Based off occurrence of the same repeating toxicity 
 
Patients will be taken off the study if their treatment has to be held for more than 
4 weeks for any reason.  
 
6.2 
Capecitabine Dose Reduction Table 
 
Starting Dose 
1000 mg/m2 BID 
Dose Level -1 
750 mg/m2 BID 
Dose Level -2 
500 mg/m2 BID 
 
Reductions table is for AE’s that are deemed related to capecitabine. Once dosing for 
capecitabine has been reduced, it should not be increased at a later time.  Doses of 
capecitabine that are omitted for toxicity should not be replaced or restored; the patient 
should simply resume his/her planned treatment cycle.  If capecitabine is held for longer 
than 2 weeks within one cycle, treatment must be permanently discontinued and the 
patient should come off study. Dose modifications should be based on the same AE 
occurrence.  
 
Grade 
Occurrence 
Action During Course 
Dose Adjustment for 
Next Treatment 
(% of starting dose) 
Grade 1 
Any 
Maintain dose level 
Maintain dose level 
Grade 2 
1st 
Interrupt until resolved to grade 0-1 
100% 
2nd 
75% 
3rd 
50% 
4th 
Discontinue permanently 
-- 
Grade 3 
1st 
Interrupt until resolved to grade 0-1 
75% 
2nd 
50% 
3rd 
Discontinue permanently 
-- 
Grade 4 
1st  
Discontinue permanently OR if MD 
deems it to be in the patient’s best 
interest to continue, interrupt until 
resolved to grade 0-1 
50% 
 
For grade 3 or 4 thromboembolic events which are related to capecitabine, hold 
capecitabine, start anticoagulation therapy Lovenox (preferred choice), and resume at the 
investigator’s discretion. 
 
Capecitabine or Tosedostat can be continued while the other drug is being held (if no 
hold criteria are met for the other drug).  
 
 
 


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6.3 
Stopping Rule for Excess Toxicity 
 
In the event of any deaths on study thought to be possibly, probably, or definitely related 
to study treatment, the study will be suspended, AEs will be assessed, and the study will 
be considered for revision or closure. 
 
 
7.0 
REGULATORY AND REPORTING REQUIREMENTS 
 
The entities providing oversight of safety and compliance with the protocol require reporting as 
outline below. 
 
The Washington University Human Research Protection Office (HRPO) requires that all events 
meeting the definition of unanticipated problem or serious noncompliance be reported as 
outlined in Section 7.6. 
 
The FDA requires that all serious and unexpected adverse events be reported as outlined in 
Section 7.7.  In addition, any fatal or life-threatening adverse experiences where there is a 
reasonable possibility of relationship to study intervention must be reported. 
 
CTI BioPharma, Inc. requires that all SAEs, irrespective of causal relationship, be reported as 
outlined in Section 7.8. 
 
7.1 
Definitions 
 
7.1.1 Adverse Events (AEs) 
 
Definition: any unfavorable medical occurrence in a human subject including any 
abnormal sign, symptom, or disease. 
 
Grading: the descriptions and grading scales found in the revised NCI Common 
Terminology Criteria for Adverse Events (CTCAE) version 4.03 will be utilized 
for all toxicity reporting.  A copy of the CTCAE version 4.03 can be downloaded 
from the CTEP website. 
 
Attribution (relatedness), Expectedness, and Seriousness: the definitions for 
the terms listed that should be used are those provided by the Department of 
Health and Human Services’ Office for Human Research Protections (OHRP).  A 
copy of this guidance can be found on OHRP’s website: 
http://www.hhs.gov/ohrp/policy/advevntguid.html 
 
7.1.2 Serious Adverse Event (SAE) 
 
Definition:  any adverse drug experience occurring at any dose that results in any 
of the following outcomes: 


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o Death 
o A life-threatening adverse drug experience 
o Inpatient hospitalization or prolongation of existing hospitalization 
o A persistent or significant disability/incapacity (i.e., a substantial 
disruption of a person’s ability to conduct normal life functions) 
o A congenital anomaly/birth defect 
o Any other experience which, based upon appropriate medical judgment, 
may jeopardize the subject and may require medical or surgical 
intervention to prevent one of the outcomes listed above 
 
All unexpected SAEs must be reported to the FDA. 
 
7.1.3 Unexpected Adverse Experience 
 
Definition: any adverse drug experience, the specificity or severity of which is 
not consistent with the current investigator brochure (or risk information, if an IB 
is not required or available). 
 
Events that are both serious AND unexpected must be reported to the FDA. 
 
7.1.4 Life-Threatening Adverse Experience 
 
Definition: any adverse drug experience that places the subject (in the view of the 
investigator) at immediate risk of death from the reaction as it occurred, i.e., it 
does not include a reaction that, had it occurred in a more severe form, might have 
caused death. 
 
Life-threatening adverse experiences must be reported to the FDA. 
 
7.1.5 Unanticipated Problems 
 
Definition: 
 
 unexpected (in terms of nature, severity, or frequency) given (a) the research 
procedures that are described in the protocol-related documents, such as the 
IRB-approved research protocol and informed consent document; and (b) the 
characteristics of the subject population being studied; 
 related or possibly related to participation in the research (“possibly related” 
means there is a reasonable possibility that the incident, experience, or 
outcome may have been caused by the procedures involved in the research); 
and 
 suggests that the research places subjects or others at a greater risk of harm 
(including physical, psychological, economic, or social harm) than was 
previously known or recognized. 
 
 


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7.1.6 Noncompliance 
 
Definition: failure to follow any applicable regulation or institutional policies that 
govern human subjects research or failure to follow the determinations of the 
IRB.  Noncompliance may occur due to lack of knowledge or due to deliberate 
choice to ignore regulations, institutional policies, or determinations of the IRB. 
 
7.1.7 Serious Noncompliance 
 
Definition: noncompliance that materially increases risks, that results in 
substantial harm to subjects or others, or that materially compromises the rights or 
welfare of participants. 
 
7.1.8 Protocol Exceptions 
 
Definition: A planned deviation from the approved protocol that are under the 
research team’s control. Exceptions apply only to a single participant or a singular 
situation. 
 
Pre-approval of all protocol exceptions must be obtained prior to the event. 
 
7.2 
Reporting to the Human Research Protection Office (HRPO) at Washington 
University 
 
The PI is required to promptly notify the IRB of the following events: 
 
 Any unanticipated problems involving risks to participants or others which occur 
at WU, any BJH or SLCH institution, or that impacts participants or the conduct 
of the study. 
 Noncompliance with federal regulations or the requirements or determinations of 
the IRB. 
 Receipt of new information that may impact the willingness of participants to 
participate or continue participation in the research study. 
 
These events must be reported to the IRB within 10 working days of the occurrence of 
the event or notification to the PI of the event.  The death of a research participant that 
qualifies as a reportable event should be reported within 1 working day of the occurrence 
of the event or notification to the PI of the event. 
 
7.3 
Reporting to the Quality Assurance and Safety Monitoring Committee 
(QASMC) at Washington University 
 
The PI is required to notify the QASMC of any unanticipated problem occurring at WU 
or any BJH or SLCH institution that has been reported to and acknowledged by HRPO as 


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reportable.  (Unanticipated problems reported to HRPO and withdrawn during the review 
process need not be reported to QASMC.) 
 
QASMC must be notified within 10 days of receipt of IRB acknowledgment via email to 
a QASMC auditor. 
 
 
7.4 
Reporting to the FDA 
 
The conduct of the study will comply with all FDA safety reporting requirements.  
PLEASE NOTE THAT REPORTING REQUIREMENTS FOR THE FDA DIFFER 
FROM REPORTING REQUIREMENTS FOR HRPO/QASMC.  It is the 
responsibility of the investigator to report any unanticipated problem to the FDA as 
follows: 
 
 Report any unexpected fatal or life-threatening adverse experiences (Section 
7.1.4) associated with use of the drug  by telephone or fax no later than 7 
calendar days after initial receipt of the information.   
 Report any serious, unexpected adverse experiences (Section 7.1.2), as well as 
results from animal studies that suggest significant clinical risk within 15 
calendar days after initial receipt of this information.   
 
All MedWatch forms will be sent by the investigator or investigator’s team to the FDA at 
the following address or by fax: 
 
Food and Drug Administration 
Center for Drug Evaluation and Research 
Division of Oncology Drug Products 
5901-B Ammendale Rd. 
Beltsville, MD 20705-1266 
FAX: 1-800-FDA-0178 
 
7.5 
Reporting to CTI BioPharma, Inc. 
 
All SAEs, irrespective of causal relationship, must be reported to CTI using their SAE 
reporting form (Appendix D) within 24 hours of becoming aware of the event via either 
Fax or e-mail. 
 
Fax: (866) 660-8967 
Email: pv@ctiseattle.com 
 
Special Considerations: 
 SAEs considered to be related (ie, assessed as possibly, probably or definitely 
related) to study drug or study procedure by the investigator shall be followed 
until the event resolves, stabilizes or the patient is lost to follow up. 


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 SAEs assessed as unrelated to study drug or study procedures shall be followed 
for 30 days after last dose of study treatment, or until the event resolves, returns to 
baseline, stabilizes or the patient is lost to follow-up, whichever comes first. 
 An SAE form should be completed for any event for which doubt exists regarding 
its seriousness. If an ongoing SAE changes in intensity, relationship to study drug, 
or as new information becomes available and/or known for the event, a follow-up 
SAE Report form should be completed and sent to the CTI within 24 hours of the 
change in SAE assessment. 
 Any SAE that occurs after study completion and is considered by the investigator 
to be related to Tosedostat should be reported to CTI. 
 
A narrative outlining the details of the SAE and treatment and outcome are to be included 
on the SAE form. The narrative must state whether there is a reasonable possibility that 
study drug caused the event. Follow-up information, such as laboratory reports, discharge 
summaries, autopsy reports, and information concerning outcome of the event, should be 
submitted as soon as the information becomes available.  
 
7.6 
Timeframe for Reporting Required Events  
 
Reportable adverse events will be tracked for 30 days following the last day of study 
treatment.  
 
8.0 
PHARMACEUTICAL INFORMATION 
 
8.1 
Tosedostat 
 
8.1.1 Tosedostat Description 
 
Tosedostat is a metalloenzyme inhibitor with pleiotropic activity against a range 
of human cancer cells in vitro and in vivo. 
Molecular formula: C21H30N2O6 
Molecular weight: 407.48 daltons 
Chemical name: 2S-[2R-(S-hydroxy-hydroxycarbamoyl-methyl)-4- 
methylpentanoylamino]-2-phenylethanoic acid cyclopentyl ester 
 
8.1.2 Pharmacokinetics and Drug Metabolism 
 
Plasma protein binding for tosedostat is high in humans.  Following IV dosing, 
the major elimination route in the rat is urine; in the dog, it is feces.  Data shows 
that the tosedostat half-life is relatively short, while CHR-79888 remains present 
in the plasma and packed cells for up to 24 hours. 
 
8.1.3 Supplier(s) 
 
Tosedostat will be provided to study participants free of charge by CTI 
BioPharma, Inc. 


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8.1.4 Dosage Form and Preparation 
 
Tosedostat comes in bottles containing 30 capsules of 60 mg per capsule. 
 
8.1.5 Administration 
 
Tosedostat should be taken orally, once daily, with a glass of water after food, 
preferably in the morning, at the same time every day to ensure an even dose 
interval. 
 
8.1.6 Special Handling Instructions 
 
None. 
 
8.2 
Capecitabine (Xeloda) 
 
8.2.1 Capecitabine Description 
 
Capecitabine is a fluoropyrimidine carbamate with antineoplastic activity.  It is an 
orally administered systemic prodrug of 5’-deoxy-5-fluorouridine (5’-DFUR) 
which is converted to 5-fluorouracil. 
 
The chemical name for capecitabine is 5’-deoxy-5-fluoro-N-[(pentyloxy) 
carbonyl]-cytidine and has a molecular weight of 359.35.  Capecitabine has the 
following structural formula: 
 
 
 
8.2.2 Clinical Pharmacology 
 
Enzymes convert capecitabine to 5-fluorouracil (5-FU) in vivo. Both normal and 
tumor cells metabolize 5-FU to 5-fluoro-2’-deoxyuridine monophosphate 
(FdUMP) and 5-fluorouridine triphosphate (FUTP). These metabolites cause cell 
injury by two different mechanisms. First, FdUMP and the folate cofactor, N5-10-
methylenetetrahydrofolate, bind to thymidylate synthase (TS) to form a covalently 
bound ternary complex. This binding inhibits the formation of thymidylate from 
2’-deoxyuridylate. Thymidylate is the necessary precursor of thymidine 
triphosphate, which is essential for the synthesis of DNA, so that a deficiency of 


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this compound can inhibit cell division. Second, nuclear transcriptional enzymes 
can mistakenly incorporate FUTP in place of uridine triphosphate (UTP) during 
the synthesis of RNA. This metabolic error can interfere with RNA processing 
and protein synthesis. 
 
8.2.3 Pharmacokinetics and Drug Metabolism 
 
Following oral administration, capecitabine reached peak blood levels in about 
1.5 hours (Tmax) with peak 5-FU levels occurring slightly later, at 2 hours. 
 
Capecitabine and its metabolites are predominantly excreted in urine. 
 
8.2.4 Supplier(s) 
 
Capecitabine is commercially available and will not be provided for by this study. 
Expenses associated with this drug will be billed to a third party payer as part of 
standard of care. 
 
8.2.5 Dosage Form and Preparation 
 
Capecitabine is supplied as bioconvex, oblong film-covered tablets for oral 
administration.  It is available in 150 mg and 500 mg tablets. 
 
8.2.6 Storage and Stability 
 
Store at 25ºC; excursions permitted to 15-30ºC.  Keep tightly closed. 
 
8.2.7 Administration 
 
Capecitabine is an oral drug to be taken twice daily within 30 minutes after the 
end of a meal. 
 
8.2.8 Special Handling Instructions 
 
Care should be exercised in the handling of capecitabine.  Capecitabine tablets 
should not be cut or crushed.  The use of gloves and safety glasses is 
recommended to avoid exposure in case of breakage of tablets.  If powder from 
broken capecitabine tablets contacts the skin, wash the skin immediately and 
thoroughly with soap and water.  If capecitabine contacts the mucous membranes, 
flush thoroughly with water. 
 
 
9.0 
CORRELATIVE STUDIES 
 
9.1 
Proteomic samples  
 


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Samples will be collected for consideration of proteomic evaluation. Serum and plasma 
samples will be collected at the following time points: 
 Baseline 
 Day 1 of each cycle beginning on Cycle 2 before dosing capecitabine and 
tosedostat 
 
All samples will be taken to Dr. Wang-Gillam’s laboratory after they are drawn.  For the 
plasma proteomic studies, collect 10 mL of blood in a lavender top K2EDTA tube with a 
Hemogard stopper.  After collection of whole blood into the EDTA tube, gently invert the 
tube 10 times.  Centrifuge the blood samples immediately under refrigerated conditions 
(2-6°C) at 1300 x g for 10 minutes.  Remove plasma into a 40 mL conical tube and leave 
approximately 1 mL of plasma overlaying the cells.  Centrifuge the sample at 2400 x g 
for 15 minutes.  Transfer aliquots (0.5 mL) to the cryovials and store at -70°C until 
analysis 
 
For the serum proteomic studies, collect 10 mL of blood in a red top silica clot activator 
serum tube with a conventional stopper.  The blood sample is allowed to sit upright for 
30 minutes at room temperature.  Centrifuge blood samples under refrigerated conditions 
at 1300 x g for 10 minutes.  Remove the serum into a 40 mL conical tube and leave the 
residual serum so as not to disturb the clot.  Centrifuge the sample at 2400 x g for 15 
minutes.  Transfer aliquots (0.5 mL) to the cryovials and store at -70°C until analysis. 
 
9.2 
Tumor Specimen Collection 
 
9.2.1 Archived Formalin Fixed Paraffin Embedded Tissue Samples 
 
Formalin fixed paraffin embedded (FFPE) samples from previous diagnostic or 
therapeutic procedures for the tumors will be requested. Tissue blocks are 
preferable; however, if the tissue block cannot be obtained, 20 unstained slides 
sectioned at 5 microns will be required.   Tumor samples must be from one FFPE 
block containing viable tumor with tumor cells from the primary pancreatic 
tumor. Tumor cells must account for at least 10% of cell nuclei in the tumor-
containing regions of the block.  Unacceptable specimens include specimens 
processed using acid decalcification (EDTA is acceptable); tumor cellularity less 
than 10% in tumor involved regions of the specimen; and frozen specimens.  
Minimum sample volume is 3-1mm punches (cores); 5-5µm scrolls; or 10-5µm 
slides.  Storage/transport conditions: FFPE blocks: ambient /room temperature. 
Place in a sealed container (bag). 
 
Next generation sequencing is performed on all coding regions of ABL1, AKT1, 
ALK, APC, ASXL1, ATM, BRAF, CEBPA, CTNNB1, DNMT3A, ERBB2, 
EGFR, ESR1, FGFR4, FLT3, IDH1, IDH2, JAK2, KIT, KRAS, MAPK1(ERK), 
MAP2K2(MEK), MET, KMT2A(MLL), MPL, MYC, MYD88, NOTCH1, 
NPM1, NRAS, PDGFRA, PIK3CA, PTEN, PTPN11, RB1, RET, RUNX1, 
STK11, TET2, TP53, VHL and WT1 to detect single nucleotide variants and 
small insertions and deletions; selected introns of ALK and KMT2A(MLL) to 


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detect rearrangements.  Next generation sequencing will be performed on initial 
tumor biopsies.    
 
A GPS requisition form is obtained and completed from the Washington 
University Genomics and Pathology Services. 
  
9.2.2 Tumor Biopsy (optional) 
 
After Cycle 2, patients will have the option of having another biopsy of the 
pancreatic tumor or metastatic site to correlate with treatment response. Patients 
who have a PR will be required to undergo biopsy if deemed safe for the patient 
and tissue is feasible to obtain.  
 
Fresh tumor samples will be obtained where feasible by CT or ultrasound-guided 
core biopsy.  The samples will be snap frozen for future comprehensive genomic 
analysis.  All biopsy samples will be processed and stored in the PI’s lab.  
 
9.2.3 Evaluation of genetic alternations that potentially associated with 
treatment response 
 
Pancreatic cancer, as all human malignancies, is caused by genetic mutations.  
Mutations in KRAS, P16, TP53 and SMAD4 genes are common (1821).  With the 
advent of improved sequencing techniques, the identification of several key 
genetic alterations has led to the development of targeted therapies, such as 
imatinib and numerous EGFR-targeted therapies (cetuximab, erlotinib).  
Identifying the key genetic alterations in pancreatic cancer may lead to a better 
understanding of carcinogenesis and the development of more effective therapies.  
It is also important to analyze the somatic mutations and correlate them with 
treatment response and overall survival as there may be certain genetic alterations 
that prove to be more chemosensitive to certain drugs than others.  
 
The Genomics and Pathology Service at Washington University (GPS@WU) 
offers next-generation sequencing of tumor somatic mutations in 42 oncogenes, 
tumor suppressors, and other cancer genes.  The rationale for performing next 
generation sequencing is to identify the key genetic alterations in each patient’s 
tumor.  This information can then be used to compare patients’ clinical 
information to see if there is a correlation between response rates, overall 
survival, and specific genetic mutations.  
 
Next generation sequencing is performed on all coding regions of ABL1, AKT1, 
ALK, APC, ASXL1, ATM, BRAF, CEBPA, CTNNB1, DNMT3A, ERBB2, 
EGFR, ESR1, FGFR4, FLT3, IDH1, IDH2, JAK2, KIT, KRAS, MAPK1(ERK), 
MAP2K2(MEK), MET, KMT2A(MLL), MPL, MYC, MYD88, NOTCH1, 
NPM1, NRAS, PDGFRA, PIK3CA, PTEN, PTPN11, RB1, RET, RUNX1, 
STK11, TET2, TP53, VHL and WT1 to detect single nucleotide variants and 
small insertions and deletions; selected introns of ALK and KMT2A(MLL) to 


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detect rearrangements.  Next generation sequencing will be performed on initial 
tumor biopsies.    
 
A GPS requisition form is obtained and completed from the Washington 
University Genomics and Pathology Services 
 
9.2.4 Assessment of Amino Acid Deprivation Response 
 
Tosedostat’s proposed mechanism of action is to deplete amino acids to limit 
production of new proteins and to stimulate a stress response (amino acid 
deprivation response), which leads to increased apoptosis.  Autophagy is the 
process by which cells deliver cellular materials to lysosomes for digestion and 
autophagy is proposed to be increased in cells with nutrient deprivation (24).  The 
kinase mTOR is a critical regulator of autophagy induction and autophagyrelated 
(Atg) genes help control autophagosome formation.  Numerous gene products 
involved in autophagy, such as ATG5, ATG8, and Beclin-1 can be assessed by 
immunohistochemistry.  The slides will be stained for metalloproteases such as 
APN/CD13 and autophagy markers, which may include but are not to limited to, 
ATG 8, ATG 5, and Becline. 
 
9.3 
Pharmacokinetic Studies 
 
Serum will be collected from the patients in the phase I portion of the study at baseline 
and on Cycle 2 Day 1 in the event of unexpected toxicities to evaluate the 
pharmacokinetics. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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10.0 
STUDY CALENDAR 
 
Baseline evaluations are to be conducted within 14 days prior to start of protocol therapy.  Scans 
and x-rays must be done no more than 3 weeks prior to the start of the protocol therapy.  Cycles 
are 21 days.  All study visits must occur with in +/-3 days of the time indicated on the calendar 
(with the exception of ECHOs which must be resulted 7 days prior to Day 1 treatment). 
 
 
Screening Baseline 
D1 of 
each cycle 
End 
of C2 
End of each 
even-numbered 
cycle 
F/UA 
Informed consent 
X 
 
 
 
 
 
H&P, VS, wt, ECOG PS 
X 
 
X 
 
 
 
CBCI 
X 
 
XI 
 
 
 
CMPI 
X 
 
XI 
 
 
 
β-hCGC 
X 
 
 
 
 
 
CA19-9 
X 
 
X 
 
 
 
Troponin-I or T 
X 
 
X 
 
 
 
BNP 
X 
 
X 
 
 
 
ECHO or MUGAK 
X 
 
XJ 
 
 
XB 
ECG 
X 
 
XD 
 
 
XB 
CT scan 
X 
 
 
 
X 
 
Tosedostat 
 
 
XG 
 
 
 
Capecitabine 
 
 
XH 
 
 
 
Research blood for proteomics 
 
X 
XE 
 
 
 
Research blood for PKs  
(phase 1 only) 
 
 
XF 
 
 
 
Archival tissueL 
 
X 
 
 
 
 
Fresh biopsy 
 
 
 
XM 
 
 
AE assessmentN 
 
X 
X 
 
 
X 
A: Every 3 months for 1 year 
B: 1 month after end of study treatment, then every 6 months until the study closes 
C: Women of childbearing potential only 
D: ECG will be done weekly during Cycle 1. If ECGs are normal (or abnormal, but not related to study drug and/or 
clinically significant), ECGs will only be required on Day 1 of each cycle starting Cycle 2. However, if cycle 1 
ECGs are abnormal and related to study drug, continue weekly ECGs.  
E: Not drawn on C1D1 
F: C2 only 
G: Daily on Days 1-21 of each cycle 
H: Daily on Days 1-14 of each cycle 
I: Weekly during Cycle 1 of Phase I 
J: The screening assessment will count as the C1D1 assessment 
K. Echocardiogram preferred; prior approval from PI or designee required for MUGA 
L: If available, archival tissue to be provided 
M. Patients who have a PR will be required to undergo biopsy if deemed safe for the patient and tissue is feasible to 
obtain. 
N: From baseline through 30 days after treatment ends.  
 
 


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11.0 
DATA SUBMISSION SCHEDULE 
 
Case report forms with appropriate source documentation will be completed according to the 
schedule listed in this section. 
 
Case Report Form 
Submission Schedule 
Original Consent Form 
Prior to registration 
Registration Form 
Eligibility Form 
On-Study Form 
Prior to starting treatment 
Treatment Form 
Correlatives Form 
Every cycle 
DLT Form 
End of Cycle 1 
Toxicity Form 
Continuous 
Treatment Summary Form 
Completion of treatment 
Follow Up Form 
Every 3 months for 1 year after end of 
treatment 
Tumor Measurement Form 
Baseline, end of every even numbered 
cycles, and end of treatment 
MedWatch Form 
See Section 7.0 for reporting 
requirements 
 
 
12.0 
MEASUREMENT OF EFFECT 
 
12.1 
Antitumor Effect – Solid Tumors 
 
For the purposes of this study, patients should be re-evaluated for response every 6 
weeks.  In addition to a baseline scan, confirmatory scans should also be obtained 6 
weeks (not less than 4) weeks following initial documentation of objective response. 
 
Response and progression will be evaluated in this study using the new international 
criteria proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) 
guideline (version 1.1) [Eur J Ca 45:228-247, 2009].  Changes in the largest diameter 
(unidimensional measurement) of the tumor lesions and the shortest diameter in the case 
of malignant lymph nodes are used in the RECIST criteria. 
 
12.2 
Disease Parameters 
 
Measurable disease:  Measurable lesions are defined as those that can be accurately 
measured in at least one dimension (longest diameter to be recorded) as >20 mm by chest 
x-ray, as >10 mm with CT scan, or >10 mm with calipers by clinical exam.  All tumor 
measurements must be recorded in millimeters (or decimal fractions of centimeters). 
 
 


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Malignant lymph nodes:  To be considered pathologically enlarged and measurable, a 
lymph node must be >15 mm in short axis when assessed by CT scan (CT scan slice 
thickness recommended to be no greater than 5 mm).  At baseline and in follow-up, only 
the short axis will be measured and followed. 
 
Non-measurable disease:  All other lesions (or sites of disease), including small lesions 
(longest diameter <10 mm or pathological lymph nodes with ≥10 to <15 mm short axis), 
are considered non-measurable disease.  Bone lesions, leptomeningeal disease, ascites, 
pleural/pericardial effusions, lymphangitis cutis/pulmonitis, inflammatory breast disease, 
and abdominal masses (not followed by CT or MRI), are considered as non-measurable. 
 
Note:  Cystic lesions that meet the criteria for radiographically defined simple cysts 
should not be considered as malignant lesions (neither measurable nor non-measurable) 
since they are, by definition, simple cysts. 
 
‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable 
lesions, if they meet the definition of measurability described above. However, if non-
cystic lesions are present in the same patient, these are preferred for selection as target 
lesions. 
 
Target lesions:  All measurable lesions up to a maximum of 2 lesions per organ and 5 
lesions in total, representative of all involved organs, should be identified as target 
lesions and recorded and measured at baseline.  Target lesions should be selected on the 
basis of their size (lesions with the longest diameter), be representative of all involved 
organs, but in addition should be those that lend themselves to reproducible repeated 
measurements.  It may be the case that, on occasion, the largest lesion does not lend itself 
to reproducible measurement in which circumstance the next largest lesion which can be 
measured reproducibly should be selected.  A sum of the diameters (longest for non-
nodal lesions, short axis for nodal lesions) for all target lesions will be calculated and 
reported as the baseline sum diameters.  If lymph nodes are to be included in the sum, 
then only the short axis is added into the sum.  The baseline sum diameters will be used 
as reference to further characterize any objective tumor regression in the measurable 
dimension of the disease. 
 
Non-target lesions:  All other lesions (or sites of disease) including any measurable 
lesions over and above the 5 target lesions should be identified as non-target lesions and 
should also be recorded at baseline.  Measurements of these lesions are not required, but 
the presence, absence, or in rare cases unequivocal progression of each should be noted 
throughout follow-up.  
 
12.3 
Methods for Evaluation of Measurable Disease 
 
All measurements should be taken and recorded in metric notation using a ruler or 
calipers.  All baseline evaluations should be performed as closely as possible to the 
beginning of treatment and never more than 4 weeks before the beginning of the 
treatment. 


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The same method of assessment and the same technique should be used to characterize 
each identified and reported lesion at baseline and during follow-up. Imaging-based 
evaluation is preferred to evaluation by clinical examination unless the lesion(s) being 
followed cannot be imaged but are assessable by clinical exam. 
 
Clinical lesions:  Clinical lesions will only be considered measurable when they are 
superficial (e.g., skin nodules and palpable lymph nodes) and 10 mm diameter as 
assessed using calipers (e.g., skin nodules).  In the case of skin lesions, documentation by 
color photography, including a ruler to estimate the size of the lesion, is recommended.  
 
Chest x-ray:  Lesions on chest x-ray are acceptable as measurable lesions when they are 
clearly defined and surrounded by aerated lung.  However, CT is preferable.  
 
Conventional CT and MRI:  This guideline has defined measurability of lesions on CT 
scan based on the assumption that CT slice thickness is 5 mm or less.  If CT scans have 
slice thickness greater than 5 mm, the minimum size for a measurable lesion should be 
twice the slice thickness.  MRI is also acceptable in certain situations (e.g. for body 
scans).   
 
Use of MRI remains a complex issue.  MRI has excellent contrast, spatial, and temporal 
resolution; however, there are many image acquisition variables involved in MRI, which 
greatly impact image quality, lesion conspicuity, and measurement.  Furthermore, the 
availability of MRI is variable globally.  As with CT, if an MRI is performed, the 
technical specifications of the scanning sequences used should be optimized for the 
evaluation of the type and site of disease.  Furthermore, as with CT, the modality used at 
follow-up should be the same as was used at baseline and the lesions should be 
measured/assessed on the same pulse sequence.  It is beyond the scope of the RECIST 
guidelines to prescribe specific MRI pulse sequence parameters for all scanners, body 
parts, and diseases.  Ideally, the same type of scanner should be used and the image 
acquisition protocol should be followed as closely as possible to prior scans.  Body scans 
should be performed with breath-hold scanning techniques, if possible. 
 
PET-CT:  At present, the low dose or attenuation correction CT portion of a combined 
PET-CT is not always of optimal diagnostic CT quality for use with RECIST 
measurements.  However, if the site can document that the CT performed as part of a 
PET-CT is of identical diagnostic quality to a diagnostic CT (with IV and oral contrast), 
then the CT portion of the PET-CT can be used for RECIST measurements and can be 
used interchangeably with conventional CT in accurately measuring cancer lesions over 
time.  Note, however, that the PET portion of the CT introduces additional data which 
may bias an investigator if it is not routinely or serially performed.   
 
Ultrasound:  Ultrasound is not useful in assessment of lesion size and should not be used 
as a method of measurement.  Ultrasound examinations cannot be reproduced in their 
entirety for independent review at a later date and, because they are operator dependent, it 
cannot be guaranteed that the same technique and measurements will be taken from one 


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assessment to the next.  If new lesions are identified by ultrasound in the course of the 
study, confirmation by CT or MRI is advised.  If there is concern about radiation 
exposure at CT, MRI may be used instead of CT in selected instances. 
 
Endoscopy, Laparoscopy:  The utilization of these techniques for objective tumor 
evaluation is not advised.  However, such techniques may be useful to confirm complete 
pathological response when biopsies are obtained or to determine relapse in trials where 
recurrence following complete response (CR) or surgical resection is an endpoint. 
 
Tumor markers:  Tumor markers alone cannot be used to assess response.  If markers 
are initially above the upper normal limit, they must normalize for a patient to be 
considered in complete clinical response.  Specific guidelines for both CA-125 response 
(in recurrent ovarian cancer) and PSA response (in recurrent prostate cancer) have been 
published [JNCI 96:487-488, 2004; J Clin Oncol 17, 3461-3467, 1999; J Clin Oncol 
26:1148-1159, 2008].  In addition, the Gynecologic Cancer Intergroup has developed 
CA-125 progression criteria which are to be integrated with objective tumor assessment 
for use in first-line trials in ovarian cancer [JNCI 92:1534-1535, 2000]. 
 
Cytology, Histology:  These techniques can be used to differentiate between partial 
responses (PR) and complete responses (CR) in rare cases (e.g., residual lesions in tumor 
types, such as germ cell tumors, where known residual benign tumors can remain). 
 
The cytological confirmation of the neoplastic origin of any effusion that appears or 
worsens during treatment when the measurable tumor has met criteria for response or 
stable disease is mandatory to differentiate between response or stable disease (an 
effusion may be a side effect of the treatment) and progressive disease. 
 
FDG-PET:  While FDG-PET response assessments need additional study, it is 
sometimes reasonable to incorporate the use of FDG-PET scanning to complement CT 
scanning in assessment of progression (particularly possible 'new' disease).  New lesions 
on the basis of FDG-PET imaging can be identified according to the following algorithm:  
 
 Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of 
PD based on a new lesion. 
 No FDG-PET at baseline and a positive FDG-PET at follow-up:  If the positive 
FDG-PET at follow-up corresponds to a new site of disease confirmed by CT, this 
is PD.  If the positive FDG-PET at follow-up is not confirmed as a new site of 
disease on CT, additional follow-up CT  scans are needed to determine if there is 
truly progression occurring at that site (if so, the date of PD will be the date of the 
initial abnormal FDG-PET scan).  If the positive FDG-PET at follow-up 
corresponds to a pre-existing site of disease on CT that is not progressing on the 
basis of the anatomic images, this is not PD. 
 FDG-PET may be used to upgrade a response to a CR in a manner similar to a 
biopsy in cases where a residual radiographic abnormality is thought to represent 
fibrosis or scarring.  The use of FDG-PET in this circumstance should be 
prospectively described in the protocol and supported by disease-specific medical 


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literature for the indication.  However, it must be acknowledged that both 
approaches may lead to false positive CR due to limitations of FDG-PET and 
biopsy resolution/sensitivity. 
  
Note:  A ‘positive’ FDG-PET scan lesion means one which is FDG avid with an uptake 
greater than twice that of the surrounding tissue on the attenuation corrected image. 
 
12.4 
Response Criteria 
 
12.4.1 Evaluation of Target Lesions 
 
Complete Response (CR):  Disappearance of all target lesions.  Any pathological 
lymph nodes (whether target or non-target) must have reduction in short axis to 
<10 mm. 
 
Partial Response (PR):  At least a 30% decrease in the sum of the diameters of 
target lesions, taking as reference the baseline sum diameters. 
 
Progressive Disease (PD):  At least a 20% increase in the sum of the diameters 
of target lesions, taking as reference the smallest sum on study (this includes the 
baseline sum if that is the smallest on study).  In addition to the relative increase 
of 20%, the sum must also demonstrate an absolute increase of at least 5 mm.  
(Note:  the appearance of one or more new lesions is also considered 
progressions). 
 
Stable Disease (SD):  Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum diameters while 
on study. 
 
12.4.2 Evaluation of Non-Target Lesions 
 
Complete Response (CR):  Disappearance of all non-target lesions and 
normalization of tumor marker level.  All lymph nodes must be non-pathological 
in size (<10 mm short axis). 
 
Note:  If tumor markers are initially above the upper normal limit, they must 
normalize for a patient to be considered in complete clinical response. 
 
Non-CR/Non-PD:  Persistence of one or more non-target lesion(s) and/or 
maintenance of tumor marker level above the normal limits. 
 
Progressive Disease (PD):  Appearance of one or more new lesions and/or 
unequivocal progression of existing non-target lesions.  Unequivocal progression 
should not normally trump target lesion status.  It must be representative of 
overall disease status change, not a single lesion increase.     
 


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Although a clear progression of “non-target” lesions only is exceptional, the 
opinion of the treating physician should prevail in such circumstances, and the 
progression status should be confirmed at a later time by the review panel (or 
Principal Investigator). 
 
12.4.3 Evaluation of Best Overall Response 
 
The best overall response is the best response recorded from the start of the 
treatment until disease progression/recurrence (taking as reference for progressive 
disease the smallest measurements recorded since the treatment started).  The 
patient's best response assignment will depend on the achievement of both 
measurement and confirmation criteria. 
    
For Patients with Measurable Disease (i.e., Target Disease) 
Target Lesions Non-Target 
Lesions 
New 
Lesions 
Overall 
Response 
Best Overall Response when 
Confirmation is Required* 
CR 
CR 
No 
CR 
>4 wks. Confirmation** 
CR 
Non-CR/Non-
PD 
No 
PR 
>4 wks. Confirmation** 
CR 
Not evaluated 
No 
PR 
PR 
Non-CR/Non-
PD/not 
evaluated 
No 
PR 
SD 
Non-CR/Non-
PD/not 
evaluated 
No 
SD 
Documented at least once >4 
wks. from baseline** 
PD 
Any 
Yes or No 
PD 
no prior SD, PR or CR 
Any 
PD*** 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
* 
See RECIST 1.1 manuscript for further details on what is evidence of a new lesion. 
** 
Only for non-randomized trials with response as primary endpoint. 
*** 
In exceptional circumstances, unequivocal progression in non-target lesions may be 
accepted as disease progression. 
Note: 
Patients with a global deterioration of health status requiring discontinuation of 
treatment without objective evidence of disease progression at that time should be reported 
as “symptomatic deterioration.”  Every effort should be made to document the objective 
progression even after discontinuation of treatment. 
 
                                      For Patients with Non-Measurable Disease (i.e., Non-Target Disease) 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD* 
Not all evaluated 
No 
not evaluated 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
*  ‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since 
SD is increasingly used as an endpoint for assessment of efficacy in some trials so to 
assign this category when no lesions can be measured is not advised 


Protocol Version: 07/11/17 
 
Page 41 of 57 
 
 
12.4.4 Duration of Response 
 
Duration of overall response:  The duration of overall response is measured 
from the time measurement criteria are met for CR or PR (whichever is first 
recorded) until the first date that recurrent or progressive disease is objectively 
documented (taking as reference for progressive disease the smallest 
measurements recorded since the treatment started). 
 
The duration of overall CR is measured from the time measurement criteria are 
first met for CR until the first date that progressive disease is objectively 
documented.  
 
Duration of stable disease:  Stable disease is measured from the start of the 
treatment until the criteria for progression are met, taking as reference the 
smallest measurements recorded since the treatment started, including the baseline 
measurements.  
 
12.4.5 Progression-Free Survival 
 
PFS is defined as the duration of time from start of treatment to time of 
progression or death, whichever occurs first. 
 
 
13.0 
DATA AND SAFETY MONITORING 
 
In compliance with the Washington University Institutional Data and Safety Monitoring Plan, 
the Principal Investigator will provide a Data and Safety Monitoring (DSM) report to the 
Washington University Quality Assurance and Safety Monitoring Committee (QASMC) semi-
annually beginning six months after accrual has opened (if at least five patients have been 
enrolled) or one year after accrual has opened (if fewer than five patients have been enrolled at 
the six-month mark). 
 
During the phase I dose escalation, the Principal Investigator will review all patient data at least 
monthly (or before each dose-escalation if occurring sooner than monthly), and provide a semi-
annual report to the Quality Assurance and Safety Monitoring Committee (QASMC).  During the 
phase II, the Principal Investigator will review all patient data at least every six months, and 
provide a semi-annual report to the QASMC. This report will include: 
 HRPO protocol number, protocol title, Principal Investigator name, data coordinator 
name, regulatory coordinator name, and statistician 
 Date of initial HRPO approval, date of most recent consent HRPO approval/revision, 
date of HRPO expiration, date of most recent QA audit, study status, and phase of 
study 
 History of study including summary of substantive amendments; summary of accrual 
suspensions including start/stop dates and reason; and summary of protocol 
exceptions, error, or breach of confidentiality including start/stop dates and reason 


Protocol Version: 07/11/17 
 
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 Study-wide target accrual and study-wide actual accrual 
 Protocol activation date 
 Average rate of accrual observed in year 1, year 2, and subsequent years 
 Expected accrual end date and accrual by cohort 
 Objectives of protocol with supporting data and list the number of participants who 
have met each objective 
 Measures of efficacy 
 Early stopping rules with supporting data and list the number of participants who 
have met the early stopping rules 
 Summary of toxicities separated by cohorts with the number of dose-limiting 
toxicities indicated 
 Abstract submissions/publications 
 Summary of any recent literature that may affect the safety or ethics of the study  
 
The study principal investigator and Research Patient Coordinator will monitor for serious 
toxicities on an ongoing basis. Once the principal investigator or Research Patient Coordinator 
becomes aware of an adverse event, the AE will be reported to the HRPO and QASMC 
according to institutional guidelines. 
 
 
14.0 
STATISTICAL CONSIDERATIONS 
 
14.1 
Sample Size 
 
In the phase I part of the study, a de-escalation 3+3 design is used to determine the 
recommended phase II dose of tosedostat when combined with capecitabine in patients 
with advanced or metastatic pancreatic adenocarcinoma.  The miminal number of patients 
needed for the phase I part of the study is 6 patients assuming no DLT is observed in 
Dose Level 1. The maximal number of patients is 12 patients.  
 
For the phase II part of the study, the primary endpoint of the study is to assess the 
progression-free survival  (PFS) of the combination therapy.  Based on historical data, the 
PFS of 2.0 months was observed wtih either 5-FU or capecitabine in the second-line 
setting, so a  median PFS of 4 months for the combination reigmen would be considered 
clininally meaningful for further development. With a sample size of 36 patients 
including 3-6 patients from the phase I portion, the study has power 0.80 to identify an 
increase of the median PFS (2.0 to 4.0 months) at a 0.05 significance level, assuming 12 
months of accrual and 6 months of follow-up. We will consider this phase II part as a 
pilot study for the PFS as endpoint; therefore a sample size of 36 is adequate. We expect 
to enroll 3-4 patients per month; therefore it is feasible to recruit 36 patients within 1 
year.  
 
14.2 
Data Analysis 
 
PFS and OS will be estimated by Kaplan-Meier product limit method. The progression-


Protocol Version: 07/11/17 
 
Page 43 of 57 
free survival and overall survival probabilities at certain time points (e.g. 3 months, 6 
months) will be presented as well. The overall response rate (ORR) and CA19-9 response 
will be characterized by summary statistics (frequency and proportion). The logistic 
regression model will be considered to explore the predictive molecular biomarkers, the 
prognostic biomarkers for treatment response, and to investigate the correlation between 
genetic alterations and response to treatment. 
 
14.3 
Interim Analysis 
 
After 10 evaluable patients have enrolled to the phase II portion of the study, an interim 
analysis will be conducted to look at response to date to assess for continuation of the 
study.  
 
 
 
 
 


Protocol Version: 07/11/17 
 
Page 44 of 57 
14. 
REFERENCES 
 
1. Siegel R, Naishadham D, Jemal A.  Cancer Statistics.  CA Cancer J Clin. 2013.  63:11-30 
2. Conroy T, Desseigne F., Ychou M, et al.  FOLFIRINOX versus gemcitabine for metastatic 
pancreatic cancer.  N Engl J Med.  2011.  364(19):1817-1825. 
3. Morertel C.  Chemotherapy of gastrointestinal cancers.  N Engl J Med.  1978.  299(19):1049-
1052. 
4. Burris H, Moore M, Andersen J, et al.  Improvements in survival and clinical benefit with 
gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized 
trial.  J Clin Oncol.  1997.  15(6):2403-2413. 
5. Von Hoff D, Ervin T, Arena F, et al.  Increased survival in pancreatic cancer with nab-
paclitaxel plus gemcitabine.  N Engl J Med.  2013.  369(18):1691-1703. 
6. Pelzer U, Schwaner I, Stieler J, et al.  Best supportive care (BSC) versus oxaliplatin, folinic 
acid and 5-fluorouracil (OFF) plus BSC in patients for second-line advanced pancreatic 
cancer: a phase III-study from the German CONKO-study group.  Eur J Cancer.  2011.  
47(11):1676-1681.  
7. Oettle H, Riess H, Stieler J, et al.  Second-Line Oxaliplatin, Folinic Acid, and Fluorouracil 
Versus Folinic Acid and Fluorouracil Alone for Gemcitabine-Refractory Pancreatic Cancer: 
Outcomes From the CONKO-003 Trial.  J Clin Oncol.  2014; Epub ahead of print.  
8. Hurwitz H, Uppal N, Wagner SA, et al.  A Randomized Double-Blind Phase 2 Study of 
Ruxolitinib or Placebo with Capecitabine as Second-line Therapy in Patients with Metastatic 
Pancreatic Cancer.  Oral presentation at ASCO 2014.   
9. Von Hoff D, Li CP, Wang-Gillam A, et al.  NAPOLI-1: Randomized Phase 3 Study of MM-
398 (NAL-IRI), with or Without 5-Fluorouracil and Leucovorin, Versus 5-Fluorouracil and 
Leucovorin, in Metastatic Pancreatic Cancer Progressed On Or Following Gemcitabine-
Based Therapy.  Oral presentation at ESMO 16th World Congress on Gastrointestinal Cancer, 
2014. 
10. Hashida H, Takabayashi A, Kanai et al.  Aminopeptidase N is involved in cell motility and 
angiogenesis: its clinical significance in human colon cancer.  Gastroenterology.  2002.  
122(2):376-386. 
11. Dubois, RN.  Leukotriene A4 signaling, inflammation, and cancer.  J Natl Cancer Inst.  2003.  
95(14):1028-1029. 
12. Chen X, Li N, Wang S, et al.  Leukotriene A4 hydrolase in rat and human esophageal 
adenocarcinoma and inhibitory effects of bestatin.  J Natl Cancer Inst.  2003.  95(14):1053-
1061.  
13. Ikeda N, Nakajima Y, Tokuhara T, et al.  Clinical significance of aminopeptidase N/CD13 
expression in human pancreatic carcinoma.  Clin Cancer Res.  2003.  9(4):1503-1508.  
14. Saric T, Graef C, Goldberg A.  Pathway for degradation of peptides generated by 
proteasomes: a key role for thimet oliopeptidase and other metallopeptidases.  J Biol Chem.  
2004.  279(45):46723-46732.   
15. Krige D, Needham L, Bawden L, et al.  CHR-2797: An antiproliferative 
aminopeptidaseinhibitor that leads to amino acid deprivation in human leukemic cells.  
Cancer Res.  2008.  68(16):6669-6679. 
16. Wickstrom M, Larsson R, Nygren P, et al.  Aminopeptidase N (CD13) as a target for cancer 
chemotherapy.  Cancer Sci.  2011.  102(3):501-508.  


Protocol Version: 07/11/17 
 
Page 45 of 57 
17. Reid A, Protheroe A, Attard G, et al.  A first-in-man phase I and pharmacokinetic study on 
CHR-2797 (Tosedostat), an inhibitor of M1 aminopeptidases, in patients with advanced solid 
tumors.  Clin Cancer Res.  2009.  15(15):4978-4985.  
18. Van Herpen C, Eskens F, de Jonge M, et al.  A phase Ib dose-escalation study to evaluate 
safety and tolerability of the addition of the aminopeptidase inhibitor tosedostat (CHR-2797) 
to paclitaxel in patients with advanced solid tumours.  Br J Cancer.  2010.  103(9):1362-
1368.  
19. Ikeda N, Nakajima Y, Tokuhara T, et al.  Clinical significance of aminopeptidase N/CD13 
expression in human pancreatic carcinoma.  Clin Cancer Res.  2003.  9(4):1503-1508. 
20. Lowenberg B, Morgan G, Ossenkoppele G, et al.  Phase I/II clinical study of Tosedostat, an 
inhibitor of aminopeptidases, in patients with acute myeloid leukemia and myelodysplasia.  J 
Clin Oncol.  2010.  28(28):4333-4338. 
21. Biankin A, Waddell N, Kassahn K, et al.  Pancreatic cancer genomes reveal aberrations in 
axon guidance pathway genes.  Nature.  2012.  491(7424):399-405.  
24. Mortimore G, and Schworer, C.  Induction of autophagy by amino-acid deprivation in 
perfused rat liver.  Nature.  1977.  270:174-176.  
 
 
We would like to thank the Alvin J. Siteman Cancer Center at Washington University School of 
Medicine and Barnes-Jewish Hospital in St. Louis, Missouri, for the use of the Clinical Trials 
Core which provided protocol development services. The Siteman Cancer Center is supported in 
part by an NCI Cancer Center Support Grant #P30 CA91842. 
 
 
 


Protocol Version: 07/11/17 
 
Page 46 of 57 
APPENDIX A: ECOG Performance Status Scale 
 
 
Grade 
 
 
Description 
0 
Normal activity.  Fully active, able to carry on all pre-disease 
performance without restriction. 
1 
Symptoms, but ambulatory.  Restricted in physically strenuous 
activity, but ambulatory and able to carry out work of a light or 
sedentary nature (e.g., light housework, office work). 
2 
In bed <50% of the time.  Ambulatory and capable of all self-care, but 
unable to carry out any work activities.  Up and about more than 50% 
of waking hours. 
3 
 
In bed >50% of the time.  Capable of only limited self-care, confined 
to bed or chair more than 50% of waking hours. 
 
4 
100% bedridden.  Completely disabled.  Cannot carry on any self-care.  
Totally confined to bed or chair. 
5 
 
Dead. 
 
 
 
 


Protocol Version: 07/11/17 
 
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APPENDIX B: PATIENT’S MEDICATION DIARY 
 
Today’s Date:   
 
      
Cycle:             
Patient Name:    
 
 
      Study ID#:    
 
 
 
INSTRUCTIONS TO THE PATIENT: 
1. Take _____mg ( ___capsules) of tosedostat daily, for 21 days, in the morning after food at approximately the same time 
each day.  Take it with a glass of water.  Swallow the capsules whole and do not chew the capsules. 
2. Take _____mg in the AM ( ___tablets) and _____mg in the PM (___tablets) of capecitabine twice daily, for 14 days, after 
food at approximately the same times each day.  Take it with a glass of water.  Swallow the tablets whole and do not 
chew the tablets. 
3. Record the date, the number of capsules and tablets taken, and when you took them. 
4. If you forget to take any doses within 6 hours of the usual time, then do not take that dose.  Restart at the next time you 
would normally take a dose. 
5. If you notice any side effects, please record them in the comments section.  Record the time if you should vomit. 
6. Please return the forms to your physician or your study coordinator when you go to your next appointment.  Please bring 
your unused study medications and/or empty bottles with you to each clinic visit so that a pill count can be done. 
Day 
Date 
Tosedostat 
Capecitabine AM  
Capecitabine PM  
Comments 
Time 
# of 
capsules 
Time 
# of 
tablets 
Time 
# of 
tablets 
1 
 
 
 
 
 
 
 
 
2 
 
 
 
 
 
 
 
 
3 
 
 
 
 
 
 
 
 
4 
 
 
 
 
 
 
 
 
5 
 
 
 
 
 
 
 
 
6 
 
 
 
 
 
 
 
 
7 
 
 
 
 
 
 
 
 
8 
 
 
 
 
 
 
 
 
9 
 
 
 
 
 
 
 
 
10 
 
 
 
 
 
 
 
 
11 
 
 
 
 
 
 
 
 
12 
 
 
 
 
 
 
 
 
13 
 
 
 
 
 
 
 
 
14 
 
 
 
 
 
 
 
 
15 
 
 
 
 
 
 
DO NOT TAKE CAPECITABINE 
BEYOND DAY 14 
 
 
 
 
16 
 
 
 
 
17 
 
 
 
 
18 
 
 
 
 
19 
 
 
 
 
20 
 
 
 
 
21 
 
 
 
 
 
 
 
 
 
 
 
 


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APPENDIX C: List of QT Prolonging Medications 
 
The following table presents a list of drugs that prolong, may prolong or are unlikely to prolong the QTc. 
Please note that this list is frequently updated. For the most current list of medications, users should be 
directed to the following website: http://www.azcert.org/medical-pros/drug-lists/drug-lists.cfm. 
 
Generic Name 
Brand Names 
Risk Category 
Albuterol (salbutamol) 
Proventil®, Ventolin®, 
Ventolin-HFA®, 
Accuneb®, 
Combivent®, Vospire-
ER®, ProAir HFA®, 
Duoneb® 
Avoid in congenital long QT 
Alfuzosin 
Uroxatral® 
Possible Risk of TdP 
Amantadine 
Symmetrel®, 
Symadine® 
Conditional Risk of TdP 
Amiodarone 
Cordarone®, 
Pacerone®, Nexterone® 
Risk of TdP 
Amisulpride 
Solian®, Supitac®, 
Soltus®, Amitrex®, 
Amazeo® 
Conditional Risk of TdP 
Amitriptyline 
Elavil® (Discontinued 
6/13), Tryptomer®, 
Tryptizol®, Laroxyl®, 
Saroten®, Sarotex® 
Lentizol®, Endep® 
Conditional Risk of TdP 
Amoxapine 
Asendin®, Amokisan®, 
Asendis®, Defanyl®, 
Demolox®, Moxadil® 
Conditional Risk of TdP 
Amphetamine 
Adderal-XR®, 
Dexedrine®, 
Dextroamp® 
Avoid in congenital long QT 
Anagrelide 
Agrylin®, Xagrid® 
Risk of TdP 
Apomorphine 
Apokyn®, Ixense®, 
Spontane®, Uprima® 
Possible Risk of TdP 
Arformoterol 
Brovana® 
Avoid in congenital long QT 
Aripiprazole 
Abilify®, Aripiprex® 
Possible Risk of TdP 
Arsenic trioxide 
Trisenox® 
Risk of TdP 
Astemizole (Off US mkt) 
Hismanal® 
Risk of TdP 
Atazanavir 
Reyataz® 
Possible Risk of TdP 
Atomoxetine 
Strattera® 
Avoid in congenital long QT 
Azithromycin 
Zithromax®, Zmax® 
Risk of TdP 
Bedaquiline 
Sirturo® 
Possible Risk of TdP 
Bepridil (Off US mkt) 
Vascor® 
Risk of TdP 
Bortezomib 
Velcade®, Bortecad® 
Possible Risk of TdP 
Bosutinib 
Bosulif® 
Possible Risk of TdP 
Chloral hydrate 
Aquachloral®, Novo-
Chlorhydrate®, 
Somnos®, Noctec®, 
Conditional Risk of TdP 


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Somnote® 
Chloroquine 
Aralen® 
Risk of TdP 
Chlorpromazine 
Thorazine®, Largactil®, 
Megaphen® 
Risk of TdP 
Ciprofloxacin 
Cipro®, Cipro-XR®, 
Neofloxin® 
Conditional Risk of TdP 
Cisapride (Off US mkt) 
Propulsid® 
Risk of TdP 
Citalopram 
Celexa®, Cipramil® 
Risk of TdP 
Clarithromycin 
Biaxin®, Prevpac® 
Risk of TdP 
Clomipramine 
Anafranil® 
Conditional Risk of TdP 
Clozapine 
Clozaril®, Fazaclo®, 
Versacloz® 
Possible Risk of TdP 
Cocaine 
Cocaine 
Risk of TdP 
Crizotinib 
Xalkori® 
Possible Risk of TdP 
Dabrafenib 
Tafinlar® 
Possible Risk of TdP 
Dasatinib 
Sprycel® 
Possible Risk of TdP 
Desipramine 
Pertofrane®, 
Norpramine® 
Conditional Risk of TdP 
Dexmedetomidine 
Precedex®, Dexdor®, 
Dexdomitor® 
Possible Risk of TdP 
Dexmethylphenidate 
Focalin®, Focalin-XR® 
Avoid in congenital long QT 
Dextroamphetamine (d-
Amphetamine) 
Dexedrine®, 
dexamphetamine, 
dexamfetamine, (S)-(+)-
amphetamine, 
Dextrostat® 
Avoid in congenital long QT 
Dihydroartemisinin+piperaquine 
Eurartesim® 
Possible Risk of TdP 
Diphenhydramine 
Benadryl®, Nytol®, 
Unisom®, Sominex®, 
Dimedrol®, Daedalon® 
Conditional Risk of TdP 
Disopyramide 
Norpace® 
Risk of TdP 
Dobutamine 
Dobutrex® 
Avoid in congenital long QT 
Dofetilide 
Tikosyn® 
Risk of TdP 
Dolasetron 
Anzemet® 
Possible Risk of TdP 
Domperidone (Not on US mkt) 
Motilium®, 
Motillium®, Motinorm 
Costi®, Nomit® 
Risk of TdP 
Dopamine 
Intropine® 
Avoid in congenital long QT 
Doxepin 
Sinequan®, Silenor®, 
Aponal®, Adapine®, 
Doxal®, Deptran®, 
Sinquan® 
Conditional Risk of TdP 
Dronedarone 
Multaq® 
Risk of TdP 
Droperidol 
Inapsine®, Droleptan®, 
Dridol®, Xomolix® 
Risk of TdP 
Ephedrine 
Rynatuss®, 
Broncholate® 
Avoid in congenital long QT 
Epinephrine (Adrenaline) 
Primatene®, Bronkaid® 
Avoid in congenital long QT 
Eribulin 
Halaven® 
Possible Risk of TdP 


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Erythromycin 
E.E.S.®, Robimycin®, 
EMycin®, Erymax®, 
Ery-Tab®, Eryc 
Ranbaxy®, Erypar®, 
Eryped®, Erythrocin 
Stearate Filmtab®, 
Erythrocot®, E-Base®, 
Erythroped®, Ilosone®, 
MY-E®, Pediamycin®, 
Zineryt®, Abboticin®, 
Abboticin-ES®, 
Erycin®, PCE 
Dispertab®, 
Stiemycine®, Acnasol®, 
Tiloryth® 
Risk of TdP 
Escitalopram 
Cipralex®, Lexapro®, 
Nexito®, Anxiset-E® 
(India), Exodus® 
(Brazil), Esto® (Israel), 
Seroplex®, Elicea®, 
Lexamil®, Lexam®, 
Entact® (Greece), 
Losita® (Bangladesh), 
Reposil® (Chile), 
Animaxen® (Colombia), 
Esitalo® (Australia), 
Lexamil® (South 
Africa) 
Risk of TdP 
Famotidine 
Pepcid®, Fluxid®, 
Quamatel® 
Possible Risk of TdP 
Felbamate 
Felbatol® 
Possible Risk of TdP 
Fenfluramine (Off US mkt) 
Pondimin®, Ponderax®, 
Adafax® 
Avoid in congenital long QT 
Fingolimod 
Gilenya® 
Possible Risk of TdP 
Flecainide 
Tambocor®, 
Almarytm®, Apocard®, 
Ecrinal®, Flécaine® 
Risk of TdP 
Fluconazole 
Diflucan®, Trican® 
Conditional Risk of TdP 
Fluoxetine 
Prozac®, Sarafem®, 
Fontex® 
Conditional Risk of TdP 
Formoterol 
Foradil®, Foradile®, 
Oxeze®, Oxis®, 
Atock®, Atimos®, 
Atimos Modulite®, 
Perforomist®, Dulera®, 
Symbiocort®, 
Vannair®, Quikhale 
FB® 
Avoid in congenital long QT 
Foscarnet 
Foscavir® 
Possible Risk of TdP 
Fosphenytoin 
Cerebyx®, Prodilantin® 
Possible Risk of TdP 


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Furosemide (Frusemide) 
Lasix®, Fusid®, 
Frumex® 
Conditional Risk of TdP 
Galantamine 
Reminyl®, Nivalin®, 
Razadyne-ER®, 
Conditional Risk of TdP 
Gatifloxacin (Off US mkt) 
Tequin® 
Possible Risk of TdP 
Gemifloxacin 
Factive® 
Possible Risk of TdP 
Granisetron 
Kytril®, Sancuso®, 
Granisol® 
Possible Risk of TdP 
Grepafloxacin (Off market 
worldwide) 
Raxar® 
Risk of TdP 
Halofantrine 
Halfan® 
Risk of TdP 
Haloperidol 
Haldol® (US & UK), 
Aloperidin®, 
Bioperidolo®, 
Brotopon®, Dozic®, 
Duraperidol® 
(Germany), Einalon S®, 
Eukystol®, Halosten®, 
Keselan®, Linton®, 
Peluces®, Serenace®, 
Serenase®, 
Sigaperidol® 
Risk of TdP 
Hydrochlorothiazide 
Apo-Hydro®, Aquazide 
H®, BP Zide®, 
Dichlotride®, 
Hydrodiuril®, 
HydroSaluric®, 
Hydrochlorot®, 
Microzide®, Esidrex®, 
Oretic® 
Conditional Risk of TdP 
Ibutilide 
Corvert® 
Risk of TdP 
Iloperidone 
Fanapt®, Fanapta®, 
Zomaril® 
Possible Risk of TdP 
Imipramine (melipramine) 
Tofranil® 
Conditional Risk of TdP 
Indapamide 
Lozol®, Natrilix®, 
Insig® 
Conditional Risk of TdP 
Isoproterenol 
Medihaler-Iso®, 
Isuprel® 
Avoid in congenital long QT 
Isradipine 
Dynacirc® 
Possible Risk of TdP 
Itraconazole 
Sporanox®, Onmel® 
Conditional Risk of TdP 
Ivabradine (Not on US mkt) 
Procoralan®, Coralan®, 
Corlentor®, Coraxan®, 
Ivabid®, Bradia® 
Conditional Risk of TdP 
Ketoconazole 
Nizoral®, Sebizole®, 
Ketomed®, Keton® 
Conditional Risk of TdP 
Lapatinib 
Tykerb®, Tyverb® 
Possible Risk of TdP 
Levalbuterol (levsalbutamol) 
Xopenex®, Levolin®, 
Axazest® 
Avoid in congenital long QT 
Levofloxacin 
Levaquin®, Tavanic® 
Risk of TdP 
Levomethadyl (Off US mkt) 
Orlaam® 
Risk of TdP 


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Lisdexamfetamine 
Vyvanse® 
Avoid in congenital long QT 
Lithium 
Eskalith®, Lithobid® 
Possible Risk of TdP 
Mesoridazine (Off US mkt) 
Serentil® 
Risk of TdP 
Metaproterenol 
Metaprel®, Alupent® 
Avoid in congenital long QT 
Methadone 
Dolophine®, 
Symoron®, Amidone®, 
Methadose®, 
Physeptone®, 
Heptadon® 
Risk of TdP 
Methamphetamine 
(methamfetamine) 
Desoxyn®, Pervitin®, 
Anadrex®, 
Methedrine®, Syndrox® 
Avoid in congenital long QT 
Methylphenidate 
Ritalin®, Concerta®, 
Focalin®, Daytrana®, 
Methylin® 
Avoid in congenital long QT 
Metronidazole 
Flagyl® and many 
others 
Conditional Risk of TdP 
Midodrine 
ProAmatine®, 
Amatine®, Gutron® 
Avoid in congenital long QT 
Mifepristone 
Korlym®, Mifeprex® 
Possible Risk of TdP 
Mirabegron 
Myrbetriq® 
Possible Risk of TdP 
Mirtazapine 
Remeron 
Possible Risk of TdP 
Moexipril/HCTZ 
Uniretic®, Univasc® 
Possible Risk of TdP 
Moxifloxacin 
Avelox®, Avalox®, 
Avelon® 
Risk of TdP 
Nelfinavir 
Viracept® 
Conditional Risk of TdP 
Nicardipine 
Cardene® 
Possible Risk of TdP 
Nilotinib 
Tasigna® 
Possible Risk of TdP 
Norepinephrine (noradrenaline) 
Levophed® 
Avoid in congenital long QT 
Norfloxacin 
Noroxin®, Ambigram® 
Possible Risk of TdP 
Nortriptyline 
Pamelor®, Sensoval®, 
Aventyl®, Norpress®, 
Allegron®, Noritren®, 
Nortrilen® 
Conditional Risk of TdP 
Ofloxacin 
Floxin® 
Possible Risk of TdP 
Olanzapine 
Zyprexa®, Zydis®, 
Relprevv® 
Possible Risk of TdP 
Ondansetron 
Zofran®, Anset®, 
Ondemet®, Zuplenz®, 
Emetron®, Ondavell®, 
Emeset®, Ondisolv®, 
Setronax® 
Risk of TdP 
Oxytocin 
Pitocin®, Syntocinon® 
Possible Risk of TdP 
Paliperidone 
Invega®, Xepilon® 
Possible Risk of TdP 
Pantoprazole 
Protonix® and others 
Conditional Risk of TdP 
Paroxetine 
Paxil®, Aropax®, 
Pexeva®, Seroxat®, 
Sereupin® 
Conditional Risk of TdP 
Pasireotide 
Signifor® 
Possible Risk of TdP 
Pazopanib 
Votrient® 
Possible Risk of TdP 


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Pentamidine 
Pentam® 
Risk of TdP 
Perflutren lipid microspheres 
Definity® 
Possible Risk of TdP 
Phentermine 
Adipex P®, Adiphene® 
(India), Anoxine-AM®, 
Ionamin®, Duromine®, 
Metermine®, 
Miraprontv, Obephen®, 
Obermine®, Obestin-
30®, Phentremine®, 
Phentrol®, Phenterex®, 
Phentromin®, Pro-Fast 
SA®, Redusa®, 
Panbesy®, Obenix®, 
Oby-Trim®, 
Teramine®, Zantryl®, 
Sinpet®, Supremin®, 
Suprenza®, Umine®, 
Weltmine® 
Avoid in congenital long QT 
Phenylephrine 
Neosynephrine® 
Avoid in congenital long QT 
Phenylpropanolamine 
Acutrim®, Dexatrim® 
Avoid in congenital long QT 
Pimozide 
Orap® 
Risk of TdP 
Pipamperone (Not on US Mkt) 
Dipiperon (E.U), 
Propitan (Japan) 
Possible Risk of TdP 
Posaconazole 
Noxafil®, Posamol® 
Conditional Risk of TdP 
Probucol (Off US mkt) 
Lorelco® 
Risk of TdP 
Procainamide (Oral off US mkt) 
Pronestyl®, Procan® 
Risk of TdP 
Promethazine 
Phenergan® 
Possible Risk of TdP 
Protriptyline 
Vivactil® 
Conditional Risk of TdP 
Pseudoephedrine 
PediaCare®, Sudafed® 
Avoid in congenital long QT 
Quetiapine 
Seroquel® 
Possible Risk of TdP 
Quinidine 
Quinaglute®, 
Duraquin®, Quinact®, 
Quinidex®, Cin-Quin®, 
Quinora® 
Risk of TdP 
Quinine sulfate 
Qualaquin® 
Conditional Risk of TdP 
Ranolazine 
Ranexa®, Ranozex® 
Possible Risk of TdP 
Rilpivirine 
Edurant®, Complera®, 
Eviplera® 
Possible Risk of TdP 
Risperidone 
Risperdal® 
Possible Risk of TdP 
Ritodrine (Off US mkt) 
Yutopar® 
Avoid in congenital long QT 
Ritonavir 
Norvir® 
Conditional Risk of TdP 
Roxithromycin (Not on US Mkt) 
Rulide®, Xthrocin®, 
Roxl-150®, Roxo®, 
Surlid®, Rulide®, 
Biaxsig®, Roxar®, 
Roximycinv®, 
Roxomycin®, Rulid®, 
Tirabicin®, Coroxin® 
Possible Risk of TdP 
Salmeterol 
Serevent® 
Avoid in congenital long QT 
Saquinavir 
Invirase®(combo) 
Possible Risk of TdP 


Protocol Version: 07/11/17 
 
Page 54 of 57 
Sertindole (Not on US mkt) 
Serdolect®, Serlect® 
Possible Risk of TdP 
Sertraline 
Zoloft®, Lustral®, 
Daxid®, Altruline®, 
Besitran®, Deprax®, 
Elrval®, Emergen®, 
Gladem®, Implicane®, 
Sedoran®, Sealdin®, 
SerivoLowfin®, 
Stimuloton®, 
Tresleen®, Sertralin 
Bluefish® 
Conditional Risk of TdP 
Sevoflurane 
Ulane®, Sojourn® 
Risk of TdP 
Sibutramine (Off US mkt) 
Meridia® 
Avoid in congenital long QT 
Solifenacin 
VESIcare® 
Conditional Risk of TdP 
Sorafenib 
Nexavar® 
Possible Risk of TdP 
Sotalol 
Betapace®, Sotalex®, 
Sotacor® 
Risk of TdP 
Sparfloxacin (Off US mkt) 
Zagam® 
Risk of TdP 
Sulpiride (Not on US Mkt.) 
Dogmatil®, Dolmatil®, 
Eglonyl®, Espiride®, 
Modal®, Sulpor® 
Risk of TdP 
Sunitinib 
Sutent® 
Possible Risk of TdP 
Tacrolimus 
Prograf®, Prograf®, 
Advagraf®, Protopic® 
Possible Risk of TdP 
Tamoxifen 
Nolvadex®(discontinued 
6/13), Istubal®, 
Valodex® 
Possible Risk of TdP 
Telaprevir 
Incivek®, Incivo® 
Conditional Risk of TdP 
Telavancin 
Vibativ® 
Possible Risk of TdP 
Telithromycin 
Ketek® 
Possible Risk of TdP 
Terbutaline 
Brethine®, Bricanyl®, 
Brethaire®, Terbulin® 
Avoid in congenital long QT 
Terfenadine (Off US mkt) 
Seldane® 
Risk of TdP 
Tetrabenazine (Orphan drug in 
US) 
Nitoman®, Xenazine® 
Possible Risk of TdP 
Thioridazine 
Mellaril®, 
Novoridazine®, 
Thioril® 
Risk of TdP 
Tizanidine 
Zanaflex®, Sirdalud® 
Possible Risk of TdP 
Tolterodine 
Detrol®, Detrusitol® 
Possible Risk of TdP 
Toremifene 
Fareston® 
Possible Risk of TdP 
Trazodone 
Desyrel® (discontinued 
6/13), Oleptro®, 
Beneficat®, Deprax®, 
Desirel®, Molipaxin®, 
Thombran®, Trazorel®, 
Trialodine®, Trittico®, 
Mesyrel® 
Conditional Risk of TdP 
Trimethoprim-Sulfa 
Septra®, Bactrim®, 
Sulfatrim®, Biseptol®, 
Conditional Risk of TdP 


Protocol Version: 07/11/17 
 
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Co-trimoxazole®, 
Cotrim®, Septrin®, 
Trisul® 
Trimipramine 
Surmontil®, 
Rhotrimine®, Stangyl® 
Conditional Risk of TdP 
Vandetanib 
Caprelsa® 
Risk of TdP 
Vardenafil 
Levitra® 
Possible Risk of TdP 
Vemurafenib 
Zelboraf® 
Possible Risk of TdP 
Venlafaxine 
Effexor®, Efexor® 
Possible Risk of TdP 
Voriconazole 
VFend® 
Conditional Risk of TdP 
Vorinostat 
Zolinza® 
Possible Risk of TdP 
Ziprasidone 
Geodon®, Zeldox® 
Possible Risk of TdP 
 
 
 


Protocol Version: 07/11/17 
 
Page 0 of 57 
APPENDIX D: CTI SAE form 
                                       
     SERIOUS ADVERSE EVENT (SAE) REPORT FORM                        PROTOCOL #: T55001 
Subject#:                 
               SITE  /  SATELLITE/ SUBJ             
Investigator: 
           
Country: 
           
 REPORT 
 Initial                      
                            
 Followup #___        
                                                                                     DD               MMM             YYYY 
  Sex:  
 Male   
 Female 
Date of  Birth:        
                       DD                 MMM                  YYYY 
Height:             
in    
cm 
Weight:           
 lb    
kg 
 Patient’s Primary Disease:___________________________________________ Stage: _________ Date of diagnosis: _______________________ 
 
RELEVANT MEDICAL HISTORY, PREEXISTING CONDITIONS, CONCURRENT ILLNESSES    Attach additional information as needed.   
 
 
 
Serious Adverse Event Term 
Diagnosis (suspected or confirmed); 
symptoms if unknown  
Grade 
CTCAE 
(ver. 4)  
Onset Date 
(meets 
serious 
criteria)  
DDMMMYYYY 
Reason 
Event 
is Serious 
 
Use code 
numbers 
listed below 
Relationship of SAE 
to each Study Drug 
 
Use code numbers listed 
below 
Action taken for each 
Study Drug as a result 
of this SAE 
 
Use code numbers listed 
below 
 
SAE 
abated 
after drug 
stopped? 
 
Yes/No /NA 
SAE 
reappeared 
when drug 
restarted? 
 
Yes/No /NA 
End Date 
 (no longer 
meets 
serious 
criteria) 
DDMMMYYYY 
Outcome 
of event  
 
Use code 
numbers 
listed 
below 
TST 
CAP 
PAC 
CAP 
1   
 
 
 
 
 
 
 
 
 
 
 
2  
 
 
 
 
 
 
 
 
 
 
 
3  
 
 
 
 
 
 
 
 
 
 
 
Reason event is Serious:    
1: Death (cause of death)  
2: Life threatening (immediate risk of death) 
3: Hospitalization (initial or prolonged) 
4: Persistent/ significant disability /  Incapacity  
5: Congenital anomaly / Birth Defect 
6: Other Serious (Important medical events) 
 Relationship  to  Study Drug: 
1: Possibly  
2: Unlikely  
 
Action taken with Study Drug as a result of this SAE: 
1: Dose increased (specify dose and dates) 
2: None (No action taken)    
3: Dose reduced (specify dose and dates) 
4: Drug interrupted (Skipped/Delayed/Interrupted) 
5: Drug withdrawn (Permanently discontinued) 
6: N/A  (Study drug not applicable to this patient)  
7: Unknown 
Outcome of event: 
1: Recovered  
2: Recovered with sequelae (specify 
sequelae in narrative) 
3: Recovering 
4: Not recovered  
5: Fatal (is the cause of death) 
6: Unknown (describe in narrative) 
IF HOSPITALIZED:         Admission Date:              Discharge Date:       
                                                                                                               DD             MMM                  YYYY                                                                                    DD             MMM                  YYYY 
IF PATIENT DIED:  Cause(s) of Death: (primary)_________________________________________ (secondary) _________________________________________ 
 
 
Autopsy performed?     Yes (attach certificate)      No      Pending      Certificate not available 
 Date of Death:   
 
 
           DD             MMM                  YYYY 
 


Protocol Version: 07/11/17 
 
Page 1 of 57 
 
Investigator:      
Subject#:                 
PROTOCOL #:  
 
 
STUDY DRUG INFORMATION 
Start of Therapy 
Current Therapy 
Study Drug Name 
Lot No. 
Exp. 
Date 
Dose  
Route & 
Freq. 
MFR Name 
Initial 
Dose 
(mg) 
Initial  
Start Date 
(DD-MMM-YYYY) 
Current 
Cycle # 
Current 
Dose 
(mg) 
Current Cycle  
Start Date 
(DD-MMM-YYYY) 
Last Dose Date 
(before SAE 
onset) (DD-MMM-
YYYY) 
Tosedostat  
 
 
 
CTI BioPharma 
      
      
 
      
      
      
Capecitabine (CAP) 
 
 
 
 
      
      
 
      
      
      
 
 
 
 
 
      
      
 
      
      
      
 
CONCOMITANT MEDICAL PRODUCTS AND THERAPY DATES    Attach additional information as needed.   
 
 
RELEVANT TESTS/LABORATORY DATA (Include dates) Attach additional information as needed.   
 
 
 
 DESCRIBE EVENT OR PROBLEM       Describe from onset through resolution. Include treatments for the event, and rationale for causality 
 
 
 
 
 
 
 
 
 
 INVESTIGATOR’S SIGNATURE  
Reporter Name:                                                                                     
 Physician 
Pharmacist 
 Nurse 
Other___________  
Phone:                 
 
 Investigator’s Name 
__________________________________________________ 
   __________________________________________________ 
  ___________________________ 
 
 
          
 
 
      (Print)  
 
 
            Investigator’s Signature  
 
                          Date