PTCy + Sirolimus/VIC-1911 as GVHD Prophylaxis in Myeloablative PBSC Transplantation
Phase: PHASE1
Conditions: Acute Leukemia, Myelodysplastic Syndromes, Myeloproliferative Neoplasm, Lymphoma
Sponsor: Masonic Cancer Center, University of Minnesota

Masonic Cancer Center 
University of Minnesota 
 
 
PTCy + Sirolimus/VIC-1911 as GVHD prophylaxis in myeloablative PBSC 
transplantation 
CRPC #2021LS006 
MT2021-01 
 
IND # 158005 
 
 
 
IND Sponsor: 
Shernan G. Holtan, MD 
 
Principal Investigator, UMN: 
Punita Grover, MBBS 
 
UMN Collaborators: 
Najla El Jurdi, MD 
Stephanie Terezakis, MD 
Joshua Hou, MD 
 
 
Biostatistician/Bioinformatics: 
Qing Cao, MS 
Jinhua Wang, PhD, MBA 
 
Roswell Park Collaborators: 
Brian Betts, MD 
 
 
 
 
Version Date: 
January 8, 2024 
Confidential 
 
 
 
 

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Revision History 
 
Revision 
# 
Version Date 
Summary of Changes 
Consent 
Revision 
 
08/09/2021 
Original version to FDA 
n/a 
 
10/05/2021 
Response to FDA potential hold and non-hold 
comments: 
Major changes: 
Synopsis, Section 1.1, Section 2.5, Section 3.0, section 
12, Section 13, Section 14  – updated statistics to 
change threshold and include definition of biologic 
efficacy 
Synopsis, Section 1.3 – updated and expanded 
correlative objectives 
Synopsis, Section 4.0 – updated inclusion/exclusion 
criteria 
Section 2.5 – expanded rationale for dose 
Section 3.0 – clarified definitions of DLT 
Section 6.5 – added dose reduction table for sirolimus 
Section 6.6 – added VIC-1911 dose adjustments for 
concurrent CYP3A inhibitors; clarified dose 
Modifications for Non-Hematological Toxicities Related 
to VIC-1911 
Section 8.0, Section 9.1 – added lipase levels for 
expected toxicity monitoring 
Section 10.2 – editing AE documentation guidelines 
Section 14.4 – Added TRM, relapse, GVHD, graft failure 
to early stopping rules 
Minor Edits: 
Synopsis, Section 2.4, Section 3.0 – removed references 
to multi center 
Section 9.1, Section 11.1 – minor edits to study 
calendar timing; edited that blood tests will be 
processed at Dr. Betts’ lab and not TTL, removed 
references to TTL 
Y – 
removed 
assent, 
updated 
consent to 
adult only, 
edited typo 
in calendar 
 
10/13/21 
Response to FDA Clinical Information Request: 
clarification of “unexpected” adverse event definition, 
update dosing per clinical pharmacology inquiry  
N 
 
10/22/21 
Synopsis – Clarified design/objectives of Phase II trial 
Synopsis, Section 1.2, Section 13 - added secondary 
objectives for QOL and CMV monitoring 
Synopsis, Section 14.3 - revised phase II enrollment goal 
to 57 total subjects 
Section 9.1 – Added QOL to study calendar 
Section 14 – Updated statistical considerations in 
response to FDA comments  
N 

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Revision 
# 
Version Date 
Summary of Changes 
Consent 
Revision 
Added references 
New Appendix III – FACT-QOL survey 
 
11/29/2021 
In response to CPRC Stipulations: 
Synopsis, Section 1, Section 3, Section 12, Section 13 – 
Phase II updated to estimate grade II –IV (changed from 
grade III-IV) aGVHD as a measure of long term efficacy; 
clarified secondary objective is estimate of grade III-IV 
aGVHD at 100 days;  
Synopsis - enrollment plan clarified that 3-9 patients 
will be treated at recommended phase II dose, and up 
to 58 patients to be enrolled in phase II 
Section 1.1 – fixed typographical error reference to 
aGVHD endpoint 
Section 2 – updated results and analysis of local 
experience with PTCy/TAC/MMF; clarified rationale for 
study treatment 
Section 4.0 – clarified lower age eligibility 
inconsistencies 
Section 7.2.3 and 7.3.3 – clarified that SOC drugs will be 
billed to patient insurance 
Section 14 – Updated statistics to clarify model with 
historical control; updated stopping rules to new 
enrollment plan 
N 
 
1/04/2022 
Synopsis, Section 4.2 – exclusion criteria – clarification 
of timing of post transplant maintenance therapy 
Section 7.1 – updated packaging information 
 
 
5/19/2022 
 
 
 
 
 
 
 
Update to collaborators, biostatistician 
Synopsis, Section 4.2 – exclusion criteria – added active 
smoking as exclusion criterion, included HCT-CI 
guidance  
Section 5.5 - replacement guidelines for nonevaluable 
Synopsis - corrected error in PK schedule  
Section 9.1 - clarified PKs are for phase 1 subjects only 
Section 10.5 - updated “MCC SAE report form” to 
“University of MN SAE report” in expedited reporting 
guidance 
 
 
10/12/2022 
Synopsis, Schema, Section 6.2 – change in sirolimus 
taper (start at d+100) 
Synopsis, Schema, Section 1.2 – added secondary 
objective to investigate peripheral blood 
transcriptomics 
Section 6.6 – revised VIC-1911 doses with 
coadministration of CYP 3A inhibitors 
Section 14.2 Bioinformatics plan clarified 
Y – changed 
date for for 
sirolimus 
dosing to 
d100 

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Revision 
# 
Version Date 
Summary of Changes 
Consent 
Revision 
Section 14.4 minor clarification in sample size for 
stopping rule calculation 
Minor corrections for readability/consistency of sample 
collection dates.  
 
8/16/2023 
Synopsis, schema, section 6.2, section 9.1, Appendix II – 
added busulfan/fludarabine alternative myeloablative 
conditioning regimen, updated dates of TBI treatment 
plan to move allopurinol to day -4 to reflect new 
admission guideline 
Synopsis, Schema, section 6.4 – updated dosing for 
post-transplant cyclophosphamide (PTCy) to reflect 
updated pharmacy guidelines 
Synopsis, section 4.2 – updated exclusion criterion re: 
smoking from any history of smoking within 6 months 
of protocol-directed activities, to daily smokers/users of 
e-cigarettes or vaping within 1 month, and removed 
exclusion for subjects unable to receive TBI 
Synopsis, schema, section 1, section 2.3, section 3, 
section 6, section 10, section 13 and section 14 – 
updated study phase language from “phase I/II” or 
“phase II” to “phase I dose finding/phase I extension” at 
request of pharmaceutical partner Vitrac 
Section 2.4 – clarifying the study structure, part 1 a 
dose escalation to identify MTD, and then part 2 an 
expansion at MTD for preliminary safety and efficacy 
data. 
Section 2.3, 2.4, 6.1 and 6.2 – removed references to a 
proposed additionl 90 mg dose level that PI and Vitrac 
decided was not required  
Section 9.1 – updated location of Brian Betts Lab 
Section 13 – added specific definition of 
relapse/progression 
Section 14 – edited to include Phase I extension 
objectives 
 
Y – new 
conditioning 
regimen 
risks to be 
updated 
 
11/15/2023 
Synopsis, section 1.3, section 9.1, section 13, section 
14.2: pharmacokinetics studies completed on subjects 
in phase I dose finding cohort; sufficient data has 
obtained that they will not be required in phase I 
extension and have been removed to spare patients 
unnecessary blood draw/possibly lengthy outpatient 
observations 
Section 6.3 – corrected error in footnote in table re: 
busulfan dosng 
Y 

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Revision 
# 
Version Date 
Summary of Changes 
Consent 
Revision 
Section 9 – updated study calendar to reflect that 
radiation therapy consult only required for subjects 
receiving TBI 
Section 10.4 – corrected erroneous reference to phase 
II to phase I extension 
 
01/08/2024 
Updated to change UMN Site PI to Punita Grover, MBBS 
Y 
 
 
 
 
IND sponsor/ Study PI Contact Information: 
Shernan G. Holtan, MD 
Hematology, Oncology and Transplantation 
Department of Medicine 
MMC 480  
420 Delaware Street SE 
Minneapolis, MN  55455 
612-301-1095 (phone) 
612-625-6919 (fax) 
sgholtan@umn.edu (email) 
 
UMN PI Contact Information:  
Punita Grover, MBBS 
Hematology, Oncology and Transplantation 
Department of Medicine 
MMC 480  
420 Delaware Street SE 
Minneapolis, MN  55455 
612-625-8942 (phone) 
612-625-6919 (fax) 
groverp@umn.edu (email) 
 
 

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Table of Contents 
 
Contents 
Revision History ...................................................................................................................................... 2 
Key Abbreviations ................................................................................................................................. 10 
Protocol Synopsis ................................................................................................................................. 12 
Protocol Schema ................................................................................................................................... 16 
1 
Objectives ..................................................................................................................................... 17 
1.1 
Primary Objective ................................................................................................................. 17 
1.2 
Secondary Objectives ........................................................................................................... 17 
1.3 
Correlative (or Exploratory) Objectives ................................................................................ 17 
2 
Background and Rationale............................................................................................................ 19 
2.1 
Graft-versus-Host Disease and Current Standard of Care .................................................... 19 
2.2 
PTCY/Sirolimus/MMF ........................................................................................................... 21 
2.3 
VIC-1911, an Aurora Kinase A Inhibitor ................................................................................ 21 
2.4 
Rationale for the Study Treatment ....................................................................................... 22 
2.5 
Rationale for Dose ................................................................................................................ 23 
3 
Overview ....................................................................................................................................... 24 
4 
Patient Selection ........................................................................................................................... 25 
4.1 
Inclusion Criteria ................................................................................................................... 26 
4.2 
Exclusion Criteria .................................................................................................................. 26 
5 
Participant Registration and Study Enrollment ............................................................................ 27 
5.1 
Registration with the Masonic Cancer Center Clinical Trials Office ..................................... 27 
5.2 
Study Enrollment with the Masonic Cancer Center Clinical Trials Office ............................. 27 
5.3 
Dose Level Assignment ......................................................................................................... 27 
5.4 
Patients Who Do Not Begin Study Treatment ...................................................................... 28 
5.5 
Patients Who Do Not Complete Study Treatment ........................................................ 28 
6 
Study Treatment Plan ................................................................................................................... 28 
6.1 
Pre-transplant conditioning regimen: TBI ............................................................................ 28 
6.2 Pre-transplant alternative conditioning regimen for participants with Busulfan/Fludarabine . 29 
6.3 
Stem Cell Selection and Infusion .......................................................................................... 30 
6.3.1 Related Donor Peripheral Blood ........................................................................................... 30 

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6.3.2 Unrelated Donor Peripheral Blood ....................................................................................... 31 
6.3.3 Infusion ................................................................................................................................. 31 
6.4 
Post-Transplant Cyclophosphamide (days +3 and +4) ......................................................... 32 
6.5 
VIC-1911 starting Day +5 ...................................................................................................... 32 
6.6 
Sirolimus starting Day +5 ...................................................................................................... 33 
6.7 
Dose Delays/Dose Modification for VIC-1911 ...................................................................... 33 
6.8 
Dose Delays/Dose Modification for Sirolimus ...................................................................... 35 
6.9 
General Concomitant Medication Guidelines ...................................................................... 35 
6.10 
Duration of Study Treatment ............................................................................................... 36 
6.11 
Duration of Study Participation ............................................................................................ 37 
7 
Study Agent Information .............................................................................................................. 37 
7.1 
VIC-1911 ............................................................................................................................... 37 
7.1.1 
Other Names ................................................................................................................ 37 
7.1.2 
Product Description ...................................................................................................... 37 
7.1.3 
Procurement ................................................................................................................. 38 
7.1.4 
Storage Requirements .................................................................................................. 38 
7.1.5 
Preparation and Administration ................................................................................... 38 
7.1.6 
Drug Accountability and Destruction ........................................................................... 38 
7.1.7 
Warnings and Precautions ............................................................................................ 38 
7.1.8 
Expected Toxicities ....................................................................................................... 39 
7.2 
Sirolimus ............................................................................................................................... 40 
7.2.1 
Other Names ................................................................................................................ 40 
7.2.2 
Product Description ...................................................................................................... 40 
7.2.3 
Procurement ................................................................................................................. 41 
7.2.4 
Storage Requirements .................................................................................................. 41 
7.2.5 
Preparation and Administration ................................................................................... 41 
7.2.6 
Stability ......................................................................................................................... 41 
7.2.7 
Drug Accountability and Destruction ........................................................................... 41 
7.2.8 
Warnings and Precautions ............................................................................................ 41 
7.2.9 
Expected Toxicities ....................................................................................................... 42 
7.3 
Cyclophosphamide ............................................................................................................... 42 
7.3.1 
Other Names ................................................................................................................ 42 

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7.3.2 
Product Description ...................................................................................................... 42 
7.3.3 
Procurement ................................................................................................................. 42 
7.3.4 
Storage Requirements .................................................................................................. 42 
7.3.5 
Preparation and Administration ................................................................................... 43 
7.3.6 
Stability ......................................................................................................................... 43 
7.3.7 
Drug Accountability and Destruction ........................................................................... 43 
7.3.8 
Warnings and Precautions ............................................................................................ 43 
7.3.9 
Expected Toxicities ....................................................................................................... 43 
8 
Dose Delays/Dose Modifications or Management of Selected Toxicities .................................... 43 
9 
Study Calendar ............................................................................................................................. 44 
9.1 
Required Evaluations ............................................................................................................ 44 
10 
Event Monitoring, Documentation, and Reporting .................................................................. 47 
10.1 
Event Terminology ................................................................................................................ 47 
10.2 
AE Monitoring and Documentation Requirements .............................................................. 49 
10.3 
SAE and Death Documentation ............................................................................................ 49 
10.4 
Dose Limiting Toxicity Event/Early Stopping Rule Documentation and Reporting .............. 49 
10.5 
Expedited Reporting Requirements (MCC) .......................................................................... 50 
11 
Study Data Collection and Study Monitoring ........................................................................... 51 
11.1 
Data Management ................................................................................................................ 51 
11.2 
Case Report Forms ............................................................................................................... 51 
11.3 
Data and Safety Monitoring Plan (DSMP) ............................................................................ 52 
11.4 
Study Related Monitoring .................................................................................................... 52 
11.5 
Record Retention .................................................................................................................. 53 
12 
Measurement of Effect............................................................................................................. 53 
13 
Study Design and Endpoints ..................................................................................................... 53 
14 
Statistical Considerations ......................................................................................................... 54 
14.1 
Study Design ......................................................................................................................... 54 
14.2 
Statistical Analysis and Bioinformatics ................................................................................. 56 
14.3 
Sample Size and Power Considerations ............................................................................... 57 
14.3.1 Phase I .................................................................................................................................. 57 
14.3.2 Phase I extension .................................................................................................................. 58 
14.4 
Monitoring Guidelines (Early Stopping Rules for Excess Toxicity) ....................................... 58 

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15 
Ethical and Regulatory Considerations ..................................................................................... 60 
15.1 
Good Clinical Practice ........................................................................................................... 60 
15.2 
Ethical Considerations .......................................................................................................... 60 
15.3 
Informed Consent ................................................................................................................. 61 
16 
References ................................................................................................................................ 62 
Appendix I – Performance Status ......................................................................................................... 66 
Appendix II – Risks of Stem Cell Transplant, TBI, Busulfan and Fludarabine ....................................... 67 
Appendix III – FACT-BMT Quality of Life Survey21 ................................................................................ 70 
 
 
 
 

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Key Abbreviations 
ABBREVIATION 
DEFINITION 
ABW 
ACTUAL BODY WEIGHT 
AdjBW 
ADJUSTED BODY WEIGHT 
AE 
 
ADVERSE EVENT 
aGVHD 
ACUTE GRAFT VERSUS HOST DISEASE 
AHC 
ACADEMIC HEALTH CENTER 
alloHCT 
ALLOGENEIC HEMATOPOIETIC CELL TRANSPLANTATION 
ALT 
ALANINE AMINOTRANSFERASE 
ANC 
ABSOLUTE NEUTROPHIL COUNT 
AST 
ASPARTATE AMINOTRANSFERASE 
CBC 
COMPLETE BLOOD COUNT 
CFR 
CODE OF FEDERAL REGULATIONS 
CMV 
CYTOMEGALOVIRUS 
CPRC 
CANCER PROTOCOL REVIEW COMMITTEE 
CR 
COMPLETE REMISSION 
CR/PR 
COMPLETE RESPONSE OR PARTIAL RESPONSE  
CRF 
CASE REPORT FORM 
CTCAE 
COMMON TOXICITY CRITERIA ADVERSE EVENT 
CTEP  
CANCER THERAPY EVALUATION PROGRAM 
CTO 
CLINICAL TRIALS OFFICE 
CTSI 
CLINICAL AND TRANSLATIONAL SCIENCE INSTITUTE 
DLCO 
DIFFUSING CAPACITY OF THE LUNGS FOR CARBON MONOXIDE 
DLT 
DOSE LIMITING TOXICITY 
DSMP 
DATA AND SAFETY MONITORING PLAN 
FDA 
FOOD AND DRUG ADMINISTRATION 
FEV 
FORCED EXPIRATORY VOLUME 
FVC 
FORCED VITAL CAPACITY 
GRFS 
GRAFT-VERSUS-HOST DISEASE-FREE, RELAPSE-FREE SURVIVAL 
GVHD 
GRAFT VERSUS HOST DISEASE 
GVL 
GRAFT VERSUS LEUKEMIA 
HBV 
HEPATITIS B VIRUS 
HCT-CI 
HEMATOPOIETIC CELL TRANSPLANTATION-SPECIFIC COMORBIDITY INDEX 
HCV 
HEPATITIS C VIRUS 
HIV 
HUMAN IMMUNODEFICIENCY VIRUS 
IB 
INVESTIGATOR’S BROCHURE 
IBW 
IDEAL BODY WEIGHT 
IRB 
INSTITUTIONAL REVIEW BOARD 
IV 
INTRAVENOUS 
MAC 
MYELOABLATIVE CONDITIONING WITH  
MCC 
MASONIC CANCER CENTER 
MCC-CISS 
MASONIC CANCER CENTER - CLINICAL INFORMATICS SHARES SERVICES 
MCT 
MOLECULAR CELL THERAPY FACILITY 
MMF 
MYCOPHENOLATE MOFETIL 
MR 
MIXED RESPONSE 

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ABBREVIATION 
DEFINITION 
MTOR 
MECHANISTIC TARGET OF RAPAMYCIN  
MTX 
METHOTREXATE 
NCI 
NATIONAL CANCER INSTITUTE 
NIH 
NATIONAL INSTITUTES OF HEALTH 
NK 
NATURAL KILLER 
NR 
NO RESPONSE 
ONCORE 
ONLINE ENTERPRISE RESEARCH MANAGEMENT ENVIRONMENT 
OS 
OVERALL SURVIVAL 
PBSC 
PERIPHERAL BLOOD STEM CELLS  
PCRC 
PRIMARY CLINICAL RESEARCH COORDINATOR  
PHI 
PROTECTED HEALTH INFORMATION 
PT 
PROTHROMBIN TIME  
PTCY 
POSTTRANSPLANTATION CYCLOPHOSPHAMIDE 
PTT 
PARTIAL THROMBOPLASTIN TIME  
SAE 
SERIOUS ADVERSE EVENT 
SIR 
SIROLIMUS  
SOP 
STANDARD OPERATING PROCEDURE 
TBI 
TOTAL BODY IRRADIATION  
TCR 
T-CELL RECEPTOR 
TREGS 
REGULATORY T CELLS  
ULN 
UPPER LIMIT OF NORMAL 
USP 
UNITED STATES PHARMACOPEIA 
WOCBP 
WOMEN OF CHILDBEARING POTENTIAL 
 
 
 

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Protocol Synopsis 
PTCy + Sirolimus/VIC-1911 as GVHD prophylaxis in myeloablative PBSC transplantation 
CPRC #2021LS006 
 
Study Design: 
This is a single-arm, phase I/extension study of PTCy/sirolimus plus VIC-1911 to prevent GVHD 
and relapse after alloHCT.  Determination of the optimal dose during the Phase I trial is based 
on Dose Limiting Toxicity for safety and reduction of CD4+, pH3ser10+ T cells (phosphorylated 
histone 3 serine 10 is a biomarker of Aurora kinase A activity) for efficacy. Phase I extension 
cohort will be designed to obtain estimates of grade II-IV acute graft-versus-host disease and 
relapse and powered to independently test these endpoints for the improvement over  historical 
estimates at the University of Minnesota.   
 
Patients will receive myeloablative conditioning (MAC) with total body irradiation (TBI), or an 
alternative busulfan/fludarabine regimen (BU/FLU) followed by infusion of HLA-matched related 
or unrelated peripheral blood stem cells (PBSC) on day 0 (Table 1).  Cyclophosphamide will be 
administered on days +3 and +4.  Sirolimus targeting 8-12ng/ml will begin on day +5 until day 
+100 with dose adjustment per protocol section 6.5-6.7 as needed. VIC-1911 will be 
administered as 25 mg, 50 mg, or 75 mg orally BID from day +5 to day +45 according to the rules 
of our phase I study (Table 2).  The lowest biologically active and safe dose of VIC-1911 will be 
identified as the recommended phase I extension cohort dose.  
 
Dose Limiting Toxicity for the Phase 1 component of the study is defined as (CTCAE v5): 
1. More than 48 hours of the following ocular disorders: 
a. Grade 2 or higher vitreous hemorrhage 
b. Grade 3 or higher visual acuity decreased 
c. Grade 3 or higher watery eyes 
d. Grade 3 or higher keratitis 
e. Grade 3 or higher floaters 
f. Grade 3 or higher corneal microcysts 
g. Grade 3 or higher other eye disorders  
2. Any grade 3 or above adverse event considered at least possibly related to VIC-1911, 
excluding nausea, vomiting, constipation, pain, diarrhea or rash that is adequately 
controlled with supportive care and resolves to ≤ Grade 2 within 48 hours 
 
Biologic efficacy is defined as: 
1. The proportion of patients with an average CD4+, pH3ser10+ T cell of <54%. The 
minimum desired biologic efficacy is 65% of patients by day 21 (- 3 to +7 days) having 
<54% of CD4+ pH3ser10+ T cells with no more than 30% of patients having a DLT. This 
threshold is based on the lower confidence interval of the normal, pretransplant 
frequency of %pH3ser10+, CD4+ T cells (Note: pH3ser10 is the phosphoprotein target of 
Aurora kinase A). 
 
The optimal dose will be identified using the EffTox design. 
 
After completion of the dose finding trial, the final dose will be carried forward into a phase I  
extension trial to confirm safety and obtain an estimate of long-term efficacy as measured by 
Grade II-IV acute GVHD (aGVHD) by 100 days and relapse by 12 months.  

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Primary 
Objective: 
Phase I:  To determine the safety and optimal dose of VIC-1911 when given in combination with 
standard immunosuppressive therapy in adult patients undergoing myeloablative stem cell 
transplantation. 
 
The lowest biologically active dose will be defined as the proportion of patients with an average 
CD4+, pH3ser10+ T cell of <54%. The minimum desired biologic efficacy is 65% of patients by day 
21 (- 3 to +7 days) with <30% of patients experiencing a DLT. 
 
Phase I extension cohort:  To confirm safety and obtain an estimate of long-term efficacy as 
measured by grade II-IV aGVHD assessed by 100 days and relapse assessed by 1 year 
Secondary 
Objectives: 
Phase I dose-finding and extension cohort 
• 
To analyze the frequency of CD4+, pS6+ [marker of mTOR activity], CD4+, pSTAT3+ [marker 
of IL-6/JAK2 activity] and CD4+, pSTAT5+ [marker of IL-2 activity] cells at pre-conditioning, 
+21, and +100.   
• 
To investigate whether peripheral blood transcriptomics correlate with GVHD and/or 
relapse. Transcriptomics analyses will focus on GVL (LCK, PDCD1, and INFG ) versus GVHD 
(AURKA and STAT3) gene assessments at d+21, +60, and +100.  
• 
To determine the cumulative incidences of grade III-IV acute (day +100) and chronic GVHD 
(day +365). 
• 
To compare GRFS (defined as grade II-IV and III-IV acute GVHD by day +100, chronic GVHD 
(NIH consensus criteria) by day +365, and relapse by day +365) to the standard PTCY plus 
tacrolimus/mycophenolate mofetil regimen from MT2015-29 
• 
To compare duration of initial transplant hospitalization to patients age 18+ who received 
treatment on MT2015-29 
• 
To analyze the frequency of CMV reactivation and disease through day +180 
• 
To measure Quality of life through day +100 
Correlative 
Objectives: 
Phase I - Pharmacokinetic (PK) parameters: For the first 3 patients enrolled at each dose level in 
the phase I dose finding portion of this study, pharmacokinetic sampling of plasma VIC levels will 
be drawn on  +5 and 15 at the following timepoints: pre-dose, +30 minutes, +1 hours, +2 hours,+ 
6 hours, and +24 hours (pre-morning dose).  These studies will be batched and performed by 
collaborators at VITRAC. 
• 
Phase I - Extended CD28, JAK2, and pSTAT5 signal transduction studies: While the 
frequency of CD4+, pH3ser10+ T cell will be used to assess biologic activity at day +21, we will 
also measure the number and frequency of CD4+ T cell expressing the following 
phosphoproteins at pre-conditioning, +21, +60, and +100:  pH3ser10, pS6, pSTAT3, and pSTAT5. 
The day +60 timepoint will allow us to observe if Aurora kinase A signal transduction flares or 
rebounds after discontinuing VIC on day +45. Treatment of acute GVHD will be at the discretion 
of the attending physician. However, we will monitor use of tacrolimus, glucocorticoids, and 
ruxolitinib to see how these medications may impact T cell phosphoproteins.  
• 
Phase I - Immune reconstitution: Immunophenotyping by flow cytometry will be 
conducted on pre-conditioning, +21, +60, and +100 for effectors of allotolerance - Tregs (CD4+, 
CD25+, CD127neg, Foxp3+); effectors of alloreactivity - allo-conventional T cell (Tconv) (CD4+, 
CD25+, CD127+) and CD4+ T helper 1/2/17 cells based on expression of T-bet, GATA3, and RORγt, 
respectively; effectors of chronic GVHD will be evaluated on day +60 and +100 including T 
follicular helper cells (Tfh:CD4+, CXCR5+, CD45RAneg), transitional (CD19+, IgD+, CD38Hi, 
CD27+) B cells, and pregerminal (CD19+, CD21Lo, CD27neg); and  effectors of GVL including 
CD8+, perforin+, granzyme B+ T cells on day +60 and +100. Total B cells, CD4/CD8 T cells, and 

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natural killer (NK) cells will be acquired from clinical immune reconstitution panels on Pre-
conditioning, +21, +60, and +100. 
• 
Phase I - Functional Assays: Treg suppression assays will be performed using magnetic 
bead isolated peripheral Tregs at days +21 and +60 from peripheral blood (Treg:T effector ratios 
ranging from 0:1, 1:30, 1:10, 1:3, and 1:1). Non-Treg T cells from the patient will serve as 
responders against CD3/CD28 bead- or pre-transplant host dendritic cell-stimulation. Given that 
TAC can also limit GVL mediated by NK cells, we will evaluate the cytolytic activity of isolated NK 
cells (day +21, +60, and +100) against K562 target cells as well as proliferation with IL-2/IL-15 
stimulation.  
• 
Phase I - CD3+ T cell transcriptomics: While we have designed PTCy/SIR/VIC to 
comprehensively limit CD28 signal transduction, we will seek out and identify other possible 
immune escape mechanisms using single cell RNA-seq on purified CD3+ T cells and then validate 
these findings with NanoString. Samples from patients (myeloablative conditioning) treated with 
PTCy/SIR/MMF from our UMN biobank, acquired on pre-conditioning, +21, +60, and +100 (+/- 3 
days) will serve as a comparison group for these studies. 
      
Phase I extension 
• 
Phase I extension - Extended CD28, JAK2, and pSTAT5 signal transduction studies: While 
the frequency of CD4+, pH3ser10+ T cell will be used to assess biologic activity at day +21, we 
will also measure the number and frequency of CD4+ T cell expressing the following 
phosphoproteins at pre-conditioning, +21, +60, and +100:  pH3ser10, pS6, pSTAT3, and pSTAT5. 
The day +60 timepoint will allow us to observe if Aurora kinase A signal transduction flares or 
rebounds after discontinuing VIC on day +45. Treatment of acute GVHD will be at the discretion 
of the attending physician. However, we will monitor use of tacrolimus, glucocorticoids, and 
ruxolitinib to see how these medications may impact T cell phosphoproteins.  
• 
Phase I extension - Immune reconstitution: Immunophenotyping by flow cytometry will 
be conducted on pre-conditioning, +21, +60, and +100 for effectors of allotolerance - Tregs 
(CD4+, CD25+, CD127neg, Foxp3+); effectors of alloreactivity - allo-conventional T cell (Tconv) 
(CD4+, CD25+, CD127+) and CD4+ T helper 1/2/17 cells based on expression of T-bet, GATA3, 
and RORγt, respectively; effectors of chronic GVHD will be evaluated on day +60 and +100 
including T follicular helper cells (Tfh:CD4+, CXCR5+, CD45RAneg), transitional (CD19+, IgD+, 
CD38Hi, CD27+) B cells, and pregerminal (CD19+, CD21Lo, CD27neg); and effectors of GVL 
including CD8+, perforin+, granzyme B+ T cells on day +60 and +100. Total B cells, CD4/CD8 T 
cells, and natural killer (NK) cells will be acquired from clinical immune reconstitution panels 
on Pre-conditioning, +21, +60, and +100. 
Patient 
Population: 
HCT recipients 18 to 60 years of age with an 8/8 HLA-matched related or unrelated peripheral 
blood allograft donor 
Inclusion 
Criteria: 
• 
diagnosis of  
o acute leukemia in complete remission, or 
o myelodysplasia with <5% blasts, or 
o myeloproliferative neoplasm/myelofibrosis with <5% marrow or circulating blasts, 
or  
o chemosensitive Hodgkin or non-Hodgkin lymphoma,  
• 
left ventricular ejection fraction ≥ 45%,  
• 
pulmonary function with FEV1, FVC, and DLCO ≥ 50% predicted,  
• 
AST and ALT < 2 times upper limit of normal 

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• 
total bilirubin <1.5 times the upper limit of normal. If the patient is suspected of having 
Gilbert syndrome, they require prior approval of the medical monitor 
• 
estimated creatinine clearance ≥ 50cc/min,  
• 
no active/uncontrolled infection,  
• 
negative HIV, HBV and HCV,  
• 
ferritin < 2000 ng/ml,  
• Karnofsky Performance Status Score ≥ 80%  
• Patients able to tolerate oral medication 
Exclusion 
Criteria: 
• HCT-CI > 4  
• Patients with a history of hypersensitivity to any of the investigational products 
• Planned post-transplant maintenance therapy to begin prior to day +75.  Patients may receive 
standard of care maintenance therapies starting at day +75 or later 
• Pregnancy or breastfeeding 
• Women or men of childbearing potential unwilling to take adequate precautions to avoid 
unintended pregnancy from the start of protocol treatment through 60 days after the last 
treatment of VIC-1911 or sirolimus 
• Active/recent daily smoker of tobacco or marijuana/user of e-cigarette or vaping within 1 
months of protocol-directed therapy – intermittent (less than daily) use permitted. 
 
Enrollment 
Plan: 
Phase I dose finding cohort:  up to 21 patients, with 3-9 treated at optimal dose as defined by 
Efftox.   
Phase I extension cohort: up to 58 additional  patients at optimal dose 
 
 
 
 

 
 
Protocol Schema 
 
 
• 
Cyclophosphamide will be administered on days +3 and +4. Cyclophosphamide to be dosed 
at ideal body weight (IBW), unless patient weight is less than IBW, in which case actual body 
weight (ABW) should be used. 
• 
Sirolimus targeting 8-12ng/ml will begin on day +5 until day +100  
• 
[Phase I] 25 mg, 50 mg, or 75 mg of VIC-1911 administered orally BID from day +5 to day 
+45; [Phase I extension cohort] The lowest biologically active and safe dose of VIC-1911 will 
be identified as the recommended phase I extension dose. 
 
Conditioning Regimens: 
                     MAC TBI:                                       OR         MAC BUSULFAN/FLUDARABINE (NO TBI) 
Research Samples:  
• 
Blood (8 green top tubes and 1 pax gene 
tube): pre-conditioning, +21, day +60, and 
+100 
• 
VIC-1911 Pharmacokinetics PK Studies:  
Plasma samples will be collected pre-dose, 
30 minutes, 1 hours, 2 hours, 6 hours, 24 
hours (pre-morning dose) in K2 EDTA tubes, 
collected at day +5 and day +15 post-transplant.  If those day fall on weekend days, the samples should 
be collected on the next earliest weekday, no later than 3 days after the target date. 
Day 
Drug/ 
Procedure 
Dose and Route 
-4 
start allopurinol 300 mg/day PO 
-4 
TBI AM, PM 
165 cGy each dose 
-3 
TBI AM, PM 
165 cGy each dose 
-2 
TBI AM, PM 
165 cGy each dose 
-1 
TBI AM, PM 
165 cGy each dose 
0 
HCT 
Day 
Drug/ 
Procedure 
Dose and Route 
-6 
-start allopurinol 300 mg/day PO 
-begin levetiracetam per institutional guidelines 
(through day-1) 
-5 
Busulfan 
130 mg/m2 IV QD over 3 hours 
Fludarabine 
40 mg/m2 IV QD 
-4 
Busulfan 
130 mg/m2 IV QD over 3 hours 
Fludarabine 
40 mg/m2 IV QD 
-3 
Busulfan 
130 mg/m2 IV QD over 3 hours 
Fludarabine 
40 mg/m2 IV QD 
-2 
Busulfan 
130 mg/m2 IV QD over 3 hours 
Fludarabine 
40 mg/m2 IV QD 
-1 
Rest 
0 
HCT 

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1 Objectives 
1.1 Primary Objective 
Phase I:  The primary objective of this study is to determine the safety and optimal dose 
of VIC-1911 when given in combination with standard immunosuppressive therapy in 
adult patients undergoing myeloablative stem cell transplantation. 
 
The lowest biologically active dose will be defined as the proportion of patients with an 
average CD4+, pH3ser10+ T cell of <54%. The minimum desired biologic efficacy is 65% of 
patients by day 21 (- 3 to +7 days) having <54% of CD4+ pH3ser10+ T cells, with no more 
than 30% of patients having a DLT. This threshold is based on the lower confidence 
interval of the normal, pretransplant frequency of %pH3ser10+, CD4+ T cells (Note: 
pH3ser10 is the phosphoprotein target of Aurora kinase A). 
 
Phase I extension:  The primary objective of this study is to confirm safety and obtain 
preliminary estimates of long-term efficacy as measured by grade II-IV aGVHD by 100 days 
and relapse by 1 year. 
 
1.2 Secondary Objectives 
In both Phase I and extension cohort, the secondary objectives of this study are: 
• To analyze the frequency of CD4+, pS6+ [marker of mTOR activity], CD4+, pSTAT3+ 
[marker of IL-6/JAK2 activity] and CD4+, pSTAT5+ [marker of IL-2 activity] cells at 
pre-conditioning, +21, and +100.   
• To investigate whether peripheral blood transcriptomics correlate with GVHD 
and/or relapse. Transcriptomics analyses will focus on GVL (LCK, PDCD1, and 
INFG) versus GVHD (AURKA and STAT3) gene assessments at d+21, +60, and 
+100.  
• To determine the cumulative incidences of grade III-IV acute (day +100) and 
chronic GVHD (day +365). 
• To compare GRFS (defined as grade II-IV and III-IV acute GVHD by day +100, 
chronic GVHD [NIH consensus criteria] by day +365, and relapse by day +365) to 
the standard PTCY plus tacrolimus/mycophenolate mofetil regimen from MT2015-
29 
• To compare duration of initial transplant hospitalization to patients age 18+ who 
received treatment on MT2015-29 
• To analyze the frequency of CMV reactivation and disease through day +180 
• 
To measure Quality of life through day +100 
1.3 Correlative (or Exploratory) Objectives 

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Phase I dose finding cohort: 
• Phase I - Pharmacokinetic (PK) parameters: For all patients enrolled in the phase I 
portion of this study, pharmacokinetic sampling of plasma VIC levels will be drawn 
on day +5 and +15 at the following time points: pre-dose, +30 min, +1, +2, +6- and 
24-hours post-dose, for up to 3 subjects at each dose level until MTD reached. 
These studies will be batched and performed by collaborators at VITRAC. 
o November 10, 2023: 3 subjects have been treated at MTD of 75 mg BID.  
Sufficient data has been obtained from subjects to date, pharmacokinetics 
will not be obtained from subjects on phase I extension. 
• Phase I - Extended CD28, JAK2, and pSTAT5 signal transduction studies: While the 
frequency of CD4+, pH3ser10+ T cell will be used to assess biologic activity at day 
+21, we will also measure the number and frequency of CD4+ T cell expressing the 
following phosphoproteins at pre-conditioning, +21, +60, and +100:  pH3ser10, 
pS6, pSTAT3, and pSTAT5. The day +60 timepoint will allow us to observe if Aurora 
kinase A signal transduction flares or rebounds after discontinuing VIC on day +45. 
Treatment of acute GVHD will be at the discretion of the attending physician. 
However, we will monitor use of tacrolimus, glucocorticoids, and ruxolitinib to see 
how these medications may impact T cell phosphoproteins.  
• Phase I - Immune reconstitution: Immunophenotyping by flow cytometry will be 
conducted on pre-conditioning, +21, +60, and +100 for effectors of allotolerance 
- Tregs (CD4+, CD25+, CD127neg, Foxp3+); effectors of alloreactivity - allo-
conventional T cell (Tconv) (CD4+, CD25+, CD127+) and CD4+ T helper 1/2/17 cells 
based on expression of T-bet, GATA3, and RORγt, respectively; effectors of chronic 
GVHD will be evaluated on day +60 and +100 including T follicular helper cells 
(Tfh:CD4+, CXCR5+, CD45RAneg), transitional (CD19+, IgD+, CD38Hi, CD27+) B 
cells, and pregerminal (CD19+, CD21Lo, CD27neg); and effectors of GVL including 
CD8+, perforin+, granzyme B+ T cells on day +60 and +100. Total B cells, CD4/CD8 
T cells, and natural killer (NK) cells will be acquired from clinical immune 
reconstitution panels on Pre-conditioning, +21, +60, and +100. 
• Phase I - Functional Assays: Treg suppression assays will be performed using 
magnetic bead isolated peripheral Tregs at days +21 and +60 from peripheral 
blood (Treg:T effector ratios ranging from 0:1, 1:30, 1:10, 1:3, and 1:1). Non-Treg 
T cells from the patient will serve as responders against CD3/CD28 bead- or pre-
transplant host dendritic cell-stimulation. Given that TAC can also limit GVL 
mediated by NK cells, we will evaluate the cytolytic activity of isolated NK cells 
(day +21, +60, and +100) against K562 target cells as well as proliferation with IL-
2/IL-15 stimulation.  

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• Phase I - CD3+ T cell transcriptomics: While we have designed PTCy/SIR/VIC to 
comprehensively limit CD28 signal transduction, we will seek out and identify 
other possible immune escape mechanisms using single cell RNA-seq on purified 
CD3+ T cells and then validate these findings with NanoString. A prospective 
cohort of patients treated with standard PTCY/SIR/MMF will serve as a control for 
the correlative experiments, with samples collected acquired on pre-conditioning, 
+21, +60, and +100 (+/- 3 days). 
• Phase I extension cohort     
• Phase I extension- Extended CD28, JAK2, and pSTAT5 signal transduction studies: 
While the frequency of CD4+, pH3ser10+ T cell will be used to assess biologic 
activity at day +21, we will also measure the number and frequency of CD4+ T cell 
expressing the following phosphoproteins at pre-conditioning, +21, +60, and 
+100:  pH3ser10, pS6, pSTAT3, and pSTAT5. The day +60 timepoint will allow us to 
observe if Aurora kinase A signal transduction flares or rebounds after 
discontinuing VIC on day +45. Treatment of acute GVHD will be at the discretion 
of the attending physician. However, we will monitor use of tacrolimus, 
glucocorticoids, and ruxolitinib to see how these medications may impact T cell 
phosphoproteins.  
• Phase I extension - Immune reconstitution: Immunophenotyping by flow 
cytometry will be conducted on pre-conditioning, +21, +60, and +100 for effectors 
of allotolerance - Tregs (CD4+, CD25+, CD127neg, Foxp3+); effectors of 
alloreactivity - allo-conventional T cell (Tconv) (CD4+, CD25+, CD127+) and CD4+ T 
helper 1/2/17 cells based on expression of T-bet, GATA3, and RORγt, respectively; 
effectors of chronic GVHD will be evaluated on day +60 and +100 including T 
follicular helper cells (Tfh:CD4+, CXCR5+, CD45RAneg), transitional (CD19+, IgD+, 
CD38Hi, CD27+) B cells, and pregerminal (CD19+, CD21Lo, CD27neg); and effectors 
of GVL including CD8+, perforin+, granzyme B+ T cells on day +60 and +100. Total 
B cells, CD4/CD8 T cells, and natural killer (NK) cells will be acquired from clinical 
immune reconstitution panels on Pre-conditioning, +21, +60, and +100. 
2 Background and Rationale 
2.1 Graft-versus-Host Disease and Current Standard of Care 
 
Allogeneic hematopoietic cell transplantation (HCT) is the only potentially curative 
treatment for many high-risk or relapsed/refractory hematologic malignancies. HCT 
with myeloablative conditioning (i.e., of sufficient intensity that autologous recovery 
of hematopoiesis is extremely unlikely) is currently the standard of care for young, fit 

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patients suitable for HCT.  However, GVHD continues to impair survival and contribute 
to post transplant morbidity, with 35-50% of patients diagnosed with this 
complication post-transplant. 
 
Acute GVHD occurs when donor T cells respond to genetically defined proteins on 
normal host cells. The attack on the host cells can cause an array of symptoms from 
skin rash, nausea, vomiting, diarrhea, hepatitis, jaundice as well as increase the risk 
for infection.  This typically occurs within the first 6 months post-HCT.  Chronic GVHD 
occurs later in most patients (average of 9-12 months post-HCT) and can lead to 
scarring and fibrosis of many organs, including the skin and subcutaneous tissues, 
mucous membranes, lungs, liver, and other organs.  The challenge is to design current 
strategies that reduce the incidence and severity of GVHD, without sacrificing graft-
versus-tumor effects. 
 
Myeloablative Transplant at the University of Minnesota 
The University of Minnesota Blood and Marrow Transplant (BMT) program has 
extensive experience in performing myeloablative HCT procedures in children and 
adults with lethal hematologic diseases.  Over three hundred patients have 
undergone HCT under protocol MT2001-02, our standard of care myeloablative HCT 
protocol that began accruing patients in 2001 with the use of cyclophosphamide and 
TBI conditioning and cyclosporine/methotrexate prophylaxis.  One year survival for 
the cohort was 62% (95% CI 62-73%).  40 percent of patients (95% CI 34-46%) treated 
on MT2001-02 developed grade II-IV acute GVHD by day +180 post-HCT.  16 percent 
of patients (95% CI 12-21%) had severe, grade III-IV acute GVHD.  The majority of 
patients who developed acute GVHD did so prior to day +60 post-HCT. Thirty-three 
percent of patients (95% CI 27-39%) treated on MT2001-02 developed chronic GVHD 
by year one1 post-HCT despite GVHD prophylaxis with cyclosporine A (CSA) and 
methotrexate (MTX).  By 2 years, the cumulative incidence of chronic GVHD increased 
to 41%. Approximately one quarter (24%, 95% CI 18-29%) of patients treated under 
MT2001-02 experienced relapse of their underlying hematologic malignancy at one-
year post-HCT.  The 1-year graft-versus-host disease-free, relapse-free survival (GRFS) 
was just 21% for myeloablative transplants1.  
In 2018, our program updated our myeloablative preparative regimen approach to 
TBI alone followed by post-transplant cyclophosphamide (PTCy), tacrolimus (TAC), 
and mycophenolate mofetil (MMF) under MT2015-29. Matched unrelated donors 
remain the major stem cell source for our transplant patients. Interim results 
demonstrate the incidence of grade II-IV acute GVHD is 25% for matched unrelated 

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donors and 16% for those receiving a matched related allograft with PTCy/TAC/MMF. 
Overall, the incidence of disease relapse is 24% at 1 year with PTCy/TAC/MMF. While 
these outcomes with PTCy/TAC/MMF are a substantial improvement from the prior 
use of CSA/MTX, our patients remain at risk of developing acute GVHD and/or relapse. 
In part continued use of TAC broadly blunts donor T cell function, impairing both T 
effectors required for graft-versus-leukemia and regulatory T cells that mediate 
durable immune tolerance. Further, our supporting data provide evidence that 
concurrent inhibition of mTOR (via SIR) and Aurora kinase A (via VIC) will effectively 
and selectively block alloreactive donor T cell co-stimulation to optimize GVHD 
prevention. We hypothesize that our current, TAC-free trial of PTCy/SIR/VIC will 
reduce grade II-IV acute GVHD to <10% and relapse to <12%. 
2.2 PTCY/Sirolimus/MMF 
To improve GVHD outcomes while sparing the toxicities of calcineurin inhibitors, the 
Moffitt group pioneered a PTCy platform using sirolimus instead of TAC as the 
immunosuppressant backbone for haploidentical peripheral blood transplantation. In 
a phase II study of 32 patients, the GVHD rates were low (18.8% for both grade II-IV 
acute GVHD and NIH moderate/severe chronic GVHD), with a relapse rate of 22.2% 
and GRFS of 49.6%2. A large study of 249 alloHCT recipients from the IRCCS San 
Raffaele Scientific Institute in Italy evaluated the efficacy of PTCy/SIR/MMF or 
PTCy/SIR in several donor sources and match grades (Greco R. et al. TCT. 2021). This 
study demonstrated a grade II-IV acute GVHD incidence of 23% at day +100 and a 1 
year relapse rate of ~25%. Essentially, PTCy/SIR/MMF eliminates the toxicities 
associated with calcineurin inhibitors, but provides the same level of immune 
suppression and similar rates of disease control as PTCy/TAC/MMF. However, 
investigations to further improve post alloHCT immune tolerance and enhanced GVL 
are clearly warranted.   
2.3 VIC-1911, an Aurora Kinase A Inhibitor 
 
An opportunity to use T cell signal transduction to improve PTCy 
Importantly, there is interest in wider use of mobilized PBSC with PTCy-based 
regimens, but this requires the addition of TAC to maintain effective GVHD 
prevention. TAC impairs the TCR with broad and detrimental effects against 
alloreactive T cells as well as beneficial Tregs and T effectors needed for allotolerance 
and GVL, alike4,5,6. Thus, replacing TAC with effective, but selective, immune 
suppression is critical. An alternative approach is to fully neutralize T-cell 
costimulation via CD28, rather than impairing TCR function with TAC. SIR inhibits 
mTOR, partially suppressing CD28 signal transduction. SIR also has beneficial effects 

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toward Tregs, supporting their function and reconstitution after alloHCT. TAC can be 
replaced with SIR when using PTCy and achieve similar rates of acute GVHD but carries 
an unresolved 35% incidence of relapse7. However, even when SIR is present, CD28 
can escape the suppressive influence of SIR by utilizing Aurora kinase A in donor T 
cells8,9. Thus, Aurora kinase A is an important resistance mechanism for SIR efficacy in 
GVHD prevention8,9. 
 
Effective blockade of CD28 activity is essential for optimal GVHD prevention. In 
preclinical studies, blocking ligand interactions between CD28 and B7 with 
neutralizing antibody significantly reduces GVHD mortality in transplanted mice10. 
Further, molecular deletion of CD28 in donor, murine T-cells similarly decreases GVHD 
severity11. Recently, abatacept, an Ig-CTLA4 fusion protein that blocks CD28 activity, 
reduced severe grade III-IV acute GVHD to 6.8% after unrelated donor alloHCT, albeit 
still paired with a calcineurin-inhibitor and MTX by design12. This data earned 
abatacept a Breakthrough Therapy Designation from the FDA for GVHD prevention in 
this setting. Further, our preliminary data shows concurrent mTOR/ Aurora kinase A 
inhibition synergistically increases the ratio of Tregs to pathogenic Th1 and Th17 cells 
in a xenogeneic GVHD model.  
 
We now propose a first-in-human, entirely TAC-free, phase I/phase 1 extension 
lGVHD prevention trial, testing the safety and efficacy of PTCy plus SIR and VIC-1911, 
a selective Aurora kinase A inhibitor (PTCy/SIR/VIC). We hypothesize PTCy/SIR/VIC will 
leverage complementary effects on Tregs, ablate CD28 signal transduction, and 
permit the successful omission of TAC from GVHD prophylaxis among recipients of 
8/8 HLA-matched related or unrelated PBSC allografts after myeloablative 
conditioning (MAC). PTCy/SIR/VIC is specifically designed to substantially reduce 
GVHD, facilitate the full potential of GVL without TAC, and maximize GRFS while using 
contemporary PBSC allografts and effective conditioning.  
2.4 Rationale for the Study Treatment 
To simultaneously reduce the competing risks of GVHD and relapse, we will combine 
comprehensive CD28 signal transduction blockade with PTCy in a phase I GVHD 
prevention trial in two parts, the first a dose finding study with 3 levels, and the 
second an extension at dose identified in part 1 to determine safety and efficacy. The 
dose finding portion of the trial will be conducted entirely at the University of 
Minnesota. We hypothesize that the TAC-free regimen, PTCy/SIR/VIC, will support 
Treg-mediated allotolerance and permit unconstrained GVL, effectively reducing 
grade II-IV acute GVHD (day +100) and relapse (day +365). Correlative studies will 
investigate mechanisms of immune suppression mediated by PTCy/SIR/VIC, in terms 

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of signal transduction, immune reconstitution, CD3+ T cell gene dysregulation via 
transcriptomics, and Treg potency. A prospective cohort of patients treated with 
standard PTCY/SIR/MMF will serve as a control for the correlative experiments. 
2.5 Rationale for Dose 
We propose to combine the selective Aurora kinase A inhibitor, VIC-1911, with SIR 
to ablate CD28 signal transduction, using a PTCy immunosuppressive backbone. 
Importantly, our phase I trial will test VIC doses well below 250 mg (25 mg, 50 mg, or 
75 mg), and the dose escalation will stop once we identify the lowest biologically 
active and safe dose of VIC. PTCy is well-suited for investigating TAC-free GVHD 
prophylaxis with concurrent mTOR and Aurora kinase A inhibition to fully control 
aberrant CD28 activity in alloreactive T cells. Like mTOR and Aurora kinase A 
blockade, PTCy favors Treg reconstitution and potency while suppressing alloreactive 
donor T cells13,14,15. We propose to combine SIR plus VIC with PTCy to spare Tregs, 
prevent GVHD with durable immune tolerance, and maximize GVL.  
 
VIC-1911 will be administered orally at 25 mg, 50 mg, or 75 mg BID from day +5 to 
day +45 according to the rules of our phase I study. The justification to administer 
VIC-1911 from days +5 to +45 is to ensure comprehensive CD28 blockade very early 
after transplant to suppress effectors of GVHD. However, prolonged deprivation of 
CD28 signals in Tregs can paradoxically impair their function16,17,18. Thus, by day +45, 
we expect single agent SIR maintenance will carry the allotolerance established by 
PTCy-allodepletion and deep CD28 blockade early post-transplant. The lowest 
biologically active and safe dose of VIC-1911 will be identified as the recommended 
phase I extension dose. The biologic activity of VIC-1911 will be informed by 
adequate reduction in pH3ser10+, CD4+ T cells (E.g., <54% at day 21). This threshold 
is based on the lower confidence interval of the normal, pretransplant frequency of 
%pH3ser10+, CD4+ T cells (Note: pH3ser10 is the phosphoprotein target of Aurora 
kinase A).9. Importantly, all patients with grade II-IV acute GVHD on the PAC/SIR/TAC 
trial had pH3ser10+ CD4+ T cells >54%9. Notably, the single patient with grade IV 
acute GVHD on the PAC/SIR/TAC trial had a 16-fold increase in pH3ser10+, CD4+ T 
cells at day +21, compared to pretransplant levels, yet the number of pS6+, CD4+ T at 
day +21 was negligible in the presence of SIR9. Unpublished data from patients with 
acute GVHD that failed standard SIR/TAC alone also averaged 84.3% pH3ser10+ CD4+ 
T cells at time of GVHD diagnosis. Therefore, we will assess VIC-1911 biologic activity 
by measuring the frequency of pH3ser10+, CD4+ T cells at day +21 and safety will be 
informed by DLT assessments.  

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3 Overview  
This is a single-arm, phase I dose finding study of PTCY/sirolimus plus VIC-1911 to prevent 
grade II-IV acute GVHD and reduce relapse after alloHCT.  The trial is powered to determine 
if Aurora kinase A inhibition with VIC-1911 reduces the frequency CD4+, pH3ser10+ T cells 
(phosphorylated histone 3 serine 10 is a biomarker of Aurora kinase A activity) and improves 
aGVHD and relapse after alloHCT, compared to historic data at the University of Minnesota.   
 
Patients will receive myeloablative conditioning (MAC) with total body irradiation (TBI) 
followed by infusion of HLA-matched related or unrelated peripheral blood stem cells (PBSC) 
on day 0.  Cyclophosphamide will be administered on days +3 and +4.  Sirolimus targeting 8-
12ng/ml will begin on day +5 until day +100, dose adjustment or taper if needed per section 
6.5. VIC-1911 will be administered as 25 mg, 50 mg, or 75 mg orally BID from day +5 to day 
+45 according to the rules of our phase I study.  The lowest biologically active and safe dose 
of VIC-1911 will be identified as the recommended phase I extension dose.  
 
Dose Limiting Toxicity for the Phase 1 dose finding component is defined as (CTCAE v5): 
1. 
The following ocular disorders: 
a. Grade 2 or higher vitreous hemorrhage not explained by thrombocytopenia 
b. Grade 3 or higher visual acuity decrease 
c. Grade 3 or higher watery eyes 
d. Grade 3 or higher keratitis 
e. Grade 3 or higher floaters 
f. Grade 3 or higher corneal microcyst 
g. Grade 3 or higher other eye disorders 
2. 
Any grade 3 or above unexpected adverse event considered at least possibly 
related to VIC-1911. “Unexpected” is defined as a suspected adverse reaction is 
that is not listed in protocol-related documents (e.g. protocol, consent 
documents, investigator brochure), or is not listed at the specificity or severity that 
has been observed or given the characteristics of the subject population being 
studied.  Included in this definition is higher than expected rates of adverse events 
than would be expected in the setting of transplant at the University of Minnesota 
as reflected in our stopping rules for excess toxicity (Section 14.4). 
Biologic efficacy is defined as: 
The proportion of patients with an average CD4+, pH3ser10+ T cell of <54%.  
 

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The maximum desired toxicity is 30% of patients having a DLT by day 28 and the minimum 
desired efficacy is 65% of patients with an average CD4+, pH3ser10+ T cell of <54% by day 21 
(- 3 to +7 days).  
 
The optimal dose will be identified using the EffTox design. Three dose levels of VIC-1911 will 
be tested (25 mg, 50 mg, or 75 mg BID). EffTox is an adaptive Bayesian design to facilitate 
seamless phase I dose-finding. In this trial, the measure for efficacy in the Phase I dose finding 
component (CD4+, pH3ser10+ T cell <54% by day 21) differs from the Phase I extension 
component our co-primary endpoints. Two parameters are required in the Phase I dose 
finding trial in addition to the desired toxicity and efficacy. The first is the trade-off function, 
which has been calculated as 1.79 based on points that are of equal utility: (1) the maximum 
permissible probability of toxicity when efficacy is guaranteed, (2) the minimum required 
probability of efficacy when toxicity is impossible and (3) a point in between that is considered 
equally desirable. The 2nd is the mean effective sample size (ESS) calculated as 0.90 based on 
the expected toxicity and efficacy at each dose, which is well within the advised range of 0.5 
to 1.5. This framework combines experience from patients in the earlier part of the trial with 
clinicians’ initial estimates of DLT’s, efficacy and trade-off at each dose. 
 
As the study progresses, updated probabilities of DLT and efficacy are computed before each 
new cohort of three patients is enrolled and the last patient reaches Day 28 (end of the 
assessment period) prior to enrollment of a subsequent cohort.  All patients in a cohort must 
also achieve neutrophil engraftment prior to day 28 before enrollment of a subsequent 
cohort. Each subsequent cohort will be assigned to the most appropriate dose based on these 
updated probabilities. To promote patient safety: 1) patients will be enrolled in cohorts of 3 
patients starting at the 1st dose; and 2) dose levels will not be skipped when escalating. The 
optimal dose will be identified by one of the following criteria: (1) the sample size of 21 is 
exhausted, (2) 9 patients are sequentially enrolled at the same dose. 
 
After completion of the dose finding trial, the final doses will be carried forward into a phase 
I extension trial to confirm safety and obtain preliminary estimates of long-term efficacy as 
measured by rates of aGVHD and relapse. 
4 Patient Selection 
Study entry is open to patients 18 years of age and older regardless of gender, race, or ethnic 
background. While there will be every effort to seek out and include minority patients, the 
patient population the patient population is dependent upon the transplant population at 
the University of Minnesota. 

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A potential participant must meet all of the inclusion and exclusion criteria to be considered 
eligible for study participation.  
4.1 
Inclusion Criteria  
4.1.1 Diagnosis of  
o acute leukemia in complete remission, or 
o myelodysplasia with <5% blasts, or 
o myeloproliferative neoplasm/myelofibrosis with <5% marrow or circulating 
blasts, or  
o chemosensitive Hodgkin or non-Hodgkin lymphoma 
4.1.2 Age 18 years or older 
4.1.3 Performance status of ≥ 80% Karnofsky  
4.1.4 Adequate organ function within 28 days of study registration defined as: 
o left ventricular ejection fraction ≥ 45% 
o pulmonary function with FEV1, FVC, and DLCO ≥ 50% predicted 
o AST and ALT < 2 times upper limit of normal 
o total bilirubin <1.5 times the upper limit of normal. If the patient is suspected 
of having Gilbert syndrome, they require prior approval of the medical 
monitor 
o estimated creatinine clearance ≥ 50cc/min 
o no active/uncontrolled infection 
o negative HIV, HBV and HCV 
o ferritin < 2000 ng/ml 
4.1.5 Patients able to tolerate oral medication 
4.1.6 Women of childbearing potential and men with partners of child-bearing 
potential must agree to use of contraception for the duration of treatment 
through 60 days after the last treatment of VIC-1911 or sirolimus 
4.1.7 Able to provide written voluntary consent prior to the performance of any 
research related tests or procedures. 
4.2 
Exclusion Criteria 
4.2.1 HCT-CI > 4. Physicians determining subject’s hematopoietic cell transplant 
comorbidity index (HCT-CI) score for subjects enrolling on study should use 
Sorror's guidance to standardize the interpretation of this instrument across 
patients. 
4.2.2 Use of planned post-transplant maintenance therapy to begin prior to day +75.  
Patients may receive standard of care maintenance therapies starting at day 
+75 or later 

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4.2.3 Patients with a history of hypersensitivity to any of the investigational 
products 
4.2.4 Pregnant or breastfeeding as agents used in this study are Pregnancy Category 
C: Drugs which, owing to their pharmacological effects, have caused or may be 
suspected of causing, harmful effects on the human fetus or neonate without 
causing malformations, and Pregnancy category D: There is positive evidence 
of human fetal risk based on adverse reaction data from investigational or 
marketing experience or studies in humans, but potential benefits may 
warrant use of the drug in pregnant women despite potential risks. Females 
of childbearing potential must have a negative pregnancy test (serum or urine) 
within 28 days of study registration. 
4.2.5 Women or men of childbearing potential unwilling to take adequate 
precautions to avoid unintended pregnancy from the start of protocol 
treatment through 60 days after the last treatment of VIC-1911 or sirolimus 
4.2.6 Participants must not be daily smokers of tobacco, marijuana or daily users of 
e-cigarettes/vaporizer pens within 1 month of study enrollment. Intermittent 
use (less than once per day) permitted. 
5 Participant Registration and Study Enrollment 
To be eligible for this study, the patient must sign the treatment consent and meet each 
inclusion criteria listed and none of the exclusion on the eligibility checklist based on the 
eligibility assessment documented in the patient’s medical record. A copy of the eligibility 
checklist is under attachments within the study in OnCore. 
Written consent must be obtained prior to the performance of any research related tests 
or procedures. Consent is usually obtained before final eligibility is determined. 
5.1 
Registration with the Masonic Cancer Center Clinical Trials Office 
Any patient who has been consented is to be registered in OnCore by the Primary 
Clinical Research Coordinator (PCRC) or designee. If a patient is consented, but not 
enrolled, the patient’s record is updated in OnCore as a screen failure and reason for 
exclusion recorded. 
5.2 
Study Enrollment with the Masonic Cancer Center Clinical Trials Office 
Study enrollment occurs after final eligibility is determined.  
5.3 
Dose Level Assignment  
Up to 3 dose levels of VIC-1911 will be tested in this study. The Primary Clinical 
Research Coordinator (PCRC) or designee will assign the patient’s dose level in 

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OnCore. The dose level of VIC-1911 will be assigned based on the currently enrolling 
dose for that phase of the trial. 
5.4 
Patients Who Do Not Begin Study Treatment 
If a patient is enrolled in the study and is later found not able to begin study treatment 
(beginning with the conditioning regimen), the patient will be removed from study 
and treated at the physician’s discretion. The study staff will update OnCore of the 
patient’s non-treatment status (off study). The reason for removal from study prior to 
starting study treatment will be clearly indicated in OnCore. The patient will be 
replaced to complete enrollment. 
5.5 
Patients Who Do Not Complete Study Treatment 
A patient must receive scheduled VIC-1911 through day +21 without confounding 
medical complications (including but not limited to those requiring high-dose 
corticosteroids or other immune modulators) to be assessed for response. If a patient 
does not qualify for response assessment, they will be considered not evaluable and 
can be replaced with another study participant. 
6 Study Treatment Plan 
In order to provide optimal patient care and to account for individual medical conditions, 
investigator discretion may be used in the prescribing of all supportive care drug therapy 
(i.e. acetaminophen, diphenhydramine, antimicrobials, etc. 
6.1 Pre-transplant conditioning regimen: TBI 
Table 2: Treatment Plan - Myeloablative Conditioning (MAC) with TBI 
Day 
Drug/Procedure 
Dose and Route 
-4 
start allopurinol 300 mg/day PO 
-4 
TBI AM, PM 
165 cGy each dose 
-3 
TBI AM, PM 
165 cGy each dose 
-2 
TBI AM, PM 
165 cGy each dose 
-1 
TBI AM, PM 
165 cGy each dose 
0 
HCT 
Per Institutional practice 
+3 
Cyclophosphamide 
50 mg/kg 
+4 
Cyclophosphamide 
50 mg/kg 
+5 
Begin VIC-1911 
Begin Sirolimus 
Per dose level cohort: 25 mg, 50 mg, or 75 mg  
targeting 8-12ng/ml 
 
TBI will be given on days -4 through day -1 using the following institutional guidelines: 
• 1320 cGy administered in 8 fractions of 165 cGy each with 2 fractions being given 
each day  

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• Each fraction will be 165 cGy prescribed to the mid-plane at the level of the 
umbilicus 
• The dose rate will be 10 to 19 cGy/minute  
• The two daily fractions are given at least 6 hours apart. 
 
Testicular boosts should be used for all males with ALL (and according to institutional 
practice for other diseases). 
 
Refer to Appendix II for risks associated with TBI. 
6.2 Pre-transplant alternative conditioning regimen for participants with 
Busulfan/Fludarabine 
Table 3:Treatment Plan - Myeloablative Conditioning (MAC) With Busulfan/Fludarabine 
Day 
Drug 
Dose and Route 
-6 
-start allopurinol 300 mg/day PO 
-begin levetiracetam per institutional guidelines through day-1 
-5 
Busulfan1 
130 mg/m2 IV once daily over 3 hours 
Fludarabine 
40 mg/m2 IV 
-4 
Busulfan 
IV once daily over 3 hours 
Fludarabine 
40 mg/m2 IV 
-3 
Busulfan 
IV once daily over 3 hours 
Fludarabine 
40 mg/m2 IV 
-2 
Busulfan 
IV once daily over 3 hours. 
Fludarabine 
40 mg/m2 IV 
-1 
Rest 
0 
HCT2 
Per institutional practice 
+3 
Cyclophosphamide 
50 mg/kg 
+4 
Cyclophosphamide 
50 mg/kg 
+5 
Begin VIC-1911 
Begin Sirolimus 
Per dose level cohort: 25 mg, 50 mg, or 75 mg  
targeting 8-12ng/ml 
1 Busulfan: Initial dosing 130 mg/m2/dose for patients age 18 years or older. Therapeutic drug monitoring per 
Institutional Standard of Care. if available model-based dosing utilizing Bayesian methodology. 
2 Refer to section 6.2.1 for note on timing of infusion if donor requires additional apheresis 
 
Patients should not take azole anti-fungal drugs for one week prior to beginning 
conditioning chemotherapy. 
Fludarabine (day -5, -4, -3 and -2) 
Fludarabine will be given at a dose of 40 mg/m2 IV, administered as a 1 hour infusion per 
institutional guidelines on day -5 through day -2.  Dose adjustments will be made for patients 
with renal impairment defined as CrCL < 70mL/minute.  Fludarabine dose MAY also be 

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reduced if there is prior malignancy involvement of the central nervous system with 
intrathecal chemotherapy and/or cranio-spinal irradiation. 
Busulfan (day -5, -4, -3 and -2) 
Dosing Guidelines based on Therapeutic Drug Monitoring (TDM):   
Busulfan dosing and administration and therapeutic drug monitoring (TDM) per 
institutional guidelines. Initial busulfan dosing will be determined by model-based 
dosing utilizing Bayesian pharmacokinetic software with a cumulative area under the 
curve (cAUC) of 82.1 mg*hr/L. For patients age 18 or older, initial dose of 130 
mg/m2/dose will be utilized.  
Busulfan area under the curve (AUC) analyses will be calculated per University of 
Minnesota BMT SOC guidelines for all BMT patients. Busulfan therapeutic drug 
monitoring (TDM) will be used to target a cumulative exposure for the entire course 
cAUC= 78 -86.2 mg*h/L (with a target of 82.1 mg*h/L) . Results of TDM performed 
with the first dose will inform subsequent busulfan dosing. Refer to Busulfan SOC 
Guidelines for blood sample collection process, busulfan results reporting and TDM 
procedures. If this method of pharmacokinetic monitoring is not available at other 
sites, blood samples will be sent to the Fairview Hospital Laboratory (Lab Code 
LAB6416) and analyzed by pharmacists at the University of Minnesota. 
Levetiracetam (Keppra)  
As seizures have occurred following high dose busulfan, all patients will be treated 
with Keppra beginning day -6 and continuing until day -1 per institutional guidelines.  
Refer to Appendix II for risks associated with this treatment plan. 
6.3 Stem Cell Selection and Infusion  
The stem cells will be infused per cell source specific institutional guidelines.  
6.3.1 Related Donor Peripheral Blood 
Related donors will be selected, evaluated and collected according to 
institutional guidelines (MT2012-14C: Procedure Guidelines For Related 
Hematopoietic Stem Cell Donors). A target collection of 5 x 106 CD34+ 
cells/kg will be requested in the case of peripheral blood stem cells as the 
graft source.  Note that if a related donor undergoes a second apheresis 
session to collect the target number of peripheral blood stem cells, the 
product should be held at MCT until both collections have been completed. 
The entire collection yield should be infused on the same day, the patient 

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in effect has two “Day 0s” (a rest day, then an infusion day) and the days of 
post-transplant cyclophosphamide should be adjusted accordingly to be 
days +3 and +4 post-stem cell infusion. The post-transplant sirolimus and 
VIC-1911 should be adjusted accordingly to be days +5 post-stem cell 
infusion. 
6.3.2 Unrelated Donor Peripheral Blood 
Unrelated donor PBSC will be collected in the usual manner using 
established techniques determined by the National Marrow Donor 
Program. Collection of the products will follow registry practice and 
guidelines.  A target collection of 5 x 106 CD34+ cells/kg will be requested 
in the case of peripheral blood stem cells as the graft source with a 
minimum of 2 million CD34+ cells/kg. 
6.3.3 Infusion 
Recommended Pre-medication: acetaminophen 15 mg/kg (max 650 mg) PO 
and diphenhydramine 0.5 mg/kg (25 mg) PO/IV  
Extra hydration is recommended per institutional guidelines for ABO 
mismatched and cryopreserved grafts. 
Vital signs will be checked before and after the infusion, and one hour post 
infusion per University of Minnesota transplant guidelines.  More frequent 
vital signs may be required as clinically indicated.   
Refer to Appendix II for risks associated with stem cell infusion. 
Table 3: Phase I dose finding/phase 1 extension GVHD Prevention Trial Schema 

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6.4 Post-Transplant Cyclophosphamide (days +3 and +4)  
Cyclophosphamide will be administered on days +3 and +4.  Cyclophosphamide will 
be dosed according to the recipient’s ideal body weight (IBW), unless the patient 
weighs less than IBW, in which case the drug will be dosed according to their actual 
body weight (ABW) 
Hydration and uroprotection with mesna will be given according to institutional 
standards. Cyclophosphamide 50mg/kg will be given as an IV infusion over 1-2 hours 
(depending on volume) on Days +3 post-transplant (between 60 and 72 hours after 
stem cell infusion) and on Day +4 post-transplant (approximately 24 hours after Day 
+3 cyclophosphamide).  
Refer to Table 7 for toxicities associated with Cyclophosphamide 
6.5 VIC-1911 starting Day +5 
6.5.1 Phase 1:  25 mg, 50 mg, or 75 mg of VIC-1911 administered orally BID from 
day +5 to day +45. The Primary Clinical Research Coordinator (PCRC) or 
designee will assign the patient’s dose level in OnCore. All VIC-1911 doses 
will be given in the fasting state (ie, for at least 1 hour before or 2 hours 
after the morning and evening meals). 
6.5.2 Phase I extension: The lowest biologically active and safe dose of VIC-1911 
will be identified as the recommended phase I extension dose. All VIC-1911 

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doses will be given in the fasting state (ie, for at least 1 hour before or 2 
hours after the morning and evening meals). 
6.5.3 Recommended supportive care for the duration of VIC-1911 treatment 
(day +4 to +45) to reduce the risk of ocular toxicity: 
6.5.3.1 Prednisolone acetate ophthalmic solution 1% twice daily 
6.5.3.2 Brimonidine tartrate ophthalmic solution 0.2% twice daily 
6.6 Sirolimus starting Day +5 
Sirolimus targeting 8-12ng/ml will begin on day +5 until day +100 
● Loading Dose on Day +5:  Sirolimus 5 mg/m2/day PO ONCE (max of 8 mg/day) 
● Maintenance Dose starting Day +6:  Sirolimus 2.5 mg/m2/day PO DAILY  
Sirolimus dose should be reduced according to institutional guidelines for 
concomitant voriconazole or other drugs with strong interactions. Refer to Table 6 for 
toxicities associated with sirolimus. 
Dose reductions for sirolimus when using concurrent voriconazole or Posaconazole 
are as follows: 
Table 6A: Dose reductions for sirolimus when using concurrent 
voriconazole or posaconazole 
Sirolimus 
Reduce sirolimus dose by 66-90% 
In the case of persistent, otherwise unexplained cytopenias (hemoglobin <8 g/dL, 
ANC <1.0 e3/µL, OR platelets <50,000 e3/µL), sirolimus may be tapered per 
institutional guidelines. 
6.7 Dose Delays/Dose Modification for VIC-1911 
A maximum of two dose reductions are allowed per patient. Dose Reductions for VIC-
1911 should be made according to the dose levels outlined in Section 6.4. 
• Dose reductions are not permitted in Dose Level 1. 
• Only one dose reduction is permitted in Dose Level 2. 
• A maximum of 2 dose reductions are allowed per patient in Dose Level 3 across 
the entire duration of their treatment. 
 
Should the toxicities that require further dose reduction recur after the maximum 
dose reductions or dose reduction is not permitted based on the patient’s current 
dose level, the affected patient should be discontinued from treatment. 

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Patients requiring a dose reduction will not be allowed to re-escalate the dose 
throughout the rest of treatment. If during any cycle a patient experiences a drug-
related toxicity that results in the patient receiving less than 80% of the intended 
dose, then the patient requires a dose reduction by 1 level when resuming therapy. 
Patients experiencing study drug-related toxicities that require a delay in schedule 
VIC-1911 dosing for > 14 days will require a dose reduction when resuming therapy. 
Patients experiencing study drug-related toxicities that require a delay in scheduled 
VIC-1911 dosing for > 28 days will be discontinued from further treatment in this 
study. Details of procedures and criteria for dose reduction are shown as follows: 
• Table 3 provides the criteria and procedure for making VIC-1911 dose 
modifications for hematologic toxicity considered related to VIC-1911 within a 
cycle. 
• Table 4 provides the criteria and procedure for making VIC-1911 dose 
modifications for non-hematologic toxicity considered related to VIC-1911 
within a cycle. 
• Table 5 provides common toxicities for VIC-1911 
 
 
Table 3: Dose Modifications for Hematologic Toxicity.   
 
Note these modifications take effect only in the setting of secondary cytopenias AFTER 
engraftment (defined as the 3rd consecutive day of ANC ≥ 1000 for neutrophils and the 3rd 
consecutive day of ≥75,000 for platelets). 
 
ANC ≥ 1000/mm3 and Platelets 
≥ 75,000/mm3 
No dose reduction (treat on time) 
ANC < 1000/mm3 or Platelets 
< 75,000/mm3 
Hold 
Febrile Neutropenia 
or 
Any Grade 4 thrombocytopenia, or Grade 3 
thrombocytopenia associated with bleeding  
or 
Any Grade 4 neutropenia lasting > 7 days 
Hold 
Upon resuming dosing, decrease to 
next lower level and do not re- 
escalate throughout the rest of 
treatment. 
 
 
 
Table 4: Dose Modifications for Non-Hematological Toxicities Related to VIC-1911 

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CTCAE Gradea of Non- 
Hematologic Toxicity 
Dose Hold/Resumption 
Resumption dose 
Grade 1 or 2 
Maintain treatment at the 
same  dose level 
No dose adjustment 
Grade 3 or higher unexpected 
AE 
Hold until AE is Grade 0 or 1 
Reduce VIC-1911 by 1 
dose level 
a At the discretion of the Investigator, patients may continue on study medication 
at the same dose without a reduction or an interruption for AEs (irrespective of 
grade) considered unlikely to become serious or life-threatening (including, but 
not limited to, fatigue and dry skin). 
6.8 Dose Delays/Dose Modification for Sirolimus 
Dose adjustments and withholding of sirolimus for elevated blood levels will occur 
based upon institutional guidelines for dosing and monitoring sirolimus 
In the case of persistent, otherwise unexplained cytopenias (hemoglobin <8 g/dL, 
ANC <1.0 e3/µL, OR platelets <50,000 e3/µL), sirolimus may be tapered per 
institutional guidelines. 
 
6.9 General Concomitant Medication Guidelines 
All immune-modulating medications and therapies that are administered during the 
study must be recorded in the patient’s CRF and in the source documents. 
Concomitant medications for other medical conditions are permitted as clinically 
indicated, subject to specific protocol requirements outlined below. Additional 
concomitant medications administered to manage reportable adverse events (AEs) 
per section 10.2 should be recorded in the patient CRF, with the AE being treated with 
the medication listed as the indication for use. 
 
• 
Administer hematologic support as medically indicated (blood transfusions, G-
CSF, etc) according to the institutional site standards. If there are no standard 
procedures for the use of growth factors, follow American Society of Clinical 
Oncology (ASCO) “Guidelines for Use of Hematopoietic Colony-Stimulating 
Factors” available at www.asco.org. 
 
The primary route of elimination of VIC-1911 is glucuronidation. The major metabolite 
is the acyl glucuronide conjugate (M1), representing 31% of the total radioactivity 
peak after 4 hours in a human hepatocyte study. The only other metabolite identified 
(M2) represented < 1% of the total peak area and was not conclusively shown as a 
separate component.  
 

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An in vitro study with human liver microsomes demonstrated that VIC-1911 has the 
potential to inhibit CYP2C8 and CYP3A4/5, including metabolism-dependent 
inhibition. However, for CYP2C8, the inhibition seen upon pre-incubation with NADPH 
was reversible, indicating that it may be mediated by metabolites of VIC-1911. The 
IC50 of metabolism-dependent inhibition for CYP2C8 (14 μM, equivalent to 7080 
ng/mL, well above the Cmax that will be achieved in this study) was less than 2-fold 
lower than that of the direct IC50, and occurred at a relatively high concentration, 
which indicates that the clinical impact may be low. For CYP3A4/5, the inhibition seen 
upon pre-incubation with NADPH was only partially reversible, and a Ki of 37 μM (for 
midazolam 1’-hydroxylation) was determined. The Ki for the other CYP3A4/5 
substrate (testosterone 6β-hydroxylation; 200 μM) was substantially higher. The 
lower Ki value of 37 μM (equivalent to 18700 ng/mL) was also a relatively high 
concentration, again, well above the Cmax that will be achieved in this study. 
Therefore, the clinical impact should be low.  
 
An in vitro human hepatocyte study indicated that at a concentration of 10 μM, VIC-
1911 may induce CYP3A4, although the concentration of VIC-1911 which showed in 
vitro induction was relatively high (10 μM, equivalent to 5060 ng/mL, again, well 
above the Cmax that will be achieved in this study. Therefore, the clinical impact 
should be low. 
 
In this study, VIC-1911 was administered once daily to 2 patients taking fluconazole, 
a moderate inhibitor of CYP3A4, with no impact on the pharmacokinetics of VIC-1911.  
Cmax was similar between patients given VIC-1911 once or twice daily. The AUClast was 
approximately half for patients on fluconazole when VIC-1911 was given once daily 
vs. twice daily administration for patients not on fluconazole, with no sustained 
elevated plasma concentrations after a single daily dose. By 24 hours post-first dose 
(24 hours after the dose for patients given VIC-1911 once daily), the AUC was not 
elevated post-dose after fluconazole administration. Dose-normalizing these data to 
VIC-1911 once or twice daily administration from other VIC-1911 studies in which 
CYP3A4 inhibitors were not routinely administered concomitantly, there is no 
evidence of a drug-drug interaction with CYP3A4 inhibitors in this study.    
  
Additionally, the following information is based on results from in vitro studies. 
Caution is advised if these drugs are given concomitantly. 
• 
P-gp 
inhibitors/inducers: 
VIC-1911 
is 
a 
substrate 
of 
P-gp. 
P-gp 
inhibitors/inducers may alter the PK and activity of VIC-1911. 
• 
OATP1B1/1B3 substrates: VIC-1911 is a potential inhibitor of OATP1B1/1B3. 
VIC-1911 may alter the PK and activity of OATP1/1B3 substrates. 
• 
OATP1B1/1B3 inhibitors: VIC-1911 is a substrate of OATP1B1/1B3. 
OATP1B1/1B3 inhibitors may alter the PK and activity of VIC-1911. 
6.10 Duration of Study Treatment 
Treatment continues until one year unless any of the following occurs:  

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• Patient develops GVHD requiring systemic investigational intervention 
• Patient develops relapse requiring systemic intervention 
• Unacceptable toxicity 
• One of the study drugs must be permanently discontinued 
• Patient requests or patient is non-compliant 
6.11 Duration of Study Participation 
Patients will be followed for GVHD and standard BMT survival data to a maximum of 
12 months from the start of study treatment unless one of the following occurs: 
• Consent is withdrawn 
• The patient is unevaluable 
7 Study Agent Information 
7.1 VIC-1911 
7.1.1 Other Names 
Previously called TAS-119 
7.1.2 Product Description  
Molecular Formula 
Molecular 
Weight 
Appearance 
C23H22Cl2FN5O3 HCl 
542.82 
White to off-white solid 
pH-Solubility Profile 
Solvent (20° C) 
mg/mL 
 
USP Definition 
Water 
 0.169 
Very slightly soluble 
Methanol 
344.1 
 Freely soluble 
Ethanol (absolute) 
32.84 
Sparingly soluble 
0.1 mol/L HCl 
1.298 
Slightly soluble 
0.1 mol/L NaOH 
1.679 
Slightly soluble 
 
VIC-1911 drug products are immediate release, film coated tablets. The tablets 
are packaged in 50 mL High Density Polyethylene (HDPE) bottles. The bottles are 
sealed with a solid medicinal safe cap. Each bottle contains 60 tablets. There are 
2 strengths: 10 mg and 25 mg. The different strengths are clearly differentiated by 
shape and color as follows: 
• VIC-1911 Tablet (10 mg): round shape, white to off-white tablet  
• 
VIC-1911 Tablet (25 mg): caplet shape, white to off-white tablet  

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7.1.3 Procurement  
VITRAC Therapeutics, LLC (VITRAC) will supply VIC-1911 at no charge to patients 
participating in this clinical trial.  
The investigator shall take responsibility for and shall take all steps to maintain 
appropriate records and ensure appropriate supply, storage, handling, 
distribution, and usage of investigational product in accordance with the protocol 
and any applicable laws and regulations. 
7.1.4 Storage Requirements 
Store in bottles between 15° and 25° C, and protect from light. 
7.1.5 Preparation and Administration 
• 
Store VIC-1911 at room temperature (15°C – 25 °C). 
• 
Only remove the amount of VIC-1911 needed at the time of dosing. 
• 
Do not remove doses in advance of the next scheduled dosing. 
• 
Bring all used and unused bottles to the site at each visit. 
• 
Keep VIC-1911 bottles in a safe place and out of sight or reach of children. 
• 
VIC-1911 should be taken in the fasting state (ie, at least 1 hour 
before or 2 hours after the  morning or evening meal) with a glass 
of water. 
• 
Doses are not to be replaced if the patient misses a dose or vomits a 
dose. 
• 
Patients should make every effort to take doses on schedule. 
• 
Record all doses taken or missed in the Patient Diary. 
7.1.6 Drug Accountability and Destruction 
VIC-1911 must be dispensed only from official study sites and to eligible patients 
under the supervision of the site investigator. VIC-1911 should be stored in a 
secure area according to local regulations.  It is the responsibility of the site 
investigator to ensure that study drug is only dispensed to patients. After final 
drug reconciliation, unused VIC-1911 will be disposed at the site following 
procedures for the disposal of anticancer drugs. 
7.1.7 Warnings and Precautions 
At the present time, there is limited clinical experience with VIC-1911 in 
monotherapy in humans. Therefore, investigators should be observant for any 
signs of toxicity. 

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Refer to the Investigator Brochure for additional information 
7.1.8 Expected Toxicities 
Below (Table 5) is a cumulative list of serious related adverse events reported from 
any VIC-1911 (TAS-119) clinical trials through 01 May 2017.  
Table 5: SAEs 
Common (≥ 10%) 
Less Common (≥ 5%) 
Rare (≤ 2% or less) 
Anemia 
Corneal changes 
(microepithelial cysts, 
keratitis, punctate keratitis) 
Blepharitis 
Vision blurred 
Chest pain 
Cataract 
Abdominal 
pain/discomfort 
Pain in extremity 
Conjunctival hemorrhage 
Constipation 
Pyrexia 
Eye irritation 
Diarrhea 
Upper respiratory tract 
infection 
Eye pain 
Nausea 
Blood bilirubin increased 
Dry eye 
Vomiting 
Blood glucose increased 
Conjunctivitis 
Fatigue 
Blood albumin increased 
Lacrimation increased 
Decreased appetite 
Blood potassium decreased 
Ulcerative keratitis 
Pain (general, back, flank, 
musculoskeletal) 
Blood sodium decreased 
Visual acuity reduced 
Urinary tract infection 
Blood calcium decreased 
Intraocular pressure 
increased 
ALT increased 
Blood phosphorus decreased 
Vitreal hemorrhage 
AST increased 
Hematuria (blood in urine) 
Retinopathy 
ALP increased 
Hemoptysis 
Colitis (including ulcerative) 
Blood creatinine 
increased 
Alopecia 
Dry mouth/throat 
Gamma-
glutamyltransferase 
increased 
Pruritis 
Dyspepsia 
Lipase increased 
Hypertension 
Hemorrhoids (including 
hemorrhagic hemorrhoids) 
Weight decreased 
Abdominal distention 
Esophageal obstruction 
Headache 
Dysgeusia (altered taste) 
Oral pain 
Cough 
Arthralgia 
Mucosal inflammation 
Dyspnea (difficulty 
breathing) 
Weight increased 
Stomatitis 
Rash (including maculo-
papular, pustular) 
Edema peripheral 
Dysphonia (difficulty 
speaking) 
Pruritis (itching) 
Candida infection 
Chills 
Hypotension 
WBC count decreased 
Pancreatitis 
 
Flushing (skin) 
Jaundice 
 
 
Cholangitis 
 
 
Lung infection/pneumonia 

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Table 5: SAEs 
Common (≥ 10%) 
Less Common (≥ 5%) 
Rare (≤ 2% or less) 
 
 
Neutrophil count decreased 
 
 
Febrile neutropenia 
 
 
Dizziness 
 
 
Somnolence 
 
 
Anxiety 
 
 
Insomnia 
 
 
Paresthesia 
 
 
Peripheral neuropathy 
 
 
Hydronephrosis 
 
 
Urinary retention 
 
7.2 Sirolimus 
7.2.1 Other Names 
Rapamune, rapamycin 
7.2.2 Product Description  
Rapamune (sirolimus) is an immunosuppressive agent. Sirolimus is a macrocyclic 
lactone produced by Streptomyces hygroscopicus. The chemical name of sirolimus 
(also 
known 
as 
rapamycin) 
is 
(3S,6R,7E,9R,10R,12R,14S,15E,17E,19E, 
21S,23S,26R,27R,34aS)-9,10,12,13,14,21,22,23,24,25,26,27,32,33,34,34a-
hexadecahydro-9,27-dihydroxy-3-[(1R)-2-[(1S, 
3R,4R)-4-hydroxy-3-
methoxycyclohexyl] 
-1-methylethyl]-10,21-dimethoxy-6,8,12, 
14,20,26-
hexamethyl-23,27-epoxy-3H-pyrido[2,1-c][1,4] 
oxaazacyclohentriacontine-
1,5,11,28,29 (4H,6H,31H)-pentone. Its molecular formula is C51H79NO13 and its 
molecular weight is 914.2. The structural formula of sirolimus is illustrated as 
follows. 
 

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Sirolimus is a white to off-white powder and is insoluble in water, but freely 
soluble in benzyl alcohol, chloroform, acetone, and acetonitrile. 
7.2.3 Procurement  
This drug is commercially available by prescription. It will be dispensed by the 
outpatient pharmacy and billed to the patient’s insurance. 
7.2.4 Storage Requirements 
Rapamune Oral Solution bottles should be stored protected from light and 
refrigerated at 2°C to 8°C (36°F to 46°F). Once the bottle is opened, the contents 
should be used within one month. If necessary, the patient may store the bottles 
at room temperatures up to 25°C (77°F) for a short period of time (e.g., not more 
than 15 days for the bottles). 
Refer to package insert for additional information. 
7.2.5 Preparation and Administration  
Per package insert 
7.2.6 Stability 
Per package insert 
7.2.7 Drug Accountability and Destruction 
Sirolimus must be dispensed only from the pharmacy and to eligible patients 
under the supervision of the study team. Sirolimus should be stored in a secure 
area according to local regulations. It is the responsibility of the site investigator 
to ensure that study drug is only dispensed to patients on this study. 
The drug will be destroyed per hospital pharmacy SOPs. 
7.2.8 Warnings and Precautions 
Refer to the current package insert for the most up to date information. 
Increased Susceptibility to Infection and the Possible Development of 
Lymphoma  
Hypersensitivity Reactions  
Angioedema 
Fluid accumulation and wound healing 
Hyperlipidemia 
Renal function 
Proteinuria 
Latent viral infections 

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Interstitial lung disease 
Skin cancer 
Interaction with Strong Inhibitors and Inducers of P-gp 
Pregnancy Category C 
7.2.9 Expected Toxicities  
Refer to the current package insert for the most up to date information. 
Table 6: Sirolimus 
Common  
Less Common 
Rare  
Nausea, Vomiting 
Diarrhea 
Hypertension 
Increased Creatinine 
Hypercholesteremia, 
Hypertriglyceridemia 
Rash 
Infections (e.g. nasopharyngitis);  
Edema;  
Weight Gain, 
Arthralgia;  
Tremor;  
Acne;  
Myelosuppression; Abdominal 
Pain; 
Fatigue;  
Myalgia;  
Chest Pain;  
Dizziness;  
Hypokalemia; 
Hypophosphatemia; 
Hyperglycemia (diabetes 
mellitus) 
Stomatitis, Wound 
Complications 
Angioedema 
Hepatotoxicity 
Hirsutism,  
Secondary Lymphoma, 
Pulmonary Hemorrhage 
Interstitial 
Lung 
Disease 
 
7.3 Cyclophosphamide 
7.3.1 Other Names 
Cytoxan 
7.3.2 Product Description  
Antineoplastic Agent, Immunosuppressant 
7.3.3 Procurement  
This drug is commercially available by prescription. It will be dispensed by the 
outpatient pharmacy and billed to the patient’s insurance. 
7.3.4 Storage Requirements 

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Refer to package insert for additional information. 
7.3.5 Preparation and Administration 
Refer to package insert for additional information. 
7.3.6 Stability 
Refer to package insert for additional information. 
7.3.7 Drug Accountability and Destruction 
Cyclophosphamide must be dispensed only from the pharmacy and to eligible 
patients under the supervision of the study team. Cyclophosphamide should be 
stored in a secure area according to local regulations. It is the responsibility of the 
site investigator to ensure that study drug is only dispensed to patients on this 
study. 
The drug will be destroyed per hospital pharmacy SOPs. 
7.3.8 Warnings and Precautions 
• To reduce the risk of hemorrhagic cystitis, Mesna and adequate hydration 
will be administered per institutional guidelines 
• Pregnancy Category D 
)Refer to the Investigator Brochure (if investigational) or Package Insert (if 
commercially available) for additional information 
7.3.9 Expected Toxicities 
Table 7: Cyclophosphamide 
Common 
Less Common 
Rare 
nausea/vomiting 
mucositis 
sterility 
severe suppression of 
blood counts 
diarrhea 
fluid weight gain/edema 
alopecia 
hemorrhagic cystitis 
 
Cardiomyopathy 
skin rash 
SIADH (Syndrome of 
Inappropriate Anti-diuretic 
Hormone) 
 
8 Dose Delays/Dose Modifications or Management of Selected Toxicities 
The NCI Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 will be 
used to grade adverse events. A copy of the CTCAE v 5.0 can be downloaded: (https:// 
ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_50). 

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Study product (VIC-1911) dose modifications are listed in Section 6.6.  
As increased lipase is a commonly observed toxicity of VIC-1911, weekly surveillance of 
lipase levels will be performed from day +5 to day +45 or while taking VIC-1911. 
Cyclophosphamide and Sirolimus 
Management of toxicities from cyclophosphamide and sirolimus will be per the package 
insert and standard institutional guidelines.  
9 Study Calendar 
All clinical and research evaluations are listed in Table 9. Scheduled evaluations up to Day 
28 may be performed - 3 to +7 days from the targeted date; assessments to be performed 
after Day 28 may be done +/-7 days of the targeted date. In addition, targeted days may 
be altered as clinically appropriate. 
9.1 Required Evaluations 
All clinical evaluations are standard of care and will be done according to current 
institutional guidelines.  Post-transplant and some pre-transplant monitoring are 
suggested guidelines and should be tailored for each patient’s clinical case. Minor 
modifications to the patient’s care made for increased patient convenience and/or 
safety are not considered deviations. 
Patients should undergo a standard eye examination to assess their vision prior to 
initiating dosing and at intervals during the study. The standardized eye examination 
consists of the following evaluations: visual acuity, pupil shape and pupillary reflexes, 
extraocular motility and alignment, tonometry, visual field, external examination, slit-
lamp examination, and fundoscopy. Every attempt should be made to have the same 
ophthalmologist perform all of the vision assessments for a given patient.  
Table 9: Study 
Calendar 
Pre-
transplant  
work-up 
Conditioning 
Regimen 
Day 
0 
Days in Reference to the transplant 
Day 1 to 
engraftment 
Follow-up Days 
31-100 
6 months, 1 
year 
Informed consent 
X 
 
 
 
 
 
Medical history 
X 
 
 
Daily 
Weekly 
X 
Physical exam 
X 
 
 
Daily 
Weekly 
X 
Radiation Therapy 
consult1 
X 
 
 
 
 
 
Performance status 
X 
 
 
Day 28 
X (Day 100) 
X 
Height/Weight 
X 
 
 
 
 
 
GVHD evaluation 
 
 
 
Weekly 
Weekly  
Prn 

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Table 9: Study 
Calendar 
Pre-
transplant  
work-up 
Conditioning 
Regimen 
Day 
0 
Days in Reference to the transplant 
Day 1 to 
engraftment 
Follow-up Days 
31-100 
6 months, 1 
year 
CMV Surveillance 
X 
 
 
Weekly 
Weekly 
Prn 
Toxicity Assessment 
 
 
 
Weekly 
Weekly 
X 
Monitoring for 
Stopping Rule Events 
and Reportable 
Events per Section 
10.2 Section 10.3 and 
Section 10.4 
 
 
 
Weekly 
Weekly 
Prn 
FACT-BMT Quality of 
LIfe Survey21  
(Appendix III) 
X 
 
 
Day 21 
Day 100 
 
Routine Laboratory  
CBC, diff, platelet 
X 
 
 
Daily 
Weekly 
X 
PT/PTT 
X 
 
 
As clinically indicated 
Full metabolic panel 
X 
 
 
2x/weekly 
Weekly 
X 
Basic metabolic 
panel 
 
 
 
Daily 
 
 
Urine or serum 
pregnancy test for 
females of 
childbearing 
potential 
X 
 
 
 
 
 
Chimerism – 
CD3/CD33 
X 
 
 
Day 21 - 3 to 
+7 days 
Day 100 +/- 7 
days 
Prn 
Lipase levels 
 
 
 
Weekly from day +5 through day 
+45* 
 
Intervention 
TBI1 
 
Days -4, -3,  
-2, -1 
 
 
 
 
Busulfan2 
 
Days -5, -4,  
-3, -2 
 
 
 
 
Fludarabine2 
 
Days -5, -4,  
-3, -2 
 
 
 
 
Stem Cell Infusion 
 
 
X 
 
 
 
Cyclophosphamide 
 
 
 
Days +3, +4 
 
 
Eye Drops 
 
 
 
Prednisolone acetate 
ophthalmic solution 1% BID 
and 
 

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Table 9: Study 
Calendar 
Pre-
transplant  
work-up 
Conditioning 
Regimen 
Day 
0 
Days in Reference to the transplant 
Day 1 to 
engraftment 
Follow-up Days 
31-100 
6 months, 1 
year 
11.1.1 Brimonidine tartrate 
ophthalmic solution 0.2% BID 
Days +4 to +45 
VIC-1911 
 
 
 
Day +5 through +45 
 
Sirolimus 
 
 
 
Day +5 through +100 
 
Research Blood Draw 
VIC-1911 
Pharmacokinetics 
 
 
 
Day 5, Day 
15* 
 
 
Research samples (8 
green top tubes, 1 
pax gene tube) 
Pre-
transplant 
 
 
Day 21 - 3 to 
+7 days 
Day 60 +/- 7 
days 
Day 100 +/- 
7 days 
Procedures  
Ophthalmologic  
Evaluation  
Pre-
transplant 
 
 
Day 28 +/- 3 
days 
Day 100 +/- 7 
days 
Prn 
EKG 
X 
 
 
As clinically 
indicated 
As clinically 
indicated 
As clinically 
indicated  
TTE 
X 
 
 
As clinically 
indicated 
 
 
Chest x-ray 
X 
 
 
As clinically 
indicated 
 
 
Bone 
Marrow 
Biopsy/Aspirate 
with specific studies 
(e.g. 
morphology, 
immunophenotyping, 
FISH, 
cytogenetics, 
PCR, etc.) as clinically 
indicated 
X 
 
 
X (Day 28 - 3 
to +7 days 
X (Day 100 +/- 7 
days) 
X 
PFT 
X 
 
 
 
 
 
 * for subjects on Phase I (N=up to 9) while taking VIC-1911 
1for subjects on TBI conditioning regimen 
2for subjects on alternative busulfan/fludarabine regimen  
 
If day 5 or 15 falls on a weekend or holiday, PK samples can be obtained on the closest weekday 
occurring after the post-transplant day, no more than 3 days later. Plasma samples will be 
collected pre-dose, +30 minutes, +1 hours, +2 hours, +6 hours, and +24 hours (pre-morning dose) 
for the first 3 subjects at each dose level. Pharmacokinetics will not be obtained for the 6 subjects 
in the phase 1 expansion cohort.  
 
 
Research Related Tests and Procedures 

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Research sample collection is tied to the clinical care schedule of events and their 
associated window for performance. Therefore, if a clinical time point does not occur or 
is altered, the research related time point will be adjusted (or eliminated) as appropriate.  
 
It is recognized that with novel therapies as used in this study, the timing of protocol 
directed research samples may miss important patient specific events. For this reason, up 
to 3 extra samples for a total of 180 ml of blood may be drawn at additional time points 
that are not specified above.  
 
Translational Therapy Lab will receive the required blood draws on pre-conditioning, 
+21, +60, and +100 and complete preliminary processing. De-identified samples without 
PHI will be batch shipped to:  
 
Roswell Park Comprehensive Cancer Center 
Brian C. Betts MD Lab 
665 Elm Street 
Buffalo, New York 14203 
c/o Clinical Practice Plan 
Betts Lab will run laboratory and correlative studies related to the clinical trial. 
10 Event Monitoring, Documentation, and Reporting 
Toxicity and adverse events will be classified and graded according to NCI's Common 
Terminology Criteria for Adverse Events V 5.0 (CTCAE) and reported on the schedule 
below. A copy of the CTCAE can be downloaded from the CTEP home page.  
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_50). 
The following definitions of adverse events (AEs) and serious adverse events (SAEs) will 
determine whether the event requires expedited reporting via the SAE Report Form in 
addition to routine documentation in the OnCore AE case report form (CRF).  
Note:  for the purposes of this study, the study related treatment of VIC-1911 is 
considered the investigational product, “study drug.” 
10.1 Event Terminology 
Adverse Event:  Any untoward medical occurrence associated with the use of a drug 
in humans, whether or not considered drug related. 
 
Serious Adverse Event:  An adverse event is considered “serious” if, in the view of 
either the investigator or sponsor, it results in any of the following outcomes:  
• Death 

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• A life-threatening adverse event 
• Inpatient hospitalization or prolongation of existing hospitalization 
• A persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions 
• A congenital anomaly/birth defect 
• Important medical events that may not result in death, be life-threatening, or 
require hospitalization may be considered serious when, based upon appropriate 
medical judgment, they may jeopardize the patient or subject and may require 
medical or surgical intervention to prevent one of the outcomes listed in this 
definition.  
 
Unexpected Event: An adverse event or suspected adverse reaction is considered 
“unexpected” if it is not listed in protocol-related documents (e.g. protocol, consent 
documents, investigator brochure), or is not listed at the specificity or severity that 
has been observed or given the characteristics of the subject population being 
studied.   
 
Attribution: is the relationship between an adverse event or serious adverse event 
and the study drug. Attribution is assigned as follows: 
• Definite – The AE is clearly related to the study drug 
• Probable – the AE is likely related to the study drug 
• Possible – the AE may be related to the study drug 
• Unlikely – the AE is doubtfully related to the study drug 
• Unrelated – the AE is clearly not related to the study drug 
 
Attribution must be assigned by the treating physician or the PI. 
 
The following definitions are from the Masonic Cancer Center’s Data and Safety 
Monitoring Plan (https://z.umn.edu/dsmp) 
 
Major Deviation: A deviation or violation that impacts the risks and benefits of the 
research; may impact subject safety, affect the integrity of research data and/or affect 
a subject’s willingness to participate in the research. Deviations that place a subject 
at risk, but do not result in harm are considered to be major deviations. 
 
Minor Deviation: A deviation or violation that does not impact subject safety, 
compromise the integrity of research data and/or affect a subject’s willingness to 
participate in the research. 

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10.2 AE Monitoring and Documentation Requirements 
Adverse event collection for the purposes of this study will focus on events felt to be 
related to VIC-1911 or events that cannot be attributed to other causes (i.e. 
transplant-related, co-morbidities).  
Monitoring for adverse events will begin with the first dose of VIC-1911 through the 
30 days after the last dose of VIC-1911. 
Adverse event documentation for the purposes of this study will focus on:  
• unexpected grade 4 or greater events  
• expected toxicities felt to be related to the VIC-1911 
o Grade 2 or higher vitreous haemorrhage unrelated to thrombocytopenia 
o Grade 3 or higher visual acuity decrease 
o Grade 3 or higher watery eyes 
o Grade 3 or higher keratitis 
o Grade 3 or higher floaters 
o Grade 3 or higher corneal microcyst,  or other eye disorders 
o Any grade 3 or above unexpected adverse event considered at least possibly 
related to VIC-1911. 
• unexpected adverse events that cannot be attributed to the transplant procedure 
or other causes (i.e. underlying disease, co-morbidities) 
 
After the End of Treatment visit, monitoring for adverse events will become less 
frequent based on the schedule in Table 9 and only events that are unexpected and 
at least possibly related to VIC-1911 will be documented upon knowledge. 
10.3 SAE and Death Documentation  
Any event meeting the definition of a serious adverse event (SAE) requires 
documentation using the MCC SAE Report Form in OnCore.  
Deaths, including due to disease, within the follow-up period will be recorded as an 
SAE. Deaths due to disease should be recorded as a Grade 5 “Neoplasms benign, 
malignant and unspecified (including cysts and polyps) – Other (Progressive Disease).  
In addition, upon knowledge, the death date and cause must be reported in the 
patient follow-up tab in OnCore using the comment field in the survival status section 
to record the cause.  
10.4 Dose Limiting Toxicity Event/Early Stopping Rule Documentation and Reporting 

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All patients enrolled in Phase I dose-finding cohort are monitored for dose limiting 
toxicity (DLT) and excessive toxicity (early stopping events) specific to the Component. 
Refer to Section 3 and Section 14.4 for definitions.  
In addition to documenting the event in the study’s CRF’s, all DLTand SR events are to 
be documented on the Event Form found in OnCore per Masonic Cancer Center 
procedures. 
An event that counts as a DLT does not necessarily constitute a SAE and should be 
reported as such only if they meet the criteria for reporting as defined in Section 10.5. 
DLTs do not apply to the Phase I extension portion of the study.  All toxicities will be 
graded and determined to be an SAE as appropriate. 
10.5 Expedited Reporting Requirements (MCC) 
As the study sponsor, the Masonic Cancer Center has the following expedited 
reporting responsibilities (Table 10) for events documented in Section 10.2, Section 
10.3 and Section 10.4: 
Table 10: Reporting Requirements 
Agency 
reporting to 
Criteria for reporting 
Timeframe 
Form to Use 
Submission 
address/email 
address 
U of MN IRB  
Unanticipated death of a locally enrolled 
subject(s); New or increased risk; Any adverse 
event  that require a change to the protocol or 
consent form – refer to the IRB website for 
complete details  
5 Business 
Days 
RIN 
 
Ethos 
Deviation reporting per current IRB requirements  
 
 
FDA 
 
Unexpected and fatal or unexpected and life 
threatening suspected adverse reaction 
no later than 
7 Calendar 
Days 
University of 
Minnesota SAE 
Report 
Submit to FDA as an 
amendment to IND  
 
1) Serious and unexpected suspected adverse 
reaction or 
2)  increased occurrence of serious suspected 
adverse reactions over that listed in the protocol 
or investigator 
brochure or 
3) findings from other sources (other studies, 
animal or in vitro testing) 
no later than 
15 Calendar-
Days 

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11 Study Data Collection and Study Monitoring 
11.1 Data Management 
This study will collect regulatory and clinical data using University of Minnesota CTSI’s 
instance of OnCore® (Online Enterprise Research Management Environment). 
 
The Oncore database resides on dedicated secure and PHI compliant hardware 
consisting of 3 physical servers: dev, DR, and production. The dev server is located in 
the University of Minnesota (UMN) datacenter (WBOB) and houses six database 
instances (test, train, sandbox, mcc reports, oncdm, and vendor) that are backed up 
locally because the data is refreshed from Oncore production data. The production 
server is located in the UMN datacenter (WBOB). All the data servers are managed by 
the Academic Health Center – Information Systems (AHC-IS) virtual servers which 
utilize clustered infrastructure to provide real-time failover of virtual servers. This 
real-time clustering is physically limited to the UMN data center. All relevant AHC IS 
procedures related for PHI compliant servers (as required by the Center of Excellence 
for HIPAA Data) apply to Oncore databases. 
 
The integrated data will be stored in PHI compliant servers managed by AHC IS with 
access given to those authorized users in the Clinical and Translation Science Institute 
Informatics team (CTSI BPIC and MCC CISS). The data will be integrated and extracted 
to researchers through the CTSI Informatics team and will be delivered through secure 
and compliant mechanisms (e.g. AHC IE data shelter, BOX, sftp, etc). If data de-
identification is needed, then compliant AHC IE data de-identification tools will be 
used. The informatics team will grant the IRB approved study team members access 
to data. 
 
Key study personnel are trained on the use of OnCore and will comply with protocol 
specific instructions embedded within the OnCore. 
11.2 Case Report Forms 
Participant data will be collected using protocol specific electronic case report forms 
(e-CRF) developed within OnCore based on its library of standardized forms. The e-
Masonic Cancer 
Center 
SAE 
Coordinator 
Events that meet the definition of dose limiting 
toxicity or an early study stopping rule 
At time of 
reporting 
Event Form 
mccsaes@umn.edu 

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CRF will be approved by the study’s Principal Investigator and the Biostatistician prior 
to release for use. The Study Coordinator or designee will be responsible for 
registering the patient into OnCore at time of study entry, completing e-CRF based on 
the patient specific calendar, and updating the patient record until patient death or 
end of required study participation.  
11.3 Data and Safety Monitoring Plan (DSMP) 
The study’s Data and Safety Monitoring Plan will be in compliance with the University 
of Minnesota Masonic Cancer Center's Data & Safety Monitoring Plan (DSMP), which 
can be accessed at https://z.umn.edu/dsmp 
 
For the purposes of data and safety monitoring, this study is classified as high risk 
(investigator initiated). Therefore, the following requirements will be fulfilled: 
 The Masonic Cancer Center Data and Safety Monitoring Council (DSMC) will 
review the study’s progress at least quarterly. 
 The PI will comply with at least twice-yearly monitoring of the project by the 
Masonic Cancer Center monitoring services. 
 The PI will oversee the submission of all reportable adverse events per the 
definition of reportable in Section 10.5 to the Masonic Cancer Center’s SAE 
Coordinator, the University of Minnesota IRB, and the FDA.  
In addition, at the time of the continuing review with the University of Minnesota IRB, 
a copy of the report with any attachments will be submitted to the Cancer Protocol 
Review Committee (CPRC). 
 
IND Annual Reports 
In accordance with regulation 21 CFR § 312.33, the Sponsor-Investigator will submit a 
progress report annually. The report will be submitted within 60 days of the 
anniversary date that the IND went into effect.  
11.4 Study Related Monitoring 
The IND sponsor/investigator will permit study-related monitoring, audits, and 
inspections by the Masonic Cancer Center or their designee, IRB, government 
regulatory bodies, and University of Minnesota compliance groups. All study related 
documents (e.g. source documents, regulatory documents, data collection 
instruments, study data, etc.) will be made available. The S/I will ensure the capability 
for inspections of applicable study-related facilities (e.g. pharmacy, diagnostic 
laboratory, etc.) will be available for trial related monitoring, audits, or regulatory 
inspections. 

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11.5 Record Retention 
The investigator will retain study records including source data, copies of case report 
form, consent forms, HIPAA authorizations, and all study correspondence in a secured 
facility for at least 6 years after the study file is closed with the IRB and FDA.  
 
In addition, the Clinical Trials Office (CTO) will keep a master log of all patients 
participating in the study with sufficient information to allow retrieval of the medical 
records for that patient.  
 
Please contact the CTO before destroying any study related records. 
12  Measurement of Effect 
Phase I: 
o Safety of VIC-1911 with PTCy and SIR after alloHCT 
o Identify the recommended phase I extension dose of VIC-1911 
Phase I extension:  
o Time-to-event grade II-IV acute GVHD by 100 days 
o Relapse by 1 year 
o Safety 
13  Study Design and Endpoints  
This is a Phase I dose-finding study with extension at MTD of VIC-1911 combined with 
PTCY and sirolimus for the prevention of acute GVHD after matched related or unrelated 
peripheral blood stem cell allografts.  The primary endpoint of the phase I trial is to 
determine the safety of VIC-1911 with PTCy and SIR as GVHD prophylaxis after allo HCT.  
Once the optimal dose is identified along with estimates of safety, the objective will be to 
confirm safety and obtain preliminary estimates of longer-term efficacy as measured by 
the co-primary endpoints of grade II-IV acute graft-versus-host disease (aGVHD) by 100 
days and relapse by 1 year in the phase I extension trial.   
The definition of relapse will be the same used in BMT CTN 1703: “Relapse is defined by 
either morphological or cytogenetic evidence of acute leukemia or MDS consistent with 
pre-transplant features, or radiologic evidence of lymphoma, documented or not by 
biopsy. Progression of disease applies to patients with lymphoproliferative diseases 
(lymphoma or chronic lymphocytic leukemia) not in remission prior to transplantation. 
The event is defined as increase in size of prior sites of disease or evidence of new sites 

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of disease, documented or not by biopsy. Institution of any therapy to treat persistent, 
progressive or relapsed disease, including the withdrawal of immunosuppressive therapy 
or donor lymphocyte infusion, will be considered evidence of relapse/progression 
regardless of whether the criteria described above were met.” The presence of mutations 
by molecular techniques will not fulfill the criteria of relapse/progression if systemic 
therapy, immunosuppression withdrawal, or DLI is not given to treat it. However, in this 
event, the presence of measurable disease by molecular techniques will be noted.  
The primary analysis for Phase I and Phase I extension will be a full analysis set in that all 
patients receiving any treatment with VIC-1911 will be evaluable for DLTs and efficacy. 
Secondary trial endpoints will include pre-conditioning, +28, and +100 Treg (CD4+, CD25+, 
CD127neg, Foxp3+), allo-conventional T cell (Tconv) (CD4+, CD25+, CD127+), and T helper 
1/2/17 cells values by flow cytometry.  Day +100 T follicular helper cells (Tfh:CD4+, 
CXCR5+, CD45RAneg), CD8+ T cells, NK cells, total CD19+ B cells, transitional (CD19+, IgD+, 
CD38Hi, CD27+) B cells, and pre-germinal B cells (CD19+, CD21Lo, CD27neg) will be 
measured by flow cytometry.  Treg suppression assays will be performed using purified 
Tregs at day +21 and day +100.  The cumulative incidences of acute (day +100) and chronic 
GVHD (day +365) as well as relapse (day +365) will be monitored.  While the frequency of 
CD4+ T cell pHistone 3 serine 10 (pH3ser10) [marker of Aurora kinase A activity (10)] will 
be followed as part of the identification of the recommended phase I extension dose, we 
will also analyze the frequency of CD4+ T cell pS6 [marker of mTOR activity (20)] at pre-
conditioning, +21, and +100.  In the phase I, VIC-1911 pharmacokinetics will be measured 
as well for the first 3 patients in each dose level.  Clinical secondary endpoints will include 
GRFS as measured by GVHD relapse-free survival by 1 year, grade III-IV acute GVHD by 
day +100, chronic GVHD (NIH consensus criteria) by day +365, CMV reactivation and 
disease through day +180, and Quality of life through day +100. 
14 Statistical Considerations 
14.1 Study Design 
This single-arm Phase I dose finding with extension study of PTCY/sirolimus plus VIC-
1911 will test up to 3 dose levels of VIC-1911 for safety and short and long-term 
efficacy.  Once the optimal dose is identified in Phase I, the objective will be to confirm 
safety and obtain estimates of long-term efficacy as measured by the two co-primary 
endpoints of grade II-IV aGVHD by day 100 and relapse by 1 year.  
Phase I dose finding component: Find the optimal dose of VIC-1911:  

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The first phase is a dose finding study with the aim of establishing the optimal dose of 
VIC-1911 based on aggregate data along with the investigator’s prior beliefs of rates 
of efficacy and toxicity at each dose as well as their input for the expected and 
maximum/minimum toxicity/efficacy desired. DLTs are defined in section 3 and short-
term efficacy is defined as the proportion of patients with an average CD4+, pH3ser10+ 
T cell of <54%. The maximum desired toxicity is 30% of patients having a DLT by day 
28 and the minimum desired efficacy is 65% of patients having CD4+, pH3ser10+ T cell 
of <54% by day 21 (- 3 to +7 days) . The optimal dose will be identified using the EffTox 
design19.  
Three dose levels of VIC-1911 will be tested (25 mg, 50 mg, or 75 mg) starting with a 
dose of 25 mg. Efftox is an adaptive Bayesian design to facilitate seamless 
safety/efficacy dose-finding. In this trial, the measure for efficacy in the Phase I 
component (CD4+, pH3ser10+ T cell <54% by day 21) differs from the Phase I extension 
component (aGVHD by 100 days and relapse by 1 year). In the design, two parameters 
are required in addition to the desired toxicity and efficacy. The first is the trade-off 
function, which has been calculated as 1.79 based on points that are of equal utility: 
(1) the maximum permissible probability of toxicity when efficacy is guaranteed, (2) 
the minimum required probability of efficacy when toxicity is impossible and (3) a 
point in between that is considered equally desirable. The 2nd is the mean effective 
sample size (ESS) calculated as 0.9 based on the expected toxicity and efficacy at each 
dose, which is well within the advised range of 0.5 to 1.5. This framework combines 
experience from patients in the earlier part of the trial with clinicians’ initial estimates 
of DLT’s, efficacy and trade-off at each dose. 
As the study progresses, updated probabilities of DLT and efficacy are computed 
before each new cohort of three patients is enrolled and the last patient reaches Day 
28 (end of the assessment period) prior to enrollment of a subsequent cohort. Each 
subsequent cohort will be assigned to the most appropriate dose based on these 
updated probabilities. To promote patient safety: 1) we will enroll cohorts of 3 
patients starting at the 1st dose and 2) dose levels will not be skipped when escalating. 
The optimal dose will be identified by one of the minimum of the following criteria: 
(1) the sample size of 21 is exhausted and (2) 9 patients are sequentially enrolled at 
the same dose. Implementation of Efftox will be carried out by software published by 
the 
MD 
Anderson 
Cancer 
Center 
at 
https://biostatistics.mdanderson.org/SoftwareDownload/. 
Phase I Expansion: Studying efficacy of VIC-1911 using aGVHD and relapse as the 
primary endpoints in addition to safety: 

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This 1-stage trial is designed to show a 15% improvement over an historical estimate 
of aGVHD and a 12% improvement over an historical estimate of relapse. Trial 
enrollment will only stop early for safety. The null hypothesis rate for grade II-IV 
aGVHD is ≥25% by 100 days and the null hypothesis rate for relapse is ≥24% by 1 year. 
These will be tested against a one-sided alternative that aGVHD ≤10% by 100 days and 
relapse ≤12% by 1 year using a type-I error of 2.5% to control for the multiple 
comparisons. We will potentially enroll 58 patients in the extension phase after 
completion of Phase I.  
14.2 Statistical Analysis and Bioinformatics 
The proportion of patients with an average CD4+, pH3ser10+ T cell <54% and safety 
endpoints will be assessed with descriptive statistics such as medians, ranges, 
frequencies and proportions as well as plots at baseline, day +21 and day +100. Other 
immune measures will be similarly estimated. The optimal dose will be determined 
by design. GVHD and relapse curves along with their competing risk will be estimated 
with cumulative incidence along with 95% confidence intervals treating non-event 
mortality as a competing risk. GVHD will be compared to a null value using a one-sided 
exact test and relapse be tested using a one-sample one-sided log-rank test. Kaplan-
Meier curves and 95% confidence intervals will be used to estimate GRFS.  Duration 
of hospitalization will be measured using median, range and interquartile range. CMV 
reactivation and CMV disease will be estimated using cumulative incidence treating 
non-CMV mortality as a competing risk. FACT quality of life measures along with its 
subscales will be measured through day +100, descriptively analyzed and possibly 
assessed with general linear mixed models. Pharmacokinetics and other correlative 
measure will be descriptive.  
For comparison to historical controls where VIC-1911 was not part of the conditioning, 
we may perform regression analyses on the secondary endpoint of GFRS. This will 
include patients from our current study as well as a set of control patients age 18+ 
from MT2015-29 at our center. The historical cohort used similar conditioning. Given 
the use of historical controls, we will adjust for potential confounding using Fine and 
Gray regression by including the pre-specified factors of age (continuous), donor type 
(matched sibling versus haploidentical versus unrelated donor), disease-risk index 
(low risk versus intermediate risk versus high/very high risk) and comorbidity (HCT-CI: 
low risk versus intermediate versus high risk) . These pre-specified factors were 
determined in collaboration with investigators. No p-values will be listed. Only 
confidence intervals will be cited around the hazard ratios. 

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Bioinformatics Plan: To investigate genes associated with GVHD versus GVL, 
transcriptome profiling of 79 PBMC samples will be done following standard RNAseq 
protocols using PBMCs from patients on PTCy/SIR/VIC versus PTCy/SIR/MMF. We 
expect to have 50 million pair-end reads (2x100bp) per sample. RNA-seq sequencing 
reads in FASTQ files will be QCed, trimmed, and aligned to the reference genome and 
transcriptome. Gene counts matrix will be generated and used for downstream gene 
differential analysis, expression pattern clustering and for select gene set/pathway 
analysis. Limma model will be used for differential analyses between groups with a 
<5% false discovery rate after controlling for multiple comparisons, for assessments 
of GVL genes: LCK, PDCD1, and INFG and GVHD genes: AURKA and STAT3. We will 
further focus on modeling gene expression levels of LCK, PDCD1, and INFG (for GVL) 
plus AURKA and STAT3 (for GVHD), compared at d+21, between patients treated on 
PTCy/SIR/VIC or PTCy/SIR/MMF (n=79 for each), also collecting clinical data regarding 
relapse by day +365 and grade II-IV acute GVHD by day +100. In exploratory analyses, 
d+60 and +100 gene expression changes will be modeled and evaluated between the 
two groups using a type I error level of 0.05 without adjustment for multiple 
comparisons. We will also perform pathway analysis using both Enrichr and gene set 
enrichment analysis using GSEA with the Molecular Signatures Database (MSigDB) 
hallmark pathways collection. Logistic regression modeling and calculation of the area 
under the ROC curve for each analyte will be used to determine associations with 
outcome. Protein phosphorylation, immune reconstitution, and functional assays will 
be evaluated with descriptive statistics such as medians, ranges, proportions, and 
plots at baseline, d+21, +60, +100. 
14.3 Sample Size and Power Considerations 
14.3.1 Phase I 
We will enroll a maximum of 21 patient during Phase I. Operating characteristics for 
various ‘true’ and ‘excessive’ probabilities are listed in Tables 1 and 2.  
 
 
Table 1. Operating characteristics for EffTox with expected DLTs 
 
Dose 
(mg) 
Expected Efficacy/DLT 
Excessive Efficacy/Expected DLT 
 
Efficacy/DLT 
Probability of 
selecting dose 
Patient 
Number 
 
Efficacy/DLT 
Probability 
of 
selecting dose 
Patient 
Number 
25  
30%/5% 
0%  
3 
50%/5% 
0% 
3 
50 
65%/10% 
0%  
3 
80%/10% 
40% 
9 
75 
95%/15% 
100% 
9 
99%/15% 
60% 
9 
Table 2. Operating characteristics for EffTox with excessive DLT 
 
Expected Efficacy/Excessive DLT 
Excessive Efficacy/Excessive DLT 

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Based on these simulations, 21 patients should be sufficient and safe to define the 
optimal dose in phase I. All patients treated at the optimal dose will be carried forward 
into the Phase I extension trial.  
14.3.2 Phase I extension 
The null hypotheses for the Phase I extension trial are that grade II-IV aGVHD is > 25% 
by 100 days and relapse is > 24% by 1 year. There will be 2 tests against one-sided 
alternatives that aGVHD ≤10% by 100 days and relapse ≤12% by 1 year. Similar rates 
for these null hypotheses are taken from unpublished data for adult matched 
unrelated donor  PBSC patients enrolled on protocol MT2015-29. We expect most if 
not all patients on the current trial to have a donor source of adult matched unrelated 
donor PBSC. For power calculations, Bonferroni was used to adjust the type I error to 
maintain the experiment-wise type I error at the 0.05 level (0.05/2 = 0.025). A sample 
size of 58 patients achieves 81% power to detect an improvement to a 12% relapse 
rate using a one-sided one-sample log-rank test. This assumes that the last patient 
has follow-up of 6 months and patients are enrolled over a 30-month period. 
Distribution of relapse time is approximated by an exponential distribution. For the 
endpoint of grade II-IV aGVHD, 58 patients achieves 84% power to detect an 
improvement to at least 10% using a one-sided exact test.  
Assuming 5% or less loss to follow-up, we will increase the overall sample size for 
phase I extension to 61 (an increase of 3 patients). 
Overall, we expect that approximately 52-58 patients will be required during the 
extension (3-9 patients from the Phase I trial who are treated at the optimal dose may 
also be used during Phase I extension).  
There will be no interim analysis for futility due to a short enrollment period and a 
reasonable assumption that the treatment will be at least as efficacious as the prior 
standard of care. Monitoring will be for safety only. 
14.4 Monitoring Guidelines (Early Stopping Rules for Excess Toxicity) 
 
Phase I 
Dose 
(mg) 
 
Efficacy/DLT 
Probability of 
selecting dose 
Patient 
Number 
 
Efficacy/DLT 
Probability 
of 
selecting dose 
Patient 
Number 
25  
30%/15% 
0%  
3 
50%/15% 
20% 
6 
50 
65%/25% 
50%  
9 
80%/25% 
50% 
9 
75 
95%/45% 
40 
9 
99%/45% 
30% 
6 
None 
 
10% 
 
 
 
 

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Posterior probabilities for DLT and efficacy will be calculated after each cohort of 3 
patients using efftox. If after calculating these probabilities, efftox advocates that (i) 
no doses are tolerable and (ii) no doses are efficacious, the design will suggest 
stopping the trial.  
Phase I extension 
Monitoring for adverse events will begin with the first dose of VIC-1911 through day 
75 post-transplant20.  
Unexpected grade 4 or greater events 
The goal is to construct a boundary based on unexpected grade 4+ events such that 
the probability of early stopping is at most 10% if the rate is equal to 5% and our 
sample size is at most 58 (the maximum of patients enrolled in Phase I extension 
stage, which does not include the minimum of 3 patients treated at the recommended 
phase I extension dose during phase I). With these stipulations, the trial will be 
stopped and reviewed if 2/6, 3/14, 4/25, 5/37, 6/49 or 7 patients have events by Day 
75. If the true probability of an event is 20%, there is a 98% chance of triggering the 
monitoring boundary.  
 
Expected toxicities felt to be related to the VIC-1911: 
a. Grade 2 or higher vitreous haemorrhage 
b. Grade 3 or higher visual acuity decreased 
c. Grade 3 or higher watery eyes 
d. Grade 3 or higher keratitis 
e. Grade 3 or higher floaters 
f. Grade 3 or higher corneal microcysts,  
g. Grade 3 or higher other eye disorders 
 
The goal is to construct a boundary based on events such that the probability of early 
stopping is at most 10% if the rate is equal to 10% and our sample size is at most 58. 
With these stipulations, the trial will be stopped and reviewed if 2/2, 3/7, 4/12, 5/17, 
6/24, 7/30, 8/37, 9/43, 10/51 or 11 patients have events by Day 75. If the true 
probability of toxicity is 20%, there is a 73% chance of triggering the monitoring 
boundary.  
 
Treatment related mortality (TRM) by day 100 
The goal is to construct a boundary based on TRM such that the probability of early 
stopping is at most 10% if the rate is equal to 5% and our sample size is at most 58. 

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With these stipulations, the trial will be stopped and reviewed if 2/6, 3/14, 4/25, 5/37, 
6/49 or 7 patients have events by Day 75. If the true probability of an event is 20%, 
there is a 98% chance of triggering the monitoring boundary. 
 
Relapse by day 100 
The goal is to construct a boundary based on relapse such that the probability of early 
stopping is at most 10% if the rate is equal to 5% and our sample size is at most 58. 
With these stipulations, the trial will be stopped and reviewed if 2/6, 3/14, 4/25, 5/37, 
6/49 or 7 patients have events by Day 75. If the true probability of an event is 20%, 
there is a 98% chance of triggering the monitoring boundary. 
 
Grade III-IV acute GVHD by day 100 
The goal is to construct a boundary based on GVHD such that the probability of early 
stopping is at most 10% if the rate is equal to 5% and our sample size is at most 58. 
With these stipulations, the trial will be stopped and reviewed if 2/6, 3/14, 4/25, 5/37, 
6/49 or 7 patients have events by Day 75. If the true probability of an event is 20%, 
there is a 98% chance of triggering the monitoring boundary. 
 
Primary Graft Failure by day 42 
The goal is to construct a boundary based on graft failure such that the probability of 
early stopping is at most 10% if the rate is equal to 5% and our sample size is at most 
58. With these stipulations, the trial will be stopped and reviewed if 2/6, 3/14, 4/25, 
5/37, 6/49 or 7 patients have events by Day 75. If the true probability of an event is 
20%, there is a 98% chance of triggering the monitoring boundary. 
15 Ethical and Regulatory Considerations 
15.1 Good Clinical Practice 
The study will be conducted in accordance with the appropriate regulatory 
requirement(s). Essential clinical documents will be maintained to demonstrate the 
validity of the study and the integrity of the data collected. Master files should be 
established at the beginning of the study, maintained for the duration of the study 
and retained according to the appropriate regulations.  
15.2 Ethical Considerations 
The study will be conducted in accordance with ethical principles founded in the 
Declaration of Helsinki. The IRB will review all appropriate study documentation in 
order to safeguard the rights, safety and well-being of the patients. The study will only 

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be conducted at sites where IRB approval has been obtained. The protocol, informed 
consent, written information given to the patients, safety updates, annual progress 
reports, and any revisions to these documents will be provided to the IRB by the 
investigator.  
15.3 Informed Consent 
All potential study participants will be given a copy of the IRB-approved Consent to 
review. The investigator or designee will explain all aspects of the study in lay 
language and answer all questions regarding the study. If the participant decides to 
participate in the study, he/she will be asked to sign and date the consent document. 
Patients who refuse to participate or who withdraw from the study will be treated 
without prejudice. 
 
 

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II trials in oncology. Biometrics 61: 540-545ID: 15339291. 
21. Sorror ML. How I assess comorbidities before hematopoietic cell transplantation. Blood. 
2013;121(15):2854-2863. doi:10.1182/blood-2012-09-455063 
22. McQuellon RP, Russell GB, Cella DF, et al. Quality of life measurement in bone marrow 
transplantation: development of the Functional Assessment of Cancer Therapy-Bone 
Marrow Transplant (FACT-BMT) scale., Bone Marrow Transplant, 1997, vol. 19 4(pg. 357-
368) 

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Appendix I – Performance Status 
 
Karnofsky Performance Scale 
Percent 
Description 
100 
Normal, no complaints, no evidence of disease. 
90 
Able to carry on normal activity; minor signs or symptoms of disease. 
80 
Normal activity with effort; some signs or symptoms of disease. 
70 
Cares for self, unable to carry on normal activity or to do active work. 
60 
Requires occasional assistance, but is able to care for most of his/her needs. 
50 
Requires considerable assistance and frequent medical care. 
40 
Disabled, requires special care and assistance. 
30 
Severely disabled, hospitalization indicated.  Death not imminent. 
20 
Very sick, hospitalization indicated. Death not imminent. 
10 
Moribund, fatal processes progressing rapidly. 
0 
Dead. 
 
 
 

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Appendix II – Risks of Stem Cell Transplant, TBI, Busulfan and Fludarabine 
 
Risks of Stem Cell Transplant 
 
Risks associated with the cell infusion 
nausea and vomiting  
possible allergic reaction (including itching, hives, flushing [red face], shortness of breath, 
wheezing, chest tightness, skin rash, fever, chills, stiff muscles, or trouble breathing) 
 
Risks associated with transplant  
slow recovery of blood counts   
graft failure 
Graft-Versus-Host Disease (GVHD)  
other complications including: 
damage to the vital organs  
serious infections  
relapse of disease or a new blood cancer  
risk to the unborn 
changes in vital signs (commonly tachycardia, hypotension or hypertension) 
 
Total Body Irradiation 
Risks of TBI are listed in Table 12 
Table 12: TBI 
 
 
Common  
occurs in more than 20% of 
patients 
Less Common 
occurs in 5 to 20% of 
patients 
Rare 
occurs in fewer than 5% of 
patients 
nausea and vomiting 
diarrhea 
cataracts 
sterility 
endocrinopathies 
growth failure 
intestinal cramps 
mucositis 
pancytopenia 
electrolyte disturbances 
neutropenic fever 
infections 
dry eyes 
parotitis 
interstitial pneumonitis 
generalized erythema 
veno-occlusive disease 
Dysphagia 
vertebral deformities 
nephropathy 
risk of 2nd malignancy years later 
cholestasis 
 
 
 
 
 
 

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Busulfan 
Common  
occurs in more than 20% of 
patients 
Less Common 
occurs in 5 to 20% of patients 
Rare 
occurs in fewer than 5% of 
patients 
● low white blood cell count 
with increased risk of 
infection  
● low platelet count with 
increased risk of bleeding  
● low red blood cell count 
(anemia) which may cause 
tiredness, headache, 
dizziness  
● hair loss or thinning, 
including face and body 
hair (usually grows back 
after treatment)  
● long-term or short-term 
infertility (inability to have 
children) in men and 
women 
 
• 
tiredness (fatigue)  
• 
sores in mouth or on lips  
• 
fever  
• 
nausea  
• 
vomiting  
• 
rash  
• 
loss of appetite  
• 
diarrhea  
• 
serious infection due to 
low white blood cell 
count  
 
 
● abnormal blood tests 
results which suggest that 
the drug is affecting the 
liver  
● allergic reaction with 
hives, itching, headache, 
coughing, shortness of 
breath, or swelling of the 
face, tongue, or throat  
● scarring of lung tissue, 
with cough, difficulty 
breathing, and shortness 
of breath that may occur 
after prolonged use, or 
even months or years after 
stopping the drug  
● secondary cancers  
● darkened skin  
● heart problems with high-
dose treatment, most 
often in people with 
thalassemia or others with 
iron overload 
● hormone deficiency 
● death due lung damage, 
bone marrow failure, or 
other causes 
 
Fludarabine 
Common 
Less Common 
Rare 
● severe suppression of 
blood counts 
● diarrhea 
● anorexia 
● mucositis 
● nausea/vomiting 
● stomatitis 
● osteoporosis 
● dysuria 
● chills 
● fever 
● GI bleeding 
● peripheral 
edema 
 
● neurotoxicity 
- 
agitation and confusion 
- 
blurred vision 
- 
peripheral neuropathy 
- 
hearing loss 
- 
headache 
- 
cerebellar syndrome 
- 
blindness 
- 
coma 
- 
weakness 
● depression 
● insomnia 
● hemorrhagic cystitis (except in FA) 

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Fludarabine 
Common 
Less Common 
Rare 
● abnormal renal function test 
● autoimmune hemolytic anemia 
● deep venous thrombosis 
● aneurysms 
● pruritic skin rash 
● abnormal liver function/liver 
failure 
● constipation 
● transient ischemic attack 
● dysphagia 
● myalgia 
● arthralgia 
● renal failure 
 
 
 

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Appendix III – FACT-BMT Quality of Life Survey21 
 
Below is a list of statements that other people with your illness have said are 
important. Please circle or mark one number per line to indicate your response as it 
applies to the past 7 days. 
 
 
 
 
PHYSICAL WELL-BEING 
 
Not 
at 
all
A 
little 
bit
Some-
what 
Quitea 
bit 
Very 
much 
GP1 
I have a lack of energy 
0 
1 
2 
3 
4 
GP2 
I have nausea 
0 
1 
2 
3 
4 
GP3 
Because of my physical condition, I have 
trouble meeting the needs of my family 
 
0 
 
1 
 
2 
 
3 
 
4 
GP4 
I have pain 
0 
1 
2 
3 
4 
GP5 
I am bothered by side effects of treatment 
0 
1 
2 
3 
4 
GP6 
I feel ill 
0 
1 
2 
3 
4 
GP7 
I am forced to spend time in bed 
0 
1 
2 
3 
4 
 
 
SOCIAL/FAMILY WELL-BEING 
 
Not 
at 
all
A 
little 
bit
Some-
what 
Quitea 
bit 
Very 
much 
GS1 
I feel close to my friends 
0 
1 
2 
3 
4 
GS2 
I get emotional support from my family 
0 
1 
2 
3 
4 
GS3 
I get support from my friends 
0 
1 
2 
3 
4 
GS4 
My family has accepted my illness 
0 
1 
2 
3 
4 
GS5 
I am satisfied with family communication 
about my illness 
 
0 
 
1 
 
2 
 
3 
 
4 
GS6 
I feel close to my partner (or the person 
who is my main support) 
 
0 
 
1 
 
2 
 
3 
 
4 
Q1 
Regardless of your current level of sexual 
activity, please answer the following question. 
If you prefer not to answer it, please mark this 
box           and go to the next section. 
 
 
 
 
 
GS7 
I am satisfied with my sex life 
0 
1 
2 
3 
4 

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Please circle or mark one number per line to indicate your response as it applies to 
the past 7 days. 
 
EMOTIONAL WELL-BEING 
Not at 
all 
A little 
bit 
Some-
what 
Quitea 
bit 
Very 
much 
GE1 
I feel sad 
0 
1 
2 
3 
4 
GE2 
I am satisfied with how I am 
coping with my illness 
0 
1 
2 
3 
4 
GE3 
I am losing hope in the fight 
against my illness 
0 
1 
2 
3 
4 
GE4 
I feel nervous 
0 
1 
2 
3 
4 
GE5 
I worry about dying 
0 
1 
2 
3 
4 
GE6 
I worry that my condition will get 
worse 
0 
1 
2 
3 
4 
 
 
 
 
FUNCTIONAL WELL-BEING 
 
Not at 
all 
A little 
bit 
Some-
what 
Quitea 
bit 
Very 
much 
 
GF1 
I am able to work (include work 
at home) 
0 
1 
2 
3 
4 
GF2 
My work (include work at home) 
is fulfilling 
0 
1 
2 
3 
4 
GF3 
I am able to enjoy life 
0 
1 
2 
3 
4 
GF4 
I have accepted my illness 
0 
1 
2 
3 
4 
GF5 
I am sleeping well 
0 
1 
2 
3 
4 
GF6 
I am enjoying the things I usually 
do for fun 
0 
1 
2 
3 
4 
GF7 
I am content with the quality of 
my life right now 
0 
1 
2 
3 
4 
 
 
 

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Please circle or mark one number per line to indicate your response as it applies to 
the past 7 days. 
 
ADDITIONAL CONCERNS 
 
Not at 
all 
A little 
bit 
Some-
what 
Quite 
a bit 
Very 
much 
BMT1 
I am concerned about keeping my job 
(include work at home) 
 
0 
 
1 
 
2 
 
3 
 
4 
BMT2 
I feel distant from other people 
0 
1 
2 
3 
4 
BMT3 
I worry that the transplant will not 
work 
0 
1 
2 
3 
4 
BMT4 
The side effects of treatment are 
worse than I had imagined 
 
0 
 
1 
 
2 
 
3 
 
4 
C6 
I have a good appetite 
0 
1 
2 
3 
4 
C7 
I like the appearance of my body 
0 
1 
2 
3 
4 
BMT5 
I am able to get around by myself 
0 
1 
2 
3 
4 
BMT6 
I get tired easily 
0 
1 
2 
3 
4 
BL4 
I am interested in sex 
0 
1 
2 
3 
4 
BMT7 
I have concerns about my ability to 
have children 
0 
1 
2 
3 
4 
BMT8 
I have confidence in my nurse(s) 
0 
1 
2 
3 
4 
BMT9 
I regret having the bone marrow 
transplant 
0 
1 
2 
3 
4 
BMT10 
I can remember things 
0 
1 
2 
3 
4 
Br1 
I am able to concentrate 
0 
1 
2 
3 
4 
BMT11 
I have frequent colds/infections 
0 
1 
2 
3 
4 
BMT12 
My eyesight is blurry 
0 
1 
2 
3 
4 
BMT13 
I am bothered by a change in the way 
food tastes 
0 
1 
2 
3 
4 
BMT14 
I have tremors 
0 
1 
2 
3 
4 
B1 
I have been short of breath 
0 
1 
2 
3 
4 

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BMT15 
I am bothered by skin problems 
0 
1 
2 
3 
4 
BMT16 
I have trouble with my bowels 
0 
1 
2 
3 
4 
BMT17 
My illness is a personal hardship for 
my close family members 
 
0 
 
1 
 
2 
 
3 
 
4 
BMT18 
The cost of my treatment is a burden 
on me or my family 
 
0 
 
1 
 
2 
 
3 
 
4 
 
Translated versions of survey may be downloaded here: https://www.facit.org/measure-
languages/FACT-BMT-Languages