Clinical trial NCT01620216
Conditions: Acute Myeloid Leukemia Arising From Previous Myelodysplastic Syndrome Chronic Myelomonocytic Leukemia Recurrent Acute Lymphoblastic Leukemia Recurrent Acute Myeloid Leukemia Refractory Acute Lymphoblastic Leukemia Refractory Acute Myeloid Leukemia
Sponsor: OHSU Knight Cancer Institute
Start date: 2012-05-11; Completion date: 2017-04-30
Enrollment: 12 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This phase II trial studies how well targeted therapy works in treating patients with acute lymphoblastic leukemia or acute myelogenous leukemia that has come back after a period of improvement or does not respond to treatment. Testing patients' blood or bone marrow to find out if their type of cancer may be sensitive to a specific drug may help doctors choose more effective treatments. Dasatinib, sunitinib malate, sorafenib tosylate, ponatinib hydrochloride, pacritinib, ruxolitinib, and idelalisib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Giving targeted therapy based on cancer type may be an effective treatment for acute lymphoblastic leukemia or acute myelogenous leukemia.

Detailed description:
PRIMARY OBJECTIVE:

I. To determine the clinical activity of kinase inhibitors using pre-clinical (in-vitro) activity to select individual therapy.

SECONDARY OBJECTIVES:

I. To evaluate overall objective response rates (complete response plus partial response).

II. Determine overall survival (OS) and progression-free survival (PFS).

EXPLORATORY/CORRELATIVE OBJECTIVES:

I. Prioritize active/aberrant kinase pathways using an in vitro inhibitor screen using individual primary leukemia samples.

II. Measure "on target" in vivo kinase inhibition and signal transducer and activator of transcription (STAT)-5 phosphorylation and correlate with response to treatment.

III. Perform next generation sequencing (whole exome sequencing) for complete mutational analysis.

IV. Identify aberrant gene expression in primary leukemia samples from study subjects.

V. Evaluate pharmacokinetics for each individual kinase inhibitor during therapy.

OUTLINE: Patients are assigned to 1 of 7 treatment groups based on pre-clinical kinase inhibitor activity.

GROUP I: Patients receive dasatinib orally (PO) once daily (QD) on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

GROUP II: Patients receive sutinib malate PO QD on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

GROUP III: Patients receive sorafenib tosylate PO twice daily (BID) on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

GROUP IV: Patients receive ponatinib hydrochloride PO QD on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

GROUP V: Patients receive pacritinib PO BID on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

GROUP VI: Patients receive ruxolitinib PO BID on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

GROUP VII: Patients receive idelalisib PO BID on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up periodically.

Arms: arm 1: Patients receive dasatinib PO QD on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. arm 2: Patients receive sutinib malate PO QD on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. arm 3: Patients receive sorafenib tosylate PO BID on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. arm 4: Patients receive ponatinib hydrochloride PO QD on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity arm 5: Patients receive pacritinib PO BID on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. arm 6: Patients receive ruxolitinib PO BID on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. arm 7: Patients receive idelalisib PO BID on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Interventions: intervention 1: Antitumor Drug Screening Assay intervention 2: Dasatinib intervention 3: Idelalisib intervention 4: Laboratory Biomarker Analysis intervention 5: Pacritinib intervention 6: Pharmacological Study intervention 7: Ponatinib intervention 8: Ponatinib Hydrochloride intervention 9: Ruxolitinib intervention 10: Sorafenib intervention 11: Sorafenib Tosylate intervention 12: Sunitinib intervention 13: Sunitinib Malate
Intervention descriptions: intervention 1: Undergo pre clinical kinase inhibitor activity screening intervention 2: Given PO intervention 3: Given PO intervention 4: Correlative studies intervention 5: Given PO intervention 6: Correlative studies intervention 7: Given PO intervention 8: Given PO intervention 9: Given PO intervention 10: Given PO intervention 11: Given PO intervention 12: Given PO intervention 13: Given PO

Protocol documents:
Prot_SAP_000.pdf: 
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Oregon Health & Science University 
OHSU Knight Cancer Institute 
IRB Protocol #:7195 
BMS Protocol #: CA180-392 
Ariad Protocol #: AP24534-13-014 
ClinicalTrials.gov #: NCT01620216 
 
TITLE:    
A Phase II Proof-of-Concept Trial to Study Kinase Inhibition in Relapsed/Refractory 
Acute Leukemias: Using a Comprehensive In Vitro Kinase Inhibitor Panel to Select 
Individualized, Targeted Therapies 
 
Coordinating Center: 
 
 
 
Oregon Health & Science University (OHSU) 
 
 
 
Principal Investigator: 
Marc Loriaux, MD, PhD 
Associate Professor 
Division of Hematology and Medical Oncology 
BRB507 
Oregon Health and Science University 
3181 SW Sam Jackson Pk Rd 
Portland Oregon, 97239 
Email: loriauxm@ohsu.edu 
 
 
(503) 494-9383 
 
 
 
Clinical Principal Investigator: Stephen E.F. Spurgeon, MD 
 
 
Associate Professor of Medicine 
 
 
Division of Hematology and Medical Oncology 
 
 
Knight Cancer Institute 
 
 
(503) 494-8950 
 
 
Subsites: 
 
 
Institution 
Responsible Investigator 
Phone  
Email 
University of Utah 
Huntsman Cancer Center 
Tibor Kovacsovics, MD 
801-585-3229 
tibor.kovacsovics@hci.utah.edu 
National Institutes of 
Health (NIH), National 
Heart, Lung, and Blood 
Institute (NHLBI) 
Christopher S. Hourigan, 
MD, DPhil, FACP 
 
301-803-8029 
 
hourigan@nih.gov 
University of Texas-
Southwestern 
Robert Collins, MD 
214-648-4155 
robert.collins@utsouthwestern.edu 
 
Statistician: 
 
Motomi Mori, PhD 
 
 
Biostatistics Shared Resource 
Knight Cancer Institute 
(503) 418-1555 
 
Study Coordinator/  
Tara Macey, PhD 
Central Contact: 
 
Center for Hematologic Malignancies 
 
 
Oregon Health & Science University 


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Phone: 503-494-4603 or 503-494-9916 
 
 
Fax: 503-346-8025 
 
 
 
Supplied Agent: 
Dasatinib, Sorafenib, Sunitinib, Ponatinib, Pacritinib, 
Ruxolitinib, and Idelalisib  
 
IND/IDE: 
IDE: G110198 
 
 
Original Protocol Date: 
3/19/2012 
Protocol Revision Dates: 
7/10/2015, 06/29/2016, 11/22/2016 
 


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SCHEMA 
 
Eligibility 
Relapsed or treatment refractory acute leukemia  
 
 
 
 
Treatment Sensitivity Screening 
Evaluate primary acute leukemia sample for sensitivity to a panel of tyrosine kinase inhibitors.  
Screening may take 4-10 days  
(See Section 10.1) 
 
 
 
Patients eligible for treatment with study drug 
The treatment cycle is 28 days.  
Subject may remain on drug as long as there is therapeutic benefit. 
 
 
End of treatment or early discontinuation or Re-screen 
The treatment cycle is 28 days. 
 Subject will be removed from study when there is no longer therapeutic benefit 
 
 
 The subject may rescreen for drug sensitivity and trial re-entry  
The treatment cycle is 28 days.  
Subject may remain on drug as long as there is therapeutic benefit. 
  
 
 
End of study 
 


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OVERVIEW OF STUDY DESIGN 
 
Leukemic samples (peripheral blood or bone marrow) from patients with known or suspected 
relapsed acute leukemia (ALL or AML) will be processed to enrich for mononuclear cells. Using 
our kinase inhibitor plates, the IC50 for each kinase inhibitor will be calculated and the results 
analyzed to determine if one of the study drugs could be an effective treatment for an individual 
leukemia patient. If the screen identifies a single inhibitor that has a clinically achievable IC50, 
e.g. inhibitor “A,” and the patient meets the eligibility criteria, then they will be treated with 
inhibitor “A.” If the inhibitor screen identifies multiple treatment options and the patient meets 
the eligibility criteria for all possible therapeutics screened, then the “most effective drug” will 
be assessed using additional sensitivity parameters including: comparison with the range of 
results from other responders for each candidate drug, evaluation of best level of inhibition (IC75, 
IC90), and evaluation of additional curve fitting parameters (i.e., slope and area under the curve). 
Patients may only receive one inhibitor at a time while on study. However, if a patient’s 
diseaseprogresses (defined as a ≥ 50% increase in leukemic bone marrow blasts) while on one 
inhibitor, then  he/she is eligible to re-enroll on study if, at the time of progression, a) another 
potential inhibitor (inhibitor “B”) is identified on repeat inhibitor plate testing using mononuclear 
cells obtained at time disease progression and b) the patient still satisfies all the study eligibility 
criteria.  
 


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TABLE OF CONTENTS 
 
SCHEMA ............................................................................................................................... 1 
OVERVIEW OF STUDY DESIGN ......................................................................................... 1 
1. 
OBJECTIVES.................................................................................................................. 7 
1.1 Primary Objective ........................................................................................................ 7 
1.2 Secondary Objectives ................................................................................................... 7 
1.3 Exploratory/Correlative studies..................................................................................... 7 
2.0 
BACKGROUND ......................................................................................................... 7 
2.1 Acute Leukemias.......................................................................................................... 7 
2.1.1 
Relapsed/Refractory AML .................................................................................... 7 
2.1.2 
Relapsed/Refractory Acute Lymphoblastic Leukemia (ALL).................................. 8 
2.2 Study Agents - Product Background and Mechanism of Action...................................... 9 
2.2.1 
Dasatinib .............................................................................................................. 9 
2.2.2 
Sunitinib............................................................................................................... 9 
2.2.3 
Sorafenib .............................................................................................................. 9 
2.2.4 
Ponatinib .............................................................................................................. 9 
2.2.5 
Pacritinib .............................................................................................................. 9 
2.2.6 
Ruxolitinib ..........................................................................................................10 
2.2.7 
Idelalisib .............................................................................................................10 
2.3 Study Rationale ...........................................................................................................10 
2.4.1 
The Ex-Vivo Small Molecule Kinase Inhibitor Screen ..........................................11 
2.4.2 
Kinase Inhibitors in Acute Leukemia ....................................................................12 
2.4.3 
Using the inhibitor kinase sensitivity assay to select treatment...............................13 
2.4 Correlative Studies Background ...................................................................................14 
2.4.1 
Druggable Target Identification............................................................................14 
2.4.2 
Mechanism of Target Sensitivity - Identification of oncogenic sequence variants ...14 
2.4.3 
Identification of Aberrant Gene Expression ..........................................................14 
3 
STUDY POPULATION..................................................................................................15 
3.1 Inclusion Criteria.........................................................................................................15 
3.2 
Additional Drug specific inclusion criteria................................................................16 
3.2.1 
Dasatinib .............................................................................................................16 
3.2.2 
Sunitinib..............................................................................................................17 
3.2.3 
Sorafenib .............................................................................................................17 


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3.2.4 
Ponatinib .............................................................................................................17 
3.2.5 
Pacritinib .............................................................................................................17 
3.2.6 
Ruxolitinib ..........................................................................................................17 
3.2.7 
Idelalisib .............................................................................................................17 
3.3 Exclusion Criteria .......................................................................................................18 
3.4 Additional Drug specific exclusion criteria...................................................................18 
3.4.1 
Dasatinib .............................................................................................................18 
3.4.2 
Sunitinib..............................................................................................................18 
3.4.3 
Sorafenib .............................................................................................................19 
3.4.5 
Ponatinib .............................................................................................................19 
3.4.6 
Pacritinib .............................................................................................................19 
3.4.7 
Ruxolitinib ..........................................................................................................19 
3.4.8 
Idelalisib .............................................................................................................20 
4. 
REGISTRATION PROCEDURES ..................................................................................20 
4.1 Subject Registration ....................................................................................................20 
4.1.1 
Local registration .................................................................................................20 
4.1.2 
Multicenter Registration.......................................................................................20 
5. 
TREATMENT PLAN .....................................................................................................21 
5.1 Treatment Selection.....................................................................................................21 
5.1.1 
Screen Failure......................................................................................................22 
5.1.2 
Non-OHSU Site Screening ...................................................................................22 
5.2 Agent Administration ..................................................................................................22 
5.2.1 
Supportive care or prophylactic care for Dasatinib, Sunitinib, Sorafenib, Ponatinib, 
Pacritinib, Idelalisib and Ruxolitinib ................................................................................22 
5.2.2 
Blood Products ....................................................................................................23 
5.2.3 
Medications that inhibit Platelet Function and Anticoagulants ...............................23 
5.2.4 
Corticosteroids and Hydroxyurea .........................................................................23 
5.2.5 
Infection Prophylaxis ...........................................................................................23 
5.2.6 
Colony Stimulating Factors ..................................................................................24 
5.2.7 
Prevention of Tumor Lysis Syndrome...................................................................24 
5.2.8 
Management of Fluid Overload (Dasatinib patients only) ......................................24 
5.2.9 
Management of Skin rash.....................................................................................24 
5.3 Definition of Dose-Limiting Toxicity...........................................................................24 
5.3.1 
Hematologic dose-limiting toxicity.......................................................................24 
5.3.2 
Non-hematologic dose-limiting toxicity ................................................................25 


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5.3.3 
Drug Specific DLTs .............................................................................................25 
5.3.4 
Non-reportable, insignificant toxicities (not defined as DLT) ................................26 
5.4 General Concomitant Medication and Supportive Care Guidelines................................26 
5.4.1 
Cytochrome P450 inducers and inhibitors .............................................................26 
5.4.2 
Gastro-intestinal -anti-emetics, anti-diarrheal agents and acid suppressive therapy 
(antacids, H2 blockers, proton pump inhibitors) ...............................................................28 
5.5 Duration of Treatment .................................................................................................29 
5.6 Duration of Follow-up .................................................................................................29 
5.7 Criteria for Removal from Study..................................................................................29 
5.8 Study Discontinuation .................................................................................................29 
6. 
DOSING DELAYS/DOSE MODIFICATIONS ...............................................................29 
6.1 
Dose Modifications for Dasatinib .............................................................................30 
6.1.1 
Dasatinib Dose Modification for Hematologic Toxicity.........................................30 
6.1.2 
Dasatinib Dose Modifications for Non - Hematologic Toxicity..............................30 
6.1.3 
Dasatinib Dose Modification for QT Prolongation ................................................30 
6.2 Dose Modifications for Sunitinib .................................................................................31 
6.2.1 
Sunitinib Dose Modifications for Hematologic Toxicity........................................31 
6.2.2 
Sunitinib Dose Modifications for Non-Hematologic Toxicity ................................31 
6.2.3 
Sunitinib Dose Modification for Cardiac Toxicity .................................................31 
6.2.4 
Sunitinib Dose Modification for Hypertension ......................................................31 
6.2.5 
Sunitinib Dose Modification for Proteinuria..........................................................32 
6.3 
Dose Modifications for Sorafenib.............................................................................32 
6.3.1 
Sorafenib Dose Modifications for Hematologic Toxicity .......................................32 
6.3.2 
Sorafenib Dose Modifications for Non-hematological Toxicity .............................32 
6.3.3 
Sorafenib Dose Modifications for Toxicity related to Hypertension .......................32 
6.3.4 
Sorafinib Dose Modifications for Hand-Foot Skin Reaction ..................................33 
6.4 
Dose Modifications of Ponatinib ..................................................................................33 
6.4.1 
Ponatinib Dose Modifications for Hematologic Toxicity .......................................33 
6.4.2 
Ponatinib Dose Modifications for Non-Hematologic Adverse Reactions ................33 
6.4.3 
Ponatinib Dose Modifications for Hepatic Toxicity ...............................................34 
6.4.4 
Ponatinib Dose Modifications for Pancreatitis and Elevation of Lipase ..................34 
6.5 
Dose Modifications of Pacritinib..................................................................................35 
6.5.1 
Pactritinib Dose Modifications for Hematologic Toxicity ......................................35 
6.5.2 
Pacritinib Dose Modifications for Non-hematologic Toxicities..............................35 
6.5.3 
Pacritinib Dose Modifications for QTc Interval Prolongations and Reduction in 


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Ejection Fraction.............................................................................................................35 
6.5.4 
Pacritinib Dose Modifications for Diarrhea ...........................................................36 
6.5 
Dose Modifications of Ruxolitinib ...............................................................................36 
6.5.1 
Dose Modifications of Ruxolitinib for Hematologic Toxicity ................................36 
6.6 
Dose Modifications of Idelalisib ..................................................................................37 
6.6.1 
Idelalisib Dose Modifications for Hematologic Toxicity........................................37 
6.6.2 
Idelalisib Dose Modifications for Non-Hematologic Adverse Reactions ................37 
7. 
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS ..............................38 
7.1 
Limited Collection of Non-Serious Adverse Events ..................................................38 
7.2 Adverse Events and Potential Risks List(s)...................................................................39 
7.2.1 
Dasatinib ............................................................... Error! Bookmark not defined. 
7.2.2 
Sunitinib................................................................ Error! Bookmark not defined. 
7.2.3 
Sorafenib ............................................................... Error! Bookmark not defined. 
7.2.4 
Ponatinib .............................................................................................................39 
7.2.5 
Pacritinib ............................................................... Error! Bookmark not defined. 
7.2.6 
Ruxolitinib ............................................................ Error! Bookmark not defined. 
7.2.7 
Idelalisib ............................................................... Error! Bookmark not defined. 
7.3 Adverse Event Characteristics .....................................................................................39 
7.3.1 
Adverse Event (AE) .............................................................................................40 
7.3.2 
Serious adverse event (SAE) ................................................................................40 
7.4 OHSU IRB Reporting of Unanticipated Problems and Adverse Events .........................41 
7.5 Central Reporting of Adverse Events for Multicenter Studies........................................41 
7.6 MedWatch Reporting ..................................................................................................41 
7.7 Sponsor or Additional Reporting Requirements ............................................................42 
7.6.1 
Reporting to ARIAD............................................................................................42 
7.6.2 
Reporting to Bayer...............................................................................................42 
7.6.3 
Reporting to BMS................................................................................................43 
7.6.4 
SAE Reporting to Incyte ......................................................................................45 
7.6.5 
Reporting to Gilead..............................................................................................46 
7.6.6 
SAE Reporting to CTI Biopharma, Inc. ................................................................48 
8. 
PHARMACEUTICAL AGENT INFORMATION ...........................................................49 
8.1 
Agent Accountability...............................................................................................49 
8.2 Study Agent(s) ............................................................................................................50 
8.2.1 
Sorafenib .............................................................................................................50 


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8.2.2 
Sunitinib..............................................................................................................51 
8.2.3 
Dasatinib .............................................................................................................51 
8.2.4 
Ponatinib .............................................................................................................52 
8.2.5 
Pacritinib .............................................................................................................53 
8.2.6 
Ruxolitinib ..........................................................................................................53 
8.2.7 
Idelalisib .............................................................................................................54 
9. 
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES..........................................54 
10. 
STUDY PROCEDURES AND SCHEDULE OF EVENTS ..........................................55 
10.1 
Screening/Baseline Visit ..........................................................................................55 
10.2 
Study Treatment ......................................................................................................55 
10.3 
Discontinuation/Replacement of Study Therapy .......................................................56 
10.4 
Subject Discontinuation ...........................................................................................56 
10.5 
Early Study Termination by the Coordinating Center ................................................57 
10.6 
Follow-up Visits ......................................................................................................57 
10.7 
Schedule of Events ..................................................................................................58 
11 
MEASUREMENT OF EFFECT ......................................................................................59 
11.1 
Definition of Response for the Primary Endpoint ......................................................59 
11.2 
Evaluation of Best Overall Response........................................................................59 
11.3 
Response criteria for AML ......................................................................................59 
11.4 
Response Criteria for ALL .......................................................................................60 
11.5 
Duration of Overall Response and Stable Disease .....................................................61 
11.5.1 
Duration of overall response .............................................................................61 
11.6 
Progression-Free Survival ........................................................................................61 
11.7 
Overall Survival (OS) ..............................................................................................61 
11.8 
Response Review ....................................................................................................61 
12 
DATA REPORTING/REGULATORY REQUIREMENTS ..............................................61 
12.1 
Data Collection and Storage.....................................................................................61 
12.2 
Multicenter Guidelines ............................................................................................62 
12.3 
Protocol Review ......................................................................................................63 
12.4 
Informed Consent ....................................................................................................63 
12.5 
Changes to Protocol.................................................................................................64 
12.6 
Maintenance of Records ..........................................................................................64 
12.7 
OHSU IRB Reporting of Unanticipated Problems and Adverse Events......................64 


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12.8 
OHSU Knight Cancer Institute Data and Safety Monitoring Plan ..............................64 
12.9 
Inclusion of Women, Minorities and Children ..........................................................64 
12.9.2 
Inclusion of Children........................................................................................66 
13 
STATISTICAL CONSIDERATIONS .............................................................................66 
13.1 
Study Design ...........................................................................................................66 
13.2 
Primary and Secondary Endpoints ............................................................................66 
13.3 
Analysis Populations ...............................................................................................66 
13.4 
Statistical Analysis Plan...........................................................................................67 
13.5 
Sample Size and Power............................................................................................67 
13.6 
Handling of Missing Data ........................................................................................67 
REFERENCES.......................................................................................................................69 
APPENDIX A: Performance Status.......................................................................................... 0 
APPENDIX B: Contraception .................................................................................................. 1 
APPENDIX C: Concomitant Therapies Affecting Kinase Inhibitors .......................................... 2 
APPENDIX D: Protocol Deviations ......................................................................................... 0 
APPENDIX E: Participant Eligibility Criteria........................................................................... 0 
 
 


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1. 
OBJECTIVES   
 
1.1 
Primary Objective 
To determine the clinical activity of kinase inhibitors using pre-clinical (in-vitro) activity to 
select individual therapy. Clinical activity will be defined as > 25% decrease in bone marrow or 
peripheral blood blast counts.  
 
1.2 
Secondary Objectives 
1. To evaluate overall objective response rates (complete response plus partial response). 
2. Determine overall survival (OS) and progression-free survival (PFS). 
 
1.3 
Exploratory/Correlative studies 
1. Prioritize active/aberrant kinase pathways using an in vitro inhibitor screen using individual primary 
leukemia samples. 
2. Measure ‘on target’ in vivo kinase inhibition and STAT-5 phosphorylation and correlate with response 
to treatment. 
3. Perform Next Generation sequencing (whole exome sequencing) for complete mutational 
analysis  
4. Identify aberrant gene expression in primary leukemia samples from study subjects. 
5. Evaluate pharmacokinetics for each individual kinase inhibitor during therapy. 
 
2.0 
BACKGROUND 
 
2.1 
Acute Leukemias 
 
2.1.1 
Relapsed/Refractory AML 
 
Currently, there is no standard treatment for relapsed/refractory leukemia and studies including 
relapsed/refractory disease are heterogeneous.  Short, relapse-free intervals, poor cytogenetics, 
advanced age at relapse, and the absence of transplant in first remission all contribute to the poor 
long term outcomes in these patients after initial induction and consolidation therapy (1).  
Further, if patients are refractory to initial therapy and/or require a second salvage therapy, 
outcomes are extremely poor.  For example, a retrospective analysis study of 594 patients with 
AML undergoing second salvage therapy with standard therapies including stem cell transplant 
reported a median survival of 1.5 months with a one-year survival of 8%.  Among those attaining 
a complete remission (CR), which was 13% of the population, the CR duration was only 7 
months. On multivariate analysis, a number of poor prognostic features were identified 
including: age > 60, initial CR duration < 12 months, and second CR duration < 6 months (2).  
Importantly, standard therapies do not appear to favorably impact patients who relapse in < 12 
months (3, 4)}.  Therefore, this is a population in need of novel treatment approaches. 
 
Based on existing data and national guidelines, the general recommended treatment paradigm for 
patients with relapsed/refractory leukemia is enrollment into clinical trials or best supportive care 
if patients have refractory disease or a remission lasting < 12 months (since the initiation of 
therapy). Conversely, patients with remissions > 12 months have significant responses with re-
induction and/or salvage chemotherapy regimens. So, although clinical trials are encouraged, 
standard treatment options may lead to favorable outcomes (5) (6). We have used this paradigm 


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as a guideline for the inclusion criteria for this trial. 
 
2.1.1.1 AML in the elderly and/or unfit 
 
Elderly patients with acute leukemia have poor outcomes and thus remain a significant 
therapeutic challenge. Although 30-40% of elderly patients with AML will achieve a CR with 
standard induction, the median survival in this population is around 10 months (7). The worst 
outcomes in this population have been attributed to high risk cytogenetics, higher rates of 
secondary leukemia, increased multi-drug resistance, decreased performance status, significant 
co-morbidities, as well as poorly defined benefits of post remission consolidation, and a high 
treatment related mortality (7-10).  To better understand why elderly patients have worse 
outcomes, a number of prognostic factors have been evaluated and prognostic scores have been 
developed that incorporate both disease related and patient related factors. Based on these 
results, older AML patients can be categorized as “fit” or “unfit” for standard induction 
chemotherapy.  For example, a patient >70 years old with poor performance status (ECOG >3) 
may have a treatment related mortality of 60-70% with standard induction. As a result, elderly 
patients are often not candidates for standard cytotoxic therapies; especially in the relapsed or 
refractory setting, and are less likely to receive chemotherapy and/or to be entered on clinical 
trials (11). In the face of these challenges it is imperative that elderly patients be treated on novel 
clinical trials. In fact, currently the NCCN treatment guidelines recommend that whenever 
possible, all AML patients should be offered clinical trial participation, especially in patients > 
age 60 with poor risk disease features or a poor performance status (i.e. ECOG > 2) (12).  
 
Progress has been seen with the use of hypomethylating agents (azacytidine, decitabine) for the 
treatment of elderly AML patients who are unfit for chemotherapy. For example, Decitabine, a 
hypomethylating agent, when used as front-line therapy in elderly patients with AML in a phase 
II trial had an ORR of 26% and CR of 24%, along with an acceptable toxicity profile (13).  In 
addition, a randomized international phase III trial (Study AZA PH GL 2003 CL 001) for higher-
risk MDS patients, comparing azacytidine to a conventional care regimen (CCR) in high-risk 
MDS, included 34% patients with RAEB-T/AML WHO, which would be considered to have a 
diagnosis of AML by current diagnostic criteria. This study demonstrated superior overall 
survival compared to CCR, with a median overall survival of 24.4 months for azacytidine vs. 15 
months for CCR, a benefit that persisted for RAEB-T/WHO AML cases. Based on these results, 
hypomethylating agents are an appropriate and frequently utilized off study therapy in unfit 
elderly patients with AML.  
 
2.1.2 
Relapsed/Refractory Acute Lymphoblastic Leukemia (ALL) 
 
Outcomes in adults with relapsed ALL are extremely poor. Two large series demonstrate the 
challenge of recurrent ALL and highlight the point that the overwhelming majority of patients 
cannot be successfully salvaged with current therapies. Of 1372 adults with ALL initially treated 
on the MRC UKALL/ECOG 2933 protocol who achieved a complete remission, 609 (44%) 
relapsed. In this series the median survival after relapse was only 24 weeks and only 7% were 
long term survivors (14). In another study of 922 adult ALL patients treated per the LALA-94 
trial as initial therapy, 421 (54%) developed relapsed disease. Although 44% of patients who 
relapsed achieved a second complete remission, the median disease free survival was only 5.2 
months and the median survival was 6.3 months. Only 12% of patients in this series had 
favorable long term outcomes, the majority of which were achieved after allogeneic stem cell 


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transplantation (15). Given these results, it is largely accepted that relapsed ALL is incurable 
with current standard chemotherapy regimens. As many of these patients will not respond to 
salvage chemotherapy and/or are not candidates for transplantation, this is another population 
also in need of novel therapeutic approaches.  
 
2.2 
Study Agents - Product Background and Mechanism of Action  
  
 
2.2.1 
Dasatinib 
 
Dasatinib (Sprycel®) is an abl/src kinase inhibitor FDA approved for the treatment of adults with 
chronic, accelerated, or myeloid or lymphoid blast phase Philadelphia chromosome-positive 
(Ph+) chronic myeloid leukemia (CML) with resistance or intolerance to prior therapy including 
imatinib, and adults with Ph+ ALL with resistance or intolerance to prior therapy.  
 
2.2.2 
Sunitinib 
 
 
Sunitinib (Sutent®) is a tyrosine kinase inhibitor that is FDA approved drug for the treatment of 
renal cell carcinoma, gastrointestinal stromal cell tumor, and pancreatic neuroendocrine tumor in 
patients with unresectable locally advanced or metastatic disease. 
 
2.2.3 
Sorafenib 
 
 
Sorafenib (Nexavar®) is a tyrosine kinase inhibitor that is FDA approved and marketed for the 
treatment of unresectable hepatocellular carcinoma, advanced renal cell carcinoma, and locally 
recurrent or metastatic, progressive, differentiated thyroid carcinoma refractory to radioactive 
iodine treatment. It has also been used in combination with chemotherapy and hypomethylating 
agents in AML but is not FDA approved for this indication. 
 
2.2.4 
Ponatinib  
 
Ponatinib (Iclusig®) is an abl/src kinase inhibitor indicated for the treatment of adult patients 
with T315I-positive CML (chronic phase, accelerated phase, or blast phase) or T315I-positive 
Ph+ ALL and treatment of adult patients with chronic phase, accelerated phase, or blast phase 
CML or Ph+ ALL for whom no other tyrosine kinase inhibitor (TKI) therapy is indicated. 
 
2.2.5 
Pacritinib  
 
Pacritinib is an oral TKI with activity against two important activating kinases in the Janus 
Associated Kinase family (Janus Associated Kinase 2 [JAK2] and FMS-like tyrosine kinase 3 
[FLT3]) that are activated in some patients with AML. The JAK family of enzymes is a central 
component in signal transduction pathways, which are critical to normal blood cell growth and 
development as well as inflammatory cytokine expression and immune responses. Activating 
JAK2 mutations are implicated in certain blood-related cancers, including myeloproliferative 
neoplasms (MPNs), leukemia, and certain solid tumors. FLT3 is a gene commonly found 
mutated in patients with acute myeloid leukemia (AML).  In AML, FLT3 mutations are the most 
frequent genetic mutations observed, and are involved in the signaling pathway of autonomous 
proliferation and differentiation block in leukemia cells. As both a JAK2 and FLT3 inhibitor, 
pacritinib provides a dual inhibitory role that may prove to be a promising therapeutic strategy. 


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10 
Pacritinib is unique among JAK inhibitors in that it also inhibits IL-1 Receptor Kinase-1 (IRAK-
1), a protein previously shown to be critical in myelodysplasia, and is also active in AML blasts 
where IL-1 is a stimulatory and survival cytokine.  Pacirtinib also inhibits colony stimulating 
factor-1 receptor (CSF-1R) kinase, which may be an important stimulant in AML cells with 
monocytoid features. 
 
2.2.6 
Ruxolitinib  
 
Ruxolitinib (INCB018424 phosphate, INC424, ruxolitinib phosphate) represents a novel and 
potent inhibitor of JAK1 and JAK2.  The inhibitory characteristics of ruxolitinib is characterized 
by a 50% inhibitory concentration (IC50) of 3.3 ± 1.2 nM for JAK1, and an IC50 of 2.8 ± 1.2 nM 
for JAK2.  This is in comparison with modest to marked selectivity against TYK2 (tyrosine 
kinase 2) (IC50=19 ± 3.2 nM) and JAK3 (IC50=428 ± 243 nM), respectively.  Ruxolitinib has 
been granted Marketing Authorization Approval in the USA (approved in November 2011) for 
the treatment of intermediate or high-risk myelofibrosis, including PMF, post–polycythemia vera 
myelofibrosis and post–essential thrombocythemia myelofibrosis.  Ruxolitinib was subsequently 
approved in December 2014 for the treatment of patients with polycythemia vera who have had 
an inadequate response to or are intolerant of hydroxyurea. 
 
2.2.7 
Idelalisib  
 
PI3Kδ is a central signaling enzyme that mediates the effects of multiple receptors and is critical 
for primary survival, proliferation, and homing signaling pathways active in malignant B-cells.  
Idelalisib (Zydelig®) is a PI3Kδ inhibitor that received accelerated approval by the US FDA for 
the treatment of patients with relapsed follicular lymphoma (FL) and Small Lymphocytic 
Lymphoma (SLL) who have received at least 2 prior systemic therapies. Idelalisib is fully 
approved to be used in combination with rituximab for the treatment of patients with relapsed 
CLL, in whom rituximab alone would be considered appropriate therapy due to other co-
morbidities.  Responses for SLL and FL were reported at 58% (0% CR) and 54% (8% CR) 
respectively with a duration of response of 11.9 months in SLL and not evaluable in FL.  In 
CLL, the hazard ratio for PFS was 0.18 (95% CI; 0.10, 0.32) compared to rituximab alone (16). 
Idelalisib as monotherapy or in combination with other agents (such as bendamustine, 
chlorambucil) and immunotherapy (rituximab, ofatumumab) is shown to be tolerable and 
demonstrated clinical efficacy in clinical trials in patients with indolent (i) non-hodgkins 
lymphoma (iNHL) and CLL(17, 18). Idelalisib has not yet been widely studied in AML; 
however, PI3K/AKT signaling is important to AML and ALL leukemogenesis (19, 20) and we 
have observed pre-clinical anti-AML activity using our in vitro assay.  
 
2.3 
Study Rationale 
 
Aberrant kinase signaling promotes leukemogenesis suggesting that kinases are potential 
therapeutic targets. However, identifying one specific molecular target in acute leukemias has 
remained elusive, suggesting that multiple kinase pathways are important and that the 
mechanism of aberrant kinase activation may be unique in many patients. Further, it is likely that 
over time, standard therapy may select for specific malignant clones that depend on altered 
kinase signaling pathways throughout the course of the disease. Thus, it is imperative that we 
elucidate which kinase signaling pathways are important in individual patients and tailor their 
therapy accordingly.    


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11 
Recent developments highlight the importance of aberrant kinase-mediated signaling pathways 
in acute leukemia. The incorporation of the bcr-abl kinase inhibitors imatinib and dasatinib to 
standard chemotherapy in Ph+ALL and FLT-3 kinase inhibition in acute AML have found to be 
effective in certain leukemia patients. In addition to showing therapeutic promise, inhibition of 
these targets provides the “proof of principle” that molecular pre-identification of activating 
kinase pathways can be translated to improved therapeutic outcomes.  
 
Understanding the mechanisms underlying leukemia pathogenesis is an ongoing challenge but is 
the first step in developing more effective therapies for individual leukemia patients. Despite 
realizing that leukemia is unique in each patient, interventional trials continue to be applied to 
populations instead of individuals. Thus, it is clear that personalized treatment approaches and 
new study designs, which utilize evolving “real-time” information/feedback to rapidly inform 
individualized treatment decisions, are needed. With this in mind, we have developed a small 
molecule kinase inhibitor screen to rapidly identify therapeutic tyrosine kinase targets in 
leukemia patients while simultaneously providing individualized therapeutic options.   
 
The next step is to translate pre-clinical findings to patient care. The ability to rapidly identify 
patient-specific, commercially available (i.e., FDA approved) oral agents is easily amenable to 
clinical application. Relapsed/refractory leukemia is an excellent model to use because: 1) 
outcomes with standard therapies are poor, 2) sample acquisition (e.g. from blood or bone 
marrow) and processing are simple and standardized which allows for easy and rapid pre-clinical 
(ex-vivo) identification of important kinase targets, 3) clinical activity can be easily monitored 
via changes in bone marrow or peripheral blast counts, and 4) in-vivo kinase target validation 
can be measured frequently and in real time. By using our pre-clinical assay to identify 
individualized leukemia therapies, we will provide an important contribution to the goal of 
applying patient-tailored kinase inhibitors to all leukemia patients.  
 
If the ex-vivo screen can predict clinical activity, we hope to use this protocol as a template for 
the rapid identification of novel kinase inhibitors for individualized leukemia therapy (alone, in 
combination, or with chemotherapy).  
 
 
2.4.1 
The Ex-Vivo Small Molecule Kinase Inhibitor Screen 
 
The kinase inhibitor screen is a function-first, ex vivo assay that can identify potentially useful 
individualized treatments for patients with leukemia. Our screen currently utilizes approximately 
130 small-molecule, cell-permeable compounds including a core of 38 tyrosine kinase inhibitors 
that collectively target the majority of the tyrosine kinome. These core inhibitors have been 
screened against 300 of the 500 kinases in the kinome to determine their target specificities (21). 
Many of the compounds in the inhibitor screen are commercially available or are in clinical 
development.  
 
For these screens, enriched mononuclear cells from patients with known or suspected acute 
leukemia are plated in 384-well plates containing small-molecule inhibitors at serial dilutions 
spanning a concentration range that includes the predicted IC50. Cell viability is measured after a 
three-day incubation. The viability data is normalized to untreated controls and the IC50 for a 
given inhibitor is compared with the median IC50 values from all leukemia samples assayed. The 
results are available within 3-4 days allowing for the patient-specific identification of kinase 
inhibitors in a clinically relevant time frame.  


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12 
 
By applying the pre-clinical assay to individualized leukemia therapy, we hope to provide an 
important contribution to the goal of applying patient-tailored kinase inhibitors to all leukemia 
patients. Crucial to developing this platform is taking the initial step of prospectively using this 
assay to pre-select which inhibitors may be effective for individual patients.  Therefore, we will 
be conducting a clinical trial in patients with relapsed/refractory leukemia who first demonstrate 
in vitro kinase inhibitor sensitivity identified using the inhibitor screen as outlined above.  
 
2.4.2 
Kinase Inhibitors in Acute Leukemia 
 
In Ph+ ALL, by targeting Bcr-Abl, the addition of kinase inhibitors to chemotherapy has 
improved outcomes. The role of kinase inhibition in other leukemias is less clear; however, an 
evolving understanding of the underlying leukemogenesis has led to an increasing number of 
targeted therapeutic approaches. For example, FMS-like tyrosine kinase 3 (FLT3), a receptor 
tyrosine kinase expressed in AML has been shown to be activated by internal tandem 
duplications (ITD) in some patients(14). This has led to the development of FLT-3 directed 
kinase inhibitors which show significant in vitro activity against FLT3-ITD, and have initially 
shown some success in clinical trials. For example, Single agent administration of the first 
generation inhibitors PKC412, in relapsed AML patient with mutated FLT3-ITD, was associated 
with clinical activity (15).  A second generation FLT3 inhibitor, AC220, with higher affinity and 
an improved pharmacokinetic profile, has been associated to a 50% response rate, including 
some CRs, in patients with relapsed AML with FLT3-ITD, demonstrating the potential of 
targeted therapy in AML (22, 23). 
 
Kinase inhibitors as single agents in treating acute leukemias have  shown activity and. Both 
dasatinib and sunitinib have been used as single agents in unselected patients with AML. 
Dasatinib yielded a complete response in 1 of 9 (11%) patients, while 6 of 15 (40%) patients 
responded to sunitinib, but in both cases responses were brief (24, 25). Likewise, sorafenib has 
shown anti-leukemic activity, with a best response of stable disease observed in 11 of 15 
patients.  Although no complete or partial responses were observed with sorafenib, bone marrow 
counts decreased in 40% of treated patients (26). Pacritinib has not yet been studied in AML; 
however, it has shown significant activity in patients with myelofibrosis (27). 
 
In vitro results using our kinase assay platform shows that approximately 70% of samples 
demonstrate strong sensitivity to one or more inhibitors, and approximately 40% of samples have 
sensitivity to at least one commercially available drug. Importantly, the results yielded from this 
platformshow a heterogeneous inhibitor sensitivity profiles even within diagnosis groups; thus 
further supporting a need for individualized targeted therapies. In adult acute leukemias, the most 
common drug identified in these screens was dasatinib, with 24% of samples showing 
sensitivity. Twenty-three percent of samples were sensitive to sunitinib, and approximately 22% 
showed a high level of sensitivity to ponatinib.  Another 12% of samples showed inhibitor 
sensitivity to sorafenib.  Notbaly, the addition of ponatinib provides treatment coverage for up to 
44% of relapsed/refractory acute leukemia patients, and in a treatment cohort of 24 patients, up 
to five may be eligible for ponatinib treatment. A nearly identical coverage was also seen in a 
smaller cohort of relapsed acute leukemia patients. To date, we have also observed a response 
rate of ~85% among 46 AML samples treated with pacritinib. 
 
Over the course of 2007-2016, we have tested ruxolitinib for sensitivity on 491 patient samples 


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13 
Figure 1. Dasatinib treatment in a patient 
with JMML  
A. Inhibitor assay results. The normalized 
IC50 values for this patient were expressed 
as percent median IC50. Dasatinib is 
predicted to be an effective inhibitor for 
this patient. 
 
B. Peripheral blood counts at the time of 
recurrence after second bone marrow 
transplant. Black bar and arrows – 
dasatinib started at 60mg/m2/day. WBC 
and monocyte counts decrease after 
initiating treatment. *the patient was 
diagnosed with a klebsiella pneumonia. 
with an AML diagnosis and on 157 patient samples with an ALL diagnosis. Approximately 7% 
(32/491) of the AML samples were sensitive to Ruxolitinib, and another ~2.5% (4/157) of the 
ALL samples were similarly sensitive.  
 
Idelalisib sensitivity was tested on 567 patient samples with an AML diagnosis and on 228 
patient samples with an ALL diagnosis (2007-2016). Approximately 13% (73 of 567) of the 
AML samples were highly sensitive to idelalisib with IC50 values less than 0.1 µM. 
Approximately 15%,or 33  of 228, of tested ALL samples were sensitive to idelalisib with IC50 
values less than 0.1 µM. 
 
We are currently working with industry partners to add other commercially available drugs and 
multi-kinase inhibitors in early clinical development. The addition of these drugs could 
collectively increase coverage to over 50% of samples.  
 
2.4.3 
Using the inhibitor kinase sensitivity assay to select treatment  
 
There are no prospective and/or published data on using the small molecule inhibitor screen to 
select which patients may benefit from specific therapies. However, one case study supports this 
treatment approach.  On a compassionate use basis (case report in preparation), a child with 
multiply relapsed juvenile myelomonocytic leukemia after multiple courses of chemotherapy and 
2 rounds of allogenic transplant,  was treated according to the results of OHSU’s in vitro assay. 
At that time, a biologic sample obtained from this patient for ex vivo drug sensitivity was 
profiled using the inhibitor panel. The inhibitor assay revealed extreme sensitivity to dasatinib 
with an IC50 100-times lower than the median dasatinib IC50 for 120 other primary leukemia 
samples (Figure 1A). Subsequent treatment with dasatinib resulted in the patient having a rapid 
decrease in WBC count to within normal range (figure 1B).  One month after starting dasatinib 
the patient presented with fevers and leukocytosis.  A repeat marrow at the time showed no overt 
evidence of disease (Figure 1C), whereas cytogenetic studies identified a persistent clonal 
population.  A blood culture at that time grew Klebsiella.  Once treatment for bacteremia was 
initiated the patient had a slow resolution of his leukocytosis. Despite his aggressive disease, the 
patient had been continuously treated with dasatinib for over four months without disease 
progression which allowed for him to receive a 3rd stem cell transplant.  
 
 


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14 
2.4 
Correlative Studies Background 
 
 
2.4.1 
Druggable Target Identification 
 
Our primary approach for target identification in leukemia patients will be a functional screening 
of the tyrosine kinase signaling using a small molecule kinase inhibitor array. Rapid 
identification of activated kinase pathways is also critical to determining the unique biologic 
markers most useful for monitoring drug effect in each patient. Critical targets are determined by 
comparing the different target specificities of effective inhibitors to identify overlapping targets. 
Any targets of ineffective inhibitors are then subtracted. Due to the large number of inhibitors 
and the complexity of analysis, we have developed computer algorithms to determine which 
kinases are most likely involved in kinase inhibitor sensitivity. When possible, activation of 
signaling pathways identified by this method will be confirmed in pre-treatment samples using 
phospho-specific flow cytometry.  
 
STAT5, MAP kinase, and PI3K/AKT pathways are frequently constitutively activated in acute 
leukemias and will be monitored with phospho-specific STAT5, p38, and AKT antibodies. Total 
phosphotyrosine levels will be monitored in all cases. Where antibodies suitable for flow 
cytometry are not available for specific targets, phosphorylation status of proteins will be 
monitored by immunoblot analysis. The activation status of biologic markers will be assessed 
immediately before therapy begins and at the two and four week time points.    
 
2.4.2 
Mechanism of Target Sensitivity - Identification of oncogenic sequence variants 
 
We will use next generation sequencing based mutation profiling to screen for known oncogenic 
mutations. The current OHSU screening panel (GeneTrails) includes primers for a large number 
of oncogenic mutations seen in acute leukemias. Samples from all patients will also be prepared 
for whole exome sequencing. Germline DNA (from a skin biopsy) will be sequenced to assess 
germline/somatic status. We will evaluate the oncogenic potential of all mutant genes identified 
using a number of different methods. Initially, we will clone and express each mutant gene in 
Ba/F3 cells. Ba/F3 cells depend on IL-3 growth factor for viability; however, expression of a 
constitutively activated tyrosine kinase renders these cells capable of growth in the absence of 
IL-3.  Activation of tyrosine kinase networks will additionally be monitored by immunoblotting 
of cell extracts with an antibody specific to phosphorylated tyrosine residues. We will also 
evaluate the capacity of mutant genes to transform other cell types using focus formation assays 
(NIH 3T3 cells) and colony formation assays in methylcellulose using primary murine 
hematopoietic cells. Some human genes do not function properly in a murine cellular setting, and 
in these cases, we will evaluate the mutant genes in the human cell lines TF-1 and UT-7, which 
are both dependent on GM-CSF in a similar manner as Ba/F3 cells require IL-3. Using these 
cells, pharmacokinetic studies will be performed to study drug concentration. 
 
2.4.3 
Identification of Aberrant Gene Expression 
 
We expect that a significant proportion of inhibitor sensitive genes will be dysregulated due to 
other mechanisms such as overexpression, mis-splicing, or translocation, which would not be 
identified by either of these genomic analysis techniques. To detect these alternative oncogenic 
abnormalities we will perform Affymetrix Exon 1.0 microarray-based gene expression analysis. 
This technique involves a microarray designed to individually identify expression levels for each 


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15 
exon of all genes in the genome. As such, this platform can be used to analyze global gene 
expression levels as well as aberrant splice variants or translocations of individual genes.  To 
analyze this data, quality control, exploratory data analysis, model-based background correction 
and quantile normalization will be performed to remove systematic sources of variation. Log-
transformed normalized intensities will be analyzed using linear models fit to the individual 
transcripts to detect alternative splicing/exon usage and modifications in transcript structure 
(methods developed by Dr. McWeeney at OHSU and her group). We will focus initial data 
analysis on genes and signaling pathways identified by functional profiling, looking for aberrant 
levels of expression of the genes in the affected signaling pathways.  
  
3 
STUDY POPULATION 
 
Inclusion/exclusion criteria need not be met for the patient to sign a screening consent. Due to 
clinical urgency and uncertainty, pathology reports including marrow blast percentage, 
diagnosis, previous treatments, comorbidities, inhibitor sensitivity profile, and other 
requirements may not be completed or cannot be known when a patient begins the screening 
process. Relevant information will be gathered and data generated to determine eligibility after 
the patient signs the screening consent.  
 
3.1 
Inclusion Criteria 
1. Participants ≥ 18 years of age with relapsed/refractory leukemia with a confirmed diagnosis 
of AML or ALL, who meet the following criteria: Both men and women of all races and 
ethnic groups will be included. 
a. Individuals aged 18-64 years with salvage* treatment failures only - defined as relapsed 
or refractory to after least 1 cycle of salvage therapy.  
*Given the clinical activity and use of hypomethylating agents in AML patients, initial 
and salvage therapy may include hypomethylating agents. 
b. Age > 65 years**:  Refractory to induction chemotherapy- defined as no response to 
^initial therapy or have relapsed after initial therapy.  
**Individuals aged ≥65 years, with CMML or myelodysplasia (MDS) that transform to 
acute leukemia while actively receiving hypomethylating agents (i.e., decitibine or 
azacytidine) will be considered induction failures and are thus eligible for this trial. For 
Ph+ ALL, initial therapy and salvage therapy may include steroids and imatinib or 
dasatinib.  
2. Primary patient samples must show in vitro kinase inhibitor sensitivity as determined by the 
OHSU functional kinase inhibitor screen. For OHSU patients, functional kinase inhibitor 
screening may be performed as part of this study or through enrollment in eIRB4422 if the 
identical FDA/CLIA approved assay is used and a result is available within 2 weeks of 
starting on study drug treatment. 
3. Patients must have normal organ function as defined below:  
a. Serum creatinine < 2.0 x institutional upper limit of normal (ULN) 
b. INR < 1.5 x institutional ULN 
c. Adequate hepatic function as defined by the following criteria: 
i. Total serum bilirubin ≤1.5 x ULN, unless due to Gilbert’s syndrome 


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16 
ii. Alanine aminotransferase (ALT) ≤2.5 × ULN 
iii. Aspartate aminotransferase (AST) ≤2.5 × ULN 
4. ECOG performance status ≤ 2 (Karnofsky ≥ 60%, see Appendix A). 
5. Discontinuation of anti-coagulants and anti-platelet drugs at least 7 days prior to start of study 
drug.  
a.  Aspirin 81 mg is permitted as long as platelet count is > 50 and there is no evidence of 
active bleeding or coagulopathy (INR > 1.5, fibrinogen > 150).  
6. No uncontrolled infections as determined by the investigator 
7. No clinically significant thyroid disease (e.g. hyperthyroid/hypothyroidism)  
8. No active GVHD: Patients with a history of stem cell transplant are eligible but cannot have 
evidence of active GVHD as determined by the investigator.  
9. Must be able to take oral medication 
10. Women of childbearing potential must have a negative serum or urine pregnancy test 
(sensitivity < 25 IU HCG/L) within 72 hours prior to the start of study drug  
11. Persons of reproductive potential must agree to use an adequate method of contraception 
throughout treatment and for at least 4 weeks after study drug is stopped. Women of 
childbearing potential and men with a sexual partner of childbearing potential must be 
advised of the importance of avoiding pregnancy during trial participation and the potential 
risk factors for an unintentional pregnancy.  
12. Ability to understand and the willingness to sign a written informed consent and HIPAA 
document. 
13. Serum Na, K, Mg, and total serum Ca or ionized Ca levels must be greater than   or equal to 
the institutional lower limit of normal.   Subjects with low K or Mg levels, total corrected 
serum Ca and/or ionized Ca must be replete for protocol entry. 
 
3.2 
Additional Drug specific inclusion criteria 
3.2.1 
Dasatinib 
1. Discontinuation of any medications known to contribute significantly to the risk of QT 
prolongation at least 48 hours prior to start of study drug. Levaquin and Zofran are an 
exception. Of note, certain agents that prolong the QTc may be allowed but only after 
discussion with the chemotherapy pharmacist. Should the investigator believe that 
therapy with a potentially QT prolonging medication is vital to an individual subject’s 
care, then additional ECGs should be done at the investigator’s discretion to ensure the 
subject’s safety.  
2. Women of childbearing potential (WOCBP) must have a negative serum or urine 
pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 
hours prior to the start of study drug. 
3. Men who are sexually active with WOCBP must agree to follow instructions for 
method(s) of contraception for the duration of treatment with study drug plus 90 days 
(duration of sperm turnover) for a total of 90 days post-treatment completion. 


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17 
4. Azoospermic males and WOCBP, who are not heterosexually active, are exempt from 
contraceptive requirements.  However, WOCBP must still under pregnancy testing as 
described in this section. 
5. Investigators shall counsel WOCBP and male subjects who are sexually active with 
WOCBP on the importance of pregnancy prevention and the implications of unexpected 
pregnancy.  Investigators shall advise WOCBP and male subjects who are sexually active 
with WOCBP on the use of highly effective contraception.  Highly effective methods of 
contraception have a failure rate of <1% when used consistently and correctly. 
6. At a minimum, subjects must agree to the use of two methods of contraception, with one 
method being highly effective and the other method being either highly effective or less 
effective as listed in Appendix B. 
3.2.2 
Sunitinib 
 
None 
 
3.2.3 
Sorafenib 
1. creatinine <1.5 X ULN 
 
3.2.4 Ponatinib  
1. Female and male patients who are fertile must agree to use an effective form of 
contraception with their sexual partners from randomization through 4 months after the 
end of treatment. 
2. Discontinuation of any medications known to contribute significantly to the risk of QT 
prolongation at least 48 hours prior to start of study drug. Levaquin and Zofran are an 
exception. Of note, certain agents that prolong the QTc may be allowed but only after 
discussion with the chemotherapy pharmacist. Should the investigator believe that 
therapy with a potentially QT prolonging medication is vital to an individual subject’s 
care, then additional ECGs should be done at the investigator’s discretion to ensure the 
subject’s safety.  
3. Serum lipase and amylase ≤1.5 × ULN 
 
3.2.5 Pacritinib 
1. Discontinuation of any medications known to contribute significantly to the risk of QT 
prolongation at least 48 hours prior to start of study drug. Levaquin and Zofran are an 
exception. Of note, certain agents that prolong the QTc may be allowed but only after 
discussion with the chemotherapy pharmacist. Should the investigator believe that 
therapy with a potentially QT prolonging medication is vital to an individual subject’s 
care, then additional ECGs should be done at the investigator’s discretion to ensure the 
subject’s safety.  
 
3.2.6 Ruxolitinib 
None 
3.2.7 Idelalisib 


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18 
None 
3.3 
Exclusion Criteria 
1. Any leukemia treatment within 1 week (for cytotoxic therapy) and/or 5 half lives (for targeted 
agents) prior to starting study drug.  Corticosteroids are allowable throughout the study to treat 
concomitant medical disorders per provider discretion. Hydroxyurea is allowed prior to 
enrollment and after the start of the study drug for the control of peripheral leukemic blasts in 
subjects with leukocytosis per physician discretion. 
2.  Recent uncontrolled angina, recent > NYHA class II congestive heart failure, or recent MI 
(within 6 months) prior to start of study treatment. 
3.  Diagnosed congenital long QT syndrome 
4. Any recent history of clinically significant ventricular arrhythmias (such as ventricular 
tachycardia, ventricular fibrillation, or Torsade’s de pointes) 
5. History of clinically significant bleeding disorder unrelated to cancer. 
6. Drugs that affect the CYP3A4 system (inducers/inhibitors/substrates) are allowed but 
should be used with caution (see appendix D) depending on   specific kinase inhibitor 
used. Dietary supplements will be discouraged; however, their use may be allowed on a 
case by case basis per the discretion of the investigator after consultation with an oncology 
pharmacist. 
7. Uncontrolled intercurrent illness that would limit compliance with study requirements.  
8. Pregnant or lactating women are excluded from this study because of possible risk to the 
fetus or infant 
9. Known HIV-positive patients are excluded from the study because of possible risk of 
lethal infection when treated with marrow suppressive therapy. 
10. History of hypersensitivity to any of the kinase inhibitors included in this study. 
 
3.4 
Additional Drug specific exclusion criteria 
3.4.1 Dasatinib 
 
 
1. Known pulmonary arterial hypertension 
2. Patients may not have a clinically significant pleural or pericardial effusion.  
3. Uncontrolled hypertension: inability to maintain blood pressure below the limit of 140/90 
mmHg. 
 
4. Any history of second or third degree heart block (may be eligible if the subject currently 
has a pacemaker) 
5. Prolonged QTc interval (>450 msec for men and >470 msec for women) on pre-entry 
electrocardiogram. 
 
3.4.2 Sunitinib 
None 


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19 
3.4.3 
Sorafenib 
1. Major surgery, open biopsy, or significant traumatic injury within 30 days. 
2. Non-healing wound, ulcer, or bone fracture. 
3. Thrombotic or embolic venous or arterial events, such as cerebrovascular accident, 
including transient ischemic attacks, arterial thrombosis, deep vein thrombosis and 
pulmonary embolism within the past 6 months. 
a. Line associated DVTs which are adequately treated (line removed and/or patient 
anticoagulated) are permitted. 
4. Uncontrolled hypertension. 
5. Active bleeding during screening. 
 
3.4.5 Ponatinib 
 
1. History of acute pancreatitis within 1 year of study or history of chronic pancreatitis. 
2. QTC >450 msec for men and > 470 msec for women. 
3. Uncontrolled hypertriglyceridemia (triglycerides >450 mg/dL). 
4. Any history of myocardial infarction, stroke, or revascularization. 
5. Any history of venous thromboembolism including deep venous thrombosis or 
pulmonary embolism. 
6. Unstable angina or transient ischemic attack within 6 months prior to start of study 
treatment. 
7. Congestive heart failure within 6 months prior to enrollment, or left ventricular ejection 
fraction (LVEF) less than lower limit of normal per local institutional standards within 6 
months prior to enrollment. 
8. History of clinically significant (as determined by the treating physician) atrial 
arrhythmia. 
9. Uncontrolled hypertension (diastolic blood pressure >90 mm Hg; systolic >140 mm 
Hg).  Patients with hypertension should be under treatment on study entry to effect blood 
pressure control. 
10. History of ongoing alcohol abuse. 
11. Ocular toxicity present as measure during a comprehensive eye exam. 
3.4.6 Pacritinib 
 
1. Major surgery, open biopsy, or significant traumatic injury within 30 days. 
2. Active bleeding during screening. 
3. QTC >450 mSec for men and > 470 msec for women. 
4. NYHA Class II Congestive Heart Failure (a history of CHF is allowed as long as this has 
resolved to < NYHA Class II within 30 days of initiation of pacritinib. 
 
3.4.7 Ruxolitinib 
1. Evidence of hepatitis B virus (HBV) or hepatitis C virus (HCV) infection or risk of 


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reactivation: HBV DNA and HCV RNA must be undetectable. Subjects cannot be 
positive for hepatitis B surface antigen (HBsAg) or anti–hepatitis B core antibody. 
Subjects who have positive anti-HBs as the only evidence of prior exposure may 
participate in the study provided that there is both 1) no known history of HBV infection, 
and 2) verified receipt of hepatitis B vaccine.  
 
3.4.8 Idelalisib 
1. Ongoing drug-induced liver injury, chronic active hepatitis C (HCV), chronic active 
hepatitis B (HBV), alcoholic liver disease, non-alcoholic steatohepatitis, primary biliary 
cirrhosis, extrahepatic obstruction caused by cholelithiasis, cirrhosis of the liver, portal 
hypertension, or history of autoimmune hepatitis. 
2. Ongoing symptomatic pneumonitis. 
3. Ongoing inflammatory bowel disease or autoimmune colitis. 
4. Ongoing CMV infection, treatment, or prophylaxis within the past 28 days prior to the 
screening test for active CMV. 
5. History of serious allergic reaction including anaphylaxis and epidermal necrolysis. 
 
4. 
REGISTRATION PROCEDURES 
 
4.1 
Subject Registration 
 
A detailed instructions for subject registration exists as a separate Study Operations 
Manual. 
This is a phase II trial with an intention to treat all patients who are enrolled in this clinical trial. 
There is no randomization for treatment. Potential subjects will be seen by study investigators 
study as new patient, consult, or follow-up visits.  Referral of potential subjects to co-
investigators of this study is made as part of standard of care, with the referring physician 
seeking advice on the diagnosis, evaluation, and/or treatment of AML or ALL. 
 
4.1.1 
Local registration 
Registrations from all consented subjects must be entered into the Knight Clinical Research 
Management System (CRMS). Registration of OHSU patients will include the minimum of the 
following: 
• 
A completed Subject Enrollment Form  
• 
A completed Eligibility Checklist signed by the investigator 
• 
Signed copies of the most recently IRB-approved, informed consent form and HIPPA 
authorization 
 
4.1.2 
Multicenter Registration  
 
The 
OHSU 
coordinating 
center 
study 
team 
will 
manage 
subject 
registration.  
Investigators at participating sites will identify eligible subjects and send screening materials 
with source documents that support eligibility to OHSU in real time and in accordance with 
study protocol.  Designated Knight clinical staff must review and verify eligibility before the 


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21 
participating site may enroll and treat its subject. The OHSU coordinating center team will verify 
completeness of documents, enter registration information into the Knight CRMS, and assign a 
study number/identifier.  The coordinating center will send an email to the participating site 
indicating whether or not the subject is eligible, verify registration, and assign a participant 
number/identifier. Treatment drug selection, review of outside materials, and initiation of 
treatment must begin within 14 days of the baseline screening marrow. If initiation of treatment 
will begin after 14 days, a new baseline marrow is required.  
 
Registration for screening will include a minimum of the following: 
• A completed Subject Enrollment Form  
• A completed Eligibility Checklist signed by the investigator 
• Signed copies of the most recently IRB-approved, informed consent form and HIPAA 
authorization 
 
 
Each site must maintain a screening log of all subjects who are approached to go on study, all 
who sign informed consents, including those who withdraw consent. The log must also 
document an explanation for exclusion due to screen failure. This log will be submitted to the 
coordinating center on a regular basis. Participating sites are required to retain, in a confidential 
manner, sufficient information on each subject so that the subject may be contacted should the 
need arise. 
Registrations from all consented subjects must be entered into the Knight Clinical Research 
Management System (CRMS). 
 
 
5. 
TREATMENT PLAN 
 
5.1 
Treatment Selection 
 
Treatment selection will be based on the results of the kinase inhibitor assay and exclusion 
criteria.  Baseline peripheral blood, bone marrow aspirate, and biopsy specimens must be taken 
within 14 days or less before initiating treatment.  The baseline marrow biopsy is required for 
evaluating marrow blasts and cellularity before treatment. Drug sensitivity may be performed on 
the baseline bone marrow aspirate or peripheral blood specimen if circulating blasts are present. 
Therapeutic response will be determined using follow up bone marrow specimens noting that, 
when applicable, peripheral blood response will also be measured. A comparison of bone 
marrow blast counts between baseline and treatment samples is used to evaluate response. 
Samples taken anytime the patient is on active study treatment are considered treatment samples. 
 
IC50 values for each kinase inhibitor will be calculated from samples and the results analyzed to 
determine if one of the study drugs meets criteria to be used for treatment.  IC50 values less than 
20% of the median IC50 value for all samples tested to date (> 500 primary leukemia samples) 
are considered “sensitive”; however, potentially effective drugs will generally have IC50 values 
far below 20% of the median IC50 for that drug. If the inhibitor screen identifies multiple 
treatment options and the patient meets the eligibility criteria for all, the “most effective drug” 
will be determined using additional sensitivity parameters including comparison with the range 
of results from other responders for each candidate drug, evaluation of best level of inhibition 
(IC75, IC90), and evaluation of additional curve fitting parameters (slope and area under the 
curve).  Patients may only receive one inhibitor at a time while on study. However, if a patient 


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22 
develops progression on one inhibitor (defined as a ≥ 50% increase in leukemic bone marrow 
blasts), he/she is eligible to re-enroll on study if, at the time of progression, another potential 
inhibitor is identified on repeat inhibitor plate testing he/she still satisfies the eligibility criteria. 
If the patient has met disease progression but is still deriving clinical benefit from the current 
study drug, hypomethylating agents may be added to the treatment regimen at the PI’s discretion.  
 
5.1.1 
Screen Failure 
 
A screen failure will occur if the patient sample shows no sensitivity to trial kinase inhibitors, the 
patient is unable to receive the selected therapy for clinical reasons, or the patient chooses not to 
receive treatment. 
 
5.1.2 
Non-OHSU Site Screening 
For non-OHSU sites, screening samples will be sent by overnight delivery to OHSU for testing 
and treatment assignment. A hematopathology report describing the review of the tested/baseline 
marrow must also forwarded to OHSU. A formal report with screening results and treatment 
assignment will be forwarded to the contributing site principal investigator for inclusion in the 
patient’s chart. 
 
5.2 
Agent Administration 
Treatment will be administered on an inpatient or outpatient basis. Reported adverse events and 
potential risks associated with dasatinib, sunitinib, sorafenib, ponatinib, pacritinib, ruxolitinib, 
and idelalisib and are described in Section 7.  Appropriate dose modifications for with dasatinib,  
sunitinib, sorafenib, ponatinib, pacritinib, idelalisib and ruxolitinib are described in Section 6.  
No investigational or commercial agents or therapies other than those described below may be 
administered with the intent to treat the subject's malignancy. 
 
 
The patient will be asked to maintain a medication diary for each dose.  The medication diary 
will be returned to clinic staff at the end of each course. In addition, returned oral medication 
will be evaluated and compared to the amount dispensed to assess compliance with regimen. 
 
5.2.1 
Supportive care or prophylactic care for Dasatinib, Sunitinib, Sorafenib, Ponatinib, 
Agent 
Premedications; 
Precautions 
Total 
Daily Dose 
Route 
Schedule 
Dasatinib 
Antacid therapy should be avoided 2 hours 
before and 2 hours after dasatinib ingestion 
140 mg 
Oral 
QD 
Sunitinib 
Take with or without food 
50 mg 
oral 
QD 
Sorafenib 
Take without food  
(at least 1 hour before or 2 hours after eating 
800 mg 
Oral 
400 mg BID 
Ponatinib 
Take with or without food  
Antacid therapy should be avoided 2 hours 
before and 2 hours after ponatinib ingestion;  
45 mg 
Oral 
QD 
Pacritinib 
Take with or without food. 
400 mg 
Oral 
200 mg BID 
Ruxolitinib 
Take with or without food.  
20 mg 
Oral 
10 mg BID 
Idelalisib 
Take with or without food 
300 mg 
Oral 
150 mg BID 


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23 
Pacritinib, Idelalisib and Ruxolitinib  
 
Supportive care will be administered per institution guidelines. It should be noted that, although 
there may be a class effect for kinase inhibition, each kinase inhibitor has a unique toxicity 
profile. 
 
5.2.2 
Blood Products 
 
All blood products are to be irradiated and leukocyte-reduced.  Also, CMV negative patients 
should receive CMV negative blood products.  Blood products will be administered per 
institutional standards as defined by the enrolling institution’s blood bank.  
 
5.2.3 
Medications that inhibit Platelet Function and Anticoagulants 
 
Caution should be exercised if patients are required to take medications that inhibit platelet 
function or anticoagulants.  Subjects enrolled in this study should not take concomitant 
medications which durably inhibit platelet function. For such medications, a wash-out period of 
7 days is required prior to starting kinase inhibitor therapy. Aspirin (up to 81 mg) is permitted as 
long as platelet count is > 50 and there is no evidence of active bleeding or coagulopathy (INR > 
1.5, fibrinogen > 150. (Agents which inhibit platelet function transiently or inhibit coagulation 
by other mechanisms are restricted). 
 
Medications which directly and durably inhibit platelet function include: 
Aspirin or aspirin-containing combinations, clopidogrel, dipyridamole, tirofiban, dipyridamole, 
epoprostenol, eptifibatide, cilostazol, abciximab, ticlopidine, cilostazol 
 
Medications which directly and durably inhibit anticoagulation include: 
Warfarin, heparin/low molecular weight heparin (LMWH) [e.g., danaparoid, dalteparin, 
tinzaparin, enoxaparin] exceptions are prophylactic doses of LMWH prophylaxis to prevent 
catheter thrombosis and DVT. Heparin and/or TPA administered for flushes of IV lines are 
permitted. 
 
5.2.4 
Corticosteroids and Hydroxyurea 
 
Corticosteroids up to and including 20 mg of prednisone (or equivalent) is allowable throughout 
the study. Doses > 20 mg prednisone (or equivalent) are NOT permitted unless cleared by the 
study PI.. 
 
Hydroxyurea is allowed prior to enrollment and after the start of the study drug for the control of 
peripheral leukemic blasts in subjects with leukocytosis per physician discretion. 
 
5.2.5 
Infection Prophylaxis 
 
The general use of prophylactic antibiotics will be used per the discretion of the treating 
physician.  Certain antibiotics may have interactions with specific kinase inhibitors and thus, this 
must be reviewed closely prior to study enrollment and again while the patient is on study. When 
necessary, dose reductions and/or prophylaxis alternatives should be made after discussions with 
the PI at the coordinating center and after reviewing with OHSU oncology pharmacy.  


Version date: 10/03/2017 
24 
 
5.2.5 
Treatment of Neutropenic Fever 
 
Follow per institutional and standard of care guidelines 
 
5.2.6 
Colony Stimulating Factors 
 
Follow per institutional and standard of care guidelines 
 
5.2.7 
Prevention of Tumor Lysis Syndrome 
 
Prophylaxis with allopurinol 300 mg po q day is recommended to prevent the rare event of 
Tumor Lysis Syndrome in patients with markedly elevated numbers of circulating malignant 
cells.  If deemed appropriate by the treating physician, rasburicase may also be use per 
investigator determination. 
 
5.2.8 
Management of Fluid Overload (Dasatinib patients only) 
 
If patients experience fluid overload which often manifest as pleural effusions, the appropriate 
measures will be taken including: 
• Chest x-ray as clinically indicated for dyspnea 
• Early initiation of diuretics as clinically indicated including furosemide and/or 
spironolactone 
• Use of steroids as clinically indicated 
• Thoracentesis as clinically indicated e.g. if symptomatic pleural effusions do not respond 
to medical management e.g. diuretics and 
steroids 
• Dose interruptions as outlined per protocol-this will depend on grade  
• 12-lead ECG and/or echocardiogram as clinically indicated 
 
5.2.9 
Management of Skin rash 
 
Some kinase inhibitors are associated with skin rash and/or hand-foot syndrome. Depending on 
severity, appropriate measures may include dose reductions and/or cessation of study drug. 
Depending on the kinase used, other supportive measures e.g. emollients, steroids etc. may be 
used per investigator judgment. 
 
5.3 
Definition of Dose-Limiting Toxicity  
 
Toxicities will be graded in severity according to the guidelines outlined in the NCI-CTCAE 
v4.03.  Dose-limiting hematologic and non-hematologic toxicities will be defined differently.  In 
order to be declared a dose-limiting toxicity, an adverse experience must be determined related 
(definitely, probably, or possibly) to study drug.  All DLTs must be reported to the coordinating 
center within 24 hours of occurrence.  Only prolonged Grade 4 hematologic toxicities and ≥ 
Grade 3 non-hematologic toxicities will be reported. It should be noted that some study drugs 
have unique toxicities and therefore some Grade 2 non-hematologic related toxicities may be 
counted as a DLT. These are outlined below: 
 
5.3.1 
Hematologic dose-limiting toxicity 


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25 
 
Any prolonged  Grade ≥4 neutropenia or thrombocytopenia lasting  14 or more days, or as 
defined by NCI CTCAE v 4.03, leukemia-specific criteria-marrow cellularity <5% on Day 28 or 
later from the start of study drug without evidence of leukemia) at least 42 days after the 
initiation of Cycle 1 therapy. Leukemia-specific grading should be used for cytopenias (based on 
percentage decrease from baseline: >75% = Grade 4)- considered by the investigator to be 
related to study drug. It should be noted that many patients with leukemia have significant 
thrombocytopenia, anemia, and neutropenia from their disease and thus, if hematologic toxicity 
is determined to be from disease (opposed to study drug toxicity) then this will not be considered 
to be a DLT.   
 
5.3.2 
Non-hematologic dose-limiting toxicity 
 
Non-hematologic DLTs will be defined as any ≥ Grade 3 non-hematologic toxicity considered 
by the investigator to be related to study drug. Certain drugs may require dose interruptions 
and/or dose reductions based on specific toxicities that may be Grade 2 as follows:  
In addition to the criteria defined above, reportable drug-specific significant DLTs that require 
dose interruption and modification are outlined below: 
 
5.3.3 
Drug Specific DLTs 
 
5.3.3.1 Dasatinib 
• QTc >480 msec for men and >500 msec for women 
 
5.3.3.2 Sunitinib 
• 
Grade ≥2 symptomatic or persistent hypertension (HTN) or diastolic BP > 110. 
 
5.3.3.3 Sorafenib 
• Grade >2 Hand-Foot Skin Toxicity. 
• Grade ≥2 symptomatic or persistent hypertension (HTN) or diastolic BP > 110. 
 
5.3.3.4 Ponatinib  
• Grade ≥2 transaminitis 
• Grade ≥2 transaminitis with concurrent Grade ≥ 2 hyperbilirubinemia 
• Grade ≥2 radiologic evidence of pancreatitis 
 
5.3.3.5 Pacritinib 
• Grade >3 Diarrhea 
• Grade >2 Dizziness 
• QTc >480 msec for men and >500 msec for women 
 
5.3.3.6 Ruxolitinib 
• 
Grade >3 or 4 hemorrhage event. 
 
5.3.3.7 Idelalisib 
• Stevens Johnson Syndrome or toxic epidermal necrolysis of any grade 
• Pneumocystis (PCP) pneumonia of any grade 


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26 
• Clinically significant (unequivocal) CMV infection of any grade 
• ≥ grade 2 diarrhea 
• ≥ grade 3 transaminitis 
• ≥ grade 2 pneumonitis 
 
5.3.4 
Non-reportable, insignificant toxicities (not defined as DLT) 
• Grade 2-3 nausea, diarrhea, dehydration, or vomiting lasting <48 hours that in the opinion 
of the investigator results from inadequate compliance with supportive care measures 
• Grade 3 acidosis or alkalosis that which responds to medical intervention by returning to 
≤ Grade 2 within 48 hours 
• Grade 2-3 elevation of liver function tests (LFTs) without associated clinical symptoms, 
lasting for ≤7 days in duration 
• Grade 2-3 elevation of amylase without associated clinical symptoms 
• Grade 
2-3 
hypocalcemia, 
hypokalemia, 
hypomagnesemia, 
hyponatremia, 
or 
hypophosphatemia and which  
responds to medical intervention  
• Grade 2 or 3 weight loss 
• Grade 2-3 infection that is controlled on antimicrobial therapy 
• Grade 2-3 fatigue lasting ≤7 days in duration 
• 
Management and dose modifications associated with the above adverse events are 
outlined in Section 6. 
 
5.4 
General Concomitant Medication and Supportive Care Guidelines 
 
5.4.1 
Cytochrome P450 inducers and inhibitors 
 
Because there is a potential for interaction of study agent(s) with other concomitantly 
administered drugs through the cytochrome P450 system, the case report form must capture the 
concurrent use of all other drugs, over-the-counter medications, or alternative therapies.  The 
principal investigator should be alerted if the subject is taking any agent known to affect or with 
the potential to affect selected CYP450 isoenzymes (Refer to Appendix C for a list of inducers 
and inhibitors). 
Supportive care with be administered per institutional guidelines.  Of note, some supportive care 
medications, for example, antibiotics and antifungals that are routinely used in the care of acute 
leukemia patients may involve the CYP3A4 metabolism as outlined below. These agents may be 
used after documented consultation with an oncology pharmacist. See also Appendix B for lists 
of medications that act on CYP and PGP substrates.  
 
Drugs that induce CYP3A4 activity may decrease kinase inhibitor plasma concentrations. In 
patients in whom CYP3A4 inducers are indicated, alternative agents with less enzyme induction 
potential should be used. Likewise exposure to a CYP3A4 inhibitor may increase exposure to 
certain kinase inhibitors. A summary of dose modifications for each respective study agent when 
administerd in combination with CYP3A4 inhibitors is shown in Table 1.  
 
Table 1. Study agent dose adjustments when used concomitantly with CYP3A4 inhibitor  
Target Dose 
Dose with Moderate 
Dose with Strong Inhibitor 


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27 
Inhibitor 
Dasatinib 
100 mg daily 
50 mg daily 
20 mg daily 
140 mg daily 
70 mg daily 
40 mg daily 
Sunitinib 
50 mg daily 
No adjustment 
37.5 mg daily 
Sorafenib 
800 mg daily 
No dose reduction 
No dose reduction 
Ponatinib  
45 mg daily 
No adjustment 
30 mg daily 
Pacritinib 
400 mg 
No dose reduction 
No dose reduction 
Ruxolitinib 
20 mg  
15 mg daily 
10 mg daily 
Idelalisib 
300 mg 
No dose reduction  
No dose reduction 
 
Dasatinib: Dasatinib is a CYP3A4 substrate. Concomitant use of dasatinib and drugs that inhibit 
CYP3A4 may increase exposure to certain kinase inhibitors. Close monitoring for toxicity and a 
dose reduction should be considered as listed in the tables below if systemic administration of a 
potent CYP3A4 inhibitor cannot be avoided. 
 
Sunitinib:  If an inducer is required for patient care sunitinib may be increased to 62.5 mg daily. 
 
Sorafenib: CYP3A4 inducers should be avoided when prescribed sorafenib.   
 
Ponatinib:  If ponatinib must be administered with a CYP3A4 inducer, a dose increase in kinase 
inhibitor should be considered.  
 
Pacritinib: No dose adjustments of pacritinib are needed when used concomitantly with 
moderate or strong CYP 3A4 inhibitors. 
 
Ruxolitinib: When possible, CYP3A4 inhibitors should be avoided as they may have effects on 
ruxolitinib levels, and alternative therapies should be sought if available.  Drugs that are weak 
inhibitors of CYP3A4 or are CYP 3A4 inducers require no dose adjustment for the starting dose 
but the investigators may choose to adjust the dose at their discretion.   
 


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For strong CYP3A4 Inhibitors or Fluconazole, ruxolitinib dose should be reduced, interrupted, or 
discontinued as recommended. Avoid use of ruxolitinib with fluconazole doses greater than 200 
mg.  
 
Idelalisib: No dose adjustments are needed. However, the following should be considered: 
Idelalisib adjustments: idelalisib is a strong CYP3A inhibitor at the registered dose of 150 mg 
twice daily, but is expected to be a moderate CYP3A inhibitor at the lower dose of 50 mg twice 
daily. The metabolite of idelalisib, GS-563117, is a competitive and time dependent inhibitor of 
CYP3A; accordingly coadministration of idelalisib 150 mg twice daily with midazolam, a probe 
CYP3A substrate, resulted in an approximately 5-fold increase in midazolam systemic exposure 
(AUC). Coadministration of CYP3A substrates with idelalisib may result in an increase in their 
systemic exposures (eg, certain antiarrhythmics, calcium channel blockers, benzodiazepines, 
HMG-CoA reductase inhibitors, phosphodiesterase-5 [PDE5] inhibitors, and warfarin).  
 
Particular caution is recommended during coadministration of idelalisib with drugs that are 
highly dependent on CYP3A for clearance and for which elevated plasma concentrations are 
associated with serious and/or life-threatening events, including narrow therapeutic index 
CYP3A substrates (eg, alfentanil, cyclosporine, sirolimus, tacrolimus, cisapride, pimozide, 
fentanyl, quinidine, ergotamine, dihydroergotamine, astemizole, terfenadine) with idelalisib.  
 
The investigator should review the prescribing information of the concomitant medication for 
guidance on coadministration with a CYP3A inhibitor. In addition, data suggest that when 
idelalisib is administered with potent inducers of CYP3A (such as rifampin) that idelalisib 
exposure is significantly reduced. As such, potent inducers or inhibitors of CYP3A should be 
avoided. However, no specific dose modifications are recommended for moderate or strong 
inhibitors and agents undergoing CYP3A may be allowed after consultation with the oncology 
pharmacist. 
 
Dose adjustments are based on estimates with inhibitors or inducers of similar strength. Doses 
may be increased or decreased based upon individual patient tolerance. Subjects should be 
advised not to consume substantial quantities of grapefruit juice and other citrus products should 
be approved by the treatment team prior to use. 
 
5.4.2 
Gastro-intestinal -anti-emetics, anti-diarrheal agents and acid suppressive therapy 
(antacids, H2 blockers, proton pump inhibitors) 
 
Study participants may receive anti-emetic therapy as needed during their treatment which may 
include ondansteron, prochlorperazine, haloperidol and lorazepam.  Some kinase inhibitors have 
been associated with diarrhea and patients will be administered anti-diarrheals per investigator’s 
discretion. First line agents include loperamide.  
 
Nonclinical data demonstrates that the solubility of certain kinase inhibitors are pH dependent. 
H2 blockers or proton pump inhibitors will be avoided if possible in subjects receiving dasatinib, 
or ponatinib.  The use of antacids should be considered in place of H2 blockers or proton pump 
inhibitors in patients receiving kinase inhibitor therapy. However, if antacid therapy is needed, 
simultaneous administration should be avoided and the antacid dose should be administered 2 
hours after the dose of inhibitor. Sorafenib, sunitinib, ruxolitinib and idelalisib may be taken 
without regard to the above acid reducing agents. 


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29 
 
5.5 
Duration of Treatment 
 
Treatment will continue uninterrupted for a minimum of one treatment cycle (28 days), until 
treatment is approved for this indication or until one of the following criteria applies: 
• Disease progression (defined as a ≥ 50% increase in leukemic bone marrow blasts) 
• Intercurrent illness that prevents further administration of treatment 
• Unacceptable adverse events(s) 
• Subject decides to withdraw from the study 
• General or specific changes in the subject's condition render the subject unacceptable for 
further treatment in the judgment of the investigator 
• For any reason, at the Sponsor or Investigator’s discretion 
 
5.6 
Duration of Follow-up 
 
All patients enrolled in the trial, regardless of the number of cycles completed, will be followed 
for disease progression and survival status. Subject will be followed by review of the medical 
record until death. Subjects removed from study for unacceptable adverse event(s) will be 
followed until death. If a subject withdraws consent for further treatment, the subject’s 
willingness to continue in the follow-up phase of the study will be determined. 
 
5.7 
Criteria for Removal from Study 
 
Subjects will be removed from study when any of the criteria listed in Section 10.4 applies. The 
reason for study removal and the date the subject was removed must be documented in the Case 
Report Form. 
 
5.8 
Study Discontinuation 
 
This study may be temporarily suspended or prematurely terminated if there is sufficient 
reasonable cause.  Reasons for terminating the study may include the following: 
• 
Toxicity 
• 
Incomplete or inaccurate data recording 
• 
Lack of adherence to the protocol or applicable regulatory guidelines in the conduct of 
the study 
 
6. 
DOSING DELAYS/DOSE MODIFICATIONS 
 
Because this study is designed to test the screening assay’s ability to predict effective therapies, 
dose delays and modifications are limited. Study drugs should be maintained at their highest 
doses to maximize the potential for a treatment effect.  However,  a study drug may be held for 
up to 5 days after which study drug will be restarted for a full 28 day cycle. If holding drug, the 
investigator should assess AEs daily to determine if subject is appropriate for re-initiation of 
treatment. If a treatment delay is longer than 5 days the subject will be removed from the study. 
At that point, if appropriate, they may be rescreened.  
 
Study drug should be held for a maximum duration of 5 days in the presence of a DLT (defined 
in section 5.3): 


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30 
• 
Grade ≥ 3 drug-related non-hematologic toxicity except for the exceptions listed above 
and prolonged Grade ≥ 4 hematologic toxicity until the toxicity resolves or returns to 
Grade 1 for non-hematologic toxicity, 
• 
Grade 2 for hematologic toxicity, or back to baseline.  
 
If the toxicity does not resolve after holding drug for up to 5 days then the subject will be 
removed from the study. In the event of such toxicity, study drug will be re-administered at 
lower dose levels noting that dose reductions will only be performed for non-hematologic 
toxicity. Dose interruption and/or dose reduction will vary depending on the drug and the 
toxicity. This schema is outlined for each specific drug in section 6.1. Interruption and/or dose 
reduction of study drug(s) should be assessed on a case by case basis based on the study drug’s 
probable causality of the toxicity. The coordinating center must be notified regarding any dose 
interruption or dose reduction within 24 hours of occurrence. 
 
As noted above, during dose interruptions, hydroxyurea (HU) or corticosteroids (prednisone > 20 
mg) may be used per the discretion of the treating physician. However, HU must be discontinued 
at re-initiation of study treatment. 
 
For hematologic toxicity, the use of hematopoietic growth factors, such as granulocyte colony-stimulating factor and 
granulocyte-macrophage colony-stimulating factor, is permitted on study; these agents may be used to support blood 
counts as clinically indicated to minimize treatment interruptions.  
 
6.1 
Dose Modifications for Dasatinib 
 
6.1.1 
Dasatinib Dose Modification for Hematologic Toxicity 
 
 
No dose reductions are to be performed as patients are expected to have pancytopenia requiring 
transfusions. The exception is drug related toxicity that satisfy the DLT criteria as defined in 
section 5.3. 
 
6.1.2 
Dasatinib Dose Modifications for Non - Hematologic Toxicity 
 
Grade 
Dose Modification 
1  
No dose modification 
 
3 
 
 
Stop dasatinib hold up to 5 days 
When AE returns to < grade 1 or baseline, resume dasatinib at 100 mg QD. If after 7 days, no 
additional toxicity is seen, increase to 140 mg QD (original dose). 
If toxicity recurs, then dasatinib should be dose reduced to 100 mg QD and the subject should be 
continued on this dose for the duration of the study. If the AE recurs despite dose reduction, then the 
patient should be taken off study. 
Grade 4 
Stop Dasatinib, hold up to 5 days 
When AE returns to < grade 1 or baseline, resume dasatinib at 100 mg QD. Subject will continue at 
this dose for the duration of the study 
If AE recurs, remove subject from study 
 
6.1.3 
Dasatinib Dose Modification for QT Prolongation 
 
If QTc > 480 msec for men or > 500 msec for women: 
1. Stop dasatinib for up to 5 days 


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31 
2. Perform an analysis of serum electrolytes (including potassium and magnesium) and correct 
to WNL if required. 
3. Review concomitant medications for drug interactions 
4. Resume dasatinib at prior dose if QTc returns to < 450 msec for men and < 470 for women 
and to within 20 msec of baseline. 
5. If QTc is between 450 msec and 480 msec for men or between 470 msec and 500 msec for 
women after 7 days reduce the dose to 100 mg daily 
6. If following dose-reduction, the QTc returns to >480 msec for men or > 500 msec for 
women, dasatinib should be discontinued 
7. An ECG should be repeated 7 days after any dose adjustment. 
 
6.2 
Dose Modifications for Sunitinib  
 
6.2.1 
Sunitinib Dose Modifications for Hematologic Toxicity  
 
No dose reductions are to be performed as patients are expected to have pancytopenia requiring 
transfusions. The exception is drug related toxicity that satisfy the hematologic DLT criteria as 
defined in section 5.3. 
 
6.2.2 
Sunitinib Dose Modifications for Non-Hematologic Toxicity 
 
6.2.3 
Sunitinib Dose Modification for Cardiac Toxicity 
1. For Grade 3 systolic (LV) dysfunction hold sunitinib for up to 5 days. 
2. If toxicity resolves to < Grade 3, restart sunitinib at 37.5 mg once daily.  
3. If no recurrence of cardiac toxicity after 7 days, increase to 50 mg once daily. If no toxicity is 
seen, subject should be maintained at this dose. 
4. If toxicity recurs at 50 mg dose, hold sunitinib up to 5 days and if toxicity resolves to < grade 
3, restart sunitinib at 37.5 mg daily and maintain this dose for the remainder of the study. 
5. If toxicity recurs at 37.5 mg at any time on the study, discontinue sunitinib and remove 
patient from the study. 
 
6.2.4 
Sunitinib Dose Modification for Hypertension  
 
Grade (CTCAE v4.0) 
Antihypertensive Therapy 
Blood Pressure 
Monitoring 
Sunitinib Dose 
Grade 2 (symptomatic) 
Initiate monotherapy (suggest 
dihydropyridine calcium-
channel blocker) 
Increase frequency and 
monitor (by health 
professional) every 2 days 
until stabilized 
No change 
Grade 
Dose Modification 
1 or 2 
No dose modification 
 
3 -4 
 
 
 
Stop sunitinib 
Can hold up to 5 days 
When AE returns to < grade 1 or baseline, resume sunitinib at dose -1 (37.5 mg QD]).  If 
tolerated for 7 days, dose can be increased to original dose (50 mg QD).  If toxicity recurs at this 
dose, dose will be reduced to 37.5 mg QD and patient will continue on this dose for the duration 
of the study.  
If toxicity recurs after dose reduction, patient will be removed from the study 


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Grade 2 (symptomatic/ 
persistent) 
OR 
Diastolic BP > 110 mm Hg 
OR 
Grade 3 
Add agent(s):  
Ca++ channel blocker (if not 
already used), K+ channel 
opener (angiotensin blockers), 
beta-blocker, thiazide diuretic 
 
Increase frequency and 
monitor every 2 days until 
stabilized; continue every 
other day monitoring to 
stabilization after dosing 
restarted. 
Hold* sunitinib for up to 5 
days until symptoms resolve 
and/or diastolic BP < 100 
mm/Hg. 
Resume sunitinib treatment at 
37.5 mg daily. If tolerated for 
7 days (no > grade 2 HTN), 
increase to original/starting 
dose. If recurs at original dose 
despite anti-HTN agents, 
remove from protocol 
Grade 4 
 
 
Discontinue sunitinib 
 
6.2.5 
Sunitinib Dose Modification for Proteinuria 
1. For Grade 3 proteinuria, interrupt sunitinib treatment for up to 5 days. 
2. If proteinuria resolves to < Grade 3, restart sunitinib at 37.5 mg daily.  
3. If toxicity recurs at 50 mg daily, interrupt sunitinib treatment for up to 75days and if 
proteinuria resolves to < Grade 3, restart sunitinib at 37.5 mg daily. 
4. If toxicity recurs at 37.5 mg, stop sunitinib and remove from the study. 
 
6.3 
Dose Modifications for Sorafenib 
 
6.3.1 
Sorafenib Dose Modifications for Hematologic Toxicity  
 
No specific dose reductions are to be performed as patients are expected to have pancytopenia 
requiring transfusions. The exception is drug related toxicity that satisfy the hematologic DLT 
criteria as defined in section 5.3. 
 
6.3.2 
Sorafenib Dose Modifications for Non-hematological Toxicity 
 
Toxicity 
Grade 1 
Grade 2 
Grade 3* 
Grade 4* 
Non-
hematologic 
Note: Specific 
dose 
modifications 
for hypertension 
and hand-foot 
skin reactions 
Continue at the 
same dose level. 
Continue at the 
same dose level. 
Withhold dose for up to 5 
days until toxicity is grade 
<1, then resume treatment 
at a reduced dose of 400 
mg p.o. qd. If patient 
tolerates this dose for 7 
days, he/she can receive 
the original treatment 
dose (400 mg BID). If the 
subject experiences 
another toxicity despite 
dose reduction (400 mg 
QD), he/she will be 
removed from the study.  
Withhold dose 
until toxicity is 
grade <1, then 
reduce dose to 400 
mg qd and resume 
treatment, or 
discontinue at the 
discretion of the 
principal 
investigator. 
 
6.3.3 
Sorafenib Dose Modifications for Toxicity related to Hypertension 
 
Hypertension is a known and potentially serious adverse event associated with Sorafenib 
treatment. Dose modifications are based on average daily blood pressure. Only grade 3 
hypertension will be captured for study purposes.   
 


Version date: 10/03/2017 
33 
Grade 
Antihypertensive 
       Therapy 
Blood Pressure  
Monitoring 
Sorafenib Dose 
Grade 1 
None 
Routine 
No change 
Grade 2 
(asymptomatic) 
Initiate 
monotherapy 
(suggest 
dihydropyridine 
calcium-channel 
blocker) 
Increase frequency 
and monitor  
No change 
Grade 2 
(symptomatic/ 
persistent) 
OR 
Diastolic BP > 110 
mm Hg 
OR 
Grade 3 
Add agent(s):  
Ca++ channel 
blocker (if not 
already used), K+ 
channel opener 
(angiotensin 
blockers), beta-
blocker, thiazide 
diuretic 
 
Continue inpatient 
monitoring per 
ward guidelines 
Hold* Sorafenib for up to 5 days until 
symptoms resolve and diastolic BP < 100 
mm/Hg. 
Restart at 400 mg daily. If tolerated for 7 
days (no > grade 2 HTN), increase to 
original/starting dose  (800 mg BID). If this 
recurs at original dose, decrease to or 400 
mg QD. If toxicity recurs, then patient will 
stay on the reduced dose (400 mg QD) for 
the duration of the study. If the toxicity 
recurs on the lower dose (400 mg QD) 
despite anti-HTN agents, remove from 
protocol 
 
6.3.4 
Sorafinib Dose Modifications for Hand-Foot Skin Reaction 
 
If Grade 2 or 3: 
1. Decrease sorafenib to 400 mg daily  
2. If toxicity does not return to grade 0-1 despite dose reduction, interrupt sorafenib treatment for 
up to 5 days, until toxicity has resolved to grade 0–1 
3. If no further toxicity is seen after 5 days can restart, if toxicity is maintained at Gr. 0-1 for 
another 7 days can increase dose again to full dose.  
4. If toxicity recurs, stop sorafenib and remove subject from study.  
 
6.4 
Dose Modifications of Ponatinib 
 
6.4.1 
Ponatinib Dose Modifications for Hematologic Toxicity 
 
No dose reductions are to be performed as patients are expected to have pancytopenia requiring 
transfusions. The exception is drug related toxicity that satisfy the DLT criteria as defined in 
section 5.3. 
 
6.4.2 
Ponatinib Dose Modifications for Non-Hematologic Adverse Reactions 
 
If a serious non-hematologic adverse reaction occurs, modify the dose or interrupt treatment. Do 
not restart ponatinib in patients with arterial or venous occlusive reactions unless the potential 
benefit outweighs the risk of recurrent arterial or venous occlusions and the patient has no other 
treatment options. For serious reactions other than arterial or venous occlusion, do not restart 
ponatinib until the serious event has resolved or the potential benefit of resuming therapy is 
judged to outweigh the risk. These scenarios are outlined below.  
 
 


Version date: 10/03/2017 
34 
Grade 1 or transient Grade 2 
No intervention 
Grade 2 lasting ≥7 days with optimal 
care (except hepatic toxicity and 
pancreatitis recommendations described 
in the tables below) 
Hold ponatinib for up to 5 days; Resume at 45 mg after recovery to ≤ 
grade 1 
Recurrence at 45 mg: 
Hold ponatinib for up to 5 days; Resume at 30 mg after recovery to ≤ 
grade 1 
Grade 3 or 4 
Hold ponatinib for up to 5 days; When AE returns to < grade 1 or 
baseline, resume at 30 mg after recovery to ≤ grade 1.  
If toxicity recurs, then ponatinib should be dose reduced to 30 mg QD 
and the subject should be continued on this dose for the duration of the 
study. If the AE recurs despite dose reduction, then the patient should 
be taken off study. 
 
 
6.4.3 
Ponatinib Dose Modifications for Hepatic Toxicity 
 
Elevation of liver transaminase > 3x 
ULN* (Grade 2 or higher) 
Occurrence at 45 mg: 
Interrupt ponatinib for up to 5 days and monitor hepatic function 
Resume ponatinib at 30 mg after recovery to ≤ Grade 1 (< 3 × ULN) 
Resume ponatinib at 30 mg after recovery to ≤ Grade 1 (< 3 × ULN). 
Continue on this dose for the remainder of the study. 
If toxicity recurs at 30 mg: Remove from study 
Elevation of AST or ALT ≥ 3 x 
ULN concurrent with a Grade 2 
elevation of bilirubin> 2 x ULN and 
alkaline phosphatase < 2 x ULN 
Discontinue ponatinib 
  *ULN = Upper Limit of Normal for the lab 
 
 
6.4.4 
Ponatinib Dose Modifications for Pancreatitis and Elevation of Lipase 
 
Asymptomatic Grade 3 or 4 
elevation of lipase (> 2 x ULN*) or 
asymptomatic radiologic 
pancreatitis (Grade 2 pancreatitis) 
Interrupt Ponatinib for up to 5 days and resume at 30 mg after recovery to 
≤ Grade 1 (< 1.5 x ULN) 
Occurrence at 30 mg: 
Discontinue ponatinib, remove from study 
 
Symptomatic Grade 3 pancreatitis 
Occurrence at 45 mg: 
Interrupt ponatinib for up to 5 days and resume at 30 mg after complete 
resolution of symptoms and after recovery of lipase elevation to ≤ Grade 1 
If toxicity does not occur after 7 days of treatment at this dose, restart 
ponatinib at 45 mg once daily. If toxicity recurs, interrupt drug for up to 7 
days.   
Resume ponatinib at 30 mg after recovery to ≤ Grade 1 (< 3 × ULN). 
Continue on this dose for the remainder of the study. 
Occurrence at 30 mg: 
Discontinue ponatinib, remove from study 


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35 
Grade 4 symptomatic pancreatitis 
Discontinue ponatinib and remove from study 
 
6.5 
Dose Modifications of Pacritinib 
 
In addition to drug related toxicity that satisfy the DLT criteria as defined in section 5.3, specific 
dose adjustments/interruptions may be warranted. Available doses for this study are 200 mg BID 
(starting dose) and 200 mg QD ( dose level -1). No further dose reductions will be allowed. 
 
6.5.1 
Pactritinib Dose Modifications for Hematologic Toxicity 
 
In addition to drug related toxicity that satisfy the DLT criteria as defined in section 5.3, specific 
dose adjustments/interruptions may be warranted. 
 
Treatment Toxicity and Dosage Management: Hematologic Toxicities and Related Complications 
CTCAE Toxicity 
Grade 
Management/Action 
Grade 4 hemorrhage 
(life-threatening 
consequences; urgent 
intervention 
indicated) 
Discontinue pacritinib permanently 
 
6.5.2 
Pacritinib Dose Modifications for Non-hematologic Toxicities 
 
Event 
Grade 
Management/action 
Any non-hematologic 
event that was related 
to the study drug 
1 or 2 
No change 
3 
Hold treatment. Treatment may resume if toxicity is resolved to 
grade ≤1 or returned to baseline. Starting dose may be at the same 
level if the toxicity resolves within 7 days or decreased by 25% 
daily at the discretion of the investigator after discussion with the 
sponsor. Toxicity lasting >7 days requires doses reduction by ≥25% 
daily at the discretion of the investigator after discussion with the 
sponsor. Dose reductions were accomplished using available 
strengths of the study drug, rounding down if necessary.  
4 
Hold treatment. Treatment may resume if toxicity is resolved to 
grade ≤1 or returned to baseline at the discretion of the investigator 
after discussion with the sponsor. A 25% daily dose decrease is 
required at treatment resumption. Dose reductions were 
accomplished using available strengths of the study drug, rounding 
down if necessary. 
 
 
6.5.3 
Pacritinib Dose Modifications for QTc Interval Prolongations and Reduction in Ejection 
Fraction 
 


Version date: 10/03/2017 
36 
 Treatment Toxicity and Dosage Management: QTc Interval Prolongation and  
Reduction in Ejection Fraction 
CTCAE Toxicity 
Grade 
Management/Action 
1 
No change. 
2 (first occurrence) 
 
Hold treatment for up to 5 days. If toxicity resolves to grade ≤1 within 5 days, 
treatment may be resumed at the same level or the next lower dosage (200 mg 
QD).   
 
Toxicity that does not resolve to grade ≤1 within 5 days requires treatment 
discontinuation. 
2 (second occurrence) 
Discontinue treatment.   
3 and 4 
Discontinue treatment.   
 
Discontinue treatment with pacritinib for all other grade 4 cardiac toxicities. 
 
6.5.4 
Pacritinib Dose Modifications for Diarrhea 
 
Treatment Toxicity and Dosage Management: Diarrhea 
CTCAE Toxicity 
Grade 
Management/Action 
1 or 2 
No change. 
3 
 
Hold treatment.   
 
If the toxicity resolves to grade ≤1 or to the baseline grade within 5 days, 
treatment may be resumed at the same level or the next lower dosage (200 mg 
QD).   
o If the toxicity recurs after restart at the same dosage level, treatment 
may only be resumed at the next lower dosage level (200 mg). 
o If the toxicity resolves to grade ≤1 or to the baseline grade after 
more than 5 days, treatment may be resumed only at the next lower 
dosage level (200 mg QD).   
o If the toxicity recurs after restart at the lower dosage level (00 mg 
QD), pacritinib treatment must be discontinued. 
4 
 
Hold treatment.   
 
If the toxicity resolves to grade ≤1 or to the baseline grade within 5 days, 
treatment may be resumed, but dosage will be reduced by 1 dosage level (200 mg 
QD) from the level at which the toxicity was observed.   
 
6.5 
Dose Modifications of Ruxolitinib 
 
6.5.1 
Dose Modifications of Ruxolitinib for Hematologic Toxicity 
 
No dose reductions are to be performed as patients are expected to have pancytopenia requiring 
transfusions.  In addition to drug related toxicity that satisfy the DLT criteria as defined in 
section 5.3, specific dose adjustments/interruptions may be warranted. 
 
6.5.2 
Dose Modifications for Non-Hematologic Adverse Reactions 
 
The following dose adjustments will be made for patients with a GFR < 60. 
 
• 
CrCl 15 to 59 mL/minute, 5 mg PO BID 
 


Version date: 10/03/2017 
37 
Toxicity 
Maximum Dose When Restarting Ruxolitinib 
Treatment 
Ongoing (lasting > 24 hours) Grade 3 
or higher hemorrhage event. 
First occurrence: hold for up to 5 days until Grade 1 or 
baseline and resume at 15 mg twice daily 
 
Second occurrence:  hold for up to 5 days until Grade 1 
or baseline and resume at 10 mg twice daily 
 
There are no additional ruxolitinib specific drug interruption/hold criteria for non-hematologic 
toxicity. The exception is drug related toxicity that satisfy the DLT criteria as defined in section 
5.3. 
 
6.6 
Dose Modifications of Idelalisib 
 
6.6.1 Idelalisib Dose Modifications for Hematologic Toxicity 
 
No dose reductions are to be performed as patients are expected to have pancytopenia requiring 
transfusions. The exception is drug related neutropenia. 
 
6.6.2 Idelalisib Dose Modifications for Non-Hematologic Adverse Reactions 
 
Stevens-Johnson 
Syndrome/Toxic Epidermal 
Necrolysis (any grade) 
Discontinue idelalisib. Interrupt any co-administered medications 
potentially associated with SJS or TEN. 
 
Institute systemic immunosuppression per institutional standards. 
Bowel perforation 
Discontinue idelalisib. 
Diarrhea  
 
For Grade 2, withhold idelalisib up to 5 days until Grade ≤ 1. 
Provide anti-diarrheal (e.g., loperamide). Resume idelalisib at 
previous dose level. If rechallenge results in recurrence, resume at 
lower dose level (100 mg po BID). Consider addition of anti-
inflammatory (e.g., sulfasalazine, budesonide). If toxicity persists or 
recurs following dose reduction discontinue idelalisib.  
 
For Grade 3 or 4, Withhold study drug for up to 5 days.  Rule out 
infectious etiology including CMV. Consider anti-diarrheal 
(e.g., loperamide) and/or addition of anti-inflammatory agent (e.g., 
sulfasalazine, budesonide). At Grade ≤1, may resume at lower dose 
level (100 mg po BID) or discontinue study drug at investigator 
discretion. 
 
If toxicity persists or recurs following a dose reduction permanently 
discontinue idelalisib per provider discretion.  
Pneumonitis 
For Grade 3 or higher, withhold study drug up and discontinue 
permanently. Institute systemic corticosteroids. 


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38 
Pneumocystis pneumonia (any 
grade) 
Discontinue idelalisib. 
Unequivocal CMV infection (any 
grade) 
Discontinue idelalisib and undergo effective antiviral treatment 
according to established clinical guidelines. 
Transaminase elevations (Grade 
3 or 4) 
Grade 3 or 4 elevations can be managed by temporarily withholding 
idelalisib (up to 5 days). 
 
7. 
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS 
 
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial. The 
following list of AEs (Section 7.1) and the characteristics of an observed AE (Section 7.2) will 
determine whether the event requires expedited reporting. Any grade 3 toxicities or higher will 
be tracked as outlined in the table below. 
 
7.1 
Limited Collection of Non-Serious Adverse Events 
 
Many AEs are expected during induction chemotherapy with high rates especially of 
hematologic and infectious complications and so a limited number of AE will be collected for 
this trial.  The chart below shows which AEs will be collected and tracked.  The principal 
investigator will be responsible for determining the expectedness/relationship of the AE to the 
study drug as appropriate for grade 3/4 AEs.  AE collection will begin on the first day of the start 
of the induction chemotherapy and continue until 30 days post last dose of study drug.   
 
ADVERSE EVENT TRACKING REQUIREMENTS 
Grade of adverse 
Event 
Unexpected in 
Induction 
Setting 
Expected in 
Induction setting 
Unrelated to study 
drugs 
Related to Study Drugs 
Grade 1 
Not tracked 
Not tracked 
Not tracked 
Not tracked  
Grade 2 
Not tracked 
Not Tracked 
Not tracked 
Not tracked 
Grade 3 
Tracked and 
reportable 
Tracked and 
reportable 
Tracked and 
reportable 
Tracked and reportable  
Grade 4 
Tracked and 
reportable 
Tracked and 
reportable 
Tracked and 
reportable 
Tracked and reportable  
Grade 5 
Tracked and 
reportable 
Tracked and 
reportable 
Tracked and 
reportable 
Tracked and reportable  
Serious Adverse 
Events 
Tracked and 
reported 
Tracked and 
reported 
Tracked and 
reported 
Tracked and reported 
Note: would track adverse events that would lead to dose reductions including cardiac toxicities, 


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39 
hypertension, pancreatitis, LFT elevation and QTc prolongation as well as hand-skin foot rash 
 
7.2 
Adverse Events and Potential Risks List(s)  
Complete details are available in the prescribing information for each drug used in this study. 
Pacritinib details are available in the Investigator’s Brochure. 
 
 Adverse Events of Special Interest (AESIs) are listed below.  
 
7.2.1 
Ponatinib 
 
Adverse Events of Special Interest (AESIs): Vascular occlusive events have been identified as 
AESIs for ponatinib.  These include arterial and venous thrombotic and occlusive adverse events 
that meet the criteria for SAEs (cross-refer to the section where the serious criteria are described 
and defined) and those adverse events that do not meet the SAE criteria. 
 
AESIs require ongoing monitoring by investigators and rapid identification and communication 
by the investigator to the study sponsor.  All AESIs, whether SAEs or not, must be reported 
within 2 business days of the study sponsor awareness to ARIAD.  ARIAD has determined that 
the events listed below (whether considered serious or non-serious by investigators) should be 
considered AESIs:  
• 
Myocardial infarction: The Third Universal Definition of Myocardial Infarction (28) is 
used to define MI  
• 
Angina (newly diagnosed or worsening of existing angina or unstable angina) 
• 
Coronary artery disease (CAD) (newly diagnosed or worsening of existing CAD) or 
symptoms that may reflect cardiovascular disease (28) 
• 
Cerebrovascular ischemic disease including ischemic or hemorrhagic stroke, vascular 
stenosis, transient ischemic accident (TIA), cerebrovascular occlusive disease documented on 
diagnostic neuroimaging, or symptoms that may reflect cerebrovascular disease(29)   
• 
New onset or worsening of peripheral artery occlusive disease (e.g., renal artery, 
mesenteric artery, femoral artery) or symptoms that may reflect peripheral vascular disease  
• 
Retinal vascular thrombosis, both venous and arterial  
• 
Venous thromboembolism where significant compromise of organ function or other 
significant consequences could result (e.g., pulmonary embolism, portal vein thrombosis, 
renal vein thrombosis) or symptoms that may reflect venous thrombosis 
 
 
7.2 
Adverse Event Characteristics  
 
CTCAE term (AE description) and grade:  The descriptions and grading scales found in the 
revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be 
utilized for AE reporting.  All appropriate treatment areas should have access to a copy of the 
CTCAE version 4.0.  A copy of the CTCAE version 4.0 can be downloaded from the CTEP web 
site: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.   
 


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40 
Expectedness: Adverse Events can be ‘Unexpected’ or ‘Expected’ (see Section 7.1 above for 
expected AEs) based on available safety data. Define any events of interest that may require 
special reporting. 
 
Attribution of the AE: 
• Definite – the AE is clearly related to the study treatment. 
• Possible – the AE may be related to the study treatment. 
• Unrelated – the AE is clearly NOT related to the study treatment. 
 
7.3.1 
Adverse Event (AE) 
 
An adverse event (AE) is any undesirable sign, symptom or medical condition or experience that 
develops or worsens in severity after starting the first dose of study treatment or any procedure 
specified in the protocol, even if the event is not considered to be related to the study. Abnormal 
laboratory values or diagnostic test results constitute adverse events only if they induce clinical 
signs or symptoms or require treatment or further diagnostic tests.  
 
7.3.2 
Serious adverse event (SAE) 
A serious adverse event (SAE) is any adverse event, occurring at any dose and regardless of 
causality that:  
• Results in death 
• Is life-threatening. Life-threatening means that the person was at immediate risk of death 
from the reaction as it occurred, i.e., it does not include a reaction which hypothetically 
might have caused death had it occurred in a more severe form. 
• Requires or prolongs inpatient hospitalization (i.e., the event required at least a 24-hour 
hospitalization or prolonged a hospitalization beyond the expected length of stay). 
Hospitalization admissions and/or surgical operations scheduled to occur during the study 
period, but planned prior to study entry are not considered SAEs if the illness or disease 
existed before the person was enrolled in the trial, provided that it did not deteriorate in an 
unexpected manner during the trial (e.g., surgery performed earlier than planned). 
• Results in persistent or significant disability/incapacity. Disability is defined as a substantial 
disruption of a person’s ability to conduct normal life functions. 
• Is a congenital anomaly or birth defect; or 
• Is an important medical event when, based upon appropriate medical judgment, it may 
jeopardize the participant and require medical or surgical intervention to prevent one of the 
outcomes listed above. Examples of such medical events include allergic bronchospasm 
requiring intensive treatment in an emergency room or at home; blood dyscrasias or 
convulsions that do not result in inpatient hospitalization, or the development of drug 
dependency or drug abuse. 
• 
Events not considered to be serious adverse events are hospitalizations for: 
• Routine treatment or monitoring of the studied indication not associated with any 
deterioration in condition, or for elective procedures. 
• Elective or pre-planned treatment for a pre-existing condition that did not worsen. 
• Emergency outpatient treatment for an event not fulfilling the serious criteria outlined above 
and not resulting in inpatient admission. 
• Respite care. 
 


Version date: 10/03/2017 
41 
7.3 
OHSU IRB Reporting of Unanticipated Problems and Adverse Events 
 
Unanticipated Problems (UP) and Adverse Events (AE) will be reported to OHSU IRB 
according to the policies, procedures and guidelines posted on the OHSU IRB web site  
 
Fatal and life-threatening events must be reported to OHSU IRB within 7 calendar days after the 
PI learns of the event. If any of these require a change (as determined by the PI or the IRB) to the 
protocol or consent form, the PI will make those changes promptly and submit the revised 
documents to the OHSU IRB. 
 
 
All other UP reports will be submitted to OHSU IRB no later than 15 calendar days of 
notification of the event.  If the event requires changes as determined by the PI or the IRB) to the 
protocol or consent form, the PI will make the changes promptly and submit the revised 
documents to the IRB.  UP and AE reports are submitted through OHSU e-IRB and will be 
reviewed by OHSU IRB.   
 
7.4 
Central Reporting of Adverse Events for Multicenter Studies  
The SAE/UP reporting for multicenter investigator initiated clinical trials will follow the 
guidelines outlined in the OHSU Knight Cancer Institute Multi-Center Investigator Initiated 
Trials Coordinating Center Operations Manual.  
 
A participating site must report an SAE to the to the institution’s local IRB for action as required, 
as well as to the OHSU coordinating center study team by phone, fax, or email within 24 hours 
of learning of the event. The participating center will send the coordinating center materials 
regarding the SAE  
 
The OHSU coordinating center study team will review and submit SAEs to the FDA, OHSU 
IRB, and any other required contacts as required by the Knight Data Safety Monitoring Plan. The 
principal investigator at the Coordinating Center is responsible for distributing IND and/or IDE 
Action Letters or Safety Reports, as applicable, to participating institutions for review and 
submission to their institution’s local IRB. 
 
7.5 
MedWatch Reporting  
 
For 
this 
investigator-initiated 
study, 
the 
investigator 
is 
the 
study 
sponsor. 
The 
investigator/sponsor is required to report adverse experiences to the FDA through the MedWatch 
reporting program, even if the trial involves a commercially available agent. Adverse 
experiences to be reported include any unexpected (not listed in the package label), serious 
adverse experiences with a suspected association to the study drug. 
 
Adverse events that occur during clinical studies are to be reported to FDA as specified in the 
investigational new drug/biologic regulations using the FDA 3500A Mandatory Reporting form, 
which is available online.   
 
This is available as a .pdf document for printing.   
 
When the serious adverse event is reported to the FDA, copies of the MedWatch 3500A form 
and supporting materials will be submitted to the OHSU Knight Cancer Institute and the IRB.   A 


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42 
copy of the MedWatch 3500A form and supporting materials will be kept on file in the study 
regulatory binder. 
 
7.6 
Sponsor or Additional Reporting Requirements 
 
Unexpected fatal or life-threatening experiences associated with the use of the study treatment 
will be reported to FDA as soon as possible but in no event later than 7 calendar days after initial 
receipt of the information. 
 
All other serious unexpected experiences associated with the use of the study treatment will be 
reported to FDA as soon as possible but in no event later than 15 calendar days after initial 
receipt of the information. 
 
Events will be reported to the FDA by telephone (1-800-FDA-1088) or by fax (1-800-FDA-
0178) using Form FDA 3500A (Mandatory Reporting Form for investigational agents) or FDA 
Form 3500 (Voluntary Reporting Form for commercial agents). Forms are available at 
http://www.fda.gov/medwatch/getforms.htm.  
 
All events reported to the FDA will also be reported to drug manufacturer representative within 
24 hours of reporting. A copy of the FDA report will also be faxed to the drug manufacturer 
representative. 
 
7.6.1 
Reporting to ARIAD 
 
All serious adverse events, whether “reportable” as defined in this protocol or not, must be 
reported to ARIAD. All expedited (7/15 day) reports will be sent to ARIAD simultaneously or 
within 24 hours of study sponsor’s submission to the competent authorities. Non-expedited SAE 
reports (except for AESIs) can be batched by the study sponsor and sent to ARIAD on a monthly 
basis. Also, any event of a vascular occlusive nature, either serious or non-serious, must be 
reported to ARIAD within 2 business days of the study sponsor’s awareness.  
The study PI or designee is responsible for faxing SAE reports to ARIAD Pharmaceuticals, Inc., 
at 1 (888) 472-7965.  Reports may be emailed if fax is not available to ARIADPost-
PVGSM@ppdi.com. 
 
7.6.2 
Reporting to Bayer 
 
Each serious adverse event must be followed up until resolution or stabilization, by submission 
of updated reports to the designated person. An isolated laboratory abnormality that is assigned 
grade 4, according to CTC definition, is not reportable as an SAE; unless the investigator 
assesses that the event meets standard ICH criteria for an SAE.  CTC grade 4 baseline laboratory 
abnormalities that are part of the disease profile should not be reported as an SAE, specifically 
when they are allowed or not excluded by the protocol inclusion/exclusion criteria.   
 
When required, and according to local law and regulations, serious adverse events must be 
reported to the Ethics Committee and Regulatory Authorities.  
 
All serious adverse events should be reported to Bayer within 24 hours.  In the event of such an 
event, the investigator should refer to the Pharmacovigilance section of the contract for reporting 


Version date: 10/03/2017 
43 
procedures. 
 
The Investigator may report serious adverse drug reactions (SADRs) using either: 
• 
An 
ADEERS 
form 
(Adverse 
Event 
Expedited 
Reporting 
System) 
available 
at 
http://ctep.cancer.gov/reporting/adeers.html, OR  
• 
A MedWatch form available at http://www.fda.gov/medwatch/  
All reports shall be sent electronically to:  
Electronic Mailbox: 
DrugSafety.GPV.US@bayer.com    
Facsimile: 
 
(973) 709-2185  
Address: 
 
Global Pharmacovigilance - USA  
Mail only: 
 
Bayer HealthCare          
 
 
 
P.O. Box 915   
 
 
 
Whippany, NJ 07981-0915   
Address: 
 
100 Bayer Blvd., Whippany, NJ 07981  
Reports for all Bayer products can also be phoned in via our Clinical Communications Dept.: 1-
888-842-2937 
 
7.6.3 
Reporting to BMS 
• All Serious Adverse Events (SAEs) that occur following the subject’s written consent to 
participate in the study through 30 days of discontinuation of dosing must be reported to 
BMS Worldwide Safety. 
• In addition to the definition of SAEs above, BMS also includes the following a SAE: 
Potential drug induced liver injury (DILI) is also considered an important medical event; 
Suspected transmission of an infectious agent (e.g., pathogenic or nonpathogenic) via the 
study drug is an SAE; Although pregnancy, overdose, and cancer are not always serious by 
regulatory definition, these events must be handled as SAEs. 
• If the BMS safety address is not included in the protocol document (e.g. multicenter studies 
where events are reported centrally), the procedure for safety reporting must be 
reviewed/approved by the BMS Protocol Manager.  Procedures for such reporting must be 
reviewed and approved by BMS prior to study activation. 
• The BMS SAE form should be used to report SAEs.  If the BMS form cannot be used, 
another acceptable form (i.e. CIOMS or Medwatch) must be reviewed and approved by 
BMS.  The BMS protocol ID number must be included on whatever form is submitted by the 
Sponsor/Investigator. 
• Following the subject’s written consent to participate in the study, all SAEs, whether related 
or not related to study drug, are collected, including those thought to be associated with 
protocol-specified procedures. The investigator should report any SAE occurring after these 
time periods that is believed to be related to study drug or protocol-specified procedure.  
• In accordance with local regulations, BMS will notify investigators of all reported SAEs that 
are suspected (related to the investigational product) and unexpected (i.e., not previously 
described in the IB). In the European Union (EU), an event meeting these criteria is termed a 
Suspected, Unexpected Serious Adverse Reaction (SUSAR). Investigator notification of 
these events will be in the form of an expedited safety report (ESR).  
o Other important findings which may be reported by the as an ESR include: increased 
frequency of a clinically significant expected SAE, an SAE considered associated with 
study procedures that could modify the conduct of the study, lack of efficacy that poses 
significant hazard to study subjects, clinically significant safety finding from a 
nonclinical (e.g., animal) study, important safety recommendations from a study data 


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44 
monitoring committee, or sponsor decision to end or temporarily halt a clinical study for 
safety reasons. 
o Upon receiving an ESR from BMS, the investigator must review and retain the ESR with 
the IB. Where required by local regulations or when there is a central IRB/IEC for the 
study, the sponsor will submit the ESR to the appropriate IRB/IEC. The investigator and 
IRB/IEC will determine if the informed consent requires revision. The investigator 
should also comply with the IRB/IEC procedures for reporting any other safety 
information.  
o In addition, suspected serious adverse reactions (whether expected or unexpected) shall 
be reported by BMS to the relevant competent health authorities in all concerned 
countries according to local regulations (either as expedited and/or in aggregate reports). 
 
SAEs, whether related or not related to study drug, and pregnancies must be reported to BMS 
within 24 hours. SAEs must be recorded on BMS or an approved form; pregnancies on a 
Pregnancy Surveillance Form. 
 
SAE Email Address:  Worldwide.Safety@BMS.com 
SAE Facsimile Number:  609-818-3804 
 
If only limited information is initially available, follow-up reports are required. (Note: Follow-up 
SAE reports should include the same investigator term(s) initially reported.)  
If an ongoing SAE changes in its intensity or relationship to study drug or if new information 
becomes available, a follow-up SAE report should be sent within 24 hours to the BMS (or 
designee) using the same procedure used for transmitting the initial SAE report.  
 
All SAEs should be followed to resolution or stabilization. 
 
For studies conducted under an Investigator IND in the US include the following: 
For studies conducted under an Investigator IND in the US, any event that is both serious and 
unexpected must be reported to the Food and Drug Administration (FDA) as soon as possible 
and no later than 7 days (for a death or life-threatening event) or 15 days (for all other SAEs) 
after the investigator’s or institution’s initial receipt of the information. BMS will be provided 
with a simultaneous copy of all adverse events filed with the FDA.  
 
SAEs 
should 
be reported on MedWatch Form 3500A, which can be accessed at: 
http://www.accessdata.fda.gov/scripts/medwatch/. 
MedWatch SAE forms should be sent to the FDA at: 
MEDWATCH 
5600 Fishers Lane 
Rockville, MD 20852-9787 
Fax: 1-800-FDA-0178 (1-800-332-0178) 
http://www.accessdata.fda.gov/scripts/med
watch/ 
 
• An SAE report should be completed for any event where doubt exists regarding its 
seriousness.  
• For studies with long-term follow-up periods in which safety data are being reported, include 
the timing of SAE collection in the protocol. 


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45 
• If the investigator believes that an SAE is not related to study drug, but is potentially related 
to the conditions of the study (such as withdrawal of previous therapy or a complication of a 
study procedure), the relationship should be specified in the narrative section of the SAE 
Report Form. 
• If only limited information is initially available, follow-up reports are required. (Note: 
Follow-up SAE reports should include the same investigator term(s) initially reported.) 
o If an ongoing SAE changes in its intensity or relationship to study drug or if new 
information becomes available, a follow-up SAE report should be sent within 24 hours to 
BMS using the same procedure used for transmitting the initial SAE report. All SAEs 
should be followed to resolution or stabilization.  All SAEs should be followed to 
resolution or stabilization. 
 
7.6.4 
SAE Reporting to Incyte 
 
Initial reports 
 
The Investigator reports to Incyte every SAE, regardless of suspected causality, which occurs 
after the subject has signed informed consent and up to the time that subject has completed the 
trial, including any post-treatment follow-up required by the protocol.  Such cases are regarded 
as originating in the IST for the purpose of notification to Incyte. 
 
The investigational site notifies Incyte of an SAE within 24 hours of the Investigator becoming 
aware of the SAE, regardless of causality to the investigational product.   
 
The investigational site records all SAE details on the Serious Adverse Event Report Form, or on 
the SAE form being used by the Investigator conducting the trial, and e-mails the report to Incyte 
via the address: IncytePhVOpsIST@incyte.com. 
 
If necessary, the Incyte PhV representative or designee queries the investigational site (within 48 
hours of receipt) for additional information to ensure a valid case prior to distributing the report 
for internal Incyte review.   
  
The Incyte PhV representative, in conjunction with the Incyte review team, ensures that all 
information available at the time, which is relevant to the medical/safety evaluation of the report, 
is collected and included without compromising the timeframes for regulatory reporting.   
 
If only partial information is available, the report will not be delayed and must be reported to 
satisfy the reporting timeframe.  Any additional information should be collected for a follow-up 
report to Health Authorities (HAs). 
 
Follow-up reports 
 
When new information regarding the SAE becomes available, the investigational site personnel 
update all relevant data on the appropriate SAE Report Form, or equivalent, with any new or 
changed information and send the follow-up SAE report to Incyte within 24 hours of becoming 
aware of the new information, via e-mail to IncytePhVOpsIST@incyte.com; 
ablithe@incyte.com. 
This includes any SAE that is upgraded to fatal or life-threatening. 


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46 
 
Incyte’s PhV Service Provider tracks any critical outstanding follow-up information and 
questions, and contacts the investigational site via a faxed Data Clarification Form (DCF) to 
request the information until all outstanding queries are resolved.   
 
Regulatory Reporting  
 
If an event is serious, unexpected, and suspected to be related to the investigational product, the 
event is considered to be reportable to Health Authorities (HAs) as a Suspected Unexpected 
Serious Adverse Reaction (SUSAR).   
 
An event is determined to be unexpected if it is not listed in the current Reference Safety 
Information (e.g., Investigator’s Brochure (IB)) or when the specificity or severity of the event is 
not consistent with the current Reference Safety Information.   
Fatal or life-threatening SUSARs must be reported to the required HA(s) within 7 calendar days 
after the Sponsor’s initial receipt of information.   
 
All other SUSARs must be reported to the required HA(s) within 15 calendar days after 
Sponsor’s initial receipt of information. 
 
The Sponsor-Investigator reports all SUSARs to the FDA under the Investigator’s IND.  
Incyte is responsible for the following: 
• 
Meeting expedited reporting requirements to HAs in their respective territories 
• 
Cross-reporting any SUSAR originating from the IST to the applicable Incyte IND(s) 
• 
Distributing Investigator Notifications to Investigators participating in the applicable Incyte 
IND(s) 
 
PROCEDURE FOR REPORTING PREGNANCY 
 
Data on fetal outcome are collected for regulatory reporting and drug safety evaluation.  Follow-
up should be conducted for each pregnancy to determine outcome, including spontaneous or 
voluntary termination, details of the birth, and the presence or absence of any birth defects, 
congenital abnormalities, or maternal and/or newborn complications. Within 30 days of learning 
of the pregnancy, the investigational site completes the Clinical Trial Pregnancy Form (sections 
I, II, and question 18 in section III) or equivalent, and e-mails the report to Incyte at 
IncytePhVOpsIST@incyte.com. 
 
7.6.5 
Reporting to Gilead 
 
All SAEs, regardless of cause or relationship, that occurs after the subject first consents to 
participate in the study (i.e., signing the informed consent) and throughout the duration of the 
study, including the protocol-required post treatment follow-up period, must be reported to the 
CRF/eCRF database and Gilead Drug Safety and Public Health (DSPH) as instructed. This also 
includes any SAEs resulting from protocol-associated procedures performed after informed 
consent is signed. 
 
Any SAEs and deaths that occur after the post treatment follow-up visit but within 30 days of the 
last dose of study IMP, regardless of causality, should also be reported.  


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47 
 
Investigators are not obligated to actively seek SAEs after the protocol defined follow up period. 
However, if the investigator learns of any SAEs that occur after study participation has 
concluded and the event is deemed relevant to the use of IMP, he/she should promptly document 
and report the event to Gilead DSPH 
• All AEs and SAEs will be recorded in the eCRF database within the timelines outlined in the 
CRF/eCRF completion guideline.  
Electronic Serious Adverse Event (eSAE) Reporting Process  
• Site personnel record all SAE data in the eCRF database and from there transmit the SAE 
information to Gilead DSPH within 24 hours of the investigator’s knowledge of the event. 
Detailed instructions can be found in the eCRF completion guidelines. 
• If for any reason it is not possible to record the SAE information electronically, i.e., the 
eCRF database is not functioning, record the SAE on the paper serious adverse event 
reporting form and submit within 24 hours to: 
Gilead DSPH: 
Fax: (866) 660-8967 
1-650-522-5477 
 
Email: pv@ctiseattleSafety_FC@Gilead.com  
 
• As soon as it is possible to do so, any SAE reported via paper must be transcribed into the 
eCRF Database according to instructions in the eCRF completion guidelines. 
• If an SAE has been reported via a paper form because the eCRF database has been locked, no 
further action is necessary. 
• For fatal or life-threatening events, copies of hospital case reports, autopsy reports, and other 
documents are also to be submitted by e-mail or fax when requested and applicable. 
Transmission of such documents should occur without personal subject identification, 
maintaining the traceability of a document to the subject identifiers. 
• Additional information may be requested to ensure the timely completion of accurate safety 
reports. 
• Any medications necessary for treatment of the SAE must be recorded onto the concomitant 
medication section of the subject’s eCRF and the event description section of the SAE form. 
 
Pregnancy 
The investigator should report pregnancies in female study subjects that are identified after 
initiation of study medication and throughout the study, including the post study drug follow-up 
period to Gilead DSPH using the pregnancy report form within 24 hours of becoming aware of 
the pregnancy.  
 
The pregnancy itself is not considered an AE nor is an induced elective abortion to terminate a 
pregnancy without medical reasons. 
 
Any premature termination of pregnancy (e.g., a spontaneous abortion, an induced therapeutic 
abortion due to complications or other medical reasons) must be reported within 24 hours as an 
SAE. The underlying medical reason for this procedure should be recorded as the AE term. 
A spontaneous abortion is always considered to be an SAE. Furthermore, any SAE occurring as 
an adverse pregnancy outcome post study must be reported to Gilead DSPH.  
 
The subject should receive appropriate monitoring and care until the conclusion of the 
pregnancy. The outcome should be reported to Gilead DSPH using the pregnancy outcome report 


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48 
form. If the end of the pregnancy occurs after the study has been completed, the outcome should 
be reported directly to Gilead DSPH.  
 
Pregnancies of female partners of male study subjects exposed to Gilead or other study drugs 
must also be reported and relevant information should be submitted to Gilead DSPH using the 
pregnancy and pregnancy outcome forms within 24 hours. Monitoring of the subject should 
continue until the conclusion of the pregnancy. If the end of the pregnancy occurs after the study 
has been completed, the outcome should be reported directly to Gilead DSPH: 
Gilead DSPH contact information is as follows: 
• Gilead DSPH: 
Fax: 1-650-522-5477 
 
 
 
Email: Safety_FC@Gilead.com  
 
Reporting Other Special Considerations: Special Situations 
SAEs consideredAll other special situation reports must be reported on the special situations 
report form and forwarded to be related (ie, assessed as possibly, probably or definitely related) 
to study drug or study procedure by the Gilead DSPH within 24 hours of the investigator shall 
becoming aware of the situation. These reports must consist of situations that involve study IMP 
and/or Gilead concomitant medications, but do not apply to non-Gilead concomitant 
medications.  
 
Special situations involving non-Gilead concomitant medications does not need to be reported on 
the special situation report form; however, for special situations that result in AEs due to a 
non-Gilead concomitant medication, the AE should be reported on the AE form.  
 
Any inappropriate use of concomitant medications prohibited by this protocol should not be 
reported as “misuse,” but may be more appropriately documented as a protocol deviation. 
Refer to the eCRF completion guidelines for full instructions on the mechanism of special 
situations reporting. 
 
All clinical sequelae in relation to these special situation reports will be reported as AEs or SAEs 
at the same time using the AE eCRF and/or the SAE report form. Details of the symptoms and 
signs, clinical management, and outcome will be reported, when available. 
 
7.6.6 
SAE Reporting to CTI Biopharma, Inc. 
 
All SAEs, irrespective of causal relationship, must be reported to CTI within 24 hours of 
becoming aware of the event via either Fax or e-mail.  Please use the CTI SAE form (Appendix 
D). 
 
Fax: (866) 660-8967 
Email: pv@ctiseattle.com 
 
Special Considerations: 
• SAEs considered to be related (ie, assessed as possibly, probably or definitely related) to 
study drug or study procedure by the investigator shall be followed until the event resolves, 
stabilizes or the patient is lost to follow up. 


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49 
• SAEs assessed as unrelated to study drug or study procedures shall be followed for 30 days 
after last dose of study treatment, or until the event resolves, returns to baseline, stabilizes or 
the patient is lost to follow-up, whichever comes first. 
• An SAE form should be completed for any event for which doubt exists regarding its 
seriousness. If an ongoing SAE changes in intensity, relationship to study drug, or as new 
information becomes available and/or known for the event, a follow-up SAE Report form 
should be completed and sent to the CTI within 24 hours of the change in SAE assessment. 
• Any SAE that occurs after study completion and is considered by the investigator to be 
related to pacritinib should be reported to CTI. 
 
A narrative outlining the details of the SAE and treatment and outcome are to be included on the 
SAE form. The narrative must state whether there is a reasonable possibility that study drug 
caused the event. Follow-up information, such as laboratory reports, discharge summaries, 
autopsy reports, and information concerning outcome of the event, should be submitted as soon 
as the information becomes available.  
 
 
8. 
PHARMACEUTICAL AGENT INFORMATION 
A list of the adverse events and potential risks associated with the investigational or commercial 
agents administered in this study can be found in Section 7.1. 
 
8.1 
Agent Accountability 
The Investigator, or a responsible party designated by the Investigator at each site, must maintain 
a careful record of the inventory and disposition of the study agent.  (See the NCI Investigator’s 
Handbook for Procedures for Drug Accountability and Storage).   
http://ctep.cancer.gov/investigatorResources/investigators_handbook.htm 
Responsibility for drug accountability at the study site rests with the Investigator; however, the 
Investigator may assign some of the drug accountability duties to an appropriate pharmacist or 
designee. Inventory and accountability records must be maintained and readily available for 
inspection by the study monitor and are open to inspection at any time by any applicable 
regulatory authorities. 
 
The Investigator or designee will be expected to collect and retain all used, unused, and partially 
used containers of study medication until the end of the study. The Investigator or designee must 
maintain records that document: 
• 
investigational product delivery to the study site 
• 
the inventory at the site 
• 
use by each subject including pill/unit counts from each supply dispensed 
• 
return to the Investigator or designee 
 
These records should include dates, quantities, batch/serial numbers (if available), and the unique 
code numbers (if available) assigned to the investigational product and study subjects. 
The investigational product must be used only in accordance with the protocol. The Investigator 
will also maintain records adequately documenting that the subjects were provided the correct 
study medication specified. 
 
Completed accountability records will be archived by the site. At the completion of the study, the 
Investigator or designee will oversee shipment of any remaining study drug back to the 


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50 
manufacturer for destruction according to institutional standard operating procedures. If local 
procedures mandate site destruction of investigational supply, prior written approval must be 
obtained from the manufacturer or manufacturer’s study drug distributor. 
Please refer to the Pharmacy Manual located in the separate Study Operations Manual for 
details on drug supply, ordering, and shipment process. 
 
8.2 
Study Agent(s)   
 
Study Agents 
Anticipated Start dose if no modifications 
Sorafenib 
400 mg po bid 
Sunitinib 
50 mg po QD 
Dasatinib 
140 mg po QD 
Ponatinib 
45mg po QD 
Ruxolitinib  
Initial doses of 5, 10, 15 or 20 mg po BID 
will be administered based on platelet 
counts at the start of the study (C1D1) 
Idelalisib  
150 mg po BID 
Pacritinib 
200 mg po BID 
 
8.2.1 
Sorafenib  
 
Product description: Sorafenib (Nexavar®), a multikinase inhibitor targeting several                       
serine/threonine and receptor tyrosine kinases, is the tosylate salt of sorafenib. Each, red, round 
film-coated tablet contains sorafenib tosylate (274 mg) equivalent to 200 mg of sorafenib and the 
following inactive ingredients: croscarmellose sodium, microcrystalline cellulose, hypromellose, 
sodium lauryl sulphate, magnesium stearate, polyethylene glycol, titanium dioxide and ferric 
oxide red. 
 
Product Identification:  Sorafenib is provided in one strength: Oral Tablet, 200mg. 
 
Packaging and Labeling of sorafenib:   Sorafenib tablets are supplied as round, biconvex, red 
film-coated tables, debossed with the “Bayer cross” on the side and “200” on the other side, each 
containing sorafenib tosylate equivalent to 200 mg of sorafenib.  Bottles contain 120 tablets. 
 
Storage andHandling of sorafenib:  Store at 25o C (77oF); excursions permitted to 15-30o C 
(59-86oF).  Store in a dry place. 
 
Dispensing:  It is the responsibility of the investigator to ensure that sorafenib is only dispensed 
to study subjects.  Sorafenib must be dispensed only from official study sites by authorized 
personnel according to local regulations.  The investigator (or assigned designee, i.e. study 
pharmacist) will dispense the proper number of tablets to the subject to satisfy dosing 
requirements for the study. The containers provided to the subject should be labeled with proper 
instructions for use.  The lot numbers, dosing start dates and the number of tablets must be 
recorded on the drug accountability pages of record for the site.  The subject must be instructed 
to return all unused sorafenib in the provided packaging at each subsequent visit. 
 
Dosage of sorafenib:  The recommended daily dose of sorafenib is 400 mg (2 x 200 mg tablets) 
taken twice daily, without food (at least 1 hour before or 2 hours after eating).  If the morning or 


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51 
the evening dose is delayed for more than 4 hours, the subject should skip this dose and resume 
dosing with the next dose per the original schedule in order to prevent overdosing. Treatment 
will begin on Day 1 of the study and continue daily until disease progression or until an 
unacceptable toxicity occurs which would require delay, modification or discontinuation of study 
therapy. 
 
8.2.2 
Sunitinib 
 
Product Description: Sunitinib malate (SUTENT®) is a yellow to orange powder with a pKa of 
8.95. The solubility of sunitinib malate in aqueous media over the range pH 1.2 to pH6.8 is in 
excess of 25 mg/mL. Capsules are supplied as printed hard shell capsules containing sunitinib 
malate equivalent to 12.5 mg, 25 mg or 50 mg of sunitinib together with mannitol, 
croscarmellose sodium, povidone (K-25) and magnesium stearate as inactive ingredients. 
 
Product Identification: Sunitinib is provided in three different strengths including a 12.5 mg 
capsule, 25mg and a 50 mg capsule.  Both are hard gelatin capsules with orange cap and orange 
body, printed with white Pfizer and 12.5 or 25 or 50mg respectively. 
 
Packaging: Sunitinib is packaged in bottles of 28 
 
Storage, Handling and Dispensing of Sunitinib:   Sunitinib should be stored at 25oC (77o F).  
Excursions permitted to 15-30oC (59-86oF).  Store in the original container, protect from light 
and moisture.  Dispensing is to be that consistent with ward properties for oral chemotherapy 
treatments.  
 
Dispensing: Subjects will take the sunitinib once daily by mouth with or without food.  
 
Dosage of Sunitinib:  The starting dose of sunitinib is one 50mg oral dose, taken once daily.   
 
8.2.3 Dasatinib 
 
Product Description: Dasatinib tablets are white to off-white, biconvex, film-coated tablets 
containing 
dasatinib, 
with 
the 
following 
inactive 
ingredients: 
lactose 
monohydrate, 
microcrystalline cellulose, croscarmellose sodium, hydroxypropyl cellulose, and magnesium 
stearate.  The tablet coating consists of hypromellose, titanium dioxide, and polyethylene glycol. 
 
Product Identification:  Dasatinib is provided in number of different strengths: 
• 20 mg: Each white-to-off-white, biconvex, round, film-coated tablet with "BMS" 
debossed on one side and "527" on the other side, contains dasatinib 20 mg. 
• 50 mg: Each white-to-off-white, biconvex, oval, film-coated tablet with "BMS" debossed 
on one side and "528" on the other side, contains dasatinib 50 mg. 
• 70 mg: Each white-to-off-white, biconvex, round, film-coated tablet with "BMS" 
debossed on one side and "524" on the other side, contains dasatinib 70 mg. 
• 80 mg: Each white-to-off-white, biconvex, triangular, film-coated tablet with "BMS" and 
"80" (BMS over 80) debossed on one side and "855" on the other side contains dasatinib 
80 mg. 
• 100 mg: Each white-to-off-white, biconvex, oval, film-coated tablet with "BMS 100" 
debossed on one side and "852" on the other side, contains dasatinib 100 mg. 


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• 140 mg: Each white-to-off-white, biconvex, round, film-coated tablet with "BMS" and 
"140" (BMS over 140) debossed on one side and "857" on the other side contains 
dasatinib 140 mg.  
Each bottle is labeled in an open label manner. Labels contain, at a minimum, the following 
information: product name, tablet strength, batch number, directions for use, storage conditions, 
and appropriate caution statements. 
 
Storage, Handling and Dispensing of Dasatinib: Bottles containing dasatinib tablets should be 
stored at 15-25°C.  The investigation product should be stored in a secure area according to local 
regulations. The investigator is responsible for ensuring that it is dispensed only to study subjects 
and only from official study sites by authorized personnel, as dictated by local regulations.  The 
investigator is responsible for ensuring that the investigational product is stored under the 
appropriate environmental conditions (temperature, light, and humidity).  If concerns regarding 
the quality or appearance of the investigational product arise, do not dispense the investigational 
product, and contact BMS immediately.  Handling and disposal of the dasatinib will be per 
OHSU guidelines for oral antineoplastic agents and unused tablets in the provided packaging 
will be returned to study staff.   
 
Dosage of Dasatinib:  Dosages are routinely 100mg a day (either as 100mg daily or 50mg bid) 
or 140mg daily. Although the 100 mg dose had been found to be better tolerated, is effective in 
CML, and has been the dose safely combined with cytotoxic chemotherapy, given the potential 
for rapid progression, target protein turnover, poorly defined dose-specific PD/PK in AML, the 
140 mg dose has been chosen for this study. If a dose is missed this should be documented and 
the missed dose is not to be replaced.  However if vomiting occurs within 30 minutes of intake, 
that dose may be repeated.  Dasatinib may be taken without regard to food; the tablets should not 
be broken, crushed, or chewed.  Thus, the tablet should be swallowed whole.  Antacid therapy 
should be avoided 2 hours before and two hours after dasatinib ingestion.  Dose interruptions and 
adjustments will be made for drug toxicity. 
 
8.2.4 Ponatinib 
 
Product Description: Ponatinib (Iclusig®) is a kinase inhibitor indicated for the treatment of 
CML (chronic, accelerated and blast phase), ALL with BCR-ABL positivity.   It is an off-white 
to yellow powder. The solubility decreases with increasing pH.  Ponatinib tablets are available as 
white, round, film coated tablets for oral administration.  Each tablet contains ponatinib 
hydrochloride equivalent to 15 or 45mg ponatinib with the following inactive ingredients: lactose 
monohydrate, microcrystalline cellulose, sodium starch glycolate, colloidal silicon dioxide, 
magnesium stearate and a tablet coating.  The tablet coating consists of talc, polyethylene glycol, 
polyvinyl alcohol and titanium dioxide. 
 
Product Identification:  Ponatinib is a round, white, film-coated tablets with debossed “A5” on 
one side and plain on the other side.   
 
Packaging and Labeling of Ponatinib:  Ponatinib tablets are supplied in tamper resistant 
bottles with 30-180 tablets in each bottle.    
 
Storage, Handling and Dispensing of Ponatinib: Ponatinib tablets, either 15mg or 45mg, 
should be stored at 25o C (77oF); excursions between 15o-30oC (59o-86oF).  The Investigator (or 


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53 
assigned designee, i.e., study pharmacist) will dispense the proper number of capsules to the 
subject to satisfy dosing requirements for the study.  The containers provided to the subject 
should be labeled with proper instructions for use.  The lot numbers, dosing start dates and the 
number of capsules for each dosage strength must be recorded on the drug accountability pages 
of record for the site.   
 
Dosage of Ponatinib:  The recommended dose of ponatinib is 45 mg every 24 hours.  The 
tablets need to be taken whole and should not be crushed or dissolved. Patients will take the 
prescribed number of tablets with water, with or without food, at approximately the same time 
each day. Subjects should not consume grapefruit products and other foods that are known to 
inhibit CYP3A4 at all times during ponatinib treatment.  If a dose is missed either due to patient, 
pharmacy, or provider error, this must be documented.  Patients who forget to take their dose 
more than 6 hours after it is due should not make up the missed dose. Patients who vomit after 
taking their dose should not make up that dose, but take the next dose at the planned time, if 
clinically indicated. 
 
8.2.5 
Pacritinib 
 
Product Description: Pacritinib is an oral tyrosine kinase inhibitor (TKI) with activity against 
two important activating mutations: Janus Associated Kinase 2 (JAK2) and FMS-like tyrosine 
kinase 3 (FLT3). For use in clinical studies as an oral agent, pacritinib is supplied as size #0 hard 
gelatin capsules with gray bodies and red caps. Capsules contain 100 mg pacritinib (free base) and 
the following inactive ingredients: microcrystalline cellulose NF, polyethylene glycol 8000 NF, and 
magnesium stearate NF. The capsule gelatin is bovine derived.  
 
Product Identification:  Pharmacies at investigational sites will receive subject-specific vials 
containing 120 capsules of pacritinib packaged in 200 mL high-density polyethylene bottles with 
child-resistant closures. 
 
Storage, Handling and Dispensing of Pacritinib: Drug product should be stored in the 
pharmacy, hospital, clinic, or warehouse at controlled room temperature, 20°C to 25°C (68°F to 
77°F), with excursions allowed between 15°C to 30°C (59°F to 86°F). Patients should be instructed 
that storage temperatures for pacritinib in the home should be below 30°C (86°F).  
 
Dosage of Pacritinib:  The recommended dose of pacritinib is - 200 mg BID..  The tablets need 
to be taken whole and should not be crushed or dissolved. Patients will take the prescribed 
number of tablets with water, with or without food, at approximately the same time each day. 
Subjects should not consume grapefruit products and other foods that are known to inhibit 
CYP3A4 at all times during -pacritinib treatment.  If a dose is missed either due to patient, 
pharmacy, or provider error, this must be documented.  Patients who forget to take their dose 
more than 6 hours after it is due should not make up the missed dose. Patients who vomit after 
taking their dose should not make up that dose, but take the next dose at the planned time, if 
clinically indicated. 
 
8.2.6 
Ruxolitinib 
 
Availability: Ruxolitinib will be provided by Incyte Corporation and shipped directly to each 
site by Incyte or its distributor.  Each site will be responsible for contacting Incyte or its 


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54 
distributor for study drug supply. 
 
Route of administration:  Doses should be taken by mouth in the morning and evening, 
approximately 12 hours apart, and without regards to food. 
 
Study Drug Packaging, Labeling and Preparation:  Ruxolitinib Phosphate tablets will be 
provided as 5 mg tablets packaged as 60 count in high-density polyethylene bottles.  All bottles 
of Incyte investigational product contain the following language: “Caution: New Drug—Limited 
by Federal law to investigational use.” 
IIncyte will be responsible for quality and stability of the drug for shipment to sites. Incyte will 
also communicate any information related to manufacturing issues and expiration dates for each 
site’s shipment. 
 
Study Drug Storage and Stability:  The bottles of tablets should be stored at room temperature, 
15°C to 30°C (59°F to 86°F).  Stability studies will be conducted on clinical batches to support 
the clinical trial. 
 
8.2.7 
Idelalisib 
 
Availability: Idelalisib will be provided by Gilead Science and shipped directly to each site by 
Gilead or its distributor.  Each site will be responsible for contacting Gilead or its distributor for 
study drug supply. 
 
Route of administration:  Doses should be taken by mouth in the morning and evening, 
approximately 12 hours apart, and without regards to food. 
 
Study Drug Packaging, Labeling and Preparation:  Idelalisib will be provided in tablets 
intended for oral administration. Each tablet contains either 100 mg or 150 mg of idelalisib with 
the following inactive ingredients: microcrystalline cellulose, hydroxypropyl cellulose, 
croscarmellose sodium, sodium starch glycolate, magnesium stearate and a tablet coating. The 
tablet coating consists of polyethylene glycol, talc, polyvinyl alcohol, and titanium dioxide and 
of FD&C Yellow #6/Sunset Yellow FCF Aluminum Lake (for the 100 mg tablet) and red iron 
oxide (for the 150 mg tablet).   
150 mg tablets: pink, oval-shaped, film-coated tablet debossed with “GSI” on one side and “150” 
on the other side.  
100 mg tablets: orange, oval-shaped, film-coated tablet debossed with “GSI” on one side and 
“100” on the other side.. Idelalisib tablets are packaged in white, high density polyethylene 
(HDPE) bottles. Each bottle contains 60 tablets and polyester packing material.  Each bottle is 
enclosed with a white, continuous thread, child-resistant polypropylene screw cap with an 
induction-sealed and aluminum-faced liner.  Study drug(s) to be distributed to centers in the US 
and other participating countries shall be labeled to meet applicable requirements of the United 
States Food and Drug Administration (FDA), EU Guideline to Good Manufacturing Practice - 
Annex 13 (Investigational Medicinal Products), and/or other local regulations. 
 
9. 
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES 
 
Refer to Section 2.4. 
 


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55 
10. 
STUDY PROCEDURES AND SCHEDULE OF EVENTS 
 
10.1 
Screening/Baseline Visit 
 
Screening assessments will be performed at standard of care visits scheduled for known or 
suspected relapsed/refractory acute leukemia.  The patient will be offered a Screening Consent to 
determine trial eligibility. Once consent is obtained, a peripheral blood and bone marrow biopsy 
sample taken at this or a subsequent SOC visit will be used for drug sensitivity testing and for 
baseline peripheral blood and marrow blast counts. If the patient is found to be eligible to receive 
study treatment, treatment must begin within 14 days after obtaining the baseline marrow and 
peripheral blood samples. At OHSU, the results from IRB 4422 (PI Loriaux) may be used to 
determine sensitivity/eligibility if the sample was obtained within 14 days of starting treatment 
using the IDE approved inhibitor assay. Baseline samples are required to assess treatment 
efficacy, and these samples should be taken as close to the initiation of treatment as possible. If 
treatment has not begun within 14 days, new baseline marrow and peripheral blood samples must 
be obtained before treatment can begin. Patients that are eligible for treatment will sign a second 
consent approving treatment with study drug and undergo any additional screening required for 
treatment.  
 
Investigators at participating sites will identify potential subjects, send baseline samples by 
overnight delivery, and send source documents that support eligibility to OHSU within 10 days 
and in accordance with study protocol.  The OHSU coordinating center team will verify 
eligibility, completeness of documents, enter registration information into the Knight CRMS, and 
assign a study number/identifier.  The coordinating center will send an email including a formal 
inhibitor screening report with eligibility/treatment assignment to the participating site, verify 
registration, and assign a participant number/identifier. Study treatment cannot begin until 
OHSU has provided documentation of the registration and eligibility to the subsite. 
A detailed description of protocol required procedures and assessments is provided in the 
Schedule of Events (Section 10.7). Refer to the Study Operations Manual for specific enrollment 
instructions.   
 
For non OHSU sites, samples will be shipped to OHSU per the separate sample manual 
instructions.  
 
10.2 
Study Treatment  
 
For the majority of kinase inhibitors used, each 4 week (28 day) period that a subject is on study 
will be considered a study cycle.  Additional testing or assessment should be performed as 
medically indicated.  
 
Study visits will include the following assessments: (+/-3 days) 
• 
Physical examination will occur every 2 weeks (14 days ± 3 days) for every cycle the subject 
is on study. 
• 
ECOG performance status at each PE 
• 
Vital signs (weight, blood pressure, pulse, body temperature) at each PE 
• 
ECG (12- Lead) during screening (≤ 14 days before treatment) and as clinically indicated per 
provider discretion.  
• 
Bone marrow aspirate and biopsy on days 14 and 28 (±3 days) of cycle 1 and then as 


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56 
clinically indicated. The inhibitor assay will be performed on all marrow samples with 
adequate cell numbers to monitor drug sensitivity. 
• 
Hematology (CBC with 5 part differential, hemoglobin and platelets) collected on day 1,7, 
14, 21, 28 of Cycle 1, then day 14 and 28 each additional cycle (±3 day window)   
• 
Serum chemistries collected on days 1 and 14 of each cycle (±3 day window) (sodium, 
potassium, chloride, carbon dioxide, glucose, blood urea nitrogen, creatinine, total bilirubin, 
ALT, AST, total protein, alkaline phosphatase, albumin, uric acid, calcium lactic 
dehydrogenase [LDH], phosphate, magnesium) Concomitant medication 
• 
Adverse event assessment.  Toxicities and adverse experiences will be assessed at each visit 
using the NCI Common Toxicity Criteria for Adverse Events v4.0 (CTCAE, see appendix 
B).  
 
Pharmacokinetic Research Sample Collection:  
Peripheral blood samples will be collected (between 2-5 cc green top) at the following time 
points. Samples will be banked for future studies. Samples will be shipped to OHSU per 
instructions in the separate sample manual. 
• 
Pre-PK sample collected at screening or Cycle 1, day 1 prior to study drug administration 
• 
Cycle 1 day 7, 14 and 21 pharmacokinetic at predose and 4 hours post dose, then pre dose on 
day 1 of each subsequent cycle 
• 
At progression, single pharmacokinetic collected 
 
10.3Discontinuation/Replacement of Study Therapy 
 
Subjects who demonstrate progression will be immediately taken off of their assigned study 
drug.  Although the primary endpoint for the study is a >25% decrease in bone marrow blast 
count at any evaluable time point within the 28 day treatment window, patients who do not meet 
the primary outcome are eligible to stay on drug if they have stable disease and are tolerating 
treatment.  Once a patient is discontinued from treatment at the discretion of the investigator, and 
if the subject so chooses, the subject may be considered for an alternative secondary study drug 
based on re-testing in the ex-vivo inhibitor/kinase target identification process. However, prior to 
study enrollment, the subject will need to meet all eligibility criteria and re-consent for the trial. 
Subject will re-start Cycle 1 and level of tumor measurement at that time will become the new 
baseline.  
 
OHSU Coordinating Center should be notified within one working day of any patient that 
is taken off study.  
 
10.4 
Subject Discontinuation 
Study drug must be immediately discontinued for the following reasons: 
• 
Disease progression  
• 
Voluntary subject withdrawal of consent 
• 
Investigator’s decision that is in the subject’s best interest to withdrawal 
• 
If the subject becomes pregnant 
• 
Noncompliance 
• 
Significant protocol violation 
• 
For any reason, at the Investigator’s discretion 
 


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57 
10.5 
Early Study Termination by the Coordinating Center 
Reasonse for early study termination include: 
• 
Unsatisfactory Enrollment 
• 
Toxicity 
• 
Incomplete or inaccurate data recording   
• 
Lack of adherence to the protocol or applicable regulatory guidelines in the conduct of the 
study 
 
If a subject withdraws consent for any further participation in the study, he or she should be 
contacted to obtain information about the reason(s) for discontinuation and collection of any 
potential adverse events.  For all other reasons for discontinuation from the study treatment 
phase, the subject should return to the clinic for the end of treatment visit within 5 days of 
discontinuing study drug. If a subject has disease progression during a study visit, this visit can 
qualify as the end of treatment visit and long-term follow-up clinical assessments. 
 
10.6 
Follow-up Visits 
 
Refer to Section 10.2 for a detailed description of study procedures.  Follow-up is independent of 
response status.  


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58 
10.7 
Schedule of Events  
  
 Screening 
Cycle 1* (C1D28 = C2D1) 
Cycle 2 and beyond 
End of 
Treatment 
Follow-up 
per SOC 
 
Day 
1 
Day 
7 
Day 
14 
Day 
21 
Day 
28 
Day 
1 
Day 
14 
Day 
28 
 
 
Visit Window 
≤ 14 days before treatment 
 
 
±3 
days 
±3 
days 
±3 
days 
±3 
days 
±3 
days 
±3 
days 
±3 
days 
 
 
    Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
Inclusion/ Exclusion 
Review 
X 
 
 
 
 
 
 
 
 
 
 
Medical History and 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
Disease and Previous 
anti-neo-plastic history 
X 
 
 
 
 
 
 
 
 
 
 
Physical Examination 
X 
X 
 
X 
 
 
X 
X 
 
X 
X 
  Vital signs, including   
blood pressure 
X 
X 
 
X 
 
 
X 
X 
 
X 
X 
ECOG Performance 
Status 
X 
X 
 
X 
 
 
X 
X 
 
X 
X 
CBC with diff, 
including # of 
atypical/blasts seen 
X 
X 
X 
X 
X 
X1 
 
X2 
X1,2 
X 
X 
  Serum Chemistries3    
X 
X 
 
X 
 
 
X 
X 
 
X 
X 
 Serum Lipase & 
Amylase (ponatinib only 
after screening) (lipase 
for sorafenib only after 
screening) 
X 
X 
 
X 
 
 
X 
X 
 
 
 
  Lipid Panel 
X 
 
 
 
 
 
 
 
 
 
 
INR/PTT 
X 
 
 
 
 
 
 
 
 
 
 
Pregnancy test4 
X 
 
 
 
 
 
 
 
 
 
 
Urinalysis (dipstick and 
Micro)5 
X 
 
 
 
 
 
 
 
 
 
 
ECG (12 lead)6 
X 
As clinically indicated per investigator discretion 
CXR (dasatinib only) 
(PA/LAT)7 
X 
As clinically indicated per investigator discretion 
Bone marrow biopsy 
cytogenetics and FISH8 
X 
 
 
X 
 
X 
 
 
X2,8 
 
Baseline bone marrow 
and peripheral blood for 
ex-vivo inhibitor kinase 
target identification, 
correlative studies, SOC 
cytogenetics, SOC 
FISH, skin biopsy one 
time during study  
X 
 
 
 
X 
 
X 
 
X 
X 
 
Pharmacokinetic 
peripheral blood  
X9 
X9 
X10 
X10 
X10 
 
X11 
 
X12 
 
Adverse Events (30 
days post last dose 
study drug) 
 
Continuous 
X 
X 
Concomitant 
medications  
 
Continuous 
X 
X 
Disease status and 
Survival  
 
X 
X 
X 
*In general, assessments/procedures are to be performed on Day 1 and prior to the first dose of treatment for each cycle unless otherwise 
specified. Treatment cycles are 28 days; however the treatment cycle interval may be increased due to toxicity according to the dose 
modification guidelines provided in Section 6. If the interval is increased, all procedures except imaging should be performed based 
on the new dosing schedule. 
1Performed as part of bone marrow analysis  
2As clinically indicated 
3Chemistry includes sodium, potassium, chloride, carbon dioxide, glucose, blood urea nitrogen, creatinine,    
    total bilirubin, ALT, AST, total protein, alkaline phosphatase, albumin, uric acid, calcium. Lactate  
    dehydrogenase (LDH), phosphorus, magnesium 
4Pregnancy (if applicable) must be performed within 72 hours of starting study drug. 


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59 
5Per package insert for sunitinib, perform baseline and periodic urinalyses during treatment, with follow up measurement of 24-hour 
urine protein as clinically indicated.  
6And as clinically indicated with any dose adjustments for cardiac toxicity  
7Chest x-ray obtained at baseline for dasatinib and then as clinically indicated per investigator discretion 
8FISH will be conducted per institutional guidelines; Day 28 marrow for cycle 2 and beyond is per provider discretion based on the 
disease status of the patient. 
9Screening OR Day 1 (pre-dose) PK sample may be used as a baseline sample. If taken on C1D1, it must be prior to  administration of 
study drug. 
10Pre-dose and 4 hours post dose 
11Pre-dose only 
12At relapse 
 
11 
MEASUREMENT OF EFFECT 
 
For the purposes of this study, patients will be evaluated for response by SOC and weekly 
peripheral blood blast counts and by marrow blast counts at days 14 and 28 of cycle one. After 
cycle 1, bone marrow assessments will be performed as clinically indicated.   
 
11.1 
Definition of Response for the Primary Endpoint 
 
The primary objective, defined as a ≥ 25% decrease in bone marrow blast count from baseline, 
and overall response rates (PR plus CR) will be determined for each study subject throughout the 
study period.  
 
11.2 
Evaluation of Best Overall Response 
 
The best overall response is the best response recorded from the start of the treatment through the 
end of cycle 1 or until disease progression/recurrence (taking as reference for progressive disease 
the smallest measurements recorded since the treatment started). Bone marrow blast counts will 
be followed at pre-determined intervals and used to monitor response.  
 
Partial responses and complete responses will be determined (secondary objectives) using formal 
AML and ALL response criteria defined in Section 11.3 and 11.4.  
 
11.3 
Response criteria for AML  
 
Response Criterion 
Time of Assessment 
Neutrophils (µL) 
Platelets (µL) 
Bone 
Marrow 
Blasts (%) 
Other 
Early treatment assessment 
7-10 days after therapy 
NA 
NA 
<5 
 
Morphologic leukemia-free state 
Varies by protocol 
NA 
NA 
<5 
Flow cytometry EMD 
Morphologic CR 
Varies by protocol 
>1000 
>100,000 
<5 
Transfusion EMD 
Cytogenetic CR 
Varies by protocol 
>1000 
>100,000 
<5 
Cytogenics – normal, EMD 
Molecular CR 
Varies by protocol 
>1000 
>100,000 
<5 
Molecular – negative, 
EMD 
Partial remission 
Varies by protocol 
>1000 
>100,000 
> 50 or 
decrease to 5-
25 
Blasts <5% if Auer rod 
positive 
EMD, extramedullary disease; CR, complete remission 
Modified from Cheson et al(30)  
 
AML Complete Remission (CR) is defined as all of the following: 
• 
Peripheral blood counts: 
o ANC ≥ 1,000/mm3 
o Platelet count ≥ 100,000/mm3 
• 
Bone marrow: 


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60 
o No Auer rods 
o <5% blast cells in a 200-cell differential 
• 
No extramedullary leukemia 
 
 
AML Complete remission with incomplete hematopoietic recovery (CRi) is defined as all of 
the following: 
• 
Satisfying all criteria for CR except for 
o ANC < 1,000/mm3 and/or 
o Platelet count < 100,000/mm3,but not requiring platelet transfusion 
 
AML Confirmed complete remission with or without complete hematopoietic recovery is 
defined as the following: 
• 
Satisfying all criteria for CR or CRi at least 30 days after initial determination of CR  
 
AML Complete remission with persistent morphologic dysplasia (CRd) is defined as the 
following: 
• 
CR or CRi as defined above but marrow and/or peripheral blood show persistent dysplasia, 
as determined by hematopathology review. Local slides may be requested to be sent to 
coordinating site for additional review as per Coordinating Center PI request 
 
AML Cytogenetic complete remission (CRc) is defined as the following: 
• 
CR or CRi as defined above with disappearance of previous (pre-study) cytogenetic 
abnormalities, i.e., return to normal karyotype 
 
Partial remission (PR) is defined as all of the following: 
• 
 Peripheral blood counts: 
o ANC ≥ 1,000/mm3 (≥ 1.0 x 109/L); 
o Platelet count ≥ 100,000/mm3 (≥ 100.0 x 109/L). 
• 
Bone marrow: 
o Decrease in the pre-treatment blast percentage by at least 50%, and reduction to a value 
between 5% and 25% of the nucleated cell differential count 
o If Auer rods are present, reduction in blast percentage to < 5%. 
• 
No extramedullary leukemia. 
 
Progression is defined as a ≥ 50% increase in leukemic bone marrow blasts. 
 
11.4 
Response Criteria for ALL 
 
ALL Complete Response (CR) 
• 
Complete Hematologic Response (CHR) is defined as the following: 
o Bone marrow cellularity greater than 20% with maturation of all cell lines and less than 
5% blasts 
o Recovery of granulocyte count to greater than 1,500mm3 and platelet count greater than 
100,000mm3, and no leukemic blasts in the peripheral blood 
o Resolution of any detectable extramedullary leukemia. Isolated and stable splenomegaly 
is not considered extramedullary disease 
• 
Complete Cytogenetic Response (CCyR) is defined as: 


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61 
o Absence of previously detected abnormalities in bone marrow by       conventional 
cytogenetic metaphases or FISH 
• 
Progression is defined as a ≥ 50% increase in leukemic bone marrow blasts 
 
ALL Minimal Residual Disease (MRD)  
• 
For Bone Marrow Involvement only 
o Detection of residual blast cells by flow, with a sensitivity of 10-2 AND 
o For Ph+ ALL, RT-PCR for BCR/ABL with a sensitivity of 10-3  
 
ALL Partial Response (PR)  
• 
For Bone Marrow Involvement 
o Reduction of ≥50% of blasts 
 
ALL Progression is defined as a ≥ 50% increase in leukemic bone marrow blasts 
 
11.5 
Duration of Overall Response and Stable Disease  
 
11.5.1 Duration of overall response 
The duration of overall response is measured from the time measurement criteria are met for CR 
or PR (whichever is first recorded) until the first date that recurrent or progressive disease is 
objectively documented (taking as reference for progressive disease the smallest measurements 
recorded since the treatment started). 
 
The duration of overall CR is measured from the time measurement criteria are first met for CR 
until the first date that recurrent disease is objectively documented. 
 
11.5.2 Duration of Stable Disease 
Stable disease is measured from the start of the treatment until the criteria for progression are 
met, taking as reference the smallest measurements recorded since the treatment started.  
 
11.6 
Progression-Free Survival 
Time from the start of study drug treatment to death, regardless of cause of death, or date of 
disease progression defined as a ≥ 50% increase in leukemic bone marrow blasts, whichever 
occurs first.  
 
11.7 
Overall Survival (OS)  
Time from the date of subject registration to death, regardless of causes of death. Those who are 
alive at the end of the study are censored at the date of last contact.  
 
11.8 
Response Review 
At the completion of the study, assessment of response e.g. changes in blasts counts (peripheral 
or bone marrow) will be reviewed by an independent OHSU hematopathologist and assessed by 
an independent clinician.    
 
12 
DATA REPORTING/REGULATORY REQUIREMENTS 
12.1 
Data Collection and Storage 
 
Information for each participant will be collected and entered directly into an existing electronic 


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62 
relational database. Each site will be responsible for entry of data for patients accrued at that site 
with all correlative data entered by personnel at OHSU, as detailed below. 
 
iMedidata Rave, the database that will be used for this trial, was built to house voluminous, 
diverse data sets in a three-dimensional, relational setting whereby all information for a given 
patient can be viewed and correlated with all other pieces of information. This database was 
launched in October 2011. It is a web-based interface that references data, which is stored on a 
secure server such that all information collected for any patient can be traced through a hierarchy 
to show the exact lineage of that information stream. In addition, a sophisticated query/report 
function allows for complex analyses of data that has been collected and can thus facilitate 
integration of diverse data types. This database is supported by a web-portal login, and team 
members currently teams at all trial sites will have login credentials and have been trained in 
procedures for entering, accessing and storing data. This will facilitate information being stored 
in a unified format and location, which will be important for the long-distance collaborations of 
this trial. 
 
This database utilizes a tiered user format whereby each user is defined based on access to 
read/edit each field as well as privileges of viewing protected health information (PHI). Since 
every data field is strictly defined as to whether PHI is present in that field, users lacking PHI 
privileges will be completely shielded from viewing such information. In addition, all 
information is stored on an encrypted server and access to the database is password protected. 
Finally, this database undergoes a rigorous back-up and audit trail such that information is never 
in danger of being permanently lost. Hence, the security and integrity of this database far 
surpasses requirements for data storage. 
Clinical and demographic information about each patient (i.e. gender, race, ethnicity, date of 
birth, white blood cell count, extended differentials, karyotype/cytogenetics, etc.) will be entered 
directly into this database by each site at which a new patient is enrolled onto the trial. Data from 
correlative studies will be entered by laboratory personnel at OHSU.  
 
Quality assurance will be conducted as outlined in section 12.7 under data safety and monitoring. 
Per OHSU guidelines (refer to Appendix D– “Human Research Protection Program – 
Investigator Guidance for Protocol Deviations”), moderate and major protocol deviations will be 
captured in iMedidata Rave®. Minor administrative deviations that are not otherwise 
documented in the system will also be captured in the regulatory study binder and if patient-
specific in iMedidata Rave®. Minor protocol deviations that are procedure related (study 
procedure not performed/results not available) will be captured in the study database by study 
staff by recording that a procedure was not done.  An example of a minor protocol deviation is a 
blood draw that did not occur.  Note - If modification of the study medication dose was made 
without the required test results being available, then a protocol deviation would be recorded on 
the Protocol Deviation log and reported.  At the end of a study, minor protocol deviations will be 
summarized. 
 
12.2 
Multicenter Guidelines 
This protocol will adhere to the guidelines of the OHSU Knight Multi-Center Investigator 
Initiated Trials Coordinating Center Operations Manual.   
 
OHSU Coordinating Center will manage trial data in the following ways:  
• 
Confirm that all sites have received and are using the most recent version of the protocol. 


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63 
The protocol must not be rewritten modified by anyone other than the OHSU Knight 
Principal Investigator. Documentation of the version that was sent to the site must be kept in 
the regulatory binders.  
• 
Confirm that the protocol and informed consent form have local IRB approval at each site 
prior to registration of the first subject. Documentation of IRB approval from other sites for 
continuing review must be submitted and kept in the binder.  
• 
Provide centralized subject registration in the clinical research management system 
• 
Ensure collection and review of applicable source documents and case report by the OHSU 
PI to ensure protocol compliance 
• 
Maintain documentation for all SAE reports and submit a summary of all AE, SAE and 
unanticipated problems (UP) to the Knight DSMP 
• 
Prepare quarterly summary reports of SAEs and UPs from all sites 
• 
Ensure that relevant IRB correspondence and study status changes are communicated to all 
participating sites within five business days. Any changes that affect patient safety of study 
enrollments will be communicated immediately 
• 
Submit documentation to the FDA such as protocol amendments, annual reports, SAE reports 
for unexpected, fatal or life-threatening events that are associated with the use of the study 
drug 
 
Participating sites must submit regulatory documents including, but not limited to the following:  
• 
Current CV (signed and dated) for each investigator 
• 
Current medical license number for physician investigators 
• 
Current signed FDA Form 1572 
• 
Certificate of completion of institution-required human subject training course, the NIH 
online training in the protection of human research subjects or other appropriate training 
• 
Documentation of institutional Conflict of Interest 
• 
IRB approved site-specific ICF (must be reviewed and approved by OHSU PI and study team 
prior to submission to the local IRB 
• 
All IRB approved documents and approval memos 
• 
Delegation log 
• 
Data Safety and Monitoring Plan (DSMP) 
• 
iMedidata data entry completed within 21 business days of study visit 
 
12.3 
Protocol Review 
The protocol and informed consent form for this study must be reviewed and approved in writing 
by the OHSU Knight Cancer Institute Clinical Research Review Committee (CRRC) and the 
appropriate Institutional Review Board (IRB) prior to any subject being consented on this study.  
All sites must have IRB approval of protocol by the IRB of record before consenting any 
subjects. 
 
12.4 
Informed Consent 
Written informed consent will be obtained from all subjects, or the legally authorized 
representative of the subject, participating in this trial, as stated in the Informed Consent section 
of the case of Federal Regulations, Title 21, Part 50.  If a subject’s signature cannot be obtained, 
and for all subjects under the age of 18, the investigator must ensure that the informed consent is 
signed by the subject’s legally authorized representative. Documentation of the consent process 
and a copy of the signed consent shall be maintained in the subject’s medical record.  
 


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64 
All study sites must have IRB approval of ICF by the IRB of records before consenting any 
subjects. 
 
12.5 
Changes to Protocol  
Any modification of this protocol must be documented in the form of a protocol revision or 
amendment approved by the CRRC and IRB, before the revision or amendment may be 
implemented.  The only circumstance in which the amendment may be initiated without 
regulatory approval is for a change necessary to eliminate an apparent and immediate hazard to 
the subject.  In that event, the investigator must notify the CRRC and IRB in writing within 10 
working days after the implementation. Investigators holding the IDE must notify FDA of 
substantive changes to the protocol. 
 
Participating study site must submit proposed changes to protocol to the OHSU Coordinating 
Center for review and endorsement before participating site may implement changes.  
 
12.6 
Maintenance of Records 
If the investigator relocates or for any reason withdraws from the study, the study records must 
be transferred to an agreed upon designee, such as another institution, another investigator, or the 
OHSU Knight Cancer Institute Clinical Trials Office.  Records must be maintained according to 
sponsor or FDA requirements.  
 
12.7 
OHSU IRB Reporting of Unanticipated Problems and Adverse Events 
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 7.0 
(Adverse Events: List and Reporting Requirements). 
 
12.8 
OHSU Knight Cancer Institute Data and Safety Monitoring Plan 
In addition to complete study and pharmacy files, complete records must be maintained on each 
subject treated on this protocol.  OHSU Knight Cancer Institute, through the auditing function of 
the Knight Clinical Trials Office, is responsible for ensuring that all member investigators and 
affiliate investigators conduct clinical research studies in compliance with local IRB standards, 
FDA regulations and NIH policies and in accordance with the Data and Safety Monitoring Plan 
policies and procedures (http://ohsucancer.com/crm).  
 
 
 
 
 
Locally initiated studies will be audited by OHSU Knight CI Auditor.  Newly approved studies 
may be audited any time after enrollment has been initiated.  Each OHSU Knight approved 
treatment protocol will be audited on an annual basis in accordance with the Knight Data and 
Safety Monitoring Plan.   
 
Participating Sites  
It is the responsibility of each participating site’s principal investigator to ensure that the study is 
conducted in compliance with local IRB standards, FDA regulations, and NIH policies. It is also 
the responsibility of each site’s principal investigator to ensure that quality assurance audits at 
their site are conducted according to their institution’s policies and procedures.  The quality 
assurance audit process provides assurance that reported data accurately reflects the data in the 
primary subject record. 
 
12.9 
Inclusion of Women, Minorities and Children 
 


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65 
12.9.1 Inclusion of Women and Minorities 
No OHSU Knight Cancer Institute study will focus on any particular gender, racial or ethnic 
subset. No subject will be excluded from the study on the basis of gender, racial or ethnic origin. 
Male, female and minority volunteers will be recruited for this study from the general population 
and approximately 50% men and 50% women will be studied. The projected gender, racial, and 
ethnic composition of the study will represent that of the state of Oregon.  
 
Table 1: Population Demographics - Oregon (% )              
Source:   U.S. Census Bureau, 2010    *Totals may not equal 100 due to rounding. 
 
Table 2: Projected Accrual for the Present Study  
Ethnic Category 
Sex/Gender 
Females 
Males 
Unknown 
Total 
Hispanic or Latino 
1 
1 
0-1 
2 
Not Hispanic or Latino 
24 
24 
0-1 
22 
Unknown 
0-1 
0-1 
0-1 
0-1 
Ethnic Category: Total of all 
subjects* 
25 
25 
0-1 
 
50 
* 
Racial Category 
 
American Indian or Alaskan 
Native 
0-1 
0-1 
0-1 
0-1 
Asian 
0-1 
0-1 
0-1 
0-1 
Black or African American 
0-1 
0-1 
0-1 
0-1 
Native Hawaiian or other Pacific 
Islander 
0-1 
0-1 
0-1 
0-1 
White 
23 
23 
0-1 
0-1 
More than one race 
0-1 
0-1 
0-1 
0-1 
Unknown 
0-1 
0-1 
0-1 
0-1 
Racial Category: Total of all 
subjects* 
25 
25 
0-1 
50 
Source:   Adapted from U.S. Census Bureau, 2010    *Totals may not equal 100 due to rounding. 
Ethnic Category 
Sex/Gender 
Females 
Males 
Total 
Hispanic or Latino 
 
 
11.7 
Not Hispanic or Latino 
 
 
88.3 
Ethnic Category: Total of all subjects* 
 
 
100* 
Racial Category 
 
American Indian or Alaskan Native 
 
 
1.4 
Asian 
 
 
3.7 
Black or African American 
 
 
1.8 
Native Hawaiian or other Pacific Islander 
 
 
0.3 
White 
 
 
83.6 
More than one race 
 
 
3.8 
Unknown/Other 
 
 
5.3 
Racial Category: Total of all subjects* 
 
 
100* 
TOTALS 
50.4 
49.6 
100* 


Version date: 10/03/2017 
66 
 
12.9.2 Inclusion of Children 
In accordance with NIH guidelines on the inclusion of children as participants in research involving 
human subjects, children under the age of 18 years must be included in all human subjects’ 
research, conducted or supported by the NIH, unless there are clear and compelling reasons not to 
include them. Therefore, proposals for research involving human subjects must include a 
description of plans for the inclusion of children. 
 
This protocol does not include children for the following reason: No dosing or adverse event data 
are currently available on the use of this study agent in this way in subjects <21 years of age, 
therefore, children are excluded from this study but will be eligible for future pediatric trials with 
this study agent. 
 
13 
STATISTICAL CONSIDERATIONS 
 
13.1 
Study Design 
This is a phase II, proof-of-concept trial to evaluate an individualized therapy strategy based on 
the results from the unique in-vitro inhibitor screen developed at OHSU. A total of 24 patients 
(not including screen failures) who meet the eligibility criteria will be enrolled and assigned to 
an individualized therapy based on the results of the in-vitro inhibitor screen. Because of 
heterogeneity of patients, this study is designed as a single stage, fixed sample size trial. 
Specifically, there will be no interim analyses or stopping rules due to toxicity, or lack of 
efficacy. Adverse events will be monitored by the study team as well as the Knight Cancer 
Institute Data and Safety Monitoring Committee (DSMC). 
 
13.2 
Primary and Secondary Endpoints 
The primary endpoint is clinical activity, defined as a ≥ 25% decrease in bone marrow blast 
counts or a >25% decrease in peripheral blood blasts at any evaluable time point within the 28-
day treatment window. Blast percentages are not interchangeable between peripheral blood and 
marrow. Secondary endpoints are: overall objective response rates (complete and partial), 
progression-free survival and overall survival, and to determine clinical activity (defined as > 
25% decrease in bone marrow blast counts or a >25% decrease in peripheral blood blasts) in 
subjects who have failed the initial inhibitor but are then treated with another inhibitor identified 
on repeat pre-clinical (in-vitro) activity testing. 
 
Exploratory endpoints include identification and characterization of active/aberrant kinase 
pathways and correlation with treatment response, mutational analysis using next generation 
sequencing, and characterization of aberrant gene expression in primary leukemia samples. 
 
13.3 
Analysis Populations 
An intent-to-treat (ITT) analysis set includes patients who meet the screening criteria and are 
assigned to one of the study drugs regardless of actual dose of the drug received. A safety 
analysis set includes patients who complete at least one dose of the assigned drug, while the per-
protocol analysis set includes patients who complete 28 days of the assigned treatment. The ITT 
analysis set is used to evaluate the primary and secondary efficacy endpoints, while the safety 
analysis set is used to evaluate the toxicity and safety endpoints. To better understand the effects 
of the assay-guided treatment strategy, we will also evaluate the primary and secondary 
endpoints using the per-protocol analysis set. 
 


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67 
13.4 
Statistical Analysis Plan 
Patient demographic and clinical characteristics, including in vitro inhibitor cytotoxicity (IC50), 
will be summarized using descriptive statistics (e.g., proportions for categorical variables, and 
mean/standard deviation for continuous variables). For the primary endpoint, we will estimate 
the proportion of patients with clinical activity (≥ 25% decrease in blast percentage within the 
28-day treatment window). We will consider the approach worthy of further consideration if we 
observe at least 4 patients with clinical activity among 24 patients, or equivalently the proportion 
of patients with clinical activity is significantly greater than 5% (historical rate) at a one-sided 
5% significance level.  Patients who fail to have a blast count measured within the 28 day 
treatment cycle will be considered as non-responders (no clinical activity) in the ITT analysis. 
For the secondary binary endpoints (e.g., target response, clinical activity in subjects who have 
failed the initial inhibitor but are then treated with another inhibitor identified on repeat pre-
clinical (in-vitro) activity testing, objective response), we will present the proportion of patients 
achieving the endpoint along with its 95% exact binomial confidence interval. For time-to-event 
endpoints (e.g., OS, PFS), Kaplan-Meier method will be used to estimate the survival curve. 
Adverse events will be tabulated and summarized according to the NCI CTCAE v. 4.0 as well as 
key reporting criteria (i.e., grade or seriousness, unanticipated, treatment attribution). For 
correlative/exploratory studies, we will use either t-test (normally distributed variables) or 
Wilcoxon rank sum test (non-normally distributed variables) to determine whether the mean of 
continuous biomarkers or patient factors (e.g., IC50 inhibitor cytotoxicity and kinase 
target/pathway inhibition level) are significantly different between responding or non-responding 
patients. 
 
13.5 
Sample Size and Power 
The sample size is derived under the following null (H0) and alternative (H1) hypotheses: 
H0: p = .05  versus  H1: p > .05 
The parameter p represents the proportion of patients who achieve the primary endpoint, i.e. ≥ 
25% decrease in bone marrow blast counts at any evaluable time point within the 28 day 
treatment window. Based on one-sided, exact binomial distribution, the sample size of 24 
patients will provide 81% power at p = .22 (desired response) with 3% significance level (5% 
target level). If there are 4 or more responses, we conclude that the response rate is significantly 
better than the historical rate (5%), and the approach worthy of further investigation. The sample 
size calculation is performed using PASS 2008 [Hintze J (2008), NCSS, LLS. Kaysville, Utah, 
www.ncss.com] using “Inequality Tests for One Proportion: Exact Binomial Test”. We expect 
that 20% of screened patients will be eligible for the trial, and therefore a total of 120 patients 
will be screened.   
 
13.6 
Handling of Missing Data 
We will use all available data and will not impute missing data. Generally, missing data will be 
coded as missing or unknown and will be included in the intent-to-treat (ITT) analyses. For the 
primary endpoint, those without a blast count performed within the 28 day treatment cycle will 
be considered as non-responders (no clinical activity) in the ITT analysis. 
 
 
 
 
 
 


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69 
 
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APPENDIX A: Performance Status 
 
 
ECOG Performance Status Scale 
 
 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity.  Fully active, able to 
carry on all pre-disease performance 
without restriction. 
100 
Normal, no complaints, no evidence of 
disease. 
90 
Able to carry on normal activity; minor 
signs or symptoms of disease. 
1 
Symptoms, but ambulatory.  
Restricted in physically strenuous 
activity, but ambulatory and able to 
carry out work of a light or sedentary 
nature (e.g., light housework, office 
work). 
80 
Normal activity with effort; some signs 
or symptoms of disease. 
70 
Cares for self, unable to carry on 
normal activity or to do active work. 
2 
In bed <50% of the time.  Ambulatory 
and capable of all self-care, but 
unable to carry out any work 
activities.  Up and about more than 
50% of waking hours. 
60 
Requires occasional assistance, but is 
able to care for most of his/her needs. 
50 
Requires considerable assistance and 
frequent medical care. 
3 
In bed >50% of the time.  Capable of 
only limited self-care, confined to bed 
or chair more than 50% of waking 
hours. 
40 
Disabled, requires special care and 
assistance. 
30 
Severely disabled, hospitalization 
indicated.  Death not imminent. 
4 
100% bedridden.  Completely 
disabled.  Cannot carry on any self-
care.  Totally confined to bed or chair. 
20 
Very sick, hospitalization indicated. 
Death not imminent. 
10 
Moribund, fatal processes progressing 
rapidly. 
5 
Dead. 
0 
Dead. 
 
 


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APPENDIX B: Contraception 
 
BMS defines contraception as the following:  
 
HIGHLY EFFECTIVE METHODS OF CONTRACEPTION 
• Male condoms with spermicide 
• Hormonal methods of contraception including combined oral contraceptive pills, vaginal 
ring, injectables, implants and intrauterine devices (IUDs) such as Mirena by WOCBP 
subject or male subject’s WOCBP partner (previous language flexible as appropriate per 
Directive as based on current knowledge of effects of study drug (s) on hormone 
exposures and as agreed upon by MST Lead and Medical Monitor in consultation with 
the compound Lead Clinical Pharmacologist.). Female partners of male subjects 
participating in the study may use hormone based contraceptives as one of the acceptable 
methods of contraception since they will not be receiving study drug  
• IUDs, such as ParaGard 
• Tubal ligation 
• Vasectomy. 
• Complete Abstinence* 
• *Complete abstinence is defined as complete avoidance of heterosexual intercourse and 
is an acceptable form of contraception for all study drugs. Female subjects must continue 
to have pregnancy tests. Acceptable alternate methods of highly effective contraception 
must be discussed in the event that the subject chooses to forego complete abstinence 
 
 
LESS EFFECTIVE METHODS OF CONTRACEPTION 
• Diaphragm with spermicide 
• Cervical cap with spermicide 
• Vaginal sponge 
• Male Condom without spermicide  
• Progestin only pills by WOCBP subject or male subject’s WOCBP partner (inclusion flexible 
as appropriate per Directive as based on current knowledge of effects of study drug (s) on 
hormone exposures and as agreed upon by MST Lead and Medical Monitor in consultation 
with the compound Lead Clinical Pharmacologist) 
• Female Condom*. * A male and female condom must not be used together 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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APPENDIX C: Concomitant Therapies Affecting Kinase Inhibitors 
 
The following restricted therapies are permitted with caution when medically indicated. Their 
specific interactions with on study kinase inhibitor therapy may vary depending on the kinase 
inhibitor used. The use medications that affect CYP3A4 metabolism may be permitted after 
consultation with an oncology pharmacist. 
 
CYP3A4 Inducers (see Table) 
• Drugs that induce CYP3A4 activity may decrease kinase inhibitor plasma concentrations. In 
subjects in whom CYP3A4 inducers are indicated, alternative agents with less enzyme 
induction potential should be used.  If dasatinib, ponatinib or sorafenib must be administered 
with a CYP3A4 inducer, a dose increase in kinase inhibitor should be considered. If an 
inducer is required for subject care sunitinib may be increased to 62.5 mg daily and if 
tolerated for 28 days further increased to 87.5 mg daily. 
 
CYP3A4 Inhibitors (see Table) 
• Dasatinib is a CYP3A4 substrate. Concomitant use of dasatinib and drugs that inhibit 
CYP3A4) may increase exposure to certain kinase inhibitors. Close monitoring for toxicity 
and a dose reduction should be considered as listed in the tables below if systemic 
administration of a potent CYP3A4 inhibitor cannot be avoided. 
• 
Ponatinib may increase the blood levels and effects of PGP substrates 
• 
Dasatinib, sorafenib, pacritinib, ruxolitinib, idelalisib, and sunitinib do not cause 
significant changes in the blood levels of other medications. 
 
Common CYP3A4 Substrates 
• CYP3A4 substrates known to have a narrow therapeutic index such as alfentanil, astemizole, 
terfenadine, cisapride, cyclosporine, fentanyl, pimozide, quinidine, sirolimus, tacrolimus, or 
ergot alkaloids (ergotamine, dihydroergotamine) should be administered with caution in 
subjects receiving certain kinase inhibitors. 
 
Common CYP2C8 Substrates 
• Amiodarone, bubproprion, pioglitazone, repaglinide, rosiglitazone, and tretinoin. 
 
Common CYP2C9 Substrates 
• Carvedilol, celecoxib, dapsone, fluoxetine, fluvastatin, glimipramide, glipizide, losartan, 
monteleukast, nateglinide, phenytoin, sulfadiazine, sulfamethoxazole, tamoxifen, torsemide, 
trimethoprim, voriconazole, warfarin, zafrilukast and zopiclone.   
 
Common 2D6 Substrates 
• Amitriptyline, aripiprazole, captopril, carvedilol, codeine, desipramine, dextromethorphan, 
doxepin, duloxetine, flecainide, fluoxetine, haloperidol, imipramine, lidocaine, metoprolol, 
mexilitine, 
mirtazapine, 
nebivolol, 
nefazodone, 
nortriptyline, paroxetine, perphenazine, 
pindolol, 
procainamide, promethazine, propafenone, propranolol, risperidone, ritonavir, 
sertraline, tamosifen, tamsulosin, thioridazine, tolteradine, tramadol, and venlafaxine.  
 
Common UGT1A1 Substrates 
• Acetaminophen, atorvastatin, carvedilol, clofibrate, ethinylestradiol, ezetimibe, gemfibrozi, 
naltrexone, nicotine, simvastastin, and telmisartan. 


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Common PGP Substrates 
• Aliskiren, 
colchicine, 
dabigatran, 
digoxin, 
everolimus, 
fexofenadine, 
marovirac, 
posaconazole, ranolazine, saxigliptan, sirolimus, sitagliptin, and tolvaptan. 
 
Known Inducers & Inhibitors of CYP Isoenzymes 
Inducers of CYP 3A4 
 
Aminoglutethamide 
Carbamazepine 
Fosphenytoin 
Nafcillin 
Nevirapine 
Oxcarbazepine 
Phenobarbital 
Phenytoin 
Primidone 
Rifabutin 
Rifampin 
Rifapentine 
St John’s wort 
CYP 3A4  Inhibitors (M=Moderate, S=Strong) 
 
Amiodarone-M 
Amprenavir-S 
Aprepitant-M 
Atazanavir-S 
Cimetidine-M 
Clarithromycin-S 
Clotrimazole-M 
Conivaptan-S 
Cyclosporine-M 
Delavirdine-S 
Diltiazem-M 
Enoxacin-S 
Erythromycin-M 
Fluconazole-M 
Fosamprenavir-S 
Grapefruit juice-M/S – treat as S 
Imatinib-S 
Indinavir-S 
Isoniazid-S 
Itraconazole-S 
Ketoconazole-S 
Metronidazole-M 
Miconazole-S 
Nefazodone-S 
Nelfinavir-S 
Nicardipine-S 
Norfloxacin-M 
Posaconazole-S 
Propofol-S 
Quinidine-S 
Ritonavir-S 
Saquinavir-M 
Sertraline-M 
Telithromycin-S 
Troleandomycin-M 
Verapamil-M 
Voriconazole-S 
  
 


Version date: 10/03/2017 
0 
APPENDIX D: Protocol Deviations 
 
 
 


 
A Phase II Proof-of-Concept Trial to Study Kinase Inhibition in Relapsed/Refractory Acute 
Leukemias: Using a Comprehensive In Vitro Kinase Inhibitor Panel to Select Individualized, 
Targeted Therapies 
IRB # 7195 
SUBJECT ID: _________________                                              INITIALS: _________________ 
 
 
Preparer’s Signature/Initials:                                                               Date: 
Protocol Version Date 10/03/2017 
 
Page 0 
   Registration Packet v4 
APPENDIX E: Participant Eligibility Criteria 
 
INCLUSION CRITERIA 
Each subject must meet all of the following inclusion criteria to be enrolled: 
# 
3.1 CRITERIA 
YES 
NO 
Values 
3.11 
Participants ≥ 18 years of age with 
relapsed/refractory leukemia with a confirmed 
diagnosis of AML or ALL, who meet the 
following criteria: Both men and women of all 
races and ethnic groups will be included. 
a. Individuals aged 18-64 years with 
salvage* treatment failures only - 
defined as relapsed or refractory to 
after least 1 cycle of salvage therapy.  
*Given the clinical activity and use of  
hypomethylating agents in AML 
patients, initial and salvage therapy 
may include hypomethylating agents. 
b. Age > 65 years**:  Refractory to 
induction chemotherapy- defined as 
no response to ^initial therapy or have 
relapsed after initial therapy.  
**Individuals aged ≥65 years, with 
CMML or myelodysplasia (MDS) that 
transform to acute leukemia while 
actively receiving hypomethylating 
agents (i.e., decitibine or azacytidine) 
will be considered induction failures 
and are thus eligible for this trial. For 
Ph+ ALL, initial therapy and salvage 
therapy may include steroids and 
imatinib or dasatinib.  
 
 
 
 
 
 
 
Date of Birth:  
__ __ / __ __ / __ __ 
 
3.1.2 
Primary patient samples must show in vitro 
kinase inhibitor sensitivity as determined by 
the OHSU functional kinase inhibitor screen. 
For OHSU patients, functional kinase 
inhibitor screening may be performed as part 
 
 
 
 
 
Date of assay result: 
__ __ / __ __ / __ __ 


 
A Phase II Proof-of-Concept Trial to Study Kinase Inhibition in Relapsed/Refractory Acute 
Leukemias: Using a Comprehensive In Vitro Kinase Inhibitor Panel to Select Individualized, 
Targeted Therapies 
IRB # 7195 
SUBJECT ID: _________________                                              INITIALS: _________________ 
 
 
Preparer’s Signature/Initials:                                                               Date: 
Protocol Version Date 10/03/2017 
 
Page 1 
   Registration Packet v4 
of this study or through enrollment in 
eIRB4422 if the identical FDA/CLIA 
approved assay is used and a result is 
available within 2 weeks of starting on study 
drug treatment. 
Study drug selected: 
________________________ 
3.1.3 
Patients must have normal organ function as 
defined below: 
Serum creatinine < 2.0 x institutional 
upper limit of normal (ULN) 
INR < 1.5 x institutional ULN 
Adequate hepatic function as defined 
by the following criteria: 
Total serum bilirubin ≤1.5 x ULN, 
unless due to Gilbert’s syndrome 
Alanine aminotransferase (ALT) 
≤2.5 × ULN 
Aspartate aminotransferase (AST) 
≤2.5 × ULN 
 
 
Creatinine 
value: ___________ 
Date: __ __ / __ __ / __ __ 
INR 
value: ___________ 
Date: __ __ / __ __ / __ __ 
Serum bilirubin 
value: ___________ 
Date: __ __ / __ __ / __ __ 
ALT 
value: ___________ 
Date: __ __ / __ __ / __ __ 
AST 
value: ___________ 
Date: __ __ / __ __ / __ __ 
3.1.4 
ECOG performance status ≤ 2 (Karnofsky ≥ 
60%, see Appendix A). 
 
 
ECOG value: ___________ 
Karnofsky Status: __________ 
Date: __ __ / __ __ / __ __ 
3.1.5 
Discontinuation of anti-coagulants and anti-
platelet drugs at least 7 days prior to start of 
study drug. Aspirin 81 mg is permitted as long 
as platelet count is > 50 and there is no 
evidence of active bleeding or coagulopathy 
(INR > 1.5, fibrinogen > 150. 
 
 
Date anticoagulant or anti-platelet 
discontinued: 
__ __ / __ __ / __ __ 
 
3.1.6 
No uncontrolled infections as determined by 
the investigator 
 
 
 
3.1.7 
No clinically significant thyroid disease (e.g. 
hyperthyroid/hypothyroidism) 
 
 
 


 
A Phase II Proof-of-Concept Trial to Study Kinase Inhibition in Relapsed/Refractory Acute 
Leukemias: Using a Comprehensive In Vitro Kinase Inhibitor Panel to Select Individualized, 
Targeted Therapies 
IRB # 7195 
SUBJECT ID: _________________                                              INITIALS: _________________ 
 
 
Preparer’s Signature/Initials:                                                               Date: 
Protocol Version Date 10/03/2017 
 
Page 2 
   Registration Packet v4 
3.1.8 
No active GVHD: Patients with a history of 
stem cell transplant are eligible but cannot 
have evidence of active GVHD as determined 
by the investigator. 
 
 
 
3.1.9 
Must be able to take oral medication. 
 
 
 
3.1.10 
Women of childbearing potential must have a 
negative serum or urine pregnancy test 
(sensitivity < 25 IU HCG/L) within 72 hours 
prior to the start of study drug. 
 
 
Date pregnancy test: 
__ __ / __ __ / __ __ 
Time pregnancy test: 
__ __ : __ __ (24 clock) 
3.1.11 
Persons of reproductive potential must agree 
to use an adequate method of contraception 
throughout treatment and for at least 4 weeks 
after study drug is stopped. Women of 
childbearing potential and men with a sexual 
partner of childbearing potential must be 
advised of the importance of avoiding 
pregnancy during trial participation and the 
potential risk factors for an unintentional 
pregnancy. 
 
 
 
 
 
Type of Contraception: 
___________________________
___________________________ 
 
3.1.12 
Ability to understand and the willingness to 
sign a written informed consent and HIPAA 
document. 
 
 
 
3.1.13 
Serum Na, K, Mg, and total serum Ca or 
ionized Ca levels must be greater than or 
equal to the institutional lower limit of 
normal.  Subjects with low K or Mg levels, 
total corrected serum Ca and/or ionized Ca 
must be replete for protocol entry. 
 
 
Date: __ __ / __ __ / __ __ 
Na value: ___________ 
K value: ___________ 
Mg value: ___________ 
Serum Ca value: ___________ 
Ionized Ca value: ___________ 
DRUG SPECIFIC INCLUSION CRITERIA  
Each subject must meet the specific inclusion criteria to be administered a specific study drug:  
Drug  
CRITERIA 
YES 
NO 
VALUES  
Ponatinib 
Female and male patients who are 
fertile must agree to use an effective 
form of contraception with their sexual 
partners from randomization through 4 
 
 
 


 
A Phase II Proof-of-Concept Trial to Study Kinase Inhibition in Relapsed/Refractory Acute 
Leukemias: Using a Comprehensive In Vitro Kinase Inhibitor Panel to Select Individualized, 
Targeted Therapies 
IRB # 7195 
SUBJECT ID: _________________                                              INITIALS: _________________ 
 
 
Preparer’s Signature/Initials:                                                               Date: 
Protocol Version Date 10/03/2017 
 
Page 3 
   Registration Packet v4 
months after the end of treatment. 
Discontinuation of any medications 
known to contribute significantly to the 
risk of QT prolongation at least 48 
hours prior to start of study drug. 
Levaquin and Zofran are an exception. 
Of note, certain agents that prolong the 
QTc may be allowed but only after 
discussion with the chemotherapy 
pharmacist. Should the investigator 
believe that therapy with a potentially 
QT prolonging medication is vital to an 
individual 
subject’s 
care, 
then 
additional ECGs should be done at the 
investigator’s discretion to ensure the 
subject’s safety.  
 
 
 
QT prolongation medication: 
___________________________ 
Date Discontinued:  
__ __ / __ __ / __ __ 
Serum lipase and amylase ≤1.5 × ULN 
 
 
Serum lipase 
value: ___________ 
Date: __ __ / __ __ / __ __ 
Serum Amylase 
value: ___________ 
Date: __ __ / __ __ / __ __ 
Dasatinib 
Discontinuation of any medications 
known to contribute significantly to the 
risk of QT prolongation at least 48 
hours prior to start of study drug. 
Levaquin and Zofran are an exception. 
Of note, certain agents that prolong the 
QTc may be allowed but only after 
discussion with the chemotherapy 
pharmacist. Should the investigator 
believe that therapy with a potentially 
QT prolonging medication is vital to an 
individual 
subject’s 
care, 
then 
additional ECGs should be done at the 
investigator’s discretion to ensure the 
subject’s safety.  
 
 
QT prolongation medication: 
___________________________ 
Date Discontinued:  
__ __ / __ __ / __ __ 


 
A Phase II Proof-of-Concept Trial to Study Kinase Inhibition in Relapsed/Refractory Acute 
Leukemias: Using a Comprehensive In Vitro Kinase Inhibitor Panel to Select Individualized, 
Targeted Therapies 
IRB # 7195 
SUBJECT ID: _________________                                              INITIALS: _________________ 
 
 
Preparer’s Signature/Initials:                                                               Date: 
Protocol Version Date 10/03/2017 
 
Page 4 
   Registration Packet v4 
Women of childbearing potential 
(WOCBP) must have a negative serum 
or urine pregnancy test (minimum 
sensitivity 25 IU/L or equivalent units 
of HCG) within 24 hours prior to the 
start of study drug. 
 
 
 
Men who are sexually active with 
WOCBP must agree to follow 
instructions for method(s) of 
contraception for the duration of 
treatment with study drug plus 90 days 
(duration of sperm turnover) for a total 
of 90 days post-treatment completion. 
 
 
 
Azoospermic males and WOCBP, who 
are not heterosexually active, are 
exempt from contraceptive 
requirements.  However, WOCBP must 
still under pregnancy testing as 
described in this section. 
 
 
 
Investigators shall counsel WOCBP and 
male subjects who are sexually active 
with WOCBP on the importance of 
pregnancy prevention and the 
implications of unexpected pregnancy.  
Investigators shall advise WOCBP and 
male subjects who are sexually active 
with WOCBP on the use of highly 
effective contraception.  Highly 
effective methods of contraception have 
a failure rate of <1% when used 
consistently and correctly. 
 
 
 
At a minimum, subjects must agree to 
the use of two methods of 
contraception, with one method being 
highly effective and the other method 
being either highly effective or less 
effective as listed below. 
 
 
 
Sorafenib 
Creatinine <1.5 X ULN 
 
 
Creatinine: _______________ 
Date:  
__ __ / __ __ / __ __ 


 
A Phase II Proof-of-Concept Trial to Study Kinase Inhibition in Relapsed/Refractory Acute 
Leukemias: Using a Comprehensive In Vitro Kinase Inhibitor Panel to Select Individualized, 
Targeted Therapies 
IRB # 7195 
SUBJECT ID: _________________                                              INITIALS: _________________ 
 
 
Preparer’s Signature/Initials:                                                               Date: 
Protocol Version Date 10/03/2017 
 
Page 5 
   Registration Packet v4 
Pacritinib 
Discontinuation of any medications 
known to contribute significantly to 
the risk of QT prolongation at least 
48 hours prior to start of study drug. 
Levaquin 
and 
Zofran 
are 
an 
exception. Of note, certain agents 
that prolong the QTc may be 
allowed but only after discussion 
with the chemotherapy pharmacist. 
Should the investigator believe that 
therapy 
with 
a 
potentially 
QT 
prolonging medication is vital to an 
individual 
subject’s 
care, 
then 
additional ECGs should be done at 
the 
investigator’s 
discretion 
to 
ensure the subject’s safety.  
 
 
 
EXCLUSION CRITERIA 
 
Each subject must not meet any of the following exclusion criteria: 
 
 
3.3 CRITERIA 
YES 
NO 
VALUES 
  3.3.1 
Any leukemia treatment within 1 week (for 
cytotoxic therapy) and/or 5 half lives (for 
targeted agents) prior to starting study drug.  
Corticosteroids are allowable throughout the 
study to treat concomitant medical disorders 
per provider discretion. Hydroxyurea is 
allowed prior to enrollment and after the start 
of the study drug for the control of peripheral 
leukemic blasts in subjects with leukocytosis 
per physician discretion. 
 
 
Chemotherapy, radiotherapy, 
immunotherapy or investigational 
agent: 
___________________________ 
Date Discontinued:  
__ __ / __ __ / __ __ 
3.3.2 
Recent uncontrolled angina, recent >NYHA 
class III congestive heart failure, or recent MI 
(within 6 months) prior to start of study 
treatment. 
 
 
Description: 
___________________________
___________________________ 
 
3.3.3 
Diagnosed congenital long QT syndrome 
 
 
Date of Dx:  
__ __ / __ __ / __ __ 
3.3.4 
Any recent history of clinically significant 
 
 
Description: 


 
A Phase II Proof-of-Concept Trial to Study Kinase Inhibition in Relapsed/Refractory Acute 
Leukemias: Using a Comprehensive In Vitro Kinase Inhibitor Panel to Select Individualized, 
Targeted Therapies 
IRB # 7195 
SUBJECT ID: _________________                                              INITIALS: _________________ 
 
 
Preparer’s Signature/Initials:                                                               Date: 
Protocol Version Date 10/03/2017 
 
Page 6 
   Registration Packet v4 
ventricular arrhythmias (such as ventricular 
tachycardia, ventricular fibrillation, or 
Torsade’s de pointes). 
___________________________
___________________________ 
3.3.5 
History of clinically significant bleeding 
disorder unrelated to cancer. 
 
 
Description: 
___________________________ 
3.3.6 
Drugs that affect the CYP3A4 system 
(inducers/inhibitors/substrates) are allowed 
but should be used with caution (see appendix 
D) depending on   specific kinase inhibitor 
used. Dietary supplements will be 
discouraged; however, their use may be 
allowed on a case by case basis per the 
discretion of the investigator after 
consultation with an oncology pharmacist. 
 
 
 
3.3.7 
Uncontrolled intercurrent illness that would 
limit compliance with study requirements. 
 
 
 
3.3.8 
Pregnant or lactating women are excluded 
from this study because of possible risk to the 
fetus or infant 
 
 
 
3.3.9 
Known HIV-positive patients are excluded 
from the study because of possible risk of 
lethal infection when treated with marrow 
suppressive therapy. 
 
 
 
Date of dx: 
 __ __ / __ __ / __ __ 
3.3.10 
History of hypersensitivity to any of the 
kinase inhibitors included in this study. 
 
 
 
 
DRUG SPECIFIC EXCLUSION CRITERIA  
Each subject must not meet any of the following exclusion criteria for each specific study drug: 
Drug 
CRITERIA 
YES 
NO 
VALUES 
Ponatinib  
History of acute pancreatitis within 
1 year of study or history of chronic 
pancreatitis 
 
 
Date of Dx:  
__ __ / __ __ / __ __  
QTC >450 msec for men and > 470 
msec for women.  
 
 
QTcB: _______________ 
Dates of ECG: 
__ __ / __ __ / __ __ 


 
A Phase II Proof-of-Concept Trial to Study Kinase Inhibition in Relapsed/Refractory Acute 
Leukemias: Using a Comprehensive In Vitro Kinase Inhibitor Panel to Select Individualized, 
Targeted Therapies 
IRB # 7195 
SUBJECT ID: _________________                                              INITIALS: _________________ 
 
 
Preparer’s Signature/Initials:                                                               Date: 
Protocol Version Date 10/03/2017 
 
Page 7 
   Registration Packet v4 
Uncontrolled hypertriglyceridemia 
(triglycerides >450 mg/dL)  
 
 
 
Any 
history 
of 
myocardial 
infarction, 
stroke, 
or 
revascularization. 
 
 
Date of Dx:  
__ __ / __ __ / __ __ 
 
Description: 
___________________________ 
Any history of venous 
thromboembolism including deep 
venous thrombosis or pulmonary 
embolism. 
 
 
Date of Dx:  
__ __ / __ __ / __ __  
Unstable 
angina 
or 
transient 
ischemic attack within 6 months 
prior to start of study treatment. 
 
 
Date of Dx:  
__ __ / __ __ / __ __  
History of clinically significant (as 
determined 
by 
the 
treating 
physician) atrial arrhythmia. 
 
 
Date of Dx:  
__ __ / __ __ / __ __ 
Congestive hear failure within 6 
months prior to enrollment, or left 
ventricular ejection fraction (LVEF) 
less than lower limit of normal per 
local institutional standards within 6 
months prior to enrollment. 
 
 
Date of Dx:  
__ __ / __ __ / __ __  
Uncontrolled hypertension (diastolic 
blood pressure >90 mm Hg; systolic 
>140 
mm 
Hg).  
Patients 
with 
hypertension 
should 
be 
under 
treatment on study entry to effect 
blood pressure control. 
 
 
BP: 
History of ongoing alcohol abuse. 
 
 
 
Ocular toxicity present as measure 
during a comprehensive eye exam. 
 
 
Date of Exam:  
__ __ / __ __ / __ __ 
Dasatinib 
Known pulmonary arterial 
hypertension 
 
 
Date of Dx:  
__ __ / __ __ / __ __ 
Patients may not have a clinically 
 
 
Date of Dx:  


 
A Phase II Proof-of-Concept Trial to Study Kinase Inhibition in Relapsed/Refractory Acute 
Leukemias: Using a Comprehensive In Vitro Kinase Inhibitor Panel to Select Individualized, 
Targeted Therapies 
IRB # 7195 
SUBJECT ID: _________________                                              INITIALS: _________________ 
 
 
Preparer’s Signature/Initials:                                                               Date: 
Protocol Version Date 10/03/2017 
 
Page 8 
   Registration Packet v4 
significant pleural or pericardial 
effusion.  
__ __ / __ __ / __ __ 
Uncontrolled hypertension: inability 
to maintain blood pressure below the 
limit of 140/90mgHg. 
 
 
 
Any history of second or third 
degree heart block (may be eligible 
of the subject currently has a 
pacemaker) 
 
 
 
Prolonged QTc interval (>450 msec 
for men and >470 msec for women) 
on pre-entry electrocardiogram. 
 
 
Date of Sx/Bx/traumatic injury:  
__ __ / __ __ / __ __ 
Sorafenib 
Non-healing wound, ulcer, or bone 
fracture. 
 
 
 
Thrombotic or embolic venous or 
arterial events, such as 
cerebrovascular accident, including 
transient ischemic attacks, arterial 
thrombosis, deep vein thrombosis 
and pulmonary embolism within the 
past 6 months 
Line associated DVTs which are 
adequately treated (line removed 
and/or patient anticoagulated). 
 
 
 
Uncontrolled hypertension. 
 
 
 
Active bleeding during screening. 
 
 
 
Major 
surgery, open biopsy, or 
significant traumatic injury within 
30 days. 
 
 
 
Idelalisib 
Ongoing drug-induced liver injury, 
chronic active hepatitis C (HCV), 
chronic active hepatitis B (HBV), 
alcoholic liver disease, non-
alcoholic steatohepatitis, primary 
biliary cirrhosis, extrahepatic 
obstruction caused by cholelithiasis, 
 
 
 


 
A Phase II Proof-of-Concept Trial to Study Kinase Inhibition in Relapsed/Refractory Acute 
Leukemias: Using a Comprehensive In Vitro Kinase Inhibitor Panel to Select Individualized, 
Targeted Therapies 
IRB # 7195 
SUBJECT ID: _________________                                              INITIALS: _________________ 
 
 
Preparer’s Signature/Initials:                                                               Date: 
Protocol Version Date 10/03/2017 
 
Page 9 
   Registration Packet v4 
cirrhosis of the liver, portal 
hypertension, or history of 
autoimmune hepatitis. 
Ongoing symptomatic pneumonitis. 
 
 
 
Ongoing inflammatory bowel 
disease or autoimmune colitis. 
 
 
 
Ongoing CMV infection, treatment, 
or prophylaxis within the past 28 
days prior to the screening test for 
active CMV. 
 
 
 
History of serious allergic reaction 
including anaphylaxis and epidermal 
necrolysis. 
 
 
 
Ruxolitinib 
Evidence of hepatitis B virus (HBV) 
or hepatitis C virus (HCV) infection 
or risk of reactivation: HBV DNA 
and HCV RNA must be 
undetectable. Subjects cannot be 
positive for hepatitis B surface 
antigen (HBsAg) or anti–hepatitis B 
core antibody. Subjects who have 
positive anti-HBs as the only 
evidence of prior exposure may 
participate in the study provided that 
there is both 1) no known history of 
HBV infection, and 2) verified 
receipt of hepatitis B vaccine.  
 
 
 
Pacritinib 
Major 
surgery, open biopsy, or 
significant traumatic injury within 
30 days. 
 
 
 
 
Active bleeding during screening. 
 
 
 
 
QTC >450 mSec for men and > 470 
msec for women. 
 
 
 


 
A Phase II Proof-of-Concept Trial to Study Kinase Inhibition in Relapsed/Refractory Acute 
Leukemias: Using a Comprehensive In Vitro Kinase Inhibitor Panel to Select Individualized, 
Targeted Therapies 
IRB # 7195 
SUBJECT ID: _________________                                              INITIALS: _________________ 
 
 
Preparer’s Signature/Initials:                                                               Date: 
Protocol Version Date 10/03/2017 
 
Page 10 
   Registration Packet v4 
 
NYHA Class II Congestive Heart 
Failure (a history of CHF is allowed 
as long as this has resolved to < 
NYHA Class II within 30 days of 
initiation of pacritinib. 
 
 
 
 
 
ELIGIBILITY SUMMARY  
 
 Eligible 
 
 Ineligible, subject is a screen fail 
 
 Ineligible, waiver granted 
 
If waiver granted, list criteria and rationale:  
 
 
 
 
 
 
 
INVESTIGATOR NAME 
 
INVESTIGATOR SIGNATURE   
DATE  
 


 
A Phase II Proof-of-Concept Trial to Study Kinase Inhibition in Relapsed/Refractory Acute 
Leukemias: Using a Comprehensive In Vitro Kinase Inhibitor Panel to Select Individualized, 
Targeted Therapies 
IRB # 7195 
SUBJECT ID: _________________                                              INITIALS: _________________ 
 
 
Preparer’s Signature/Initials:                                                               Date: 
Protocol Version Date 10/03/2017 
 
Page 11 
   Registration Packet v4 
PARTICIPANT REGISTRATION 
 
Date Screening Consent Signed 
__ __ / __ __ / __ __  
Meets Eligibility Inclusion/Exclusion 
 Yes    
 No      
__ __ / __ __ / __ __ 
ECOG/Karnofsky Score Assessed 
 Yes    
 No      
__ __ / __ __ / __ __ 
Vitals Assessed 
 Yes    
 No      
__ __ / __ __ / __ __ 
Pregnancy test performed?  
 Yes    
 No     
 NA   __ __ / __ __ / __ __ 
Bone marrow exam completed 
 Yes    
 No     
 NA   __ __ / __ __ / __ __ 
Skin biopsy sent to central lab 
 Yes    
 No     
 NA   __ __ / __ __ / __ __ 
PK assessment performed? 
 Yes    
 No      
__ __ / __ __ / __ __ 
Chest X-ray  
 Yes    
 No      
__ __ / __ __ / __ __ 
ECG (12 lead) 
 Yes    
 No      
__ __ / __ __ / __ __ 
Chemistry performed (sodium, potassium, 
chloride, carbon dioxide, glucose, blood urea 
nitrogen, creatinine, total bilirubin, ALT, AST, total 
protein, alkaline phosphatase, uric acid, calcium, 
Lactate dehydrogenase (LDH), phosphorus, 
magnesium) 
 Yes    
 No      
__ __ / __ __ / __ __ 
CBC w/ extended differential performed  
 Yes    
 No      
__ __ / __ __ / __ __ 
INR/PTT Performed? 
 Yes    
 No      
__ __ / __ __ / __ __ 
Study Drug Selected for Treatment  
 Sorafenib   
 Ponatinib 
 Sunitinib    
 Dasatinib 
 Ruxolitinib    
 Idelalisib