A Phase Ib High-throughput Pancreas Precision Oncology Study Investigating the Feasibility, Efficacy, and Pharmacodynamics of Cell Regulatory-network Analysis Based Therapy Selection in Advanced Pancreatic Adenocarcinoma
Phase: NA
Conditions: Pancreatic Cancer
Sponsor: Columbia University

CUMC IRB#: AAAR6703  
Version Date: 30MAR2022  
NCT04476537 
 
 
 
 
A phase Ib high-throughput pancreas precision oncology study 
investigating the feasibility, efficacy, and pharmacodynamics of cell 
regulatory-network analysis based therapy selection in advanced 
pancreatic adenocarcinoma: HIPPOCRATES Part 2. 

Columbia University Medical Center 
Herbert Irving Comprehensive Cancer Center 
Version Date: 30 MAR 2022 
 
 
 
 
 
 
Herbert Irving Comprehensive Cancer Center 
Protocol 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Columbia University Medical Center 
Herbert Irving Comprehensive Cancer Center 
Version Date: 30 Mar 2022 
 
1 
 
 
CUMC IRB#:  AAAR6703 
Version Date: 30MAR2022 
 
TITLE:  A phase Ib high-throughput pancreas precision oncology study investigating the 
feasibility, efficacy, and pharmacodynamics of cell regulatory-network analysis based therapy 
selection in advanced pancreatic adenocarcinoma: HIPPOCRATES Part 2. 
 
Coordinating Center: 
 
 
Columbia University Irving Medical Center  
 
Principal Investigator: 
Gulam Abbas Manji, M.D./Ph.D. 
161 Fort Washington Avenue 
New York, NY 10032 
Telephone: 212-212-304-6357 
Email address: gam2140@cumc.columbia.edu 
 
Co-Investigators: 
Gulam Manji, M.D., Ph.D 
 
John Chabot, M.D. 
 
Susan Bates, M.D. 
 
Antonio Fojo, M.D., Ph.D 
 
Yvonne Saenger, M.D. 
 
Ruth White, M.D., Ph.D 
 
Kenneth P. Olive, Ph.D. 
 
Andrea Califano, Laurea 
 
Armando Del Portillo, M.D., Ph.D 
 
Lyndon Luk, M.D. 
 
Christine Chio, Ph.D. 
 
Serge Cremers, Ph.D. 
 
 
Statistician: 
Jianhua Hu, Ph.D. 
 
1130 Saint Nicholas Avenue, 1002A 
 
New York, NY 10032 
 
Email: jh3992@cumc.columbia.edu 
 
 
 
 
 
 
 
 
 
 
 
 

Columbia University Medical Center 
Herbert Irving Comprehensive Cancer Center 
Version Date: 30 Mar 2022 
 
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Funding Source: 
The Lustgarten Foundation 
415 Crossways Park Drive, Suite D 
Woodbury, NY 11797 
Phone: 516-737-1550 
 
     
 
Initial version: 20Jul2020 
Amended: 30Mar2022 
 
 

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Protocol Signature Page 
 
I confirm that I have read this protocol, I understand it, and I will work according to this protocol 
and to the ethical principles stated in the latest version of the Declaration of Helsinki, the 
applicable ICH guidelines for good clinical practices, and the applicable federal, state, and local 
laws, rules, and regulations relating to the conduct of the protocol. I have read and understand 
the information in the Investigators’ Brochure (or Manufacturer’s Brochure) regarding the risks 
and potential benefits. I will promptly submit the protocol to the applicable IRB for review and 
approval. Once the protocol has been approved by the IRB, I understand that any modification 
made during the course of the study must first be approved by the IRB, prior to implementation 
except when such modification is made to remove an immediate hazard to the subject. I certify 
that I, and the study staff, have received the requisite training to conduct this research protocol. I 
agree to maintain adequate and accurate records in accordance with Columbia University and 
Herbert Irving Comprehensive Cancer Center policies, Federal, state and local laws and 
regulations. I agree to maintain the confidentiality of all information received or developed in 
connection with this protocol. 
 
 
_________________________________                _______________ 
Signature of Principal Investigator                 Date 
 
 
 
_________________________________                 
Principal Investigator Name (Print) 
 
 
 
 
_________________________________                 
Name of Institution 
 
  
 
 
 
Instructions to Principal Investigator: Sign and Date this signature page and print your name. 
Return the original, completed and signed to the Clinical Protocol & Data Management Office. 
Retain a copy in the regulatory binder.  

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Table of Contents 
Protocol Signature Page ...................................................................................................................3 
1. 
PROTOCOL SYNOPSIS.....................................................................................................7 
1.1 
Trial Design Overview ...........................................................................................12 
1.2 
Trial Schema ..........................................................................................................12 
2. 
STUDY OBJECTIVES AND ENDPOINTS .....................................................................13 
2.1 
Primary Objectives & Endpoints ...........................................................................13 
2.2 
Secondary Objectives & Endpoints .......................................................................13 
2.3 
Exploratory Objectives & Endpoints .....................................................................15 
3. 
BACKGROUND & RATIONALE ...................................................................................16 
3.1 
Pancreatic Cancer ...................................................................................................16 
3.2 
Targeted Therapy in Pancreatic Cancer .................................................................16 
3.3 
OncoTreat Technology ..........................................................................................19 
3.4 
OncoTreat and Pancreatic Cancer ..........................................................................21 
3.5 
Rationale for this Clinical Study ............................................................................25 
3.6 
Rationale for Testing Capecitabine ........................................................................25 
3.7 
Rationale for Testing Imatinib ...............................................................................26 
3.8 
Rationale for Testing Ruxolitinib ..........................................................................26 
4. 
STUDY DESIGN...............................................................................................................27 
4.1 
General Design.......................................................................................................27 
4.2 
Number of Patients ................................................................................................30 
4.3 
Study Drugs ...........................................................................................................30 
4.4 
Tumor Biopsies ......................................................................................................30 
4.5 
Pharmacology: Pharmacodynamics and Pharmacokinetics ...................................31 
4.6 
Rationale for Study Design ....................................................................................33 
4.7 
Formulation, Packing, Handling, and Administration ...........................................36 
4.8 
Pharmacology Assessments ...................................................................................37 
4.9 
Dose Modifications ................................................................................................41 
5. 
SUBJECT SELECTION AND WITHDRAWAL .............................................................44 
5.1 
Inclusion Criteria ...................................................................................................44 
5.2 
Exclusion Criteria ..................................................................................................45 
5.3 
Inclusion of Women and Minorities ......................................................................47 
5.4 
Subject Recruitment ...............................................................................................47 
5.5 
Treatment Discontinuation .....................................................................................48 
5.6 
Early Study Withdrawal .........................................................................................48 
5.7 
Data Collection and Follow-Up of Withdrawan Subjects .....................................49 
5.8 
Post-Treatment Visits.............................................................................................49 
6. 
REGISTRATION PROCEDURES ...................................................................................50 
6.1 
CUMC Research Participant Registration .............................................................50 

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7. 
TREATMENT PLAN ........................................................................................................51 
7.1 
Study Treatment .....................................................................................................52 
7.2 
Duration of Therapy ...............................................................................................52 
7.3 
Duration of Follow Up ...........................................................................................52 
7.4 
Criteria for Removal from Study ...........................................................................52 
8. 
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS ............................52 
8.1 
Definitions..............................................................................................................52 
8.2 
Adverse Event Reporting Period ...........................................................................54 
8.3 
Evaluating Adverse Events ....................................................................................55 
8.4 
Recording of Adverse Events ................................................................................55 
8.5 
Reporting of Serious Adverse Events ....................................................................55 
8.6 
Reporting Process ..................................................................................................57 
            8.7 
      Reporting of Pregancy to 
Incyte…………………………………………………58 
9. 
STUDY CALENDAR .....................................................................................................589 
9.1 
Study calendar ......................................................................................................589 
9.2 
Trial Procedures ...................................................................................................677 
9.3 
Administrative Procedures ...................................................................................677 
9.4 
Clinical Procedures and Assessments ..................................................................687 
10. 
MEASUREMENT OF EFFECT........................................................................................70 
10.1 
Antitumor Effect – Solid Tumors ..........................................................................70 
10.2 
Definitions..............................................................................................................70 
10.3 
Disease Parameters ................................................................................................70 
10.4 
Methods for Evaluation of Measurable Disease ....................................................71 
10.5 
Response Criteria – RECIST Criteria ....................................................................72 
10.6 
Duration of Response ...........................................................................................744 
10.7 
Analysis of Endpoints ..........................................................................................744 
10.8 
Pharmacokinetic Outcome Measures ...................................................................755 
10.9 
Analysis of Exploratory Endpoints ......................................................................755 
10.10  Unblinding Procedures...........................................................................................75 
10.11  Stopping Rules .......................................................................................................75 
11. 
DATA REPORTING / REGULATORY REQUIREMENTS ...........................................75 
11.1 
Data Collection ......................................................................................................75 
11.2 
Data Reporting .......................................................................................................75 
11.3 
Data and Safety Monitoring Committee ................................................................76 
11.4 
Quality Control and Quality Assurance .................................................................76 
11.5 
Confidentiality .......................................................................................................77 
11.6 
Source Documents .................................................................................................77 
11.7 
Case Report Forms .................................................................................................77 
11.8 
Records Retention ................................................................................................788 
12. 
STATISTICAL CONSIDERATIONS...............................................................................78 

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13. 
PROTECTION OF HUMAN SUBJECTS ........................................................................79 
14. 
STUDY FINANCES ..........................................................................................................79 
14.1 
Conflict of Interest .................................................................................................79 
14.2 
Subject Stipends or Payments ................................................................................80 
15. 
PUBLICATION PLAN .....................................................................................................80 
16. 
REFERENCES ..................................................................................................................80 
17. 
APPENDICES ...................................................................................................................84 
17.1 
Appendix A: Eastern Cooperative Oncology Group (ECOG) Performance 
Status ......................................................................................................................84 
17.2 
Appendix B: NCI Common Terminology Criteria for Adverse Events 
(CTCAE) V4.0 Grading Scale ...............................................................................85 
17.3 
Appendix C: Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 .........85 
17.4 
Appendix D: Preclinical Studies – PDX/PDO Analyses .......................................85 
17.5 
Appendix E: LC-MS/MS Method ..........................................................................86 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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1. PROTOCOL SYNOPSIS 
This document is a protocol for a human research study. This study is to be conducted according 
to US and international standards of Good Clinical Practice (FDA Title 21 part 312 and 
International Conference on Harmonization guidelines), applicable government regulations and 
Columbia University Medical Center institutional research policies and procedures.  
 
Title 
A phase Ib high-throughout pancreas precision oncology study 
investigating the feasibility, efficacy, and pharmacodynamics of cell 
regulatory-network analysis based therapy selection in advanced 
pancreatic adenocarcinoma: HIPPOCRATES Part 2. 
Short Title 
RNA 
precision 
oncology 
in 
advanced 
pancreatic 
cancer 
(HIPPOCRATES Part 2) 
Phase 
Ib 
Methodology 
This is a single arm, open-label phase Ib trial of FDA-approved or 
investigational agents in patients with locally advanced, unresectable or 
metastatic pancreatic cancer who have progressed on one or two prior 
lines of treatment to evaluate feasibility, safety, and efficacy of the 
OncoTreat algorithm. 
Study Duration 
We estimate that the trial (Parts 1 and 2) will require up to 36 months to 
complete--15 to 18 months for tissue acquisition on Part 1 (AAAR6703) 
and an additional 15-18 for treatment and follow-up to evaluate the 
efficacy outcomes for all subjects. 
Study Center(s) 
Columbia University Irving Medical Center 

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Objectives 
1. Co-Primary objectives:  
 To evaluate the overall feasibility of using the OncoTreat 
technology to inform rational selection of off-label FDA-
approved or investigational drugs in subjects with 
advanced pancreatic cancer (PDA) who have progressed 
on one or two prior lines of therapy. This will include the 
percentage of subjects who begin an OncoTreat-
prioritized agent, defined as having received a single 
dose of study drug, and the “match rate,” defined as the 
fraction of subjects who match with at least one 
OncoTreat-prioritized agent (p-value < 1 x 10-5).  
 To evaluate the clinical efficacy of OncoTreat by 
assessing the objective response rate (ORR) for subjects 
treated with OncoTreat-prioritized drugs according to 
Response Evaluation Criteria in Solid Tumors (RECIST) 
v1.1 criteria. 
 
2. The secondary objectives of this study are to: 
 To describe the safety and tolerability, defined as the 
incidence of Grade 3/4 adverse events (AEs) in terms 
categorized and graded according to the National Cancer 
Institute Terminology Criteria for Adverse Events (NCI 
CTCAE v4.0), of using OncoTreat to inform rational 
treatment decisions in subjects with advanced PDA. The 
incidence of dose modifications, interruptions, and 
discontinuations will also be described. 
 To assess the efficacy of OncoTreat by estimating the 
disease control rate (DCR) at 16 and 24 weeks, the 
median progression-free survival (PFS), the overall 
survival (OS), and the CA 19-9 tumor marker response.  
 Assess the pharmacokinetics of each OncoTreat-
prioritized agent in subjects with advanced PDA. 
 
3. The exploratory objectives of this study are to:  
 Explore the relationship between drug exposure, 
pharmacodynamics, efficacy, and safety of each 
OncoTreat-prioritized 
agent. 
Pharmacodynamic 
response will be evaluated by comparing the master 
regulator signature of a given subject’s tumor using 

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VIPER analysis, comparing pre-treatment and on-
treatment tumor samples. The changes in master 
regulator activity between these two samples will be 
compared to that predicted from cell-based and PDX-
based treatment studies. 
 Assess whether the master regulator signature, using 
VIPER analysis, in a given subject’s tumor changes in 
response to standard-of-care treatment by comparing 
initial and secondary biopsies collected for each subject 
before and after one or two lines of systemic therapy 
(chemotherapy or clinical trial). These data will be used 
to determine whether the predicted sensitivity of a 
patient’s tumor to the first- or second-line therapy that 
they receive is predictive of the actual clinical outcomes 
that are observed during treatment.  
 Using the same data as in the bullet point above, assess 
the frequency with which chemotherapy treatments alter 
the predicted sensitivity of tumors to other OncoTreat-
prioritized agents (p-value < 1 x 10-5). 
 Compare the standard-of-care clinical DNA mutation 
analysis results with matched master regulator activity 
profiles to correlate any clinically actionable genomic 
information with the top OncoTreat-prioritized drugs (p-
value < 1 x 10-5). 
 Evaluate the feasibility of using the OncoTreat 
technology on peripheral blood circulating tumor cells 
(CTCs) by comparing master regulators generated from 
CTCs to those obtained from tumor tissue in matched 
pre- and on-treatment samples with an OncoTreat-
informed agent. 
 Identify associations between master regulator profiles 
and additional clinical, epidemiological, physiological, 
imaging, or molecular features of the subject or subject’s 
tumor. 
 Identify potential biomarkers, beyond the master 
regulator signature, using additional genomic, RNA,  
protein, and imaging platforms that are predictive or 

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prognostic of response to each OncoTreat-prioritized 
agent. 
Number of Subjects 
We will enroll 30 subjects in Part 1 (AAAR6703) of the study to obtain 
detailed predicted therapy options. We anticipate accrual over 15-18 
months. We estimate that 15 subjects will progress to Part 2, requiring 
an additional 15-18 months to complete treatment and for follow-up. 
Diagnosis and Main 
Inclusion Criteria 
Locally advanced, unresectable or metastatic pancreatic cancer who 
progressed on one or two prior lines of chemotherapy, for whom a 
precision therapy was recommended in Part 1. 
Duration of 
administration 
Treatment will continue until progressive disease, unacceptable adverse 
events, intercurrent illness that prevents further administration of 
treatment, investigator’s decision to withdraw the subject, subject 
withdrawal of consent, pregnancy of the subject, noncompliance with 
trial treatment or procedure requirements, or administrative reasons 
requiring cessation of treatment. 
Reference therapy 
Not applicable – single arm study. 

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Statistical 
Methodology 
This is a single arm, phase Ib study with 2 co-primary endpoints:  
 
1. Feasibility Endpoint: We will determine the feasibility of the 
OncoTreat platform in guiding therapy. The primary feasibility endpoint 
is whether a subject begins treatment on Part 2 based on results 
generated from the OncoTreat analysis. Previous attempts to match 
subjects based on DNA profiling yielded enrollment rates of 3-5%. We 
hypothesize that we will validate OncoTreat matches for 50% of subjects 
and that at least 30% of enrolled subjects (60% of matches) will begin 
therapy. With 30 enrolled patients we will have 84% power to detect a 
treatment rate of 30% compared to a historical treatment rate of 5% with 
alpha of 0.05. We will assess the “match rate” – the fraction of patients 
who match with at least one drug. With 30 enrolled patients, we will 
have 90% power with alpha = 0.05 to detect a 50% match rate (15 of 30 
subjects) compared to a (liberal) estimated match rate of 20% based on 
DNA profiling in pancreatic cancer.  
 
2. Clinical Endpoint: The primary clinical efficacy endpoint is the 
objective response rate for OncoTreat-prioritized drugs according to 
RECIST v1.1. The phase III trial (NAPOLI-1) that resulted in the FDA-
approval of nanoliposomal irinotecan and 5-fluorouracil in the second-
line setting demonstrated a median OS of 6.1 months versus 4.2 months 
for 5-fluorouracil monotherapy (primary endpoint), mPFS of 3.1 
months, and an ORR of 16% (compared to 1% in the 5-fluorouracil arm). 
Thus, based on historical controls, the ORR for treatment-resistant 
metastatic PDAC is expected to be no more than 16%. 
 
Using the above mentioned rates, a sample size of n = 9 achieves at 
least a 80% power to detect a difference of 25% in ORR (30% vs 5%) 
using a one-sided binomial test with a target alpha of 0.1. To be 
conservative, we use the minimum number of patients (9) expected to 
be treated in this calculation. If at the end of the study the total number 
of objective responses is greater than or equal to 2, we will be able to 
reject the historical rate of 5% at the significance level of 0.05 with 
power of 69% and OncoTreat will have demonstrated a clear signal of 
clinically meaningful improvement in the primary endpoint for patients 
with advanced, previously-treated PDA. Assuming about 30% of 
enrolled patients will receive an OncoTreat-informed treatment, N = 30 
subjects is an appropriate sample size for this prospective study. 
 
Secondary measures include DCR, PFS, and OS as well as safety and 
tolerability of OncoTreat-directed therapy. The pharmacokinetics of 
OncoTreat-prioritized drugs in PDA subjects will also be described. 
 
 
 

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1.1 
Trial Design Overview 
This is a phase 1b, single-arm, single-center, open-label clinical trial for 30 evaluable patients 
with locally advanced or metastatic pancreatic cancer (PDA). Subjects with newly diagnosed 
locally advanced or metastatic PDA will be enrolled on protocol Part 1 (AAAR6703) prior to 
tumor biopsy. OncoTreat analysis will be conducted using a New York State CLIA-certified test. 
Subjects will receive physician’s choice first-line cytotoxic chemotherapy (including 5-FU, 
gemcitabine, or capecitabine-based combinations or monotherapy) or clinical trial while 
preclinical validations of OncoTreat candidate treatments are performed. Preclinical results will 
be evaluated by the Precision Medicine Tumor Board (PMTB), which will review the data and 
prioritize a treatment based on the following criteria: 1) patient safety; 2) preclinical efficacy; 3) 
pharmacological properties; and 4) drug availability. If an agent is not identified or available at 
first progression, patients will continue on to second-line therapy (chemotherapy or clinical trial) 
and will be again assessed at the time of second progression. If an agent is identified and 
available, subjects will be enrolled on this protocol (Part 2), undergo a repeat biopsy and be 
treated on a single-arm, single-agent phase Ib clinical trial evaluating pharmacokinetics, safety, 
and efficacy in recurrent PDA patients. 
 
This study will be conducted in conformance with Good Clinical Practices.  
 
Specific procedures to be performed during the trial, as well as their prescribed times nad 
associated visit windows, are outlined in the Trial Flow Chart – Section 9.  
 
1.2 
Trial Schema 
 
 
Figure 1. Phase Ib Trial Schema. 
 

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2. STUDY OBJECTIVES AND ENDPOINTS 
 
2.1 Primary Objectives & Endpoints 
2.1.1 Objectives: 
The co-primary objectives of this study are: 
 To evaluate the overall feasibility of using the OncoTreat technology to inform 
rational selection of off-label FDA-approved or investigational drugs in subjects 
with advanced pancreatic cancer (PDA) who have progressed on one or two prior 
lines of systemic therapy. This will include the percentage of subjects who begin 
an OncoTreat-prioritized agent, defined as having received a single dose of study 
drug, and the “match rate,” defined as the fraction of subjects who match with at 
least one OncoTreat-priotitized agent (p-value < 1 x 10-5). 
 To evaluate the clinical efficacy of OncoTreat by assessing the objective 
response rate (ORR) for subjects with advanced PDA treated with OncoTreat-
prioritized drugs after disease progression on one or two prior lines of systemic 
therapy according to Response Evaluation Criteria in Solid Tumors (RECIST) 
v1.1 criteria. 
2.1.2 Endpoints: 
The co-primary endpoints of interest are:  
 The percentage of subjects who begin an OncoTreat-prioritized agent, defined as 
having received a single dose of study drug, and the “match rate,” defined as the 
fraction of subjects who match with at least one OncoTreat-priotitized agent (p-
value < 1 x 10-5). 
 ORR according to RECIST v1.1 criteria. 
2.2 Secondary Objectives & Endpoints 
*Note: The secondary objects only apply for patients who are initiated on treatment with an 
OncoTreat-prioritized FDA-approved or early-phase investigational drug. 
 
2.2.1 Objectives: 
The secondary objectives of this study are to:  
 To describe the safety and tolerability of using OncoTreat to inform rational 
treatment decision in subjects with advanced PDA who have progressed on one 
or two prior lines of therapy.  
 To assess the efficacy of OncoTreat by estimating the disease control rate (DCR) 
at 16 and 24 weeks, the median progression-free survival (PFS), the overall 
survival (OS), and the CA 19-9 tumor marker response. 
 To assess the pharmacokinetics of each OncoTreat-prioritized agent in subjects 
with advanced PDA. 

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2.2.2 Endpoints: 
Secondary endpoints of interest include: 
 Safety/tolerability  
o Incidence of Grade 3/4 adverse events (AEs) in terms categorized and 
graded according to the National Cancer Institute Terminology Criteria 
for Adverse Events (NCI CTCAE v4.0). 
o Incidence of dose modifications, interruptions, and discontinuations. 
o Note: OncoTreat-prioritized agents will be dosed at the FDA-approved 
dose (if available) or the recommended phase 2 dose for investigational 
agents. Safety endpoints as they pertain to specific drugs will not be 
assessed in this prospective study, as only a very small number of 
patients will be assigned to any one of these drugs, all of which are FDA-
approved or have been studied in early phase clinical trials and have track 
records of safety/tolerability. 
 DCR, defined as the proportion of subjects with a complete or a partial response 
as the best response or stable disease, according to RECIST v1.1 criteria. 
 PFS, defined as the time from first dose of OncoTreat-prioritized drug to the first 
occurrence of disease progression or death from any cause (whichever occurs 
first), using RECIST v1.1 criteria. 
 OS, defined as the time from first dose of OncoTreat-informed study drug to 
death due to any cause. 
 Tumor marker response of CA 19-9, defined as ≥ 50% in CA 19-9 in relation to 
the baseline level at least once during the treatment period. 
 Serum concentration or PK parameters for each OncoTreat-prioritized agent. 
 Relationship between serum concentration or PK parameters and endpoints of 
interest. 

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2.3 
Exploratory Objectives & Endpoints 
2.3.1 Objectives: 
The exploratory objectives of this study are to: 
 To explore the relationship between drug exposure, pharmacodynamics, efficacy, 
and safety of each OncoTreat-prioritized agent. Pharmacodynamic response will 
be evaluated by comparing the master regulator signature of a given subject’s 
tumor using VIPER analysis, comparing pre-treatment and on-treatment tumor 
samples. The changes in master regulator activity between these two samples will 
be compared to that predicted from cell-based and PDX-based treatment studies. 
 To assess whether the master regulator signature, using VIPER analysis, in a given 
subject’s tumor changes in response to standard-of-care treatment by comparing 
initial and secondary biopsies collected for each subject before and after one or 
two lines of systemic therapy (chemotherapy or clinical trial). These data will be 
used to determine whether the predicted sensitivity of a patient’s tumor to the first- 
or second-line therapy that they receive is predictive of the actual clinical 
outcomes that are observed during treatment. 
 Using the same data as in the bullet point above, assess the frequency with which 
chemotherapy treatments alter the predicted sensitivity of tumors to other 
OncoTreat-prioritized agents (p-value < 1 x 10-5). 
 To compare the standard-of-care clinical DNA mutation analysis results with 
matched master regulator activity profiles to correlate any clinically actionable 
genomic information with the top OncoTreat-prioritized drugs. 
 To evaluate the feasibility of using the OncoTreat technology on peripheral 
blood circulating tumor cells (CTCs) by comparing master regulators generated 
from CTCs to those obtained from tumor tissue in matched pre- and on-treatment 
samples with an OncoTreat-informed agent. 
 To identify associations between master regulator profiles and additional clinical, 
epidemiological, physiological, imaging, or molecular features of the subject or 
subject’s tumor. 
 To identify potential biomarkers, beyond the master regulator signature, using 
additional genomic, RNA, protein, and imaging platforms that are predictive or 
prognostic of response to each OncoTreat-prioritized agent (p-value < 1 x 10-5). 
2.3.2 Endpoints: 
Exploratory endpoints of interest include: 
 Pharmacodynamic response will be assessed by determining the differentially 
activated and repressed master regulator proteins between the pre-treatment 
(second) biopsy and the on-treatment (third) biopsy, and comparing these 
changes to those predicted by OncoTreat using a modified gene set enrichment 
analysis with a threshold Fasle Discovery Rate of p = 0.05. 
 Paired-sample VIPER analysis using Master Regulator profiles from the first and 
second biopsies. 

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 The fraction of drugs predicted for each patient using the first biopsy that are still 
predicted in the second biopsy. 
 The DIGGIT algorithm will be used to associate DNA alterations, found from 
enomic profiling using next-generation sequencing (NGS) assays such as CCCP 
or Foundation One, with master regulator activity. 
 Percentage of OncoTreat-prioritized agents (p-value < 1 x 10-5) that overlap 
between tumor biopsy specimens and peripheral blood CTCs. 
 
Relationship between biomarkers in blood and tumor tissue and efficacy, safety, 
PK, or other biomarker endpoints. 
 
3. BACKGROUND & RATIONALE 
 
3.1 
Pancreatic Cancer 
Pancreatic ductal adenocarcinoma (PDA) is a major health problem worldwide. It is predicted to 
be the 2nd leading cause of cancer-related death in the United States by 2030 and carries a dismal 
5-year survival of 8.2% despite 50 years of research and therapeutic developments [1, 2]. During 
2018, it is estimated that 55,440 people will be diagnosed with PDA and approximately 44,330 
people will die from PDA in the United States [2]. 
  
Currently, surgical resection offers the only therapeutic means of cure. However, only 15-20% of 
patients have resectable disease. Even among the small subset of patients who are suitable for 
surgical resection at the time of diagnosis, complete resection is followed by recurrence in >90% 
of patients without further systemic therapy, with a median time to recurrence of 6.9 months [3]. 
In the metastatic setting, the 5-year overall survival is 2% [4]. Therefore, PDA is an unmet need 
that desperately requires better medical intervention. 
 
Despite recent advances in systemic therapy, upfront cytotoxic chemotherapy for PDA has been 
disappointing with response rates of 20-30% for the most active regimens and no impact on the 
5-year survival rate [5, 6]. The majority of patients will progress after a median of 5-7 months. 
Data from the second-line NAPOLI-1 study showed that 5-fluorouracil in combination with 
nanoliposomal irinotecan improved both median PFS and OS compared with 5-fluorouracil 
alone (3.1 vs 1.5 months and 6.1 vs 4.2 months, respectively) [7]. There is currently no standard-
of-care treatment regimen available for the third-line setting, and consensus guidelines 
recommend best supportive care or participation in a clinical trial [NCCN 2018]. Thus all PDA 
patients require systemic chemotherapy, and more effective regimens are urgently needed [8]. 
 
3.2 
Targeted Therapy in Pancreatic Cancer 
For at least two decades, there has been an intensive focus on identifying and targeting specific 
mutations or pathways in PDA. The prevailing model has been that mutated oncogenic drivers 
are the ideal cancer drug targets (as epitomized by the responsiveness of c-Kit mutant GIST to 
imatinib). However, few such targets are present in PDA aside from mutant K-ras, which has 
proven pharmacologically intractable [9]. Indeed, best estimates suggest that only around 15% of 
PDA tumors harbor alterations that can be matched by current precision therapies. Moreover, 
many examples exist of tumors bearing targetable mutations that nonetheless fail to respond to 

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matched therapies and, conversely, of tumors that are unexpectedly sensitive to targeted drugs in 
the absence of a known relevant oncoprotein [10, 11]. For example, treatment of EGFR-mutant 
pancreatic tumors with the EGFR inhibitor erlotinib provides at best a modest benefit, despite 
substantial efficacy in lung cancer [12]. These observations imply that the signaling context of a 
mutation is highly relevant to therapeutic response. It is our hypothesis that the context itself– 
that is, the regulatory state of the tumor cell– is a relevant and promising therapeutic target 
(Figure 2).  
 
A novel systems biology approach, developed by Andrea Califano (co-PI) at Columbia 
University Medical Center, is uniquely positioned to extend the frontier of personalized medicine 
for patients with treatment refractory cancers, including advanced PDA. The OncoTreat 
algorithm is able to prioritize potentially effective FDA-approved and investigational oncology 
drugs, on a patient-by-patient basis, for patients currently lacking effective treatment options. In 
this prospective study, we will investigate the feasibility of using OncoTreat to inform rational 
selection of off-label FDA-approved oncology drugs for patients with advanced PDA who have 
received one or two prior lines of systemic therapy. 
 

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Figure 2. Regulatory Network Concepts and OncoTreat Framework. A) Regulatory Proteins 
(e.g. transcription fractions, co-regulators, and others) are proteins that alter the transcript abundance of target genes. 
B) The collection of genes targeted by a regulatory protein is a regulon. Their relative abundances define the activity 
of a regulatory protein. C) A regulatory protein whose activity is altered during tumor development is a Master 
Regulator (MR) of malignancy. D) A regulatory network is a global compilation of regulatory genes and their 
targets (colored circles represent major Mastor Regulators of PDA). E) MRs occupy critical nodes within signaling 
networks. While many upstream signaling molecules may acquire oncogenic mutations, they must ultimately affect 
the activity of a limited set of MRs that effect execution of their function. F) The MRs that promote or restrain 
malignancy in an individual patient’s tumor are identified from an expression profile using the VIPER algorithm. 
Similarly, the MRs altered by treatment with a drug are identified through high throughput RNA-sequencing of 
human PDA cell lines. The OncoTreat framework functions identifying drugs whose activity specifically affects the 
MRs of an individual patient. That is, drugs that inhibit the patient’s positive cancer MRs and activate the patient’s 
negative cancer MRs. 

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3.3 
OncoTreat Technology 
In the emerging field of personalized cancer medicine, therapies are prioritized based on the 
molecular characteristics of an individual patient’s tumor. In current clinical practice, this 
approach centers on the concept of oncogene addiction, whereby tumors become dependent on 
their mutated oncogenes to maintain the malignant phenotype [13] and therapies are selected 
based on genetic mutations identified by next generation sequencing platforms. However, the 
limitations of this approach are now increasingly recognized. In the MD Anderson experience, 
which parallels that of many cancer centers, only 39% of cancer patients were found with at least 
one mutation in a potentially actionable gene, 11% enrolled on a clinical trial targeting the 
alteration, and only a small fraction of the patients derived clinical benefit from this approach 
[14]. Importantly, aberrant protein activity, the central determinant of drug response in cancer, 
results from a complex array of biologic determinants, only one of which is genetic mutation in 
the corresponding gene. Genetic and epigenetic events in cognate binding partners [15], 
competitive endogenous RNAs [16], and upstream regulators [17], as well as post-translational 
modifications, complex formation and sub-cellular localization, all contribute to dysregulated 
protein activity. This complexity likely explains an important observation – although cells with 
activating mutations in a specific oncogene are generally more sensitive to corresponding 
targeted inhibitors, cells lacking these mutations can present equivalent sensitivity [10, 11]. 
Similarly, in clinical practice, and as reported in the MD Anderson experience, many tumors 
with a mutated oncogene fail to respond to seemingly appropriate targeted therapy. 
 
Over the past decade, Andrea Califano has developed a pipeline of experimentally–validated 
computational tools (referred to collectively as OncoTreat) that is designed to use RNA profiles, 
rather than DNA mutations, to examine the regulatory state of an individual patient’s tumor and 
predict a matching treatment. Using a novel systems-biology based approach, Virtual Inference 
of Protein activity by Enriched Regulon analysis (VIPER) infers the activity of regulatory 
proteins in individual tumor samples based on the gene expression of their transcriptional targets 
[18]. Conceptually, this approach recognizes that the expression of the transcriptional targets of a 
protein is a more informative reporter of that protein’s activity that the presence or absence of a 
genetic alteration. In practice, this approach requires that context (tumor) specific regulatory 
models be established that define relationships between transcriptional regulators, regulatory 
proteins, signaling proteins, and transcripts in that particular tissue context. These models 
(termed interactomes) can now be defined by analyzing large sets of tissue-matched gene 
expression profiles such as those offered by The Cancer Genome Atlas (TCGA) [19] using 
validated computational models in a systems biology based approach. Then, at the single tumor 
level and using RNA-Seq data derived from a tumor biopsy, the VIPER algorithm is used to 
infer the activity of proteins by analyzing gene expression of their transcriptional agents, as 
defined by the tumor-specific interactome. 
 
VIPER thereby identifies key proteins, termed master regulators (MRs), which play a necessary 
role in implementing a tumor’s transcriptional identity. Surprisingly, these MRs are almost never 
mutated (that is, they are not conventional oncogenes) and are therefore not identified by somatic 
genome sequencing of tumors. Rather, they constitute bottlenecks within complex networks of 
molecular interactions that are responsible for integrating the effect of multiple upstream 
pathway mutations in order to activate the regulatory programs (cancer hallmarks) that are 

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necessary for cancer cell survival. Extensive research has demonstrated that genetic or 
pharmacological targeting of master regulator proteins induces collapse of the corresponding 
tumor bottleneck, which is catastrophic for the tumor, making it virtually impossible for tumor 
cells to survive [20-24]. As part of this technology, a drug perturbation database is also 
developed for each tumor type. Here the effect of approximately 500 candidate pharmacologic 
agents, including FDA-approved drugs and investigational compounds in late stage development 
(phase II-III), on regulatory protein activity is evaluated by VIPER analysis. This need only to be 
done once to define the tumor context-specific mechanism of action for each of the compounds, 
based on drug effect on MR protein activity (Figure 2). Then, OncoTreat technology aligns each 
compound mechanism of action to the master regulators of each individual tumor, prioritizing 
them by their ability to revert the activity of aberrantly activated or inactivated master regulator 
proteins. 
 
Together, the OncoTreat methodologies have led to the elucidation of novel tumor dependencies 
and drug resistance mechanisms across numerous human malignancies – from leukemia [25, 26], 
and lymphoma [20, 27], to prostate cancer [23, 28], breast cancer [17, 24], and glioma [16, 17, 
22, 29] - with results published in high-impact peer-reviewed journals including Cell, Nature, 
and Clinical Cancer Research. These studies were instrumental in the generation of mechanistic, 
hypothesis-driven clinical trials, including the use of combination therapy in trastuzumab-
resistant ErbB2 positive breast cancer [24] (NCT02066532) and the use of ACY-1215 
(Ricolinostat) + Nab-paclitaxel in metastatic breast cancer [30] (NCT02632071). Additional 
trials are currently in development, such as to evaluate entinostat in enteropancreatic 
neuroendocrine tumors (EP-NET). A comprehensive clinical trial program of the OncoTreat 
method (the “N-of-1” Trial) has already been established at Columbia (IRB-AAAN7562). 
Moreover, the OncoTreat framework for the prioritization of drugs to target tumor checkpoints 
was validated in a recent study in gastroenteropancreatic neuroendocrine tumors (GEP-NETs) 
[31]. 
 
The aberrant activity of VIPER-inferred master regulator proteins has been shown to be 
necessary for implementing the transcriptional identity of a tumor cell, and pharmacologic 
inhibition or genetic silencing of these master regulators resulted in loss of tumor cell viability. 
Thus, master regulators represent an obvious class of causal dependencies for targeted therapy. 
Critically, many of the master regulator proteins identified by this analysis are not canonical 
mutated oncoproteins, but are instead located downstream from such oncoproteins, thus 
representing proteins whose activity is post-translationally dysregulated by various alterations in 
upstream pathways [17]. These master regulators would therefore not be identified by the 
sequencing techniques currently central to personalized cancer medicine. In summary, 
OncoTreat is a clinical platform which uses VIPER to identify the master regulators in a tumor 
and refers to the drug perturbation database to prioritize drugs and drug combinations based on 
their ability to revert the activity of master regulator proteins and thus destabilize the tumor state. 
This protocol will enable the first implementation of the OncoTreat method, a NY State CLIA-
certified assay made available by the Department of Pathology at Columbia University Medical 
Center, in patients with pancreatic ductal adenocarcinoma. 
 

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3.4 
OncoTreat and Pancreatic Cancer 
The Olive Lab at Columbia University Medical Center has invested five years’ effort in building 
the preliminary datasets required as input for a pancreatic implementation of OncoTreat. A major 
challenge was the large and variable contribution of stromal cells to the bulk mass of a tumor 
which alter the RNA profiles of bulk tumor tissue and confound computational analyses. We 
used laser capture microdissection (LCM) to isolate purified samples of malignant epithelium 
and nearby stroma from 197 human pancreatic tumors (Figure 3). RNA sequencing of these 
samples yielded high quality expression profiles for both compartments. As “benign controls,” 
we also profiled the epithelium and stroma of 26 PanIN-1 samples and 19 IPMN-adenomas. 
 
 
Figure 3. Preliminary Data. (N = 203 PDA Epithelium, 99 PDA Stroma, 26 PanIN-1a Epithelium, and 21 
PanIN-1a Stroma). A) Cresyl violet stained section of human PDA before and after LCM to isolate epithelial cells. 
B) RNA Integrity (RIN) values from all LCM-RNA-Seq samples showing excellent RNA quality. C) ~14,000 genes 
and ~16,000 transcripts were detected per sample. D) Heatmap of normalized expression of selected epithelial and 

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stromal marker genes shows near perfect distinction of microdissected samples. E) Principal Component Analysis 
(PCA) performed on all LCM-RNA-seq datasets spontaneously distinguishes sample types. 
 
How OncoTreat works: 
OncoTreat is a computational pipeline that begins with a tumor expression profile and ends with 
a list of several candidate treatment regimens. Critically, the OncoTreat assay has now received 
New York State CLIA certification and is offered through Columbia University Irving Medical 
Center Pathology’s Personalized Genomics Laboratory. The assay is highly reproducible; indeed, 
flash-frozen and paraffin embedded tissue produce virtually identical results. 
 
OncoTreat is based on two conceptual breakthroughs. The first is to focus on the activity of 
regulatory proteins rather than DNA mutations. Regulatory proteins are proteins such as 
transcription factors, cofactors, and chromatin modifiers that have a strong effect on the 
transcript abundance of other genes. If one knows all of the target genes activated and repressed 
by a regulatory protein, then its ACTIVITY may be inferred as a function of the expression of 
that group of targets; higher activity elevates the expression of activated targets while decreasing 
the expression of repressed targets (Figure 4). 
 

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Figure 4. Preliminary Master Regulator and OncoTreat Results. A) The regulon for Smad4 
inferred from the PDA epithelial regulatory network included over 200 positive and negative target genes. B) Master 
Regulator analysis found Smad to be the third-most repressed Master Regulator between PanIN and PDA epithelial 
samples, consistent with the high frequency of Smad4 mutations in PDA patients. Ranked differential gene 
expression for each target gene is represented as the distribution of positive (red) and negative (blue) lines along a 
row. Shown are distributions for a random gene that is not differentially activated between PanIN-1 vs. PDA as well 
as Smad4, in which negative targets are more highly expressed in PDA and positive targets are more highly 
expressed in PanIN-1. False discovery rate shown in parentheses. C) PLATE-Seq was performed on Aspc1 cells 
treated with 336 different FDA-approved or late clinical trial agents, and VIPER used to determine their effect on 
the activities of the top 50 MRs for each of 137 PDA patients from TCGA. Color indicates the extent of inhibition of 
patient-specific MR activity by each agent, with darker orange indicating greater inhibition. Five clusters of patients 
were observed, but two of them are merged because they share many predicted sensitivities (D1/D2). D) Validation 
of individual MRs. We identified foxm1 and pttg1 as epithelial MRs associated with PanIN to PDA progression. E) 
Western blots show effective shRNA knockdown of PTTG1 and FOXM1 with the pTRIPZ vector in Aspc1 cells, 

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leading to reduced proliferation and F) reduced colony formation G) relative to a scrambled control following 
induction with doxycycline. Please note that this depicts the effect of altering expression of just two MRs. The effect 
of inverting the activity of the entire Top50 MRs for a patient is expected to be much greater. 
 
The second conceptual breakthrough is that the activity of a drug can also be defined by its 
impact on the activity of regulatory proteins. This provides several advantages. First one doesn’t 
need to restrict precision medicine efforts to drugs with one specific target protein. Multi-
targeted agents, agents with unknown targets, off-target effects, even cytotoxic agents, can all be 
profiled for their effects on MRs. Thus, OncoTreat functions by matching the profile of 
regulatory proteins active in a patient’s tumor with the drugs that reverse the activity of those 
same regulatory proteins. This is achieved through the following steps: 
 
Step 1: Construct a “regulatory network” – a map of transcriptional relationships – for PDAC 
(Figure 2). A regulatory network is a global list of target genes for all of the regulatory proteins 
(i.e. transcription factors, cofactors, and other proteins whose activity closely alters transcript 
abundance) expressed in pancreatic cancer. Networks are derived de novo using ARACNe, an 
information theoretic algorithm developed by the Califano group, from large collections of 
expression profiles, and do NOT rely on prior knowledge of signaling pathways.  
 
Step 2: Identify patient-specific MRs. Using the information from the PDAC regulatory network, 
it is possible to calculate the activity of each MR in patient’s RNA-seq expression profile. The 
VIPER algorithm compares the activity of each regulatory protein to a reference signature 
representing non-pancreatic lineages. The idea is that the pancreatic lineage is part of what 
fundamentally defines pancreatic cancer. The top 50 MRs for each patient are integrated as the 
“target” of subsequent drug screening steps. 
 
Step 3. Determine the impact of drugs on each MR. We next perform in vitro screening to 
determine how different drugs affect the activity of every regulatory protein in the genome. 
Using a high-throughput RNA-Seq assay developed at Columbia called PLATE-SEQ, we 
screened a set of drugs (121 FDA-approved drugs and 228 Phase 2 and 3 investigational 
oncology agnets) for their effects on regulatory protein activity in Aspc1 cells (selected as the 
best match to the majority of patients in our cohort). These data may now be mined repeatedly to 
find agents for each patient. 
 
Step 4. Candidate drug selection. By integrating the above datasets, we can identify drugs that 
shut down the activity of the specific MRs active in an individual patient’s profile. This analysis 
is integrated across the top 50 MRs for each patient. Successful matches are those drugs that 
reverse the activity of many or all of these top 50 MRs. 
 
We have performed a preliminary analysis of the OncoTreat methodology on existing pancreatic 
cancer tumor profiles and found at least one matching drug for 85% of patients (using a 
conservative threshold FDR of 1 x 10-5). Moreover, at least 50% of patients have 5 or more 
matched drugs using the OncoTreat approach, providing an opportunity to screen multiple 
candidate agents for a given patient using patient-derived models such as PDXs and organoids. 
 

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3.5 
Rationale for this Clinical Study  
There are a number of clinical trials that focus on a drug and then select the rare patient whose 
tumors harbor a matching alteration. By contrast, we propose a prospective precision medicine 
trial that enrolls advanced PDA patients and then matches them to one of several hundred FDA-
approved or investigational agents. We will assess the feasibility of applying the OncoTreat 
algorithm to help inform treatment decisions in subjects with recurrent locally advanced, 
unresectable or metastastic PDA. We hypothesize that OncoTreat will be effective in identifying 
the master regulators on a tumor-by-tumor basis and determining novel treatments for these 
patients where limited options exist.  
 
Beyond initial cytotoxic chemotherapy, there is only one FDA-approved treatment regimen (5-
fluoruracil in combination with nanoliposomal irinotecan) in the second-line setting. The drug 
sensitivity profile (meeting a specified statistical threshold) generated by the OncoTreat analysis, 
performed on tissue obtained from Protocol Part 1 (AAAR6703), will be reviewed at the 
Precision Medicine Tumor Board (PMTB). If an OncoTreat-priotized FDA-approved or early 
investigational drug is identified, subjects will consent to be treated on this protocol with the 
OncoTreat-prioritized drug as their next treatment. A pre study treatment biopsy will be obtained 
to confirm the prior OncoTreat analysis. Standard response criteria measurements per RECIST 
v1.1 will be applied, and an optional biopsy during the first month of treatment on the 
OncoTreat-prioritized drug will be performed.   
 
Unfortunately, not all OncoTreat-prioritized drugs will be available to the patient, but a good 
faith effort will be made to obtain drugs either through funding from the Lustgarten Foundation, 
insurance coverage for off-label indications, pharmaceutical patient assistance programs, or 
single-patient IND. 
 
3.6 
Rationale for Testing Capecitabine 
Capecitabine, both as a single agent and in combination with other chemotherapeutic agents, has 
been evaluated in pancreatic cancer patients. A phase II trial of single-agent capecitabine was 
evaluated in 42 patients with advanced or metastatic treatment-naive pancreatic cancer [32]. 
Capecitabine was dosed at 2500 mg/m2 per day in 2 divided doses on the first 2 weeks of each 3-
week cycle. The primary endpoint was response rate. A partial response was seen in 3 of 42 
patients, and stable disease was achieved in 41%. Median survival was 182 days. With response 
to clinical benefit, positive responses were seen in pain intensity for 29% and analgesic usage in 
12%. Overall the clinical benefit response rate was 24%. Adverse effects were predominantly 
gastrointestinal events (nausea, diarrhea, and vomiting) and hand-foot syndrome, with 2 patients 
experiencing grade 4 diarrhea. 
 
Wasif Saif et al reported on two gemcitabine-refractory pancreatic cancer patients who derived 
long-term survival on capecitabine (50 months and 24 months, respectively) [33]. 
 
This precision medicine trial will use OncoTreat analysis and PDX/PDO models to select the 
patient predicted to respond to capecitabine. 
 

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3.7 
Rationale for Testing Imatinib 
Imatinib is a potent and selective inhibitor of the protein tyrosine kinase Bcr-Abl, platelet-
derived growth factor receptors (PDGFRα and PDGFRβ) and KIT. Pancreatic adenocarcinoma  
expresses PDGFRα. Use of imatinib in xenograft models resulted in transient and reversible 
reduction in tyrosine phosphorylation of PDGFRα without impacting the level of expression 
(PMID 25985771). 
 
Given its activity against both c-KIT and PDGFR kinases and its remarkable safety profile, 
imatinib has been tried in several solid tumors. The results, however, have often been deceiving. 
 
In a small study of 26 patients with unresectable pancreatic cancer, patients were randomized to 
either gemcitabine 1000 mg/m2 weekly or imatinib 800 mg daily [34]. Expression of KIT and 
PDGFRβ were determined by immunohistochemistry. No objective responses were seen in either 
roup. Median time to progression was 77 and 29 days (P=0.411) and median survival time was 
140 and 160 days (P=0.517) for gemcitabine and imatinib, respectively. Survival and treatment 
responses were independent of KIT and PDGFRβ expression in patients treated with imatinib. 
Grade 3/4 toxicities of imatinib were anemia, elevated liver enzymes, vomiting, and dyspnea. 
Patients treated with imatinib also reported more frequent diarrhea and/or altered bowel function. 
Quality of life was similar in both groups. 
 
While imatinib has not demonstrated efficacy in advanced pancreatic cancer, we will utilize 
OncoTreat analysis and PDX/PDO models as a novel precision medicine approach to select the 
patient(s) predicted to respond to imatinib. 
 
3.8 
Rationale for Testing Ruxolitinib 
Aberrant activation of the Janus-associated kinase (JAK)/signal transducer and activator of 
transcription (STAT) pathway is associated with increased malignant cell proliferation and 
survival. Ruxolitinib (Jakafi ®) is a potent, orally bioavailable inhibitor of JAK1 and JAK2 
kinases in the JAK/STAT pathway. It is approved for the treatment of intermediate-risk or high-
risk primary or secondary myelofibrosis, polycythemia vera (in patients with inadequate 
response or intolerance to hydroxyurea), and graft-versus-host disease.  
 
Cytokine-mediated signaling via the JAK/STAT pathway is central to tumor growth, survival, 
and systemic inflammation, which is associated with cancer cachexia, particularly in pancreatic 
cancer. Preclinical studies have demonstrated antiproliferative effects of JAK/STAT pathway 
inhibition in both in vitro and in vivo models of cancer, including pancreatic cancer. In 
genetically engineered murine models of pancreatic cancer, ruxolitinib inhibited tumor 
angiogenesis, controlled disease progression, and improved survival [35]. Ruxolitinib has also 
been shown to block tumor growth in a syngeneic murine PAN02 pancreatic model (Koblish HK 
et al., Cancer Res, Abstract 1336, 2015). By selectively inhibiting JAK2V617F, STAT5, and 
ERK1/2 phosphorylation, ruxolitinib was shown to reduce cellular proliferation and induce 
apoptosis in JAK2V617F+ Ba/F3 cells [36]. 
 
Pancreatic cancer results in a systemic inflammatory response which is partially mediated by the 
JAK/STAT pathway [37]. This systemic inflammatory response has been associated with a more 

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pronounced symptom burden, including cachexia syndrome, and poorer survival outcomes [38, 
39]. The rationale for evaluating the therapeutic utility of JAK inhibition in patients with 
pancreatic cancer has strong scientific merit. 
 
The effectiveness of ruxolitinib in patients with metastatic pancreatic cancer was evaluated in the 
phase II RECAP trial that included 127 patients who had previously been treated with 
gemcitabine [40]. Patients were randomized (double-blind) 1:1 to ruxolitinib 15 mg twice daily 
plus capecitabine 1000 mg/m2 twice daily (n=64) versus capecitabine 1000 mg/m2 twice daily 
plus placebo (n=63). The overall survival was 4.5 months in the ruxolitinib group and 4.3 
months in the control group – not a significant difference. However, the investigators, in a 
prespecified subgroup analysis, did detect a significant difference in the 60 patients with high 
blood levels of C-reactive protein (CRP). The median survival for patients in this subgroup who 
received ruxolitinib was 2.7 months, and the objective response rate was 6.5%, versus 1.8 
months and 3.4% for patients who received a placebo. The most common side effect for patients 
treated with ruxolitinib was anemia followed by fatigue and abdominal pain.  
 
Based on promising preliminary phase II data, two randomized phase II studies, JANUS I and 
JANUS 2, were conducted to evaluate ruxolitinib in combination with capecitabine in patients 
with advanced pancreatic cancer [41]. Previously treated patients with a CRP >10 mg/L were 
randomized 1:1 to 21-day cycles of ruxolitinib 15 mg twice daily plus capecitabine 2000 mg/m2 
per day (days 1-14) or placebo plus capecitabine. Both studies were terminated following a 
planned interim futility/efficacy analysis of JANUS 1. 
 
Although phase III results showed no added benefit of ruxolitinib over capecitabine in patients 
with advanced pancreatic cancer, we will utilize OncoTreat analysis and PDX/PDO models as a 
novel precision medicine approach to select the patient(s) predicted to respond to ruxolitinib. 
 
4. STUDY DESIGN 
This is a single center, non-randomized, open-label phase Ib study conducted at Columbia 
University Medical Center to assess the safety and feasibility of the OncoTreat framework while 
also gathering preliminary data on efficacy. 
4.1 
General Design 
(1) Subjects with newly diagnosed, treatment-naïve locally advanced, unresectable or metastatic 
pancreatic adenocarcinoma will be enrolled on Part 1 (AAAR6703). Written consent will be 
obtained. Tumor tissue, from either the primary or metastatic site, will be obtained. Tumor tissue 
acquision, handling, and processing are described in the laboratory manual. The subject will then 
begin first-line systemic treatment at the treating physician’s discretion (standard-of-care 
chemotherapy or clinical trial). 
 
(2) RNA-Seq and OncoTreat analysis are performed on the pre-treatment biopsy. At least 0.3 
cm3 of fresh frozen tissue is to be submitted (additional tissue will be utilized in the generation of 
PDX and PDO models, as described below). Prior to performance of NY State CLIA-certified 
RNA-Seq, the presence of >70% tumor on H&E stained sections will be confirmed by the 

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Department of Pathology, and the RNA integrity number of extracted RNA will be confirmed as 
being RIN > 6.  
 
(3) In order to provide preclinical validation data for each subject, we will effectly perform a 
separate preclinical trial while each subject receives first-line treatment. A the time of initial 
biopsy, additional tissue material (designated “P0” samples) will be transferred to the Olive 
laboratory and utilized to generate patient-derived xenografts (PDXs) through orthotopic 
implantation into the pancreas of NSG mice. If available, additional tissue may be used for the 
generation of patient-derived organoids (PDOs) in the laboratory of Christine Chio, for tissue 
banking, and for cryopreservation. For PDX models, the initial samples will be implanted into up 
to five animals, and engraftment and outgrowth will be monitored weekly by high resolution 
ultrasound. Subsequent screening will proceed using whichever model expands more quickly.  
 
(4) Upon outgrowth of a PDX model (designated “P1” samples), or alternatively the expansion 
of a PDO model (designated P1 organoids), samples will be expanded into additional recipient 
NSG mice to generate “P2 tumors.” These P2 tumors will be utilized to evaluate candidate 
treatments identified through OncoTreat. We will execute the preclinical studies via the “Mouse 
Hospital” infrastructure with the Olive Laboratory, which includes expertise in small animal 
imaging, surgery, drug administration, tissue sampling, histopathology, and pharmacology. 
Details describing the establishment of orthotopic PDX/PDO models, treatment tolerability 
studies, survival studies, and PK studies will be described in Appendix D. The outcome of this 
stage will be a data package summarizing the results of different drug treatments for each patient, 
which will be provided to the Precision Medicine Tumor Board. 
 
(5) The results of these preclinical studies will be evaluated by the Precision Medicine Tumor 
Board (PMTB), which will include experts in gastrointestinal (GI) medical oncology, GI surgical 
oncology, radiology, pharmacology, molecular biology, genetics, and computational biology. 
Additionally, there will be at least four non-Columbia individuals on the PMTB, including two 
oncologists, one pathologist, and one patient advocate. The PMTB will review all of the data and 
prioritize a treatment based on the following criteria:  
 Patient safety 
 Preclinical efficacy 
 Pharmacological properties 
 Drug availability. Efforts will be made to obtain the selected OncoTreat-prioritized drug 
through off-label insurance coverage, pharmaceutical patient assistance programs, or 
single-patient INDs. 
NOTE: It is anticipated that for some number of subjects, either their PDX/PDO models will fail 
to establish or the preclinical studies will not be completed before the patient progresses on 
second-line therapy. In this scenario, based on numerous studies in hematologic and other solid 
tumor malignancies using the OncoTreat technology (8-19) and the lack of an established 
standard third-line therapy for pancreatic cancer, we will calculate which of our established 
tumor models is the closest match to that patient’s tumor and use that as a surrogate instead to 
turn the preclinical experiments. This data will then be forwarded to the PMTB for review and 

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consideration. If an OncoTreat-informed drug is identified and treatment is recommended by the 
PMTB, the subject may proceed with consent for Part 2. 
 
The PMTB will convene at CUMC on a monthly or as needed basis. A quorum of at least 5 
members, including the principal investigator, one additional medical oncologist and one non-
Columbia individual, must be present for each meeting. Teleconference is permitted if a PMTB 
member is located off campus. 
 
(5) If the PMTB recommends a FDA-approved or investigational oncology drug, and the drug is 
available, the subject will consent to Part 2 and begin the study agent at the time of disease 
progression or intolerance to therapy. A pre-study treatment biopsy will be required to confirm 
that the MR dependencies of the subject’s tumor have not changed over time or in response to 
first-line therapy (a theoretical concept that needs to be formally assessed).  
 
If no FDA-approved or investigational agents are identified at the time of first disease 
progression or intolerance to first-line therapy, or the OncoTreat-prioritized drug is not available 
in a time manner for administration, the subject will continue on to physician’s choice second-
line treatment (chemotherapy or clinical trial). The subject will be followed for response 
evaluation. At the time of second disease progression or intolerance to treatment, the subject will 
be re-evaluated for enrollment on Part 2. If a FDA-approved or investigational agent is 
identified, and the drug is available, the subject may consent to Part 2 and begin the study agent 
following a pre-study treatment biopsy. If no FDA-approved or investigational agents are 
identified, or the OncoTreat-prioritized drug is not available, the subject will screen fail for Part 
2 and will be followed for response evaluation. 
 
(6) The dosing and schedule of the OncoTreat-prioritized drug will be described in the 
subprotocol for each agent. For each of the FDA-approved drugs, the dose and dosing schedule 
will be aligned with the currently approved dose and schedule in the product U.S. Package Insert 
(USPI) and Investigator’s Brochures (IBs). For the investigational agents, the dose and dosing 
schedule will be aligned with the current recommend phase 2 dose (R2PD). 
 
(7) Subjects who are initiated on an OncoTreat-prioritized drug will have an optional on-
treatment ‘pharmacodynamic’ biopsy performed within one month of initiating treatment and 
within 24 hours of the most recent dose. This biopsy will be performed as ‘proof-of-principle’ 
that OncoTreat prioritized drugs result in collapse of the master regulator architecture (also 
known as master regulator signature) of the tumor, in vivo.  
 
(8) Peripheral blood will be drawn for routine laboratory testing, tumor markers (CA 19-9), and 
research testing for biomarker analysis. Pharmacology measurements will also be drawn weekly 
during Cycle 1 of treatment. Serge Cremers, the Director of Clinical Pharmacology and 
Toxicology Laboratory (CPTL), will make available CLIA assays for every FDA-approved drug 
and will provide assays for any investigational agents that match to the subjects in the study. 
Pharmacokinetic (PK) results and toxicity may be used by the treating physician, after discussion 
with the Investigator, to modify dosing schedule as appropriate.  
 

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(9) Adverse events will be monitored and recorded (Section 8).  
 
(10) Subjects will undergo routine standard-of-care radiographic assessments (CT preferred) at 
baseline and every 8 weeks with response measured per RECIST v1.1 (Section 10). 
 
(11) Subjects will continue on study treatment until radiographic disease progression or death, 
intolerance to the study drug, or withdrawal of consent. Patients will not be permitted to continue 
study treatment after disease progression per RECIST v1.1 criteria (Section 10). 
 
4.2 
Number of Patients 
Thirty subjects will be enrolled on Part 1 and, therefore, up to a maximum of 30 subjects will 
receive OncoTreat-prioritized agents on Part 2. No subjects will be replaced. 
 
4.3 
Study Drugs 
4.3.1 Capecitabine 
The cycle length will be 21 days, and 1000 mg/m2 given orally twice per day, usually 
separated 12 hours apart, on Days 1-14 of a 21-day cycle. Capecitabine should be taken with 
water within 30 minutes after a meal. 
 
4.3.2 Imatinib 
The cycle length will be 28 days. Patients will receive imatinib 400 mg orally once daily. A 
dose increase up to 800 mg daily (given as 400 mg twice daily) may be considered by the 
investigator, as clinically indicated, in patients showing clear signs or symptoms of disease 
progression at a lower dose and in the absence of severe adverse drug reactions. 
 
4.3.3 Ruxolitinib 
The cycle length will be 28 days. Patients will receive ruxolitinib 15 mg orally twice per 
day. A dose increase up to a maximum of 25 mg twice daily may be considered by the 
investigator, as clinically indicated, in patients showing clear signs or symptoms of disease 
progression at a lower dose and/or in the absence of severe adverse drug reactions. 
 
4.4 
Tumor Biopsies 
A tissue sample, from either the primary or metastatic site, will be obtained from all treatment-
naïve subjects at the time of initial presentation. This biopsy, therefore, will serve both 
diagnostic and research purposes prior to initiation of first-line chemotherapy. Tumor tissue 
acquision, handling, and processing are described in the laboratory manual.  
 
Subjects for whom an OncoTreat-prioritized agent is identified will undergo a repeat biopsy 
prior to starting the study drug. This will confirm no change in master regulator profile, which is 
not expected, and that the OncoTreat-prioritized agent identified from the pre-treatment sample 
is no different than the agent identified now following treatment with chemotherapy. 
 
The window for each biopsy is outlined in the study calendar (Section 9). 
 

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4.5 
Pharmacology: Pharmacodynamics and Pharmacokinetics  
4.5.1 Capecitabine 
Capecitabine (N-[1-(5-deoxy-β-D-ribofuranosyl)-5-fluoro-1,2-dihydro-2-oxo-4-pyridinyl]-
n-pentyl carbamate) is a crystalline substance with a molecular weight of 359.35. It is highly 
soluble in water and stable in tablet form for at least 9 months [42]. Capecitabine is 
metabolized to the only active compound, FU, via 3 metabolic steps. Once capecitabine is 
absorbed through the intestine, liver carboxylesterase converts it to 5’-deoxy-5-
fluorocytidine (5’-DFCR). 5’DFCR is then metabolized to 5’DFUR by cytidine deaminase, 
a ubiquitous enzyme with high concentrations in the liver, plasma, and tumor tissue. Finally, 
5’DFUR is converted to the active drug FU by thymidine phosphorylase, found in amounts 
3 to 10 times higher in various solid tumors compared with normal adjacent tissue [42-44]. 
The localization of this enzyme to the liver and tumor tissue allows for targeted intratumor 
release of FU. 
 
Relative FU concentrations in colorectal tumor tissue, adjacent healthy tissue, and plasma 
were compared in 19 patients undergoing surgical resection of their primary and/or liver 
metastasis [44]. Capecitabine 1255 mg/m2 twice daily given orally within 30 minutes of 
food was administered 5 to 7 days before surgery. Samples of the aforementioned tissue 
from each patients were evaluated for concentrations of capecitabine and its metabolites as 
well as enzymes involved in its metabolism. Activity of thymidine phosphorylase was 
almost 4 times higher in colorectal tumor compared with healthy tissue. Consequently, 
concentrations of FU were 3.2 times higher in primary colorectal tumors compared with 
surrounding healthy tissue (P = 0.002). The tumor tissue: plasma ratio for the active drug 
was 21.4 and normal tissue:plasma ratio was 8.89. This selectivity was not demonstrated 
between liver metastasis and healthy liver tissue, however, with a thymidine phosphorylase 
activity ratio close to 1 and FU concentration ratio of 1.41 (P = 0.49) [44].  
 
Capecitabine has almost 100% oral bioavailability and exhibits linear increases in Cmax and 
AUC with dosage increases [45]. After 2 doses of 1250 mg/m2, the drug undergoes rapid 
absorption, with peak plasma levels of 3.9 mg/L achieved in 1.5 to 2 hours. In comparison, 
Cmax for the active metabolite FU was lower at 0.66 mg/L with a similar Tmax of 2 hours. 
AUC values for the parent drug and active metabolite for the same dosage were 5.96 mg and 
1.34 mg h/L, respectively. In a study of 34 patients undergoing 14 continuous days of 
capecitabine therapy at daily doses ranging from 502 to 3514 mg/m2, no significant 
accumulation of capecitabine or its metabolites was seen [45, 46]. 
 
A crossover study evaluated the effect of food on capecitabine pharmacokinetics in 11 
patients with colorectal cancer [47]. Doses of 666 or 1255 mg/m2 give twice daily were 
administered either after an overnight fast or within 30 minutes of finishing a standard 
breakfast on days 1 and 8. The AUC of capecitabine decreased in the presence of food but 
the AUC of the cytotoxic drug FU was only minimally affected. Dosing with food is still 
recommended, as this was how the drug was dosed in clinical trials and because the reported 
response rate and toxicity profiles reflect the administration of capecitabine within 30 
minutes of finishing a meal. 
 

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The predominant route of elimination is renal. The use of capecitabine in patients with renal 
impairment was compared in 24 patients with various solid tumors [48]. Capecitabine was 
dosed orally at 1250 mg/m2 twice daily for 2 weeks followed by a 1-week rest period. All 4 
patients with severe renal dysfunction (defined as CrCl <30 mL/min) experienced serious 
grade 3 or 4 adverse effects. From these results, it is recommended that patients with CrCl 
30 to 50 mL/min receive 75% of the recommended starting dose of capecitabine and that 
use of this agent be avoided in patients with CrCl <30 mL/min because of the potentially 
increased risk of adverse events. 
 
No dosing adjustments for patients with hepatic dysfunction are recommended with 
capecitabine. 
 
4.5.2 Imatinib 
Pharmacokinetic studies of imatinib in healthy volunteers and patients with CML, GIST, 
and other cancers show that orally administered imatinib is well-absorbed, and has an 
absolute bioavailability of 98% irrespective of oral dosage form or dosage strength [49]. 
Food has no relevant impact on the rate or extent of bioavailability. The terminal 
elimination half-life is approximately 18 hours. Imatinib plasma concentrations predictably 
increase by 2- to 3-fold when reaching steady state with 400 mg once daily administration. 
 
Imatinib is approximately 95% bound to human plasma proteins, mainly albumin and α1-
acid glycoprotein [50]. The drug is eliminated predominantly via the bile in the form of 
metabolites. The fecal to urinary excretion ratio is approximately 5:1 [51]. 
 
Imatinib is metabolized in the liver mainly by the cytochrome P450 (CYP) 3A4 or CYP3A5 
and can competitively inhibit the metabolism of drugs that are CYP3A4 or CYP3A5 
substrates. Interactions may occur between imatinib and inhibitors or induces of these 
enzymes, leading to changes in the plasma concentration of imatinib as well as 
coadministered drugs. Major induces of CYP3A4 and CYP3A5 activity may increase 
metabolism and decrease exposure to imatinib (e.g. carbamazepine, dexamethasone, 
barbituates, phenytoin, rifampin, and St. John’s Wort). Concomintant CYP3A4 and 
CYP3A5 inhibitors should be administered with caution (e.g. cimetidine, erythromycin, 
clarithromycin, ketoconazole, itraconazole, cyclosporine, grapefruit juice). 
 
Hepatic and renal dysfunction, and the presence of liver metastases, may result in more 
variable and increased exposure to the drug, although typically not necessitating dosage 
adjustment.  
 
4.5.3 Ruxolitinib 
Ruxolitinib inhibits Janus Associated Kinases (JAKs) JAK1 and JAK2 which mediate the 
signaling of a number of cytokines and growth factors that are important for hematopoiesis 
and immune function. JAK signaling involves recruitment of STATs (signal transducers and 
activators of transcription) to cytokine receptors, activation and subsequent localization of 
STATs to the nucleus leading to modulation of gene expression.  
 

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Ruxolitinib inhibits cytokine induced STAT3 phosphorylation in whole blood from healthy 
subjects with myelofibrosis patients. Ruxolitinib administration resultsin maximal inhibition 
of STAT3 phosphorylation 2 hours after dosing which returns to near baseline by 10 hours 
in both healthy subjects and myelofibrosis patients. 
 
The pharmacokinetics of ruxolitinib was evaluated in healthy volunteers in two double-
blind, randomized, placebo-controlled studies [52]. Ruxolitinib is rapidly absorbed after oral 
administration with maximal plasma concentration (Cmax) achieved within 1 to 2 hours post-
dose. Based on a mass balance study in humans, oral absorption of ruxolitinib is estimated 
to be at least 95%. Mean ruxolitinib Cmax and total exposure (AUC) increases proportionally 
over a single dose range of 5 to 200 mg. There is no clinically relevant changes in the 
pharmacokinetics of ruxolitinib upon administration with a high-fat meal, with the mean 
Cmax moderately decreased (24%) and the mean AUC nearly unchanged (4% increase). 
 
For pharmacodynamics evaluations, investigators have relied on measuring the levels of 
downstream targets of JAK signaling and assessing the change in inflammatory markers in 
response to therapy. In the initial phase I/II reported by Verstovsek and colleagues [53], 
maximal mean inhibition of p-STAT-3 expression ranged from ~40% at the lowest dose 
tested to >90% inhibition at the highest dose tested, and returned to baseline levels by 24 
hours. A dose- and time-dependent reduction of phosphorylated STAT-3 was observed with 
ruxolitinib treatment and was repoted in patients with JAK2V617 and wild-type JAK2. 
Elevated baseline levels of IL-6, IL-ra, IL-8, MIP-1β, TNF-α, and CRP were all 
dramatically reduced with ruxolitinib treatment in myelofibrosis patients. 
 
In vitro studies suggest that CYP3A4 is the major enzyme responsible for metabolism of 
ruxolitinib. Ruxolitinib is the predominant entity in humans representing approximately 
60% of the drug-related material in circulation. Two major and active metabolites were 
identified in plasma of healthy subjects representing 25% and 11% of parent AUC. These 
two metabolites have one-fifth and one-half of ruxolitini’s pharmacological activity, 
respectively. The sum total of all active metabolites contributes 18% of the overall 
pharmacodynamics of ruxolitinib. 
 
Following a single oral dose of [14C]-labeled ruxolitinib in healthy adult subjects, 
elimination was predominantly through metabolism with 74% of radioactivity excreted in 
urine and 22% excretion via feces. Unchanged drug accounted for less than 1% of the 
excreted total radioactivity. The mean elimination half-life of ruxolitinib is approximately 3 
hours and the mean half-life of ruxolitinib + metabolites is approximately 5.8 hours. 
 
4.6 
Rationale for Study Design 
4.6.1 Rationale for Capecitabine Dosage and Schedule 
The dose of capecitabine approved by the US Food and Drug Administration (FDA) for 
both metastatic colorectal and breast cancer is 1250 mg/m2 given orally twice per day, 
usually separated by 12 hours for the first 2 weeks of every 3 week cycle. 
 

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The most common dose-limited adverse effects associated with capecitabine monotherapy 
are hyperbilirubinemia, diarrhea, and hand-footy syndrome. Myelosuppression, fatigue and 
weakness, abdominal pain, and nausea have also been reported.  
 
Approximately 26% - 65% of breast cancer patients had their doses reduced by at least 20% 
in the clinical trials [54, 55]. For this reason, many investigators evaluated capecitabine at a 
lower starting dose of 1000 mg/m2 twice daily and demonstrated similar efficacy to the 
approved dose and more favorable side effect profile with an incidence of dose reduction 
ranging from 16 to 34% in phase II trials [56, 57]. A meta-analysis of phase II/III trials 
comparing toxicity profiles between 1000 mg/m2 twice daily (lower dose) and 1250 mg/m2 
twice daily (standard dose) capecitabine in breast cancer found that the 1000 mg/m2 twice 
daily had a clinically meaningful and significantly better toxicity profile than the 1250 
mg/m2 twice daily regimen [58]. 
 
4.6.2 Rationale for Imatinib Dosage and Schedule 
Imatinib has been the standard-of-care for patients with CML since 2001. In the original 
phase I trial investigating imatinib therapy, there was no maximum tolerated dose that was 
reached. Therefore, researchers chose 400 mg because it was a convenient, safe, and active 
dose. Cumulative complete response achieved in CML patients after 7 years of imatinib 
therapy is 87%. At 7 years, the overall survival rate is 86% and 94% if only CML-related 
deaths are considered. One of the key studies for imatinib is the International Randomized 
Study of Interferon Versus STI571 (IRIS) study, which was a phase III, randomized, open-
label trial that compared the standard-of-care at that time, which was interferon and low-
dose cytarabine, with imatinib 400 mg daily in patients who had early chronic phase CML 
[59]. The study was clearly in favor of imatinib in response rates. The study did not show a 
survival advantage for imatinib because 90% of patients who were on the interferon and 
cytarabine arm crossed over to imatinib therapy after a median of 9 months. 
 
The first rationale for higher imatinib doses can be explained by a clear dose-response 
relationship, which was shown in a phase I study where patients responded more when 
given higher doses of imatinib [60]. Second, some mutations of BCR-ABL can be overcome 
by high-dose imatinib. Specific mutations can still be mildly sensitive to imatinib, and in 
these cases, a dose increase may be effective. Third, studies have shown that the dose of 600 
mg imatinib given to CML patients in the accelerated phase was independently associated 
with significantly better time to transformation and better survival, compared to patients 
who received imatinib 400 mg [61]. 
 
The key study investigating standard dose imatinib versus high dose imatinib is the Tyrosine 
Kinase Inhibitor Optimization and Selectivity (TOPS) trial, a prospective, open-label, 
randomized (2:1 ratio) phase III trial that studied the efficacy of imatinib 400 mg versus 800 
mg in chronic phase CML patients [62]. In the intent-to-treat population, a significantly 
higher rate of complete cytogenetic response and major molecular response in the high-dose 
arm was recorded at 6 months. However, at 12 months, although the response rates were 
still higher than those of the standard dose arm, the differences were not significant. 
 

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In patients with advanced or metastatic GIST, who were treated with imatinib 400 mg once 
daily, mean plasma tough level (Ctrough) was higher in patients who responded to treatment. 
A target threshold of >1,100 ng/mL has been defined [63-65]. These results are similar to 
results previously found in patients with CML [66-68]. 
 
We will use therapeutic drug monitoring (TDM) in this clinical trial with the hope of 
establishing exposure-response relationship.  
 
4.6.3 Rationale for Ruxolitinib Dosage and Schedule 
A phase I/II study of ruxolitinib was conducted in JAK2V617F-positive and –negative 
myelofibrosis patients at ascending doses starting at oral doses with a twice daily schedule 
of 10 mg, 15 mg, 20 mg, and 50 mg, and once-daily dosing at 25 mg, 50 mg, 100 mg, and 
200 mg [53]. Ruxolitinib at 25 mg twice daily or 100 mg once a day was established as the 
maximum tolerated dose based on the dose-limiting toxicity of reversible thrombocytopenia. 
At 15 mg twice a day, ruxolitinib treatment was associated with sustained reductions of 
splenomegaly, resolution of constitutional symptoms, improvement in exercise tolerance 
and performance status, and meaningful weight gain. Durable improvements in symptoms 
and splenomegaly were seen in both JAK2-mutated and wild-type patients, and 52% of 
treated patients had a rapid objective response in splenomegaly >50% reduction for ≥12 
months. Marked depression in the heightened expression of proinflammatory cytokines 
were seen with ruxolitinib treatment and correlated with improvement in night sweats, 
fevers, fatigue, weight loss, and pruritus. After 12 cycles of therapy, there was a mean 
maximal suppression of JAK2V617F allele burden by a modest 13% with ruxolitinib 
treatment. 
 
Ruxolitinib was subsequently approved for the treatment of intermediate- and high-risk 
patients with myelofibrosis based on two randomized, phase III studies: COMFORT-I [69] 
and COMFORT-II [70]. In COMFORT-I, starting doses in the patients randomized to 
ruxolitinib were 15 mg twice daily for patients with baseline platelet counts of 100,000 – 
200,000 and 20 mg twice daily for those with platelet counts >200,000. There was no 
protocol-mandated dose change for anemia. Grade 3/4 anemia was the most frequent 
hematolgic adverse event and was observed in 45% and 19.2% of patients in the ruxolitinib 
and placebo arms, respectively. Grade 3/4 neutropenia was observed in 7.1% and 2% of 
patients in the ruxolitinib and placebo arms, respectively. The most common 
nonhematologic adverse event seen with any grade in the ruxolitinib-treated group was 
diarrhea (23.2% compared with 21.2% in the placebo group). Overall, ruxolitinib was a 
well-tolerated drug. 
 
Mesa et al. (Blood 2013) found that approximately 70% of patients who received ruxolitinib 
in COMFORT-I had a dose adjustment within the first 12 weeks of initiating ruxolitinib 
treatment. At week 24, 77% of patients with baseline platelet counts of 100,000 – 200,000 
and 39% of those with baseline platelet counts >200,000 had titrated to a reduced ruxolitinib 
dose relative to their starting dose. With longer-term follow-up (median 149 weeks), the 
mean dose over time in patients who continued on study was ~10 mg twice daily for patients 
starting at 15 mg twice daily and ~15 mg twice daily for those starting at 20 mg twice daily.  

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36 
 
 
In both COMFORT studies, ruxolitinib demonstrated marked and sustained clinical benefits 
in spleen size and improvement in symptom burden, and was generally well tolerated. 
Anemia and thrombocytopenia were the most frequent hematologic adverse events. The 
recommended starting dose of ruxolitinib is based on the platelet count 
(https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/202192lbl.pdf). 
 
4.7 
Formulation, Packing, Handling, and Administration 
4.7.1 Capecitabine 
Capecitabine tablets should be swallowed whole with water within 30 minutes after a meal.  
 
Capecitabine is supplied as biconvex, oblong film-coated tablets for oral administration. 
Each light peach-colored tablet contains 150 mg of capecitabine and each peach-colored 
tablet contains 500 mg of capecitabine. 
 
Capecitabine should be stored at 25°C (77°F). Excursions permitted to 15°C to 30°C (59°F 
to 86°F). Keep tightly closed. 
 
Care should be exercised in the handling of capecitabine. Capecitabine tablets should be cut 
or crushed. Procedures for the proper handling and disposal of anticancer drugs should be 
considered. Any unused product should be disposed of in accordance with local 
requirements, or drug take back programs.  
 
4.7.2 Imatinib 
Imatinib should be taken with a meal and a large glass of water. Imatinib tablets should not 
be crushed. Direct contact of crushed tablets with the skin or mucous membranes should be 
avoided. If such contact occurs, wash thoroughly as outlined in the package insert. 
 
If a dose is missed, patients should be advised to take their dose as soon as possible unless it 
is almost time for their next dose in which case the missed dose should not be taken. A 
double dose should not be taken to make up for any missed dose. 
 
Imatinib can be dissolved in water or apple juice for patients having difficulty swallowing. 
The required number of tablets should be placed in the appropriate volume of beverage 
(approximatel 50 mL for a 100 mg tablet and 200 mL for a 400 mg tablet) and stirred with a 
spoon. The suspension should be administered immediately afer complete disintegration of 
the tablet(s). 
 
Tablets come in 100 mg very dark yellow to brownish orange, film-coated tablets, round, 
biconvex with bevelled edges as well as 400 mg tablets with very dark yellow to brownish 
orange, film-coated tablets, ovaloid, biconvex with bevelled edges. 
 
Imatinib should be stored at 25°C (77°F). Excursions permitted to 15°C to 30°C (59°F to 
86°F). Protect from moisture. Dispense in a tight container. 
 

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Procedures for the proper handling and disposal of anticancer drugs should be considered. 
 
4.7.3 Ruxolitinib 
Ruxolitinib is dose orally and can be administered with or without food.  
 
If a dose is missed, the patient should not take an additional dose, but should take the next 
usual prescribed dose.  
 
Ruxolitinib phosphate is a kinase inhibitor. It is a white to off-white to light pink powder 
and is soluble in aqueous buffers across a pH range of 1 to 8.  
 
Each ruxolitinib tablet contains ruxolitinib phosphate equivalent to 5 mg, 10 mg, 15 mg, 20 
mg, and 25 mg of ruxolitinib free base together with microcrystalline cellulose, lactose 
monohydrate, magnesium stearate, colloidal silicon dioxide, sodium starch glycolate, 
povidone and hydroxypropyl cellulose. 
 
Dosage Forms and Strengths 
5 mg tablets – round and white with “INCY” on one side and “5” on the other 
10 mg tablets – round and white with “INCY” on one side and “10” on the other 
15 mg tablets – oval and white with “INCY” on one side and “15” on the other 
20 mg tablets – capsule-shaped and white with “INCY” on one side and “20” on the other 
25 mg tablets – oval and white with “INCY” on one side and “25” on the other 
 
Ruxolitinib should be stored at room temperature 20°C to 25°C (68°F to 77°F); excursions 
permitted between 15°C and 30°C (59°F and 86°F). 
 
4.8 
Pharmacology Assessments 
Serum concentration and pharmacokinetic (PK) parameters of OncoTreat-prioritized agents 
undergoing trial in subjects with advanced pancreatic cancer are going to be measured in the 
Clinical Pharmacology and Toxicology Laboratory (CPTL), Department of Pathology and Cell 
Biology, Columbia University Irving Medical Center (CUIMC). CPTL is a New York State 
CLIA-certified lab dedicated mostly to assay development for drugs in different biological 
specimens using advanced technology such as ultra-performance liquid chromatography tandem 
mass spectrometry (LC-MS/MS). In support of OncoTreat, CPTL is going to develop and offer 
assays for those FDA-approved drugs as well as investigational agents that are prescribed based 
on this methology. Assays will be developed using LC-MS/MS and target ranges for the 
Therapeutic Drug Monitoring (TDM) of these various compounds will be derived from the 
literature. The CPTL has already developed an LC-MS/MS method for the simultaneous 
quantification of capecitabine, imatinib, and ruxolitinib (see complete details of methods in 
Appendix 17.5): 
 
Table 1:  
LC-MS/MS assay method overview 
 
MRM 
RT, min 
Imatinib  
494.121>217.019* 
2.31 
494.121>934.045 

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IS: 13CD3-
Imatinib  
498.195>394.091* 
2.31 
498.195>221.044 
Ruxolitinib 
307.127>186.228 
2.65 
307.127>131.73 
IS: Ruxolitinib-
D9 
316.133>186.228 
2.61 
316.133>131.73 
Capecitabine 
360.181>244.036 
2.96 
360.181>173.994 
 IS: Ruxolitinib-
D9 
316.133>186.228 
2.61 
316.133>131.73 
*Transition used for quantification 
 
4.8.1 Capecitabine 
Capecitabine is the oncology pro-drug of 5-fluorouracil (5FU). Capecitabine is administered 
orally and undergoes mainly hepatic metabolism where it is first biotransformed into 5’-
deoxy-5-fluorocytidine (5’-DFCR) by carboxylesterases and subsequently to 5’-deoxy-5-
fluorouridine (5’-DFUR) by cytidine deaminase. Metabolism of capecitabine involves 
different enxymes, where thymidine phosphorylase converts 5’-DFUR to the active drug 
5FU [71]. 
 
Concentration levels of capecitabine and both 5’-DFCR and 5’-DFUR are measured in PK 
studies [72]. Several PK studies were assessed previously in serum for capecitabine, where 
tmax ranged from 0.5 to 2 hours, with a Cmax of 5000-9500 ng/mL and t1/2 of 34-50 min. After 
the administration of a standard dose of capecitabine, it might be expected serum 
concentrations within 5-10,000 ng/mL. 
 
Dosage: Capecitabine 1000 mg/m2 given orally twice daily, separated 12 hours apart, on 
Days 1-14 of a 21-day cycle, to be taken with water within 30 minutes after a meal. 
 
Sampling: Based on a 21-day cycle, as mentioned above, peak levels will be measured 2 
hours after administration of capecitabine on day 1 and cycle 1 day 8. 
  
Sample Handling: Peripheral blood will be collected in a tube containing 500 nM 
tetrahydrouridine (THU) to avoid ex vivo conversion of 5'-DFCR to 5'-DFUR [73] and will 
be allowed to clot for 30-60 min followed by centrifugation at 3000 rpm, 4°C, for 10 min. 
 
Sample Storage: Serum samples will be stored at -80°C. 
 
Extraction: Capecitabine will be extracted from the serum samples using the above 
mentioned protein precipitation extraction procedure. Minimum volume of blood sample 
considering duplicates for TDM (and PK) studies should be no less than 300 µL (120 µL is 
needed for one extraction). 
 
Quantification: Concentration of capecitabine will be measured by a New York State 
Department of Health (and thereby CLIA-) approved LC-MS/MS assay developed for the 

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39 
 
simultaneous quantification of OncoTreat-prioritized drugs. The method is based on an 
existing New York State DOH-approved assay for imatinib developed by CPTL for its 
clinical services, with only minor modifications.   
 
Capecitabine 
 
 
Target Range: The target ranges for peak levels will be 5,000 – 10,000 ng/mL for 
capecitabine in serum. 
 
4.8.2 Imatinib 
Imatinib is an oral tyroskine kinase inhibitor (TKI) used for the treatment of gastrointestinal 
stromal tumor (GIST), chronic myeloid leukemia (CML) and Philadelphia positive (Ph+) 
acute lymphocytic leukemia (ALL). Imatinib is administrated as imatinib mesylate, which is 
rapidly converted by non specific esterases into imatinib. Imatinib undergoes CYP-mediated 
metabolism with CYP3A4 and CYP3A5 being the major enzymes involved. N-
demethylimatinib is the predominant metabolite and it was observed with pharmacological 
activity similar to that for the parent drug [74]. Imatinib has a t1/2 of approximately 20 hours, 
and a tmax of 2-4 hours with a Cmax around 3,200 ng/mL.  
 
Dosage: Imatinib 400 mg daily. A dose increase up to 800 mg daily (given as 400 mg twice 
daily) may be considered by the investigator, as clinically indicated, in patients showing 
clear signs or symptoms of disease progression at a lower dose and in the absence of severe 
adverse drug reactions. 
 
Sampling: Trough levels of imatinib will be measured on day 2 at 24 ± 3 hours post-dose 
[67, 75]. 
 
Sample Handling: Peripheral blood will be collected in a tube and will be allowed to clot for 
30-60 min following by centrifugation at 3000 rpm, 4°C, for 10 min. 
 
Sample Storage: Serum samples will be stored at -80°C. 
 
Extraction: Imatinib will be extracted from the serum samples using the above mentioned 
protein precipitation extraction procedure. Minimum volume of blood sample considering 
duplicates for TDM (and PK) studies should be no less than 300 µL (120 µL is needed for 
one extraction). 
 
min
1.25
1.50
1.75
2.00
2.25
2.50
2.75
3.00
3.25
3.50
3.75
4.00
4.25
4.50
4.75
%
0
100
F1:MRM of 4 channels,ES+
316.133>186.228
20190717 TEST 003 Smooth(Mn,2x1)
1.157e+008
2.61
7616918.50
min
%
0
100
F2:MRM of 6 channels,ES+
360.181>173.994
20190717 TEST 003 Smooth(Mn,2x1)
1.690e+006
2.96
94340.89

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Quantification: Concentration of imatinib will be measured by a New York State 
Department of Health (and thereby CLIA-) approved LC-MS/MS assay developed for the 
simultaneous quantification of OncoTreat-prioritized drugs. The method is based on an 
existing New York State DOH-approved assay for imatinib developed by CPTL for its 
clinical services, with only minor modifications.   
 
Imatinib 
 
 
 
Target Range: The target range for imatinib trough levels will be the same as currently used 
clinically and is 1,000 – 3,200 ng/mL in serum.   
 
4.8.3 Ruxolitinib 
Ruxolitinib inhibits the Janus-associated kinase-1 and -2 (JAK 1/2) enzymes and is FDA-
approved for the treatment of myelofibrosis, polycythemia vera, and graft-versus-host 
disease. CYP3A4 is the major enzyme mediating hydroxylation of ruxolitinib. Different 
formulations are available for this drug from 5 mg to 20 mg tablets. Ruxolitinib has a t1/2 of 
2.6 – 5 hours, a tmax of 1 – 3 hours, and reaches a Cmax of 60 or 570 ng/mL for doses of 5 mg 
or 50 mg, respectively [76, 77]. 
 
Dosage: Ruxolitinib 15 mg BID given orally twice per day. A dose increase up to 25 mg 
BID may be considered by the investigator, as clinically indicated, in patients showing clear 
signs or symptoms of disease progression at a lower dose and in the absence of severe 
adverse drug reactions. 
 
Sampling: Trough levels of ruxolitinib will be measured on day 2 at 24 ± 3 hours post-dose. 
On day 2, the trough level is expected at a concentration around 3 ng/mL [77]. 
 
Sample Handing: Peripheral blood will be collected in a tube and will be allowed to clot for 
30 - 60 min following by centrifugation at 3000 rpm, 4°C, for 10 min. 
 
Extraction: Ruxolitinib will be extracted from the serum samples using the above mentioned 
protein precipitation extraction procedure. Minimum volume of blood sample considering 
duplicates for TDM (and PK) studies should be no less than 300 µL (120 µL is needed for 
one extraction). 
 
min
1.20
1.40
1.60
1.80
2.00
2.20
2.40
2.60
2.80
%
0
100
F9:MRM of 4 channels,ES+
498.195>221.044
20190717 TEST 003 Smooth(Mn,2x1)
3.211e+007
2.31
2650506.25
min
%
0
100
F9:MRM of 4 channels,ES+
494.121 > 217.019
20190717 TEST 003 Smooth(Mn,2x1)
1.759e+006
2.31
143448.30*

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41 
 
Quantification: Concentration of ruxolitinib will be measured by a New York State 
Department of Health (and thereby CLIA-) approved LC-MS/MS assay developed for the 
simultaneous quantification of OncoTreat-prioritized drugs. The method is based on an 
existing New York State DOH-approved assay for imatinib developed by CPTL for its 
clinical services, with only minor modifications.   
 
Ruxolitinib 
 
 
Target Range: The target range for ruxolitinib trough concentration in serum will be 15 - 60 
ng/mL. 
 
4.9 
Dose Modifications 
4.9.1 General Notes Regarding Dose Modification 
Reasons for dose modification or delays, the supportive measures taken, and the outcomes 
will be documented in the CRF. The severity of adverse events will be graded according to 
the NCI CTCAE v5.0 grading system. 
 For any concomintant conditions already apparent at baseline, the dose 
modifications will apply according to the corresponding shift in toxicity grade, if the 
investigator feels it is appropriate. For example, if a patient has Grade 1 asthenia at 
baseline that increases to Grade 2 during treatment, this will be considered a shift of 
one grade and treated as Grade 1 toxicity for dose-modification purposes. 
 When several toxicities with different grades of severity occur at the same time, the 
dose modifications should be according to the highest grade observed. 
 
4.9.2 Guidelines for Management of Adverse Events with Capecitabine 
Table 2 Recommended dose modifications for capecitabine: 
Toxicity (NCI 
Grade) 
During a Course of Therapy 
Dose Adjustment for Next 
Treatment (% of starting dose) 
Grade 1 
Maintain dose level 
Maintain dose level 
Grade 2 
1st appearance 
Interrupt until resolved to 
grade 0-1 
100% 
2nd appearance 
75% 
3rd appearance 
50% 
4th appearance 
Discontinue treatment 
permanently 
- 
Grade 3 
min
1.20
1.40
1.60
1.80
2.00
2.20
2.40
2.60
2.80
3.00
3.20
3.40
3.60
3.80
%
0
100
F1:MRM of 4 channels,ES+
316.133>186.228
20190717 TEST 003 Smooth(Mn,2x1)
1.157e+008
2.61
7616918.50
min
%
0
100
F1:MRM of 4 channels,ES+
307.127>186.057
20190717 TEST 003 Smooth(Mn,2x1)
3.258e+006
2.65
215209.70

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1st appearance 
Interrupt until resolved to 
grade 0-1 
75% 
2nd appearance 
50% 
3rd appearance 
Discontinue treatment 
permanently 
- 
Grade 4 
 
 
1st appearance 
Discontinue permanently 
OR 
If investigator deems it to be in 
the patient’s best interest to 
continue, interrupt until 
resolved to grade 0-1 
50% 
 
 
4.9.3 Guidelines for Management of Adverse Events with Imatinib 
4.9.3.1  
Dose Adjustments for Hepatotoxicity and Non-Hematologic Adverse 
Reactions 
 If elevations in bilirubin >3 X institutional ULN or in liver transaminases >5X 
institutional ULN, imatinib should be withheld until bilirubin levels have 
returned to a <1.5 X institutional ULN and transaminase levels to <2.5 X 
institutional ULN. Treatment may then be continued at a reduced dose (i.e. 
400 mg to 300 mg or 800 mg to 600 mg). 
 If a severe non-hematologic adverse reaction develops (such as severe 
hepatotoxicity or severe fluid retention), imatinib should be withheld until the 
event has resolved. Thereafter, treatment can be resumed as appropriate 
depending on the initial severity of the event. 
4.9.3.2 
Dose Adjustment for Hematologic Adverse Reactions 
Dose reduction or treatment interruptions for severe neutropenia and 
thrombocytopenia are recommended if ANC <1,000 and/or platelets <50,000. First, 
stop imatinib until ANC ≥1,500 and platelets ≥75,000. Next, resume treatment with 
imatinib at the original starting dose of 400 mg or 600 mg (including if previously 
taking 800 mg). If the recurrence of ANC <1,000 and/or platelets <50,000, repeat step 
1 and resume imatinib at a reduced dose (300 mg if starting dose was 400 mg, 400 mg 
if starting dose was 600 mg or 800 mg). 
 
4.9.3.3 
Dose Modifications for Concomitant Strong CYP3A4 Inhibitors 
The use of concomitant strong CYP3A4 inducers should be avoided (e.g., 
dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifampicin, 
phenobarbital). If patients must be co-administered a strong CYP3A4 inducer, based 
on pharmacokinetic studies, the dosage of imatinib should be increased by at least 
50%, and clinical response should be carefully monitored. 
 
4.9.4 Guidelines for Management of Adverse Events with Ruxolitinib 
4.9.4.1 Dose Modification Guidelines for Thrombocytopenia 

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43 
 
Treatment Interruption: Interrupt treatment for platelets less than 50,000. After recovery of 
platelet counts above this level, dosing may be restarted or increased following recovery 
of platelet counts to acceptable levels. Table 3 illustrates the maximum allowable dose 
that may be used in restarting ruxolitinib after a previous discontinuation. 
 
Table 3: 
Maximum Restarting Doses for Ruxolitinib After Safety Interruption 
Current Platelet Count 
Maximum Dose When Restarting 
Ruxolitib Treatment* 
Greater than or equal to 125,000 
20 mg twice daily 
100,000 to less than 125,000 
15 mg twice daily 
75,000 to less than 100,000 
10 mg twice daily for at least 2 weeks; if 
stable, may increase to 15 mg twice daily 
50,000 to less than 75,000 
5 mg twice daily for at least 2 weeks; if 
stable, may increase to 10 mg twice daily 
Less than 50,000 
Continue hold 
*Maximum doses are displayed. When restarting, begin with a dose at least 5 mg twice 
daily below the dose at interruption. 
 
Dose Reductions: Dose reductions should be considered if the platelet counts decrease as 
outlined in Table 4 with the goal of avoiding dose interruptions for thrombocytopenia. 
 
Table 4: 
Dosing Recommendations for Thrombocytopenia 
 
Dose at Time of Platelet Decline 
Platelet Count 
25 mg 
twice 
daily 
20 mg 
twice daily 
15 mg 
twice 
daily 
10 mg 
twice daily 
5 mg 
twice 
daily 
 
New Dose 
New Dose 
New Dose 
New Dose 
New Dose 
100,000 to less than 
125,000 
20 mg 
twice 
daily 
15 mg 
twice daily 
No change 
No change 
No change 
75,000 to less than 
100,000 
10 mg 
twice 
daily 
10 mg 
twice daily 
10 mg 
twice 
daily 
No change 
No change 
50,000 to less than 
75,000 
5 mg 
twice 
daily 
5 mg twice 
daily 
5 mg 
twice 
daily 
5 mg twice 
daily 
No change 
Less than 50,000 
Hold 
Hold 
Hold 
Hold 
Hold 
 
4.9.4.2 Dose Modification Based on Response 
If efficacy is considered insufficient and platelet and neutrophil counts are adequate, doses 
may be increased in 5 mg twice daily increments to a maximum of 25 mg twice daily. 
Doses should not be increased during the first 4 weeks of therapy and not more frequently 
than every 2 weeks. 

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4.9.4.3 Dose Adjustment with Concomitant Strong CYP3A4 Inhibitors 
On the basis of pharmacokinetic studies in healthy volunteers, when administering 
ruxolitinib with strong CYP3A4 inhibitors (such as but not limited to boceprevir, 
clarithromycin, conivaptan, grapefruit juice, indinavir, itraconazole, ketoconazole, 
lopinavir/ritonavir, mibefradil, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, 
telaprevir, telithromycin, voriconazole), the recommended starting dose is 10 mg twice 
daily for patients with a platelet count greater than or equal to 100,000. Additional dose 
modifications should be made with careful monitoring of safety and efficacy. 
5. 
SUBJECT SELECTION AND WITHDRAWAL 
Male and female subjects with locally advanced, unresectable or metastatic pancreatic ductal 
adenocarcinoma after progression on first- or second-line systemic therapy who are considered 
incurable will be enrolled on this trial.  
 
5.1 
Inclusion Criteria 
In order to be eligible for participation in this trial, the subject must: 
 Be willing and able to provide written informed consent for the trial. 
 Age ≥18 years of age on day of signing informed consent. 
 Have histologically or cytologically confirmed diagnosis of pancreatic ductal 
adenocarcinoma. 
 Have a predicted life expectancy of greater than 3 months. 
 Have measurable disease based on RECIST v1.1. 
 Have a performance status of 0 or 1 using the ECOG Performance Scale  
 Have documented radiographic or clinical progression to or documented intolerance to 5-
FU- or gemcitabine-based  systemic therapy for locally advanced, unresectable or 
metastastic disease. Patients for whom targeted therapy. 
 MSI-H/dMMR or NTRK-fusion positive tumors – 
o Subjects must have received prior treatment with approved drugs for tumors 
harboring these aberrations. 
 Have a negative urine or serum pregnancy test within 72 hours prior to receiving the first 
dose of study medication (female subjects of childbearing potential). If the urine test is 
positive or cannot be confirmed as negative, a serum pregnancy test will be required. 
 Be willing to use an adequate method of contraception for the course of the study through 
120 days after the last dose of study medication (male and female subjects of 
childbearing potential).  
 Demonstrate adequate organ function as defined below in Table 5. 
 
Table 5 
Adequate Organ Function Laboratory Values 
System 
Laboratory Value 

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Hematological  
 
     Leukocytes 
≥2,000 /mcL 
     Absolute neutrophil count (ANC) 
≥1,500 /mcL 
     Platelets  
≥100,000 /mcL 
     Hemoglobin 
≥9 g/dL without transfusion or EPO 
dependency within 7 days 
Renal 
 
     Creatinine OR 
     Measured or calculateda creatinine    
     clearance (GFR can also be used in  
     place of creatinine or CrCl) 
≤1.5 X upper limit of normal (ULN) OR 
≥60 mL/min for subject with creatinine levels 
>1.5 X institutional ULN 
Hepatic 
 
     Total bilirubin 
≤2 mg/dL or direct bilirubin ≤ ULN for those 
with total bilirubin >2 X ULN 
Subjects with Gilbert Syndrome will be 
eligible if total bilirubin is <3.0 mg/dL 
     AST (SGOT) and ALT (SGPT) 
≤2.5 X ULN OR 
≤5 X ULN for subjects with liver metastases 
     Albumin  
>3.0 mg/dL 
Coagulation 
 
     INR or PT 
     aPTT 
≤1.5 X ULN unless subject is receiving 
anticoagulant therapy as long as PT or aPTT 
is within therapeutic range of intended use of 
anticoagulants 
 
5.2 
Exclusion Criteria 
The subject must be excluded from participating in the trial if the subject: 
 Is currently participating and receiving study therapy or has participated in a study of an 
investigational agent and received study therapy, or herbal/complementary oral or IV 
medicine, within 2 weeks of the first dose of treatment. 
 All toxicities attributed to prior anti-cancer therapy other than alopecia and fatigue must 
have resolved to Grade 1 (NCI CTCAE v4.0) or baseline prior to administration of first 
dose of study drug. Subjects with toxicities attributed to prior anti-cancer therapy that are 
not expected to resolve and result in long-lasting sequalae, such as chronic neuropathy 
after platinum-based therapy, are permitted to enroll. 

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46 
 
 Has received chemotherapy or radiotherapy within 14 days of first dose of study 
medication. 
 Has a solid organ or hematologic transplant. 
 Has experienced weight loss >10% over 2 months prior to first dose of study therapy. 
 Has a diagnosed additional malignancy within 2 years prior to first dose of trial treatment 
with the exception of curatively treated basal cell carcinoma of the skin, squamous cell 
carcinoma of the skin or curatively resected in situ breast cancers. Subjects with another 
malignancy diagnosed >2 years prior to the first dose of trial medication who were 
treated with curative intent and are not undergoing active therapy will be eligible. 
 Has an active infection requiring systemic therapy. 
 Has clinically relevant ascites (defined as requiring paracentesis within 21 days of first 
dose of study drug) or with moderate radiographic ascites. A minimal amount of 
radiographic ascites is allowed. 
 Has a history or current evidence of any condition, therapy, or laboratory abnormality 
that might confound the results of the trial, interfere with the subject’s participation for 
the full duration of the trial, or is not in the best interest of the subject to participate, in 
the opinion of the investigator, including dialysis. 
 Has a known psychiatric or substance abuse disorders that would interfere with 
cooperation with the requirements of the trial. 
 Is pregnant or breastfeeding, or expecting to conceive or father children within the 
projected duration of the trial, starting with the screening visit through 120 days after the 
last dose of trial treatment. 
5.2.1 Exclusion Criteria Specific to Capecitabine 
The subject must be excluded from receiving capecitabine if the subject: 
 Requires concomitant use of phenytoin and/or warfarin due to reported increases in 
serum phenytoin levels and the international normalized ratio (INR) in patients 
receiving concomitant phenytoin and warfarin, respectively. 
 Has a known hypersensitivity to capecitabine or to any of its components. 
 Has a known hypersensitivity to 5-fluorouracil. 
5.2.2 Exclusion Criteria Specific to Imatinib 
The subject must be excluded from receiving capecitabine if the subject: 
 Requires concomitant use of anticoagulation with warfarin. Patients who require 
anticoagulation should receive low molecular weight heparin. 
 Has a left ventricular ejection fraction (LVEF) of < 45% 
 Has New York Heart Association (NYHA) class III or IV symptoms 
 Has had major surgery within 2 weeks prior to study entry 
 Has a history of ventricular tachycardia, ventricular fibrillation, ventricular flutter, 
Torsades de Pointes, or long QT syndrome 

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47 
 
5.2.3 Exclusion Criteria Specific to Ruxolitinib  
 Has a history of hypersensitivity to ruxolitinib or to any medicine with similar 
chemical compounds 
 Has a baseline corrected QT interval (QTc) > 470 ms 
5.3 
Inclusion of Women and Minorities 
Both men and women of all races and ethnic groups are eligible for this trial. 
 
Accrual Targets 
Ethnic Category 
Sex/Gender 
Females 
 
Males 
 
Total 
Hispanic or Latino 
7 
+ 
8 
= 
15 
Not Hispanic or Latino 
8 
+ 
7 
= 
15 
Ethnic Category: Total of all 
subjects 
15 
+ 
15 
= 
30 
Racial Category 
 
American Indian or Alaskan Native 
3 
+ 
3 
= 
6 
Asian 
3 
+ 
3 
= 
6 
Black or African American 
3 
+ 
3 
= 
6 
Native Hawaiian or other Pacific 
Islander 
3 
+ 
3 
= 
6 
White 
3 
+ 
3 
= 
6 
Racial Category: Total of all 
subjects 
15 
+ 
15 
= 
30 
 
 
5.4 
Subject Recruitment 
This study will be conducted at Columbia University Medical Center. Thirty subjects will be 
needed to meet the primary study endpoint. The amount of time required to complete this trial 
will depend on the rapidity of accrual. We estimate evaluation of 3-5 subjects of a month in our 
Pancreas Center with enrollment of 1-2 subjects a month to complete accrual over 30 months. 
 
Subjects will be followed for 30 additional days after completion or early discontinuation of 
treatment for safety follow-up, after which they will be off the active treatment phase of the 
study. Post-treatment long-term follow-up for disease status and survival will proceed until the 
subject has withdrawn consent, is lost to follow-up, has died, or until the Sponsor makes a 
decision to close the study. 
 
Participation is voluntary. The patient must be aware of the neoplastic nature of his/her disease 
and willingly consent after being informed of the procedures to be followed, the experimental 

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48 
 
nature of the therapy, alternatives, potential benefits, side effects, risks, and discomforts. The 
investigatory will make certain that an appropriate informed consent process is in place to ensure 
that potential research subjects, or their authorized representatives, are fully informed about the 
nature and objects of the clinical study, the potential risks and benefits of the study participation 
and their rights as research subjects. 
 
5.5 
Treatment Discontinuation 
Subjects may withdraw from treatment at any time for any reason. A subject may be dropped 
from the trial at the discretion of the investigator should any untoward effect occur. Additionally, 
a subject may be withdrawn by the investigator or Sponsor if enrollment into the trial is 
inappropriate, the trial plan is violated, or for administrative and/or other safety reasons.  
 
The investigator must discontinue study treatment for any of the following reasons:  
 Subject or or legal representative desires discontinuation of treatment (i.e., withdraws 
consent for treatment) 
 Radiographic disease progression (if confirmed by RECIST v1.1) 
 Unacceptable toxicity 
 Noncompliance with study procedures, including administration of nonprotocol therapies 
 Requirement for alternative therapy 
 Intercurrent illness or worsening of a chronic condition that prevents further 
administration of treatment 
 The subject has a confirmed positive serum pregnancy test 
 Subject is lost to follow-up 
The reason for withdrawal from treatment will be documented in the CRF. Posttreatment follow-
up for disease status and survival will continue until death unless any of the criteria for early 
study withdrawal are met (Section 10.9) 
 
Discontinuation of treatment due to progression should be recorded on the Treatment 
Disconinuation CRF as “Disease Progression” and not as an AE or a SAE (unless the event 
meets the criteria for SAE as outlined in Section 8.1). 
 
If the reason for withdrawal is AE, the subject will be followed by the Investigator as described 
in Section 8 until such events resolve, stabilize, and, according to the Investigator’s judgment, 
there is no need for further follow-up. 
 
 
 
5.6 
Early Study Withdrawal 
When a subject discontinues/withdraws prior to trial completion, all applicable activities 
scheduled for the final trial visit should be performed at the time of discontinuation. Any AEs 
which are present at the time of discontinuation/withdrawal should be followed in accordance 
with the safety requirements outlined in Section 8 Assessing and Recording Adverse Events. 

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49 
 
Subjects who discontinue for toxicity but do not withdraw consent from the study will continue 
to be followed for post-study treatment and survival as described in the Trial Flow Chart 
(Section 9).  
 
5.7 
Data Collection and Follow-Up of Withdrawan Subjects 
The End of Treatment and Follow-Up visit procedures are listed in Section 9 (Trial Flow Chart) 
and Section 9.2 (Administrative Procedures). After the end of treatment, each subject will be 
followed for 30 days for adverse event monitoring (SAEs will be collected for 30 days after the 
end of treatment as described in Section 8). Subjects who discontinue for reasons other than 
progressive disease will have post-treatment follow-up for disease status until disease 
progression, initiating a non-study cancer treatment, withdrawing consent, or becoming lost to 
follow-up. After documented disease progression, each subject will be followed by telephone for 
survival until death, withdrawal of consent, or the end of the study, whichever occurs first. 
 
5.8 
Post-Treatment Visits 
5.8.1 Safety Follow-Up Visits 
The mandatory Safety Follow-Up Visit should be conducted approximately 30 days after the 
last dose of trial treatment or before the initiation of a new anti-cancer treatment, whichever 
comes first. 
 
All AEs that occur prior to the Safety Follow-Up Visit should be recorded. Subjects with an 
AE of Grade ≥ 2 will be followed until the resolution of the AE to Grade 0-1 or until the 
beginning of a new anti-cancer therapy, whichever occurs first. SAEs that occur within 90 
days of the end of treatment or before initiation of a new anti-cancer treatment should also 
be followed and recorded.  
 
5.8.2 Follow-Up Visits 
Subjects who discontinue trial treatment for reasons other than disease progression will 
move into the follow-up phase and should be assessed Q8W by radiologic imaging to 
monitor disease status. Every effort should be made to collect information regarding disease 
status until the start of a new anti-cancer therapy, disease progression, death, or the end of 
the study. 
 
Information regarding post study anti-cancer treatment will be collected if new treatment is 
initiated.  
 
5.8.3 Survival Follow-Up 
Subjects who experience disease progression (by site assessment) or start a new anti-cancer 
therapy, will move into the survival follow-up phase. Subjects should be contacted (e.g., by 
telephone or visit) approximately every 12 weeks to assess for survival status until death, 
withdrawal of consent, or the end of the study, whichever occurs first. This will be done via 
telephone calls, subject medical records, and/or clinical visits. If the subject specifically 
withdraws consent from survival follow-up, the study staff may use a public information 
source (e.g. county records) to obtain information about survival status only. 
 

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50 
 
Post study anti-cancer therapy will be collected during survival follow-up. 
 
6. REGISTRATION PROCEDURES 
 
6.1 
 CUMC Research Participant Registration  
Confirm eligibility as defined in the section entitled Criteria for Subject Eligibility. 
 
Obtain informed consent, by following procedures defined in section entitled Informed Consent 
Procedures, along with applicable institutional policies and federal regulations. 
 
Only Investigators/Research personnel properly trained and delegated to consent subjects for this 
protocol will participate in the consenting process. Furthermore, properly delegated/trained 
Physician Investigators (e.g., MD, MD PhD) are required to sign/verify a protocol specific 
Eligibility Checklist for each subject enrolled on the study, in addition to providing the relevant 
source documentation confirmation subject eligibility. 
 
All participants must be centrally registered through the Central Registration Office 
within Herbert Irving Comprehensive Cancer Center at CUMC prior to initiation of study 
treatment. 
 
Registration hours are available Monday through Friday from 9:00am – 5:00pm EST (excluding 
holidays and weekends). Same day patient registrations (and after hour registrations) will be 
accommodated on a case by case basis provided that the study team has expressed all time 
sensitive registration concerns/cases in a timely manner to the Central Registration Office.  
 
CPDM Central Registration Procedures: 
Within 48 hours of obtaining consent (excluding holidays and weekends), a completed/signed 
IRB approved informed consent HIPAA form, and demographics forms must be submitted to the 
CPDM Central Registration Office via an email to CPDMRegistration@columbia.edu or fax to 
212.305.5292, with the subject line “AAAxxxxx Pending Subject Registration Request (PHI)”.  
Upon receipt, applicable subject information as well as a “pending eligibility” status will be 
entered into HICCC’s institutional database.  This status will remain until further source 
documentation is made available to confirm overall patient eligibility. Required materials for all 
pending registration submissions are as follows: 
 
 
Completed/signed IRB approved/stamped Informed Consent Forms, including additional 
study ICFs (e.g., tissue, DNA, etc.), as applicable. 
 
The completed/signed IRB approved HIPAA Authorization form 
 
Completed/signed CPDM ICF checklist 
 
Completed/signed HICCC personal census form 
 
Completed/signed CPDM Demographics Note to File 

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51 
 
In order to confirm eligibility status, Investigators/designees (e.g., study specific Clinical 
Research Coordinator/Research Nurse, etc.) must submit the following documentation to the 
Central Registration Office via email or fax: 
 
 
The completed/signed study specific Eligibility Checklist  (signed by an Physician level 
Investigator) 
 
Copies of source documentation necessary for each item to be verified on the CPDM 
specific Eligibility Checklist, including but not limited to: 
o Copy of required laboratory test and procedure reports (e.g., hematology, serum 
chemistry, pregnancy test when applicable, MRI reports, CT/bone scans, etc.) 
o Copy of pathology and surgical reports 
o Copy of clinic note(s) or other appropriate medical records capturing the consent process 
information, along with providing source documentation of any other items needed for 
screening/eligibility that are not captured in other source document forms (e.g., positive 
investigator statements of unique eligibility items not captured via other direct source 
documentation, concomitant medication lists, etc.) 
o Protocol deviation/waiver approvals (if applicable) 
 
Please note: subject line of email or fax should include the following: “AAAxxxxx 
Complete Subject Registration Request (PHI)”. 
Upon receipt of the above mentioned documentation, participant eligibility information will be 
verified by a qualified Central Registration Registrar. If any questions arise during the review 
process, queries in the form of emails will be addressed to the applicable study team personnel 
for clarification prior to enrollment. .All applicable finalized registration/eligibility information 
will then be entered into HICCC’s institutional CTMS database by the Central Registration 
Registrar. Upon completion, an official subject registration notification email will be sent to the 
PI/research team which will include eligibility/enrollment status, as well as subject ID 
information.  Protocol therapy may not be initiated prior to receipt of this notification from the 
Central Registration Office. 
 
All screen fail/ineligible subjects, as well as subject’s who withdraw consent prior to 
enrollment/initiation of protocol therapy must be submitted to the Central Registration office in a 
manner analogous to the procedures noted above. Applicable source documentation will be 
required within the corresponding submissions. 
 
7. 
  TREATMENT PLAN 
 

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52 
 
7.1 
Study Treatment 
The results of the OncoTreat analysis will include on FDA-approved or investigational oncology 
drugs. These results, along with the preclinical validation studies using PDX/PDO models, will 
be discussed at the PMTB. Details of the trial design are discussed in Section 4.1.  
 
7.2 
Duration of Therapy  
In the absence of treatment delays due to adverse events, treatment may continue until one of the 
following criteria applies: 
 Disease progression 
 Intercurrent illness that prevents further administration of treatment 
 Unacceptable adverse events(s) 
 Patient decides to withdraw from the study 
 General or specific changes in the patient's condition render the patient unacceptable for 
further treatment in the judgment of the investigator 
7.3 
Duration of Follow Up 
Patients will be followed for 4 weeks after completion or removal from study or until death, 
whichever occurs first.  Patients removed from study for unacceptable adverse events will be 
followed until resolution or stabilization of the adverse event. 
 
7.4 
 Criteria for Removal from Study 
Patients will be removed from study when any of the criteria listed in Section 5.4 applies.  The 
reason for study removal and the date the patient was removed will be documented in the Case 
Report Form. 
 
8. 
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS  
 
8.1 
Definitions 
8.1.1 Adverse Event 
An adverse event (AE) is any untoward or unfavorable medical occurrence in a human 
subject, including abnormal sign, symptom or disease, temporally associated with the 
subject’s participation in research, whether or not considered related to the subject’s 
participation in the research. Abnormal results of diagnostic procedures are considered to be 
adverse events if the abnormality: 
 Results in study withdrawal 
 Is associated with a serious adverse event 
 Is associated with clinical signs or symptoms 
 Leads to additional treatment or to further diagnostic tests 
 Is considered by the investigator to be of clinical significance 
8.1.2 Serious Adverse Event 
Adverse events are classified as serious or non-serious. A serious adverse event (SAE) is 
any AE that is: 

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 Fatal 
 Life-threatening 
 Requires inpatient hospitalization/prolongation of existing hospitalization, unless: 
o Routine treatment or monitoring of the studied indication, not associated with 
any deterioration in condiction (procedures such as central line placements, 
paracentesis, pain control) 
o Elective or pre-planned treatment for a pre-existing condition that is 
unrelated to the indication under study and has not worsened since the start 
of study drug 
o Treatment on an emergency outpatient basis for an event not fulfilling any of 
the definitions of an SAE given above/below and not resulting in hospital 
administrations 
o Social reasons and respite care in the absence of any deterioration in the 
patient’s general condition 
 Results in persistent or significant disability or incapacity 
 A congenital anomaly or birth defect 
 An important medical event 
Important medical events are those that may not be immediately life threatening, but are 
clearly of major clinical significance.   They may jeopardize the subject, and may require 
intervention to prevent one of the other serious outcomes noted above.  For example, drug 
overdose or abuse, a seizure that did not result in in-patient hospitalization or intensive 
treatment of bronchospasm in an emergency department would typically be considered 
serious.  
 
All adverse events that do not meet any of the criteria for serious events should be regarded 
as non-serious adverse events. 
 
8.1.3 Unanticipated Problem 
An unanticipated problem (UP) is any incident, experience or outcome involving risks to 
subjects or others in any human subjects research that meets all of the following criteria: 
 Unexpected (in terms of nature, severity or frequency) given (a) the research 
procedures that are described in the IRB-approval protocol and informed consent 
document, and (b) the characteristics of the subject population being studied; 
 Related or possibly related to participation in such research (e.g., there is a 
reasonable possibility that the incident, experience or outcome may have been 
caused by the procedures involved in such 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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8.2 
Adverse Event Reporting Period 
The study period during which adverse events must be reported is normally defined as the period 
from the initiation of any study procedures (e.g., after the first dose of study treatment) to the end 
of the study treatment (e.g., last dose of study treatment) and/or follow-up.  For this study, the 
study treatment follow-up is defined as 30 days following the last administration of study 
treatment, or 30 days following the decision to remove the subject from study treatment, 
whichever is earliest. 
 
8.2.1 Baseline/Prexisting Condition 
A baseline/preexisting condition is one that is present at the start of the study. A preexisting 
condition should be recorded as an adverse event if the frequency, intensity, or if the 
character of the condition worsens during the study period. 
 
8.2.2 General Physical Examination Findings 
At screening, any clinically significant abnormality should be recorded as a preexisting 
condition.  At the end of the study, any new clinically significant findings/abnormalities that 
meet the definition of an adverse event must also be recorded and documented as an adverse 
event. 
 
8.2.3 Post-Study Adverse Event 
All unresolved adverse events should be followed by the investigator until the events are 
resolved, the subject is lost to follow-up, or the adverse event is otherwise explained.  At the 
last scheduled visit, the investigator should instruct each subject to report any subsequent 
event(s) that the subject, or the subject’s personal physician, believes might reasonably be 
related to participation in this study.   
 
8.2.4 Abnormal Laboratory Values 
A clinical laboratory abnormality should be documented as an adverse event if any one of 
the following conditions is met: 
 The laboratory abnormality is not otherwise refuted by a repeat test to confirm the 
abnormality. 
 The abnormality suggests a disease and/or organ toxicity 
 The abnormality is of a degree that requires active management (e.g., change of 
dose, discontinuation of the drug, more frequent follow-up assessments, further 
diagnostic investigation, etc). 
8.2.5 Hospitalization, Prolonged Hospitalization, or Surgery 
Any adverse event that results in hospitalization or prolonged hospitalization should be 
documented and reported as a serious adverse event unless specifically instructed otherwise 
in this protocol.  Any condition responsible for surgery should be documented as an adverse 
event if the condition meets the criteria for an adverse event.  
 
Neither the condition, hospitalization, prolonged hospitalization, nor surgery are reported as 
an adverse event in the following circumstances: 

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 Hospitalization or prolonged hospitalization for diagnostic or elective surgical 
procedures for a preexisting condition. Surgery should not be reported as an 
outcome of an adverse event if the purpose of the surgery was elective or diagnostic 
and the outcome was uneventful. 
 Hospitalization or prolonged hospitalization required to allow efficacy measurement 
for the study.  
 Hospitalization or prolonged hospitalization for therapy of the target disease of the 
study, unless it is a worsening or increase in frequency of hospital admissions as 
judged by the clinical investigator. 
8.3 
Evaluating Adverse Events 
An investigator who is a qualified physician will evaluate all adverse events according to the 
NCI Common Terminology for Adverse Events (CTCAE), version 4.0. Any adverse event which 
changes CTCAE grade over the course of a given episode will have each change of grade 
recorded on the adverse event case report forms/worksheets.  
 
All adverse events regardless of CTCAE grade must also be evaluated for seriousness.  
 
8.4 
Recording of Adverse Events 
At each contact with the subject, the investigator must seek information on adverse events by 
specific questioning and, as appropriate, by examination. Information on all adverse events 
should be recorded immediately in the source document, and also in the appropriate adverse 
event module of the case report form (CRF). All clearly related signs, symptoms, and abnormal 
diagnostic procedures results should recorded in the source document, though should be grouped 
under one diagnosis.  
 
All adverse events occurring during the study period must be recorded. The clinical course of 
each event should be followed until resolution, stabilization, or until it has been determined that 
the study treatment or participation is not the cause. Serious adverse events that are still ongoing 
at the end of the study period must be followed up to determine the final outcome. Any serious 
adverse event that occurs after the study period and is considered to be possibly related to the 
study treatment or study participation should be recorded and reported immediately. 
 
8.5 
Reporting of Serious Adverse Events 
8.5.1 IRB Notification by Sponsor-Investigator 
Reports of all events (including follow-up information) that meet the definition of an 
unanticipated problem posing risk to subjects or others must be submitted to the IRB within 
one week (5 business days) following the occurrence of the unanticipated problem or the 
principal investigator’s acquiring knowledge of the unanticipated problem  in accordance 
with IRB policy. Additionally, the sponsor-investigator will submit a summary of all 
Unanticipated problems that occurred since the beginning of the study at the time of 
continuing review. Copies of each report and documentation of IRB notification and receipt 
will be kept in the Regulatory binder. 
 

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8.5.2    SAE Reporting to Incyte 
 
The Principal Investigator (PI) must report all Serious Adverse Events (SAEs) to 
Incyte  within 24 hours of learning of an event, regardless of the PIs causality assessment. 
This notification should be provided on a completed Serious Adverse Event (SAE) 
form.  SAE reporting for each subject begins the day the informed consent is signed by the 
patient and within 30 days after subject has completed or discontinued from the study or has 
taken last dose of the study drug, or as described in the protocol. 
 
SAEs, occurring using Incyte Study drug, are reported in accordance with the effective 
protocol.  SAEs occurring with any other commercial drug are reported to the manufacturer 
of that drug in accordance with regulations and protocol.  
 
Initial SAEs and/or subsequent follow-up reports should be reported via email to 
SafetyReporting@Incyte.com  or fax (+) 1-866-981-2057.  SAE reports should be for a 
single subject.  SAE forms should be sent with a cover sheet and any additional attachments. 
 
All adverse event information is reported to Incyte on the Principal 
Investigator’s/Institution’s Adverse Event Report Form, or a CIOMS-I or MedWatch Form 
FDA 3500A, or on an Adverse Event Report Form which may be provided by Incyte upon 
request. The Principal Investigator does not provide medical records (e.g., discharge 
summary) to Incyte, unless specifically requested. 
 
8.5.2 8.5.3 FDA Notification by Sponsor-Investigator 
The Columbia University Medical Center Sponsor-Investigator, as holder of the IND, will be 
responsible for all communication with the FDA. Columbia University Medical Center 
Principal Investigator will report to the FDA, regardless of the site of occurrence, any 
adverse event that is serious, unexpected and there is evidence to suggest a causal 
relationship between the drug and the adverse event. These must be reported to the FDA and 
any affiliate sites as soon as possible, but in no case later than 15 calendar days after the 
sponsor determines that the information qualifies for reporting.  The Sponsor-Investigator 
will also submit an IND annual report to the FDA in accordance with 21.CFR 312.33. 
 
The Columbia University Medical Center Sponsor Investigator must report to the FDA and 
any affiliate site investigators as follows: 
 Any unexpected fatal or life-threatening event must be reported as soon as possible, 
but no later than 7 calendar days after the sponsor investigator initial receipt of the 
information 
 Any findings from epidemiological studies, pooled analysis of multiple studies, or 
clinical studies, whether or not conducted under an IND, and whether or not 
conducted by the sponsor-investigator, that suggest a significant risk in humans 
exposed to the drug  must be reported as soon as possible but no later than 15 
calendar days after the sponsor-investigator determines that the information qualifies 
for reporting 

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 Any findings from animal or in vitro testing whether or not conducted under an IND, 
and whether or not conducted by the sponsor-investigator, that suggest a significant 
risk in humans exposed to the drug  must be reported as soon as possible but no later 
than 15 calendar days after the sponsor-investigator determines that the information 
qualifies for reporting 
 Any clinically important increase in the rate of a serious suspected adverse reactions  
over that listed in the protocol or Investigator Brochure 
 Expected SAEs and AEs will be included in the IND Annual Reports 
Follow-up information to a safety report should be submitted as soon as the relevant 
information is available.  However, if the results of a sponsor’s investigation show that an 
adverse drug experience not initially determined to be reportable are so reportable, the 
sponsor investigator must report such experience as soon as possible, but no later than 15 
calendar days after the determination is made. 
 
All other serious unexpected experiences associated with the use of the study treatment will 
be reported to FDA as soon as possible but in no event later than 15 calendar days after 
initial receipt of the information. 
 
8.5.4 DSMC Reporting by the Sponsor-Investigator 
Serious adverse events not constituting unanticipated problems are to be reported to the 
HICCC DSMC. Reporting should occur within 24 hours of knowledge of the SAE occurring 
at our institution or affiliate sites. 
 
8.5.5 Reporting to Drug Manufacturer by Sponsor-Investigator 
The Sponsor-Investigator will report to the investigational agent manufacturer any serious 
adverse events that meet the reporting criteria to the Institutional Review Board and/or FDA 
as described in Section 8.5 within 72 hours of becoming aware of it, so that these reports 
can be evaluated and included in the Investigator’s Brochure and for IND safety 
submissions per regulations. Reporting will occur by sending the reporting form along with 
any additional documentation sent to the regulatory authorities. 
 
At the the time of IRB renewal or at the request of the manufacturer, the Sponsor- 
Investigator will submit a summary of all Serious Adverse Events that have occurred 
inclusive of all sites to manufacturer. 
 
8.5.5  
 
8.6 
Reporting Process 
Adverse events may be submitted on FDA Form 3500A, the HICCC DSMC Serious Adverse 
Event Reporting Form, or in a narrative format.  
 
8.7 
Reporting of Pregnancy to Incyte 
An “Initial Pregnancy Report” or equivalent must be completed in full and emailed to 

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SafetyReporting@Incyte.com or faxed to (+) 1-866-981-2057 within 24 hours of discovery of a 
pregnancy of a subject who has taken the Incyte product or the pregnancy of a partner for a 
subject who has taken the Incyte product.  The “Follow-up Pregnancy Report Form” or 
equivalent must be completed and emailed to SafetyReporting@Incyte.com or faxed to (+) 1-
866-981-2057 within 30 days after delivery, so that Incyte is provided with information 
regarding the outcome of the pregnancy.  If the pregnancy results in any events which meet the 
serious criteria (i.e., miscarriage or termination), the SAE reporting process needs to be followed 
and the timelines associated with a SAE should be followed. 
 
 
9. 
 
STUDY CALENDAR 
 
The screening period for a particular subject commences when the subject undergoes the first 
study-specific screening assessment. Written informed consent must be obtained before any 
protocol-specific tests or procedures may be conducted. After informed consent is obtained, 
baseline evaluations are to be conducted within 2 weeks prior to start of protocol therapy. 
Routine laboratories – hematology, serum chemistries, and coagulation – performed prior to 
informed consent may be used if within a 2 week period to start of study treatment. Baseline 
radiographic evaluations must be done < 4 weeks prior to the start of therapy. In the event that 
the patient’s condition is deteriorating, laboratory evaluations should be repeated within 48 hours 
prior to initiation of the next cycle of therapy. 
 
9.1 
Study calendar 
 
Table 6 
Trial Flow Chart (Part 2 Only) 
 
 
 
 
 
 
 
 

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Trial Period: 
Screening 
Phase 
Treatment Weeksa 
End of Treatment 
(last dose) or 
Discontinuation 
Post-Treatment 
Treatment Week: 
 
 
1 
 
2 
 
3 
 
4 
 
5 
 
6 
 
7 
 
8 
Safety 
Follow-Up 
(30 days 
from last 
dose) 
 
Follow-Up 
Visitsb 
(Q8W) 
 
Survival 
Follow-Up 
(Phone) 
Scheduling Window 
(Days): 
-28 to -1 
 
Details are described in the study calendars for each agent. 
Administrative Procedures 
Informed Consentc 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
Criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics and 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Prior and Concomitant 
Medication Review 
 
X 
 
Details are described in the study calendars for each agent. 
 
X 
 
X 
 
 
Clinical Procedures/Assessments 
Review Adverse 
Events 
X 
Details are described in the study calendars for each agent. 
X 
X 
 
 
12-Lead ECG and 
echocardiogramp 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Examination 
X 
Details are described in the study calendars for each agent. 
X 
 
 
 
Ht (V1 only), Wt, & 
Vital Signs 
(T/P/RR/BP) 
X 
 
Details are described in the study calendars for each agent. 
X 
 
 
 
ECOG Performance 
Status 
Xm 
Details are described in the study calendars for each agent. 
X 
 
 
 
OncoTreat-Prioritized 
Agent 
 
Details are described in the study calendars for each agent. 
 
 
 
 
Post-Study Anticancer 
Therapy Status 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Q12W 
Survival Status 
 
 
 
 
 
 
 
 
 
 
 
 
Q12W 
Laboratory Procedures/Assessments 
Pregnancy Test – 
Urine or Serum β 
HCGd 
X 
 
 
 
 
 
 
 
 
 
 
 
 
PT/INR and aPTTe 
X 
 
 
 
 
 
 
 
 
 
 
 
 
CBC with 
Differentiale 
X 
Details are described in the study calendars for each agent. 
X 
 
 
 
Comprehensive 
Metabolic Panele 
X 
Details are described in the study calendars for each agent. 
X 
 
 
 
HBV, HCV, HIVe,f 
X 
 
 
 
 
 
Efficacy Measurements 
Tumor Imaging 
Xg 
Xh 
Xi 
 
 
 
Tumor markers (CA 
19-9 and CEA)e 
X 
Xn 
X 
 
 
 
Tumor Biopsies/Pharmacokinetics/Correlative Blood Studies 
Newly Obtained 
Tissue Collection 
Xj 
Xk 
X 
 
 
 
Pharmacokineticso 
(Blood Collection) 
 
Details are described in Section 4.8 
 
 
 
 
Correlative Studies 
(Blood Collection) 
 
Xl 
X 
 
 
 
 

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a. 
Unless otherwise specified, procedures/assessments are to be performed prior to dose administration on Day 1 of each cycle. 
b. Subjects who discontinue study treatment without documented disease progression should continue to be monitored for disease by radiologic imaging every 8 weeks (7 days) 
until (1) the start of new anti-cancer treatment, (2) disease progression, (3) death, or (4) the end of the study, whichever occurs first. 
c. 
Informed consent will include consent for correlative studies including biopsies and serum collections. 
d. For women of reproductive potential, a negative pregnancy test should be performed within 72 hours prior to first dose of trial treatment. Pregnancy tests (serum and/or urine) 
should be repeated if required by local guidelines.  
e. 
Laboratory screening tests should be performed within 14 days prior to first dose of study treatment. For all subjects, unresolved abnormal labs resulting in drug-related AEs 
should be followed until resolution. 
f. 
All subjects will be tested for HIV, HBV, and HCV prior to enrollment. Those who are positive for HIV, untreated active Hepatitis B, and dual infection with HBV/HCV will be 
excluded. 
g. Tumor imaging at screening: Imaging will be performed within 28 days prior to the first dose of OncoTreat-prioritized drug. Imaging should include CT chest, abdomen, and 
pelvis or MRI if CT is clinically contraindicated. 
h. The first on-study tumor imaging will be performed after 8 weeks (7 days) of treatment and will continue every 8 weeks (7 days) thereafter (or more frequently if clinically 
indicated). Timing of imaging follows calendar days and should not be adjusted due to dose interruptions. The same imaging technique, acquisition, and processing parameters 
for a subject should be used throughout the trial if possible. 
i. 
Subjects without confirmed PD who discontinue treatment will have imaging performed at the time that study treatment is discontinued (i.e. date of discontinuation 4 week 
window). If a scan was obtained within 4 weeks prior to discontinuation of treatment, then imaging at treatment discontinuation is not required. Subjects who discontinue 
treatment after confirmed PD will not need further imaging performed during the follow-up period. 
j. 
Following disease progression/intolerance to standard of care therapy, a fresh tumor biopsy (primary or metastatic site) is required to be performed after the last dose of systemic 
therapy. OncoTreat analysis will confirm the master regulator profile and the recommended OncoTreat-informed drug.  
k. An optional on-treatment tumor biopsy is requested and will be performed within one month of initiation of an OncoTreat-prioritized drug (28 days 7 days). The biopsy is to be 
done within 24 hours of administration of the most recent dose. An optional end-of-treatment tumor biopsy is also requested (7 days of completing OncoTreat-prioritized drug). 
l. 
Collect on Cycle 1 Day 1 and Cycle 2 Day 1 (prior to study treatment administration). 
m. Screening ECOG performance status should be performed within 3 days prior to the first dose of the OncoTreat-prioritized agent. 
n. Serum CA 19-9 will be collected prior to dose administration on Day 1 of each cycle. 
o. On days with PK assessments, patients should not eat breakfast or take the OncoTreat-prioritized agent at home. Upon arrival to the clinic, whole blood will be obtained pre-
morning dose for imatinib and ruxolitinib. Patients will then take the medication as instructed by the clinic staff. For capecitabine, patients will take the medication as instructed 
by the clinic staff then will have whole blood obtained for PK analysis. See Section 4.8 for details. 
Capecitabine: cycle 1 day, cycle 1 day 8 
Imatinib: cycle 1 day 2 (24 hours ± 3 hours after cycle 1 day 1 dose administration) 
Ruxolitinib: cycle 1 day 2 
p. Baseline transthoracic echocardiogram (TTE) is required for all subjects on the imatinib-treated arm. 

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9.1.1 Study calendar for capecitabine 
For complete details, please see the general study calendar (Table 4). 
 
Table 7 
Capecitabine study calendar 
 

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Trial Period: 
Screening 
Phase 
Treatment Weeks 
End of Treatment 
(last dose) or 
Discontinuation 
Post-Treatment 
Capecitabine 1000 mg/m2 D1-14 every 21 days 
Cycle 1 
Cycle 2 
Cycle 3 
Treatment Week: 
 
 
1 
 
2 
 
3 
 
4 
 
5 
 
6 
 
7 
 
8 
 
9 
 
Safety Follow-Up (30 
days from last dose) 
 
Follow-Up Visits 
(Q8W) 
 
Survival Follow-Up 
(Phone) 
Scheduling 
Window (Days): 
 
-28 to -1 
 
3d 
 
 
 
 
 
 
3d 
 
 
 
 
 
3d 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
Criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics and 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior and 
Concomitant 
Medication Review 
X 
X 
 
 
X 
 
 
X then every 
21 days 
 
 
X 
X 
 
 
Review Adverse 
Events 
X 
 
 
 
X 
 
 
X then every 
21 days 
 
 
X 
X 
 
 
12-Lead ECG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical 
Examination 
X 
X 
 
 
X 
 
 
X then every 
21 days 
 
 
X 
 
 
 
Ht (V1 only), Wt, & 
Vital Signs 
(T/P/RR/BP) 
X 
X 
 
 
X 
 
 
X then every 
21 days 
 
 
X 
 
 
 
ECOG Performance 
Status 
X 
X 
 
 
X 
 
 
X then every 
21 days 
 
 
X 
 
 
 
Dispense 
capecitabine 
 
X 
 
 
X 
 
 
X then every 
21 days 
 
 
 
 
 
 
Post-Study 
Anticancer Therapy 
Status 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Q12W 
Survival Status 
 
 
 
 
 
 
 
 
 
 
 
 
 
Q12W 
Pregnancy Test – 
Urine or Serum β 
HCG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
PT/INR and aPTTe 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
CBC with 
Differential 
X 
X 
 
 
X 
 
 
X then every 
21 days 
 
 
X 
 
 
 
Comprehensive 
Metabolic Panel 
X 
X 
 
 
X 
 
 
X then every 
21 days 
 
 
X 
 
 
 
HBV, HCV, HIV 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tumor Imaging 
X 
 
 
 
 
 
 
 
X then 
every 8 
weeks 
 
X 
 
 
 
CA 19-9 and CEA 
X 
X 
 
 
X 
 
 
X then every 
21 days 
 
 
X 
 
 
 
Newly Obtained 
Tissue Collection 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
Pharmacokinetics 
(Blood Collection) 
Details are described in Section 4.8 
 
 
 
 
Correlative Studies 
(Blood Collection) 
 
X 
 
 
X 
 
 
 
X 
 
X 
 
 
 

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9.1.2 Study calendar for imatinib 
For complete details, please see the general study calendar (Table 4). 
 
Table 8 
Imatinib study calendar 
 

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Trial Period: 
Screening 
Phase 
Treatment Weeksa 
End of Treatment 
(last dose) or 
Discontinuation 
Post-Treatment 
Imatinib 400 mg daily 
Treatment Week: 
 
 
1 
 
2 
 
3 
 
4 
 
5 
 
6 
 
7 
 
8 
 
Safety Follow-Up (30 
days from last dose) 
 
Follow-Up Visitsb 
(Q8W) 
 
Survival Follow-Up 
(Phone) 
Scheduling Window 
(Days): 
 
-28 to -1 
 
3d 
 
 
 
 
 
 
 
 
3d 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
Criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics and 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Prior and 
Concomitant 
Medication Review 
X 
X 
 
X 
 
X then every 
28 days 
 
 
 
X 
X 
 
 
Review Adverse 
Events 
X 
 
 
X 
 
X then every 
28 days 
 
 
 
X 
X 
 
 
12-Lead ECG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Physical 
Examination 
X 
X 
 
X 
 
X then every 
28 days 
 
 
 
X 
 
 
 
Ht (V1 only), Wt, & 
Vital Signs 
(T/P/RR/BP) 
X 
X 
 
X 
 
X then every 
28 days 
 
 
 
X 
 
 
 
ECOG Performance 
Status 
X 
X 
 
X 
 
X then every 
28 days 
 
 
 
X 
 
 
 
Dispense imatinib  
 
X 
 
 
 
X then every 
28 days 
 
 
 
 
 
 
 
Post-Study 
Anticancer Therapy 
Status 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Q12W 
Survival Status 
 
 
 
 
 
 
 
 
 
 
 
 
Q12W 
Pregnancy Test – 
Urine or Serum β 
HCG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
PT/INR and aPTTe 
X 
 
 
 
 
 
 
 
 
 
 
 
 
CBC with 
Differential 
X 
X 
 
X 
 
X then every 
28 days 
 
 
 
X 
 
 
 
Comprehensive 
Metabolic Panel 
X 
X 
 
X 
 
X then every 
28 days 
 
 
 
X 
 
 
 
HBV, HCV, HIV 
X 
 
 
 
 
 
Tumor Imaging 
X 
 
 
 
 
 
 
 
X then every 8 
weeks 
Xi 
 
 
 
Tumor markers (CA 
19-9 and CEA) 
X 
X 
 
X 
 
X then every 
28 days 
 
 
 
X 
 
 
 
Newly Obtained 
Tissue Collection 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
Pharmacokinetics 
(Blood Collection) 
 
Details are described in Section 4.8 
 
 
 
 
Correlative Studies 
(Blood Collection) 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
 

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9.1.3 Study calendar for ruxolitinib 
For complete details, please see the general study calendar (Table 4). 
 
Table 9 
Ruxolitinib study calendar 
 
 

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Trial Period: 
Screening 
Phase 
Treatment Weeks 
End of Treatment 
(last dose) or 
Discontinuation 
Post-Treatment 
Ruxolitinib 15 mg BID 
Treatment Week: 
 
 
1 
 
2 
 
3 
 
4 
 
5 
 
6 
 
7 
 
8 
 
9 
 
Safety Follow-Up (30 
days from last dose) 
 
Follow-Up Visits 
(Q8W) 
 
Survival Follow-Up 
(Phone) 
Scheduling 
Window (Days): 
 
-28 to -1 
 
3d 
 
 
 
 
 
 
3d 
 
 
 
 
 
3d 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
Criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics and 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior and 
Concomitant 
Medication Review 
X 
X 
 
X 
 
X 
 
 
 
X then every 
4 weeks 
X 
X 
 
 
Review Adverse 
Events 
X 
 
 
X 
 
X 
 
 
 
X then every 
4 weeks 
X 
X 
 
 
12-Lead ECG and 
echocardiogram 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical 
Examination 
X 
X 
 
X 
 
X 
 
 
 
X then every 
4 weeks 
X 
 
 
 
Ht (V1 only), Wt, & 
Vital Signs 
(T/P/RR/BP) 
X 
X 
 
X 
 
X 
 
 
 
X then every 
4 weeks 
X 
 
 
 
ECOG Performance 
Status 
X 
X 
 
X 
 
X 
 
 
 
X then every 
4 weeks 
X 
 
 
 
Dispense ruxolitinib 
 
X 
 
 
 
X 
 
 
 
X then every 
4 weeks 
 
 
 
 
Post-Study 
Anticancer Therapy 
Status 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Q12W 
Survival Status 
 
 
 
 
 
 
 
 
 
 
 
 
 
Q12W 
Pregnancy Test – 
Urine or Serum β 
HCG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
PT/INR and aPTT 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
CBC with 
Differential 
X 
X 
 
X 
 
X 
 
X 
 
X then every 
2 weeks 
X 
 
 
 
Comprehensive 
Metabolic Panel 
X 
X 
 
X 
 
X 
 
 
 
 
X 
 
 
 
HBV, HCV, HIV 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Lipid panel 
X 
 
 
 
 
 
 
 
X then every 
9 weeks 
 
 
 
 
Tumor Imaging 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
Tumor markers (CA 
19-9 and CEA) 
X 
X 
 
X 
 
X 
 
 
 
X then every 
4 weeks 
X 
 
 
 
Newly Obtained 
Tissue Collection 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
Pharmacokinetics 
(Blood Collection) 
 
Details are described in Section 4.8 
 
 
 
 
Correlative Studies 
(Blood Collection) 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
 

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9.2 
Trial Procedures 
The Trial Flow Chart (Section 9) summarizes the trial procedures to be performed at each visit. 
Individual trial procedures are described in detail below. It may be  necessary to perform these 
procedures at unscheduled time points if deemed clinically necessary by the investigator. 
Furthermore, additional evaluations/testing may be deemed necessary by the Sponsor for reasons 
related to safety. In some cases, such evaluation/testing may be potentially sensitive in nature 
(e.g. HIV, Hepatitis C, etc.), and thus local regulations may require that additional informed 
consent be obtained from the subject. In these cases, such evaluations/testing will be performed 
in accordance with those regulations. 
 
9.3 
Administrative Procedures 
9.3.1 Informed Consent 
The investigator must obtain documented consent from each potential subject or each 
subject’s legally acceptable representative prior to participating in a clinical trial.  
 
Consent must be documented by the subject’s dated signature or by the subject’s legally 
acceptable representative’s dated signature on a consent form along with the dated signature 
of the person conducting the consent discussion. A copy of the signed and dated consent 
form should be given to the subject before participation in the trial. 
 
The initial informed consent form, any subsequent revised written informed consent form, 
and any written information provided to the subject must receive the IRB/ERC’s 
approval/favorable opinion in advance of use. The subject, or his/her legally acceptable 
representative, should be informed in a timely manner if new information becomes available 
that may be relevant to the subject’s willingness to continue participation in the trial. The 
communication of this information will be provided and documented via a revised consent 
form or addendum to the original consent form that captures the subject’s dated signature or 
by the subject’s legally acceptable representative’s dated signature. 
 
The informed consent will adhere to IRB/ERC requirements, applicable to state laws, and 
federal regulations. 
 
9.3.2 Inclusion/Exclusion Criteria 
All inclusion and exclusion criteria will be reviewed by the investigator or qualified 
designee to ensure that the subject qualifies for the trial (see Section 5). 
 
9.3.3 Medical History 
A medical history will be obtained by the investigator or qualified designee. Medical history 
will include all active conditions and any condition diagnosed within the prior 10 years that 
is considered to be clinically significant by the investigator. Details regarding the disease for 
which the subject has enrolled in this study will be recorded separately and not listed as 
medical history. 
 

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9.3.4 Prior and Concomitant Medications 
Concomitant therapy includes any medication (e.g. prescription drugs, over-the-counter 
drugs, herbal or homeopathic remedies, nutritional supplements) used by a patient from 7 
days prior to screening to the treatment discontinuation visit. All such medications should be 
reported to the investigator and recorded to the Concomitant Medications Case Report Form 
(CRF). All medications related to reportable SAEs and ECIs should be recorded. 
 
9.3.5 Disease Details and Treatments 
The investigator or qualified designee will obtain prior and current details regarding disease 
status. 
 
Prior Treatment Details: The investigator or qualified designee will review all prior cancer 
treatments including systemic treatments, radiation, and surgeries. 
 
Subsequent Anti-Cancer Therapy Status: The investigator or qualified designee will review 
all new anti-neoplastic therapy initiated after the last dose of trial treatment. If a subject 
initiates a new anti-cancer therapy within 30 days after the last dose of trial treatment, the 
30-day Safety Follow-Up visit must occur before the first dose of the new therapy. Once 
new anti-cancer therapy has been initiated, the subject will move into survival follow-up. 
 
9.3.6 Long-Term Follow Up 
After completion of the posttreatment safety visit, subjects will be followed for disease and 
survival status by telephone contact or other method every three months for one year from 
treatment discontinuation, then every six months thereafter. Long-term follow-up will 
continue until the subject has withdrawn consent for further participation, is lost to follow-
up, has died, or the Sponsor makes a decision to close the study.  
 
9.4 
Clinical Procedures and Assessments 
9.4.1 Adverse Event (AE) Monitoring 
The investigator or qualified designee will assess each subject to evaluate for potential new 
or worsening AEs as specified in the Trial Flow Chart (Section 9) and more frequently if 
clinically indicated. AEs will be graded and recorded throughout the study and during the 
follow-up period according to NCI CTCAE Version 4.0 (Appendix B). Toxicities will be 
characterized in terms regarding seriousness, causality, toxicity grading, and action taken 
with regard to trial treatment. 
 
Refer to Section 8 for detailed information regarding the assessment and recording of AEs. 
 
9.4.2 Physical Exam 
The investigator or qualified designee will perform a complete physical exam during the 
screening period. Clinically significant abnormal findings should be recorded as medical 
history. A physical exam should be performed as specified in the Trial Flow Chart (Section 
9). For subsequent cycles, the investigator or qualified designee will perform a directed 
physical exam as clinically indicated prior to dosing on Day 1 of each treatment cycle. After 

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the first dose of trial treatment, new clinically significant abnormal findings should be 
recorded as AEs. 
 
9.4.3 Vital Signs 
The investigator or qualified designee will take vital signs at screening, prior to the 
administration of each dose of trial treatment, and at treatment discontinuation as specified 
in the Trial Flow Chart (Section 9). Vital signs should include temperature, pulse, 
respiratory rate, weight, and blood pressure. Height will be measured at screening only. 
 
9.4.4 Eastern Cooperative Oncology Group (ECOG) Performance Status 
The investigator or qualified designee will assess ECOG status (Appendix A) at screening, 
prior to the administration of each dose of trial treatment, and at discontinuation of trial 
treatment as specified in the Trial Flow Chart (Section 9).  
 
9.4.5 Tumor Imaging and Assessment of Disease 
CT chest, abdomen, and pelvis with contrast will be performed at baseline screening, prior 
to the administration of study drugs, and every 8 weeks thereafter. Subjects will be 
evaluated for diease response and progression according to RECIST v1.1. Disease status 
categories include complete response (CR), partial response (PR), stable disease (SD), and 
progression of disease (PD). 
 
9.4.6 Tumor Tissue Collection, Pharmacokinetics, & Correlative Studies Blood Sampling 
All patients will have tumor biopsy specimens obtained at baseline prior to study drug 
administration and then at week 4 (optional) to assess for successful collapse of the master 
regulator siguature in a given patient’s tumor. A biopsy will also be requested (optional) at 
the time of disease progression. Tissue collection, handling, processing, and storage 
instructions are described in the separate study manual. 
 
Peripheral blood will be collected for pharmacokinetic analysis only during Cycle 1. The 
timing of blood sampling will vary by study drug (Section 4.8). The exact times of 
medication administration and the times of these blood samples must be recorded on the 
appropriate CRF. A validated assay will be used to measure plasma drug concentration. 
Blood processing, handling, and storage instructions are described in Section 4.8 as well as 
in the separate study manual. 
 
Peripheral blood will be collected pre-treatment, cycle 1 day 1, and cycle 2 for future 
evaluation of biomarkers. The analyses may include genomics, transcriptomics, and 
proteomics. Assessment of ctDNA and OncoTreat analysis on circulating tumor cells 
(CTCs) may also be performed. 
 
9.4.7 Laboratory Procedures/Assessments 
Details regarding specific laboratory procedures/assessments to be performed in this trial are 
provided below. Laboratory tests for hematology, chemistry, urinalysis, and others are 
specified in the Trial Flow Chart (Section 9).  
 

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Laboratory tests for screening should be performed within 7 days prior to the first dose of 
study treatment. After Cycle 1, pre-dose laboratory procedures can be conducted up to 72 
hours prior to dosing. Results must be reviewed by the investigator or qualified designee 
and found to be acceptable prior to each dose of trial treatment.  
 
10. 
MEASUREMENT OF EFFECT 
 
10.1 
Antitumor Effect – Solid Tumors 
For the purposes of this study, patients should be re-evaluated for response every 8 weeks.  In 
addition to a baseline scan, confirmatory scans should also be obtained 8 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. 
 
10.2 
Definitions 
Evaluable for toxicity: All patients will be evaluable for toxicity from the time of their first 
treatment with an OncoTreat-prioritized agent. 
 
Evaluable for objective response: Only those patients who have measurable disease present at 
baseline, have received at least one cycle of therapy, and have had their disease re-evaluated will 
be considered evaluable for response.  These patients will have their response classified 
according to the definitions stated below.  (Note: Patients who exhibit objective disease 
progression prior to the end of cycle 1 will also be considered evaluable.) 
 
Evaluable for feasibility – primary outcome: All subjects who receive a single dose of study drug 
will be included in the primary outcome analysis of feasibility.  
 
10.3 
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 for non-nodal lesions and short axis for 
nodal lesions) 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). 
 
Note: Tumor lesions that are situated in a previously irradiated area might or might not be 
considered measurable.  If the investigator thinks it appropriate to include them, the conditions 
under which such lesions should be considered must be defined in the protocol. 
 
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 

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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. 
 
10.4 
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. 
 
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. 
 

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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. 
 
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.   
 
10.5 
Response Criteria – RECIST Criteria 
10.5.1 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. 
 
10.5.2 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. 
 

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  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. 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). 
 
10.5.3 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. 
 
Table 10 
Disease Assessment For Patients with Measurable 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. 

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10.6 
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.  
 
10.7 
Analysis of Endpoints 
Efficacy and safety endpoints that will be evaluated are listed below: 
 
Efficacy 
10.7.1 Objective Response Rate (ORR) 
ORR is defined as the proportion of the subjects in the analysis population who have a CR 
or PR. Responses are based on assessments per RECIST 1.1. 
 
10.7.2 Progression-Free Survival (PFS) 
PFS is defined as the duration of time from the first day of trial treatment to the first 
documented disease progression per RECIST 1.1 or death due to any cause, whichever 
occurs first. 
 
10.7.3 Disease Control Rate (DCR) 
DCR is defined as the percentage of subjects who have achieved CR, PR, and SD. 
Responses are based on assessments per RECIST 1.1. 
 
10.7.4 Overall Survival (OS)  
OS is defined as the time from first dose of study medication to death due to any cause. 
 
Safety 
10.7.5 Safety Endpoints 
The safety analysis will be based on subjects who experienced toxicities as defined by 
CTCAE criteria. Safety will be assessed by quantifying the toxicities and grades 
experienced by subjects who have received the study drug, including serious adverse events 
(SAEs) and events of clinical interest (ECIs).  
 
Safety will be assessed by reported adverse experiences using CTCAE, Version 4.0. The 
attribution to study treatment, time-of-onset, duration of the event, its resolution, and any 
concomitant medications administered will be recorded. AEs will be analyzed including but 
not limited to all AEs, SAEs, fatal AEs, and laboratory changes.  

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10.8 
Pharmacokinetic Outcome Measures 
Pharmacokinetic (PK) samples will be collected for all subjects (see Appendix ___ for sample 
collection details) and include the following: 
 
10.9 
Analysis of Exploratory Endpoints 
 
10.10 Unblinding Procedures 
Not applicable – this is not a blinded study. 
 
10.11 Stopping Rules 
Early trial termination will be the result of the criteria specified below: 
 Quality or quantity of data recording is inaccurate or incomplete 
 Poor adherence to protocol and regulatory requirements 
 Incidence or severity of adverse drug reaction in this or other studies indicates a potential 
health hazard to subjects 
 Plans to modify or discontinue the development of the study drug 
 
11. 
DATA REPORTING / REGULATORY REQUIREMENTS 
 
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 8 
(Adverse Events: List and Reporting Requirements). The Data Safety Monitoring Plan is 
described in Section 11.3. 
 
11.1 
Data Collection 
The Herbert Irving Comprehensive Cancer Center has an electronic clinical trials and data 
management system (CTMS) that will be used for data collection. CRFs for the study will be 
built into the CTMS, Velos, for data entry. The system has full auditing capabilities which is 
web-based and housed on a server in a fully HIPAA compliant server room with restricted access 
and video camera monitoring. All users must login with their own application username and 
password. Users off campus must first access the Virtual Private Network with their assigned 
campus username and password and then use their application credentials. Users are only able to 
see study information if they are indicated as study personnel in our electronic IRB system. 
Users are limited to access based on the role assigned in their corresponding protocol. Subject 
data is entered directly into the system, which (in the case of Columbia subjects) confirms the 
correct identity of patients via an interface with the electronic medical patient index. Staff with 
the appropriate IRB defined roles can run reports within the system for reporting purposes. 
 
11.2 
Data Reporting 
Case Report Forms (CRFs) will be completed for each subject enrolled into the clinical study 
through the CTMS. It is the investigator’s responsibility for ensuring that all clinical and 
laboratory data entered on the corresponding CRFs are complete, accurate and authentic. 
 

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11.3 
Data and Safety Monitoring Committee  
The NCI-approved Data Safety and Monitoring Committee (DSMC) of the Herbert Irving 
Comprehensive Cancer Center (HICCC) will monitor every subject who receives treatment on 
this protocol for toxicity. This protocol will adhere to the policies of the currently approved 
HICCC Data and Safety Monitoring Plan (DSMP), which is in accordance with NCI and 
CUMC-IRB policy and guidelines. The committee is chair is appointed by the HICCC Director. 
The committee consists of HICCC faculty and staff with expertise in oncology, research 
pharmacy, research nursing, and data management. The DSMC convenes twice a month to 
review patient safety and the conduct of the trial. The PI will submit data and safety monitoring 
reports to the DSMC at a frequency to be determined by the DSMC based on risk to the subjects. 
 
At the time of renewal, the study team will submit the most recent DSMC approval letter for 
safety review to the CUMC IRB. Any modifications that are required by the DSMC to ensure 
patient safety will be submitted to the IRB. All protocol deviations, violations, and eligibility 
waivers will be submitted to and approved by the DSMC prior to being reported to the IRB. All 
study data reviewed and discussed during these meetings will be kept confidential.  
 
11.4 
Quality Control and Quality Assurance 
Independent monitoring of the clinical study for protocol and GCP compliance will be conducted 
periodically by the CPDM Compliance Core on behalf of the HICCC DSMC.  Additionally, the 
Compliance Oversight Committee of the IRB at Columbia University Medical Center may audit 
the study at any time per institutional policies and procedures. The investigator-sponsor and 
Columbia University Medical Center will permit direct access of the study monitors and 
appropriate regulatory authorities to the study data and to the corresponding source data and 
documents to verify the accuracy of this data. 
 
A risk-based approach will be used by the Compliance Core to determine the frequency, number 
of subject charts, and data elements to be monitored. The Compliance Coordinator will review the 
study status and summarize enrollment, toxicities, SAEs/UPs, dose escalation, statistical endpoints 
(e.g., stopping rules), etc. for the full DSMC membership at the regularly scheduled meetings.   
 
Internal On-site Monitoring: 
 Initial, recurrent, and close-out on-site monitoring visits will also be conducted at remote 
clinical sites, as appropriate/feasible. Other sites will have monitoring performed 
remotely (see below for further details). 
 The study Monitoring Visit Log will be completed and signed by the monitor and the 
PI/CRNP/CRN and/or CRC and will be filed in the regulatory binder. 
 The Compliance Coordinator will communicate with the site coordinator/Site Principle 
Investigator to schedule the monitoring visit and arrange for access to study materials and 
documentation. 
 The assigned Compliance Coordinator will monitor IIT trials within 1 month after the 
first subject is enrolled and throughout the life of the study to ensure that the study is 
being conducted in accordance with the protocol, GCP, applicable federal and local 
regulations, and per all applicable SOPs. The Compliance Coordinator is responsible to 
notify the PI and CRNP/CRN/CRC of upcoming monitor visits and convey what 

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information and documentation will be required for the visit(s).  The Compliance 
Coordinator is responsible for verifying that informed consent is properly obtained, 
eligibility is met (via the central registration process), and all study procedures are 
conducted according to the study protocol. The Compliance Coordinator will also verify 
that the data reported in the CRF’s accurately reflect source documents, that all toxicities 
have been reported to date, and that all SAE’s/UPs/deviations/violations have been 
reported according to local IRB and HICCC DSMC requirements. The Compliance 
Coordinator will issue queries and ensure resolution in a timely and efficient manner.  
The Compliance Coordinator will also monitor for applicable regulatory compliance and 
research pharmacy compliance (if applicable) and communicate any deficiencies as 
appropriate. 
 
11.5 
Confidentiality 
Information about study subjects will be kept confidential and managed according to the 
requirements of the Health Insurance Portability and Accountability Act (HIPAA).  Those 
regulations require a signed subject authorization informing the subject of the following: 
 What protected health information (PHI) will be collected from subjects in this study 
 Who will have access to that information and why 
 Who will use or disclose that information 
 The rights of a research subject to revoke their authorization for use of their PHI 
In the event that a subject revokes authorization to collect or use PHI, the investigator, by 
regulation, retains the ability to use all information collected prior to the revocation of subject 
authorization.  For subjects that have revoked authorization to collect or use PHI, attempts 
should be made to obtain permission to collect at least vital status (e.g., that the subject is alive) 
at the end of their scheduled study period. 
 
The subject binders will be maintained with in the CPDM offices, a secured floor within the 
Herbert Irving Pavilion and only the investigator  and study staff will have access to the file. 
 
11.6 
Source Documents 
Source data is all information, original records of clinical findings, observations, or other 
activities in a clinical trial necessary for the reconstruction and evaluation of the trial.  Source 
data are contained in source documents   Examples of these original documents, and data records 
include: hospital records, clinical and office charts, laboratory notes, memoranda, subjects’ 
diaries or evaluation checklists, pharmacy dispensing records, recorded data from automated 
instruments, copies or transcriptions certified after verification as being accurate and complete, 
microfiches, photographic negatives, microfilm or magnetic media, x-rays, subject files, and 
records kept at the pharmacy, at the laboratories, and at medico-technical departments involved 
in the clinical trial. 
 
11.7 
Case Report Forms 
The study case report form (CRF) is the primary data collection instrument for the study.  All 
data requested on the CRF must be recorded.  All missing data must be explained.  If a space on 

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the CRF is left blank because the procedure was not done or the question was not asked, write 
“N/D”.  If the item is not applicable to the individual case, write “N/A”. 
 
11.8 
Records Retention 
Records relating to a specific research activity, including research records collected by 
investigators, must be maintained for at least three years after completion of the research (45 
CFR 46.115(b); 21 CFR 56.115(b); 21 CFR 312.62). This minimum retention period applies 
whether or not any subjects were enrolled in the study. If the research is FDA regulated, records 
should be retained for at least two years after approval of the investigational agent by FDA; if it 
is not approved, records should be retained at least two years after the study is terminated and 
FDA is notified (note the additional requirement below for clinical research studies). Clinical 
records, including consent forms that document clinical intervention or clinical diagnostic 
procedure research-related procedures, must be retained in medical records by the institution for 
at least seven years, per CUMC and NYP policy which is based on state law. 
 
12. 
STATISTICAL CONSIDERATIONS  
This is a single arm, phase Ib study with 2 co-primary endpoints:  
 Feasibility: The primary objective of this trial is to determine the feasibility of the 
OncoTreat platform in guiding therapy. The primary outcome is whether a subject begins 
therapy on Part 2. Previous attempts to match subjects based on DNA profiling have 
yielded enrollment rates of 3-5% [14, 78]. We hypothesize that we will validate 
OncoTreat matches for 50% of subjects and that at least 30% of enrolled subjects (60% 
of matches) will begin therapy on Part 2. With 30 enrolled patients on Part 1, we will 
have 80% power to detect a treatment rate of 30% on Part 2 compared to a historical 
treatment rate of 5% with alpha of 0.05. We will also assess the “match rate” – the 
fraction of patients who match with at leaset one drug. With 30 enrolled subjects, we will 
have 97% power with alpha = 0.05 to detect a 50% match rate (15 of 30 subjects) 
compared to a (liberal) estimated match rate of 20% based on DNA profiling in PDA.  
 Efficacy: The primary clinical efficacy endpoint is the objective response rate (ORR) 
for OncoTreat-prioritized drugs, which corresponds to the number of patients whose 
tumors demonstrate a 30% or greater reduction from baseline in the sum of the diameters 
of all target lesions amongst all evaluable patients, as assessed by standard-of-care CT 
scans. We target estimating the ORR and the corresponding 95% confidence interval. 
Secondary endpoints will include: 1) disease control rate (DCR) at 16 and 24 weeks, which 
corresponds to the number of patients whose tumors demonstrate either an objective response or 
stable disease, defined as a no more than 20% increase from baseline in the sum of the diameters 
of all target lesions; 2) median progression-free survival (mPFS), defined as the median 
duration prior to the development of disease progression or patient death; 3) overall survival 
(OS), defined as time from first dose of OncoType-informed drug to death due to any cause; and  
4) safety and tolerability, defined as the incidence of Grade 3/4 AEs in terms categorized and 
graded according to NCI CTCAE v4.0. We will estimate DCR, mPFS, and OS and their 95% 
confidence interval. 
 

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The phase III trial (NAPOLI-1) that resulted in the FDA-approval of nanoliposomal irinotecan 
and 5-fluorouracil in the second-line setting demonstrated a median overall survival of 6.1 
months versus 4.2 months for 5-fluorouracil monotherapy (primary endpoint), mPFS of 3.1 
months, and an ORR of 16% (compared to 1% in the 5-fluorouracil arm) [7]. Fifty-one (12%) 
patients had not had previous treatment for metastatic disease, 234 (56%) had received one 
previous line of metastatic treatment, and 132 (32%) had previously received two or more lines 
of metastatic treatment. The disease control rate was less than 20% and did not differ between 
treatment groups. Thus, based on historical controls, the ORR for treatment-resistant metastatic 
PDAC is expected to be no more than 16%.  
 
Using the above mentioned rates, a sample size of n = 9 achieves at least a 80% power to detect a 
difference of 25% in ORR (30% vs 5%) using a one-sided binomial test with a target alpha of 
0.1. To be conservative, we use the minimum number of patients (9) expected to be treated in 
this calculation. If at the end of the study the total number of objective responses is greater than 
or equal to 2, we will be able to reject the historical rate of 5% at the significance level of 0.05 
with power of 69% and OncoTreat will have demonstrated a clear signal of clinically meaningful 
improvement in the primary endpoint for patients with advanced, previously-treated PDA. 
Assuming about 30% of enrolled patients will receive an OncoTreat-informed treatment, N = 30 
subjects is an appropriate sample size for this prospective study. 
 
13. 
PROTECTION OF HUMAN SUBJECTS 
 
This study is to be conducted in accordance with applicable government regulations and 
Institutional research policies and procedures. 
 
This protocol and any amendments will be submitted to a properly constituted Institutional 
Review Board (IRB), in agreement with local legal prescriptions, for formal approval of the 
study conduct.  The decision of the IRB concerning the conduct of the study will be made in 
writing to the investigator and a copy of this decision will be obtained before commencement of 
this study.  
 
All subjects for this study will be provided a consent form describing this study and providing 
sufficient information for subjects to make an informed decision about their participation in this 
study. This consent form will be submitted with the protocol for review and approval by the IRB 
for the study.  The formal consent of a subject, using the IRB-approved consent form, must be 
obtained before that subject is submitted to any study procedure.  This consent form must be 
signed by the subject or legally acceptable surrogate, as outlined in the IRB approved protocol, 
and the investigator-designated research professional obtaining the consent.  
 
14. 
STUDY FINANCES 
 
14.1 
Conflict of Interest 
Any investigator who has a conlict of interest with this study (patent ownership, royalities, or 
financial gain greater than the minimum allowable by their institution, etc.) must have the 
conflict reviewed by the Columbia University Conflict of Interest Committee with a Committee-

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sanctioned conflict management plan that has been reviewed and approved prior to participation 
in this study. All CUMC investigators will follow the University conflict of interest policy. 
 
14.2 
Subject Stipends or Payments 
There are no subject payments or stipends. 
 
15. 
PUBLICATION PLAN 
 
Neither the complete nor any part of the results of the study carried out under this protocol, nor 
any of the information provided by the sponsor for the purposes of performing the study, will be 
published or passed on to any third party without the consent of the study sponsor.  Any 
investigator involved with this study is obligated to provide the sponsor with complete test 
results and all data derived from the study. 
 
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17. 
APPENDICES 
 
17.1 
Appendix A: Eastern Cooperative Oncology Group (ECOG) Performance Status 
Grade 
Description 
0 
Normal activity. Fully active, able to carry on all pre-disease performance without restriction. 

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1 
Symptoms, but ambulatory. Restricted in physically strenuous activity, but ambulatory and 
able to carry out work of a light or sedentary nature (e.g., light housework, office work). 
 
2 
In bed <50% of the time. Ambulatory and capable of all self-care, but unable to carry out any 
work activities. Up and about more than 50% of waking hours. 
 
3 
In bed >50% of the time. Capable of only limited self-care, confined to bed or chair more 
than 50% of waking hours. 
4 
100% bedridden. Completely disabled. Cannot carry on any self-care. Totally confined to bed 
or chair. 
5 
Dead. 
* As published in Am. J. Clin. Oncol.: Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., McFadden, 
E.T., Carbone, P.P.: Toxicity And Response Criteria Of The Eastern Cooperative Oncology Group. Am J Clin Oncol 
5:649-655, 1982. The Eastern Cooperative Oncology Group, Robert Comis M.D., Group Chair. 
 
17.2 
Appendix B: NCI Common Terminology Criteria for Adverse Events (CTCAE) 
V4.0 Grading Scale 
The descriptions and grading scales found in the revised NCI Common Terminology Criteria for 
Adverse Events version 4.0 will be utilized for adverse event reporting. 
 
http://www.oncology.tv/SymptomManagement/NationalCancerInstituteUpdatesC
TCAEtov403.a spx 
 
17.3 
Appendix C: Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 
Criteria for Evaluating Response in Solid Tumors RECIST version 1.1 will be used in this study 
for assessment of tumor response. While either CT or MRI may be utilized, as per RECIST 1.1, 
CT is the preferred imaging technique in this study. 
 
In addition, volumetric analysis will be explored for response assessment. 
 
17.4 
Appendix D: Preclinical Studies – PDX/PDO Analyses 
The initial biopsy from each newly diagnosed, treatment-naïve subject will be used both for 
OncoTreat profiling and to establish orthotopic PDX and/or PDO models from each patient in 
NSG mice (from an established NSG breeding colony). After outgrowth of the primary 
tumor/organoids, a portion will be banked and the bulk tumor dissected into 1-2 mm cubes for 
orthotopic re-implantation [79] into NSG recipients. For each primary tumor, we will evaluate a 
minimum of 6 and up to 10 candidate OncoTreat regimens and 2 controls (gemcitabine and 
vehicle). For each treatment, we will implant 8 tumors (5 for survival, 3 for PD analysis) plus 6 
extra in case any fail to engraft (total = 70). 
 
Tolerable schedules in mice for top-predicted drugs from our preliminary analysis have been 
developed. Additional agents will be assessed during the period when PDX/O models are 
engrafting, relying on a combination of published data and experimental assessments in mice 
using a dose escalation format and daily health, weight, and behavior assessments. 

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Upon reaching 150 mm3, tumors will be enrolled and randomized to a treatment arm and treated 
until the animal meets endpoint criteria (based on a scoring system). Tumor volumes will be 
monitored twice weekly by 3D ultrasound [80]. The primary endpoint will be response rate, as 
determined by ultrasound-measured tumor volumes. In our (The Olive Laboratory) experience, 
replicate tumors from the same donor tend to respond uniformly to treatment, making 5 animals 
sufficient for analysis of response rate and allowing us to evaluate more regimens from one 
donor sample. 
 
Three animals per treatment group will be euthanized 24 hours after receiving their third 
treatment dose for assessment of pharmacodynamics response. RNA-seq will be performed on 
bulk tissue samples, with computational filtering for human reads to assess effects on the 
epithelial compartment. VIPER analysis will be performed on the tumor profiles to determine 
whether the treatment reversed the activity of the predicted MRs relative to vehicle-treated 
tumors. In addition, tumor histopathology will be analyzed by Dr. Alina Iuga in the Department 
of Pathology. Immunohistochemistry (IHC) will also be performed to assess proliferation (Ki-67, 
phospho-histone H3) and apoptosis (cleaved caspase 3) [81, 82]. 
 
17.5 
Appendix E: LC-MS/MS Method 
Specimen/Sample Type: Serum 
Volume: 300µL 
Sample Stability: all analytes are stable in serum samples at room temperature for 5 hours, at 
4-8 °C for 3 days, and at -80 °C for at least 60 days.  
Instrument and materials: 
 
ACQUITY Xevo TQ-D with ACQUITY UPLC® CSH C18 3.0x100mm 1.7 µm column 
(Waters Corporation) 
 
Single-channel pipettes: 20µl, 100µl,200µl and 1000µl air displacement pipettes 
 
Vortex mixer 
 
Centrifuge 
 
Vials Waters Acquity UPLC H-Class System and H-Class Bio System 
 
Eppendorf Centrifuge 5427 R 
 
Balance Mettler Toledo AL54  
 
Sample preparation – extraction by protein precipitation 
1- In a 1.5 ml eppendorf tube add 120 µl sample (blank, double blank, calibrators, QC low, 
QC middle, QC high, and patient samples) 
2- Add 10 µl ISTD working solution  
3- Add 500 µl methanol 
4- Mix with vortex for 5 min 
5- Centrifuge at 14000 rpm, 15 °C, for 15 min 
6- Take 240 µl supernatant and transfer into an UHPLC autosampler vial containing 200 µl 
water and mix. 
7- Place the samples in the autosampler of the instrument and start the analytical run. 10ul 
of each sample will be injected for LC-MS/MS analysis. 

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Mobile Phase Preparation: 
1. 2M ammonium acetate in water (stock):  
77.08g ammonium acetate  
500 ml water (use up 6 months of being prepared) 
2. Mobile Phase A:  
2mM ammonium acetate and 0.1% formic acid (v/v) in water 
1.0 ml 2M ammonium acetate solution (above step 1) 
1.0 ml Formic acid  
998 ml optima grade water  
3. Mobile Phase B:  
2mM ammonium acetate and 0.1% formic acid (v/v) in methanol  
1.0 ml 2M ammonium acetate solution (above step 1) 
1.0 ml Formic acid  
998 ml optima grade Methanol 
4. Wash Solvent: 50% optima grade acetonitrile / 50% optima grade water 
5. Needle Wash: 25% optima grade methanol / 25% optima grade acetonitrile / 50% optima 
grade 2-propanol  
6. Seal Wash: 80% optima grade water / 20% optima grade methanol 
 
Liquid Chromatography settings 
File name of inlet method: Assay extension II.acm/.ftn/.qsm 
 
Time (min) 
Flow (ml/min) 
%A 
%B 
Curve 
0 
0.500 
85 
15 
6 
0.5 
0.500 
85 
15 
6 
1.20 
0.500 
60 
40 
6 
5.00 
0.500 
5 
95 
6 
5.2 
0.500 
5 
95 
6 
5.21 
0.500 
85 
15 
6 
5.50 
0.500 
85 
15 
11 
 
Xevo TQD Settings 
Ion Mode: ESI(+) 
Capillary Voltage: 1.10 kV 
Source Temperature: 150˚C 
Desolvation Gas Temperature: 600°C 
Cone Gas Flow: 50 L/Hr 
Desolvation Gas Flow: 900 L/Hr 
MS Mode: Multiple Reaction Monitoring (MRM) 

Columbia University Medical Center 
Herbert Irving Comprehensive Cancer Center 
Version Date: 30 Mar 2022 
 
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