Clinical trial NCT03557970
Conditions: Recurrent Acute Myeloid Leukemia Refractory Acute Myeloid Leukemia
Sponsor: OHSU Knight Cancer Institute
Start date: 2018-10-05; Completion date: 2020-09-28
Enrollment: 3 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This phase II trial studies how well edicotinib (JNJ-40346527) works in treating participants with acute myeloid leukemia that has come back or does not respond to treatment. JNJ-40346527 may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth.

Detailed description:
PRIMARY OBJECTIVE:

Evaluate preliminary efficacy of JNJ-40346527 in participants with relapsed/refractory AML.

I. Best objective response rate (\> PR).

SECONDARY OBJECTIVES:

Assess safety and survival associated with JNJ-40346527 to treat participants with relapsed/refractory AML. Assess the duration of disease response associated with JNJ-40346527.

I. Overall incidence of treatment-related and non-treatment related toxicity. II. Duration of response. III. 12-month event-free survival. IV. 12-month overall survival.

EXPLORATORY OBJECTIVES:

I. Evaluate the pharmacokinetics of JNJ-40346527 and effective inhibition of CSF-1R in marrow aspirates using plasma inhibitory assays, with established CSF-1R-sensitive cell lines.

II. Identify the effect of JNJ-40346527 on leukemia cells and the immune microenvironment.

III. Identify and quantify the specific subpopulation of cells that express CSF-1R in participants and correlate these with clinical response to JNJ-40346527.

IV. Analyze the frequency of mutations using genomic deoxyribonucleic acid (DNA) from leukemia participants to determine if there is a genetic signature that predicts response to JNJ-40346527.

V. Using ribonucleic acid (RNA) sequencing (RNAseq), identify an expression signature in CSF-1R+ cells that predicts patient response.

VI. Evaluate the effect of JNJ-40346527 on immune cell populations (cytotoxic T cells, etc.) and phospho-signaling proteins by mass cytometry (CyTOF) analysis in pre- and post-treatment samples in order to identify biomarkers that predict patient response and prioritize potential combination strategies for future clinical trials.

VII. Determine how leukemia cells change in response to CSF-1R inhibition by assessing cells collected pre- and post-treatment using an ex vivo sensitivity to a panel of small molecule inhibitors to determine what new drug sensitivities may emerge in AML cells after CSF-1R inhibition.

OUTLINE:

Participants receive JNJ-40346527 orally (PO) twice a day (BID) on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, participants are followed up within 2 weeks, at 4-6 weeks until death or minimum of 12 months.

Arms: arm 1: Participants receive JNJ-40346527 PO BID on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Interventions: intervention 1: Edicotinib intervention 2: Pharmacokinetic Study
Intervention descriptions: intervention 1: Given PO intervention 2: Correlative studies

Protocol documents:
Prot_SAP_000.pdf: 
 
Study Title: A Phase 2 open-label study of the CSF-1R inhibitor JNJ-40346527 
in patients with relapsed/refractory acute myeloid leukemia (AML) 
Protocol Number:  17583, NCT03557970 
Investigational product: JNJ-40346527 
Version Number:  Version 5 
Version Date: 24 MAR 2020 
Replaces: 4 
IND/IDE Status: IND139441 
Sponsor Oregon Health & Science University 
Investigational Drug & 
Funding Support: 
 
Funding:  
JNJ-40346527,  
Janssen Research & Development, LLC 
 
LLS 
  
Principal Investigator: Elie Traer, MD PhD  
Department of Medicine, Division of Hematology & Oncology 
Oregon Health & Science University 
3181 SW Sam Jackson Park Road, 
Portland, OR 97239  
Phone: 503-494-7999 
Email: traere@ohsu.edu 
 
Participating 
Investigator(s): 
Rachel Cook, MD 
Department of Medicine, Division of Hematology & Oncology 
Oregon Health & Science University 
3181 SW Sam Jackson Park Road, 
Portland, OR 97239  
Phone: 503-494-9630 
Fax: 503-494-3465 
Email: coora@ohsu.edu 
 
Uma Borate, MD 
Department of Medicine, Division of Hematology & Oncology 
Oregon Health & Science University 
3181 SW Sam Jackson Park Road, 
Portland, OR 97239  
Phone: 503-418-2294 
Email: borate@ohsu.edu 
 
 
 
Statistician: 
Jessica Minnier, PhD  
Biostatistics Shared Recourse 
Knight Cancer Institute  
Phone: 503-494-3967 
Email: minnier@ohsu.edu 
 
 


 
A Phase 2 study of the CSF-1R inhibitor, JNJ-40346527, in relapsed/refractory acute myeloid leukemia  
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PI: Elie Traer 
 
SUMMARY OF CHANGES 
 
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Section 
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Justification 
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time of this update  
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5.1.8.2; 
7.1.6 
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Appendix D 
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7.2.5;7.2.7 51 
Edited Collection Requirements Clarified SOC collection vs 
collection for lab 
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7.3.1 
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Correcting for consistency 
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7.3.3 
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Updated appendix reference 
To reference correct appendix 
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Appendix 
D 
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Protocol 
Not needed in protocol if 
uploaded to IRB separately 
(allows for easier updates to 
just the drug diary) 
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F 
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from Protocol 
Not needed in protocol if 
uploaded to IRB separately 
(allows for easier updates to 
just the Enrollment Packet) 
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Appendix 
E 
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A Phase 2 study of the CSF-1R inhibitor, JNJ-40346527, in relapsed/refractory acute myeloid leukemia  
17583  
Version # 5 
24 MAR 2020 
PI: Elie Traer 
 
SYNOPSIS 
 
Study Title 
A Phase 2 open-label study of the CSF-1R inhibitor JNJ-
40346527 in patients with relapsed/refractory acute myeloid 
leukemia (AML) 
Protocol # 17583 
Study Center: multicenter [U.S. only]    
Clinical Phase: Phase II - Single Agent  
 
Investigational 
Components:  1. In vitro Diagnostic Device  
2. Investigational Drug 
Interventional 
Study Type: Multi-arm 
 
Précis: 
 
Targeting and depleting tumor-associated macrophages is 
emerging as an attractive anti-tumor therapeutic approach, and 
the CSF-1/CSF-1R pathway is a particularly attractive molecular 
target to selectively inhibit the recruitment, activation, polarization, 
and survival of immunosuppressive tumor-associated 
macrophages. Clinical evidence suggests that drugs targeting 
intrinsic CSF-1R tyrosine kinase activity provide some degree of 
clinical benefit. This trial will evaluate the preliminary efficacy of 
the small molecule inhibitor, JNJ-40346527, which will selectively 
inhibit CSF-1R tyrosine kinase activity in patients with relapsed or 
refractory acute myeloid leukemia (AML). The underlying 
hypothesis is that JNJ-40346527 targets a subpopulation of 
supportive cells, which leads to interruption of paracrine survival 
signals to AML cells, and subsequent leukemic cell death. In this 
study, the sensitivity of participants' AML cells to the CSF-1R 
inhibitor, JNJ-40346527, will be evaluated using a functional ex 
vivo screening platform. Based on the results of this in vitro drug 
screen, participants will be assigned to either the study drug 
sensitive (i.e., Assay positive) or insensitive (i.e., Assay negative) 
arms. Both arms will receive the same treatment of JNJ-40346527 
(150mg, PO b.i.d) over a continuous 28 day cycle. Participants 
will continue to receive study agent until disease progression.   
 
Primary Objectives Evaluate preliminary efficacy of JNJ-40346527 in participants with 
relapsed/refractory AML.   
1. Best objective response rate (>PR) 
Secondary Objectives Assess safety and survival associated with JNJ-40346527 to treat 
participants with relapsed/refractory AML. Assess the duration of 
disease response associated with JNJ-40346527. 
1. Overall incidence of treatment-related and non-treatment 
related toxicity.  
2. Duration of response. 
3. 12-month event-free survival.  
4. 12-month overall survival. 


 
A Phase 2 study of the CSF-1R inhibitor, JNJ-40346527, in relapsed/refractory acute myeloid leukemia  
17583  
Version # 5 
24 MAR 2020 
PI: Elie Traer 
 
Exploratory Objectives 1. Evaluate the pharmacokinetics of JNJ-40346527 and effective 
inhibition of CSF-1R in marrow aspirates using plasma 
inhibitory assays with established CSF-1R-sensitive cell lines. 
2. Identify the effect of JNJ-40346527 on leukemia cells and the 
immune microenvironment. 
3. Analyze the frequency of mutations using genomic DNA from 
leukemia participants to determine if there is a genetic 
signature that predicts response to JNJ-40346527. 
4. Using RNA sequencing (RNAseq), identify an expression 
signature in CSF-1R+ cells that predicts patient response.  
5. Evaluate the effect of JNJ-40340346527 on immune cell 
populations (cytotoxic T cells, etc.) and phospho-signaling 
proteins by CyTOF analysis in pre- and post-treatment 
samples in order to identify biomarkers that predict patient 
response and prioritize potential combination strategies for 
future clinical trials. 
6. Determine how leukemia  cells change in response to CSF-1R 
inhibition by assessing cells collected pre- and post-treatment 
using an ex vivo sensitivity to a panel of small molecule 
inhibitors to determine what new drug sensitivities may 
emerge in AML cells after CSF-1R inhibition. 
 
Number of 
Participants 
Up to 28 participants (14 in each arm) will be enrolled. There will 
be 7 patients in Stage I and 7 patients in Stage II with the total of 
14 patients per arm. Given the expected accrual rate of 14 
participants per year, the study is expected to take 36 months (24 
months of accrual period and the minimum follow-up of 12 
months).  
Duration of Therapy 
Participants demonstrating favorable response to treatment are 
eligible to continue additional cycles of study agent until disease 
progression, death, or investigator discretion.  
Duration of Follow Up Until death or minimum of 12 months follow-up from the last dose 
of JNJ-40346527. 
Inclusion Criteria 
 
1. Ability to understand and the willingness to sign a written 
informed consent document. 
2. Age ≥18 years at time of informed consent.  Both men and 
women and members of all races and ethnic groups will be 
included.  
3. Morphologically documented relapsed/refractory AML as 
defined by World Health organization (WHO) criteria after at 
least 1 prior therapy for AML with the exception of 
hydroxyurea, and not felt to have curative treatment options 
per treating physician, or the patients themselves are unwilling 
to consider curative treatment options.  
 


 
A Phase 2 study of the CSF-1R inhibitor, JNJ-40346527, in relapsed/refractory acute myeloid leukemia  
17583  
Version # 5 
24 MAR 2020 
PI: Elie Traer 
 
4. Sufficient and viable bone marrow aspirate or peripheral blood 
collection to use for the ex vivo sensitivity assay. 
5. ECOG performance status 0 to 2 (Refer to Appendix A) 
6. Women must not be pregnant or breastfeeding. Women of 
childbearing potential must have a negative serum or urine 
pregnancy test within 14 days prior to start of study drug 
administration. 
7. Participants must agree to use an adequate method 
contraception (see Appendix C). 
8. Must be able to take oral medications. 
9. Adequate organ function as defined by the following: 
a. Serum creatinine ≤2× the upper limit of normal (ULN), or 
glomerular filtration rate >20ml/min as calculated by 
Cockgroft-Gault formula. 
b. Serum potassium, magnesium, and calcium (corrected for 
albumin) within institutional normal limits or can be 
corrected with supplementation. 
c. Total serum bilirubin ≤2.5× ULN. 
d. Serum aspartate transaminase (AST) and/or alanine 
transaminase (ALT) ≤2.5× ULN. 
 
Exclusion Criteria 
 
1. Diagnosis of acute promyelocytic leukemia (APL, or AML M3 
subtype) 
2. Active central nervous system involvement with AML 
3. Concurrent active malignancy with expected survival of less 
than 1 year. For example, candidates with treated skin 
cancers, prostate cancer, breast cancer, etc. without 
metastatic disease are candidates for therapy since their 
expected survival exceeds that of relapsed or refractory AML. 
All subjects with concurrent malignancies will be reviewed by 
the PI prior to enrollment. 
4. Clinically significant GVHD or active GVHD requiring initiation 
or escalation of treatment within 28 day screening period 
5. Clinically significant coagulation abnormality, such as 
disseminated intravascular coagulation. 
6. Participants who are currently receiving any other 
investigational agents. 
7. Previous treatment with CSF-1R kinase inhibitor or CSF-1R 
blocking antibody. 
8. Known clinically significant liver disease defined as ongoing 
drug-induced liver injury, chronic active hepatitis C (HCV), 
chronic active hepatitis B (HBV), alcoholic liver disease, non-


 
A Phase 2 study of the CSF-1R inhibitor, JNJ-40346527, in relapsed/refractory acute myeloid leukemia  
17583  
Version # 5 
24 MAR 2020 
PI: Elie Traer 
 
alcoholic steatohepatitis, primary biliary cirrhosis, extrahepatic 
obstruction caused by cholelithiasis, cirrhosis of the liver, 
portal hypertension, or history of autoimmune hepatitis. 
Untreated HIV or active hepatitis C detectable by PCR, or 
chronic hepatitis B (patients positive for hepatitis B core 
antibody who are receiving IVIG are eligible if HepB PCR is 
negative). 
9. Untreated HIV or active hepatitis C detectable by PCR, or 
chronic hepatitis B (patients positive for hepatitis B core 
antibody who are receiving IVIG are eligible if HepB PCR is 
negative). 
10. Known history of cerebrovascular accident, myocardial 
infarction, or intracranial hemorrhage within 2 months of 
enrollment. 
11. Clinically significant surgery within 2 weeks of enrollment.  
12. Per PI discretion, active infection that is not well controlled by 
antibacterial or antiviral therapy. 
13. Cancer-directed therapy within 2 weeks prior to starting 
treatment, with the exception of hydroxyurea, which is allowed 
to control white blood cell count. Hydroxyurea will be weaned 
as soon as clinically feasible. 
14. Unwillingness to receive infusion of blood products. 
15. Drugs that affect the CYP3A4 systems are allowed and 
essential for cancer patients, including anti-fungals but should 
be used with caution.  
16. Patients with uncontrolled white blood cell count (defined as 
>50 K/cu mm not controlled with hydrea). 
 
 
Investigational 
Product(s) 
JNJ-40346527 will be administered at a dose of 150 mg PO twice 
daily in continuous 28-day cycles 
 
Statistical 
Considerations 
A Simon 2-stage minimax design will be used to determine clinical 
efficacy. For each arm, 7 participants will be enrolled in the first 
stage. If there is at least 1 response among the first 7 participants, 
the trial will proceed to the second stage and enroll an additional 
7 participants. The treatment is considered promising if there are 
at least 3 responses among 14 participants. The study has 80% 
power to test the best objective response rate of 5% (poor) vs. 
30% (desirable) using one-sided 5% significance level.  
Efficacy Assessments  
Assess the best objective response rate, duration of response to 
JNJ-40346527, overall survival and event-free survival in 
participants with relapsed/refractory AML as stratified by ex vivo 


 
A Phase 2 study of the CSF-1R inhibitor, JNJ-40346527, in relapsed/refractory acute myeloid leukemia  
17583  
Version # 5 
24 MAR 2020 
PI: Elie Traer 
 
 
 
 
sensitivity.  
Safety Assessments  
Monitor Grade 3 or higher treatment-related toxicities. Study 
enrollment will be suspended if the lower 90% confidence interval 
for Grade 3 or higher treatment-related toxicity exceeds 30% 
(considered acceptable dose-limiting toxicity (DLT) incidence).   


 
A Phase 2 study of the CSF-1R inhibitor, JNJ-40346527, in relapsed/refractory acute myeloid leukemia  
17583  
Version # 5 
24 MAR 2020 
PI: Elie Traer 
 
SCHEMATIC OF STUDY DESIGN  
 
 
Figure 1. Overview of study design.  
Eligible participants with relapsed/refractory AML will undergo bone marrow biopsy and AML 
cells will be assessed for CSF-1R sensitivity to JNJ-40346527 using an ex vivo drug 
screening platform. Participants with disease sensitive to JNJ-40346527 in ex vivo screening 
will be assigned to the “assay positive” arm. Those deemed insensitive are assigned to the 
“assay negative” arm.  Patients that screen fail the assay will not be included in the study. 
Patients can rescreen per provider discretion. Both arms will receive the same treatment of 
JNJ-40346527 (150mg, PO b.i.d) over a continuous 28 day cycle. Participants will continue 
to receive study agent until disease progression.  An efficacy stopping rule will halt study 
enrollment to one or both arms if there is no response among the first 7 participants. Excess 
toxicity will also suspend enrollment if the incidence of grade 3 or higher treatment-related 
toxicity significantly exceeds 30%.   


 
A Phase 2 study of the CSF-1R inhibitor, JNJ-40346527, in relapsed/refractory acute myeloid leukemia  
17583  
Version # 5 
24 MAR 2020 
PI: Elie Traer 
 
TABLE OF CONTENTS 
SUMMARY OF CHANGES ..................................................................................................... 2 
SYNOPSIS.............................................................................................................................. 3 
SCHEMATIC OF STUDY DESIGN .......................................................................................... 8 
LIST OF TABLES ................................................................................................................. 15 
LIST OF FIGURES................................................................................................................ 16 
LIST OF ABBREVIATIONS................................................................................................... 17 
1. BACKGROUND INFORMATION AND SCIENTIFIC RATIONALE ..................................... 20 
1.1 
Overview of Relapsed/Refractory Acute Myeloid Leukemia..................................... 20 
1.2 
Colony Stimulating Factor-1 receptor ..................................................................... 20 
1.2.1 CSF-1/CSF-1R signaling and cancer ................................................................. 21 
1.3 
Overview of JNJ-40346527 .................................................................................... 22 
1.3.1 Mechanism of action for JNJ-40346527 ............................................................. 23 
1.3.2 Pre-clinical experience ...................................................................................... 23 
1.3.2.1 
Pharmacokinetics and metabolism ..................................................... 23 
1.3.2.2 
Preclinical toxicities ........................................................................... 24 
1.3.3 Clinical studies of JNJ-40346527 ....................................................................... 24 
1.3.3.1 
Pharmacokinetics in Humans............................................................. 24 
1.3.3.2 
Metabolism in Humans ...................................................................... 24 
1.3.3.3 
Drug Interactions ............................................................................... 25 
1.3.3.4 
Safety in Humans .............................................................................. 25 
1.3.3.5 
Efficacy in Humans............................................................................ 25 
1.3.4 Small Molecular Kinase Inhibitor Screen ............................................................ 26 
1.4 
Rationale ............................................................................................................... 26 
1.4.1 Dose rationale................................................................................................... 26 
1.5 
Potential Risks and Benefits................................................................................... 26 
1.5.1 Known Potential Risks....................................................................................... 26 
1.5.2 Known Potential Benefits................................................................................... 27 
1.6 
Correlative Studies Background ............................................................................. 27 
2. OBJECTIVES ................................................................................................................... 29 
2.1 
Primary Objectives................................................................................................. 29 
2.2 
Secondary Objectives ............................................................................................ 29 
2.3 
Exploratory Objectives ........................................................................................... 29 
3. STUDY DESIGN AND ENDPOINTS ................................................................................. 30 


 
A Phase 2 study of the CSF-1R inhibitor, JNJ-40346527, in relapsed/refractory acute myeloid leukemia  
17583  
Version # 5 
24 MAR 2020 
PI: Elie Traer 
 
3.1 
Description of the Study Design ............................................................................. 30 
3.2 
Study Endpoints .................................................................................................... 31 
3.2.1 Primary Endpoint............................................................................................... 31 
3.2.2 Secondary Endpoint(s) ...................................................................................... 31 
4. STUDY ENROLLMENT AND WITHDRAWAL................................................................... 32 
4.1 
Participant Inclusion Criteria................................................................................... 32 
4.2 
Participant Exclusion Criteria ................................................................................. 32 
4.3 
Strategies for Recruitment and Retention ............................................................... 33 
4.3.1 Accrual Estimates ............................................................................................. 33 
4.3.2 Inclusion of Children.......................................................................................... 34 
4.4 
Registration Procedures ........................................................................................ 34 
4.4.1 Participant Registration ..................................................................................... 34 
4.4.1.1 
OHSU Registration ............................................................................ 34 
4.4.2 Multicenter Registration ..................................................................................... 35 
4.5 
Participant Screening and Enrollment..................................................................... 35 
4.6 
Participant Withdrawal or Discontinuation............................................................... 35 
4.6.1 Handling Participant Withdrawal and Discontinuation ......................................... 36 
4.7 
Off-Study Criteria ................................................................................................... 36 
4.7.1 Screen failure.................................................................................................... 36 
4.8 
Study Discontinuation ............................................................................................ 36 
5. INVESTIGATIONAL PRODUCT ....................................................................................... 38 
5.1 
JNJ-40346527 ....................................................................................................... 38 
5.1.1 Acquisition ........................................................................................................ 38 
5.1.1.1 
Re-Supply ......................................................................................... 38 
5.1.2 Formulation, Appearance, Packaging and Labeling............................................ 38 
5.1.3 Product Storage and Stability ............................................................................ 38 
5.1.4 Compatibility ..................................................................................................... 38 
5.1.4.1 
Solubility ........................................................................................... 39 
5.1.5 Handling ........................................................................................................... 39 
5.1.6 Preparation ....................................................................................................... 39 
5.1.7 Administration ................................................................................................... 39 
5.1.8 Special Considerations for Administration .......................................................... 40 
5.1.8.1 
Participant self-administration ............................................................ 40 
5.1.8.2 
Participant Medical Diary ................................................................... 40 
5.1.9 Accountability.................................................................................................... 40 


 
A Phase 2 study of the CSF-1R inhibitor, JNJ-40346527, in relapsed/refractory acute myeloid leukemia  
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Version # 5 
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PI: Elie Traer 
 
5.1.10 Destruction and Return ................................................................................. 41 
6. TREATMENT PLAN ......................................................................................................... 42 
6.1 
Dosage and Administration .................................................................................... 42 
6.2 
Dosing Delays and Modifications............................................................................ 42 
6.2.1 Definition of dose-limiting toxicity (DLT) ............................................................. 42 
6.2.1.1 
Duration of DLT assessment.............................................................. 42 
6.2.2 Dose Delays ..................................................................................................... 42 
6.2.3 Dose Escalation ................................................................................................ 43 
6.2.4 Dose de-escalation ........................................................................................... 43 
6.2.5 General Dose Delay Guidelines......................................................................... 43 
6.3 
Treatment Period and Maintenance ....................................................................... 43 
6.4 
Concomitant Medication and Supportive Care Guidelines ....................................... 44 
6.4.1 Blood Products.................................................................................................. 44 
6.4.2 Infection prophylaxis.......................................................................................... 44 
6.4.3 Treatment of fever and neutropenia ................................................................... 45 
6.4.4 Cytochrome (CYP) inhibition.............................................................................. 45 
6.4.5 P-glycoproteins (P-GP)...................................................................................... 45 
6.4.6 Gastrointestinal ................................................................................................. 46 
6.5 
Precautionary Medications, Treatments, and Procedures ....................................... 46 
6.5.1 General precautions .......................................................................................... 46 
6.5.2 Antigenicity and Mutagenicity ............................................................................ 46 
6.5.3 Impairment of Fertility and Pregnancy ................................................................ 46 
6.5.4 Use in Renal/Hepatic Dysfunction/Failure .......................................................... 46 
6.5.5 Overdosage and Abuse Potential ...................................................................... 46 
6.5.6 Contraindications .............................................................................................. 47 
6.6 
Prohibited Medications, Treatments, and Procedures ............................................. 47 
7. STUDY PROCEDURES/EVALUATIONS AND SCHEDULE .............................................. 48 
7.1 
Study Specific Procedures ..................................................................................... 48 
7.1.1 Medical history .................................................................................................. 48 
7.1.2 Disease Assessment ......................................................................................... 48 
7.1.3 Medication history ............................................................................................. 48 
7.1.4 Physical examination......................................................................................... 48 
7.1.4.1 
Vital signs ......................................................................................... 48 
7.1.4.2 
Height and weight.............................................................................. 48 
7.1.4.3 
Performance status ........................................................................... 48 


 
A Phase 2 study of the CSF-1R inhibitor, JNJ-40346527, in relapsed/refractory acute myeloid leukemia  
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PI: Elie Traer 
 
7.1.5 Electrocardiogram (ECG) .................................................................................. 49 
7.1.6 Medical Diary .................................................................................................... 49 
7.1.7 Adverse events ................................................................................................. 49 
7.2 
Laboratory Procedures and Evaluations ................................................................. 49 
7.2.1 Hematology....................................................................................................... 49 
7.2.2 Coagulation panel ............................................................................................. 49 
7.2.3 Biochemistry ..................................................................................................... 49 
7.2.4 urinalysis........................................................................................................... 49 
7.2.5 Bone Marrow Exam........................................................................................... 49 
7.2.6 SKIN PUNCH BIOPSY ...................................................................................... 50 
7.2.7 Blood collection ................................................................................................. 50 
7.2.8 Pregnancy test .................................................................................................. 50 
7.3 
Biomarker, Correlative, and Special Studies ........................................................... 51 
7.3.1 Evaluate the pharmacokinetics of JNJ-40346527 and effective inhibition of 
CSF-1R ........................................................................................................ 51 
7.3.2 Identify and quantify the specific subpopulation of cells that express CSF-
1R in subjects and correlate with clinical response to JNJ-40346527. ............ 51 
7.3.3 Assessing a genetic signature that predicts response to JNJ-40346527. ............ 52 
7.3.4 Transcriptome analysis to identify potential qualitative differences in CSF-
1R+ cells that predict patient response. ......................................................... 52 
7.3.5 Mass cytometry evaluation of JNJ-40346527 effect on phospho-signaling 
proteins in immune cell populations............................................................... 53 
7.3.6 Screening ex vivo sensitivity to small molecule inhibitors following CSF-1R 
inhibition. ...................................................................................................... 54 
7.4 
Screening Assessments......................................................................................... 55 
7.4.1 Information to be collected on screening failures ................................................ 55 
7.5 
Assessments During Treatment ............................................................................. 55 
7.6 
End of Treatment Visit ........................................................................................... 55 
7.7 
Follow-up .............................................................................................................. 56 
7.8 
Early Termination Visit ........................................................................................... 56 
7.9 
Unscheduled Visits ................................................................................................ 56 
7.10 Schedule of Events ................................................................................................ 57 
8. EFFICACY MEASURES ................................................................................................... 60 
8.1 
Definition of Efficacy Measures .............................................................................. 60 
8.1.1 Evaluable for toxicity ......................................................................................... 60 
8.1.2 Evaluable for objective response ....................................................................... 60 
8.2 
Response Criteria for AML ..................................................................................... 60 


 
A Phase 2 study of the CSF-1R inhibitor, JNJ-40346527, in relapsed/refractory acute myeloid leukemia  
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Version # 5 
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PI: Elie Traer 
 
8.2.1 Outcome Measures in AML ............................................................................... 61 
9. SAFETY ........................................................................................................................... 62 
9.1 
Specification Of Safety Parameters ........................................................................ 62 
9.2 
Definitions ............................................................................................................. 62 
9.2.1 Adverse Event (AE)........................................................................................... 62 
9.2.2 Serious Adverse Event (SAE) ............................................................................ 62 
9.2.3 Unanticipated Problems (UP) ............................................................................ 63 
9.2.4 Severity of Event ............................................................................................... 64 
9.2.5 Assessment of Causality Relationship To Study Agent....................................... 64 
9.3 
Expectedness ........................................................................................................ 64 
9.4 
Adverse Event List(s)............................................................................................. 64 
9.4.1 Adverse Event List for JNJ-40346527 ................................................................ 65 
9.5 
Adverse Event Assessment and Follow-Up ............................................................ 65 
9.6 
Reporting Procedures ............................................................................................ 66 
9.6.1 OHSU IRB Reporting of Unanticipated Problems and Adverse Events ............... 66 
9.6.2 Central Reporting of Adverse Events for Multicenter Studies .............................. 66 
9.6.3 SAE Reporting .................................................................................................. 66 
9.6.4 Sponsor or additional reporting requirements ..................................................... 66 
9.6.5 Reporting Of Pregnancy .................................................................................... 68 
9.7 
Study Stopping Rules ............................................................................................ 68 
10. STATISTICAL CONSIDERATIONS................................................................................ 69 
10.1 Analysis Populations.............................................................................................. 69 
10.2 Description of Statistical Methods........................................................................... 69 
10.2.1 Analysis of Primary Endpoint(s) .................................................................... 69 
10.2.2 Analysis Of The Secondary Endpoint(S)........................................................ 69 
10.2.3 Analysis Of The Exploratory Endpoint(s) ....................................................... 70 
10.2.3.1 
Transcriptome analysis to identify potential qualitative 
differences in CSF-1R+ cells that predict patient response .................. 70 
10.2.4 Interim Analysis and Stopping Rules ............................................................. 70 
10.2.4.1 
Safety Stopping Rule ......................................................................... 70 
10.3 Sample Size, Power, Accrual Rate and Study Duration .......................................... 71 
10.3.1 Sample size and Power ................................................................................ 71 
10.4 Handling of Missing Data ....................................................................................... 71 
11. CLINICAL MONITORING ............................................................................................... 72 
11.1 OHSU Knight Cancer Institute Data & Safety Monitoring Plan................................. 72 


 
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11.2 Clinical Data & Safety Monitoring ........................................................................... 72 
11.3 Quality Assurance & Quality Control....................................................................... 73 
12. DATA HANDLING AND MANAGEMENT RESPONSIBILITIES ...................................... 74 
12.1 Source Data/Documents ........................................................................................ 74 
12.2 Participant & Data Confidentiality ........................................................................... 74 
12.3 Data Collection & Storage: Privacy, Confidentiality & Security................................. 74 
12.3.1 Future Use of Stored Specimens................................................................... 75 
12.4 Maintenance of Records ........................................................................................ 75 
12.5 Publication and Data Sharing Policy....................................................................... 76 
12.6 Delivery of Progress Reports to Study Funder ........................................................ 76 
13. ETHICS/PROTECTION OF HUMAN PARTICIPANTS .................................................... 77 
13.1 Ethical Standard .................................................................................................... 77 
13.2 Institutional Review Board...................................................................................... 77 
13.3 Informed Consent .................................................................................................. 77 
13.3.1 Consent Procedures and Documentation ...................................................... 77 
13.4 Protocol Review..................................................................................................... 77 
13.5 Changes to Protocol .............................................................................................. 78 
14. REFERENCES............................................................................................................... 79 
15. APPENDICES ................................................................................................................ 81 
APPENDIX A: PERFORMANCE STATUS CRITERIA ........................................................... 82 
APPENDIX B: SUMMARY OF CAUTIONARY MEDICATIONS.............................................. 83 
APPENDIX C: CONTRACEPTION ........................................................................................ 84 
APPENDIX D: HEMATOLOGICAL MALIGNANCY GENE PANEL ........................................ 85 
 
 
 
 
 


 
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LIST OF TABLES 
 
Table 1. Summary of preclinical toxicities associated with CSF-1R inhibition .......................... 24 
Table 2. Summary of JNJ-40346527 treatment emergent adverse events............................... 25 
Table 3. Projected accrual for present study based on Oregon population demographics........ 34 
Table 4. Dose delay guidelines and management of next dose forJNJ-40346527 ................... 43 
Table 5. Clinical flow cytometry antibodies tested with CSF-1R in CLIA-certified lab. .............. 51 
Table 6. Antibody panel for analysis of kinase signaling and cytokine analysis by CyTOF. ...... 53 
 
 
 


 
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LIST OF FIGURES 
 
Figure 1. Overview of study design. ..................................................................................... 8 
Figure 2. CSF-1R signaling. ................................................................................................ 20 
Figure 3. Polarization of tumor associated macrophages. ................................................ 21 
Figure 4. Toxicity stopping rule. ......................................................................................... 71 
 
 
 
 


 
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LIST OF ABBREVIATIONS 
 
AE 
Adverse event 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
AML 
Acute myeloid leukemia 
ANC 
Absolute neutrophil count 
AST 
Aspartate aminotransferase 
APL 
Acute promyelocytic leukemia 
ATC 
Anatomical Therapeutic Chemical (Classification System) 
AUC 
Area under the curve 
BMA, BMB 
Bone marrow aspiration/biopsy 
BID/b.i.d 
Twice daily 
BUN 
Blood urea nitrogen 
CBC 
Complete blood cell (count) 
CFR 
United States Code of Federal Regulations  
CK 
Creatinine kinase 
CLIA 
Clinical Laboratory Improvement Amendments 
Cmax 
maximum observed concentration 
Cmin 
minimum observed concentration 
CoC 
National Institutes of Health (NIH) Certificate of Confidentiality 
CR 
Complete remission 
CRC 
Clinical Research Coordinator 
CRMS 
Clinical research management system 
CRQA 
Clinical Research Quality & Administration 
CRRC 
Clinical Research Review Committee (OHSU) 
CRF 
Case report form 
CRMS 
Clinical research management system 
CSF-1 
Colony stimulating factor-1 
CSF-1R 
Colony stimulating factor-1 receptor 
CT 
Computerized tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTEP 
Cancer Therapy Evaluation Program 
CTMS 
Clinical Trial Management System 
CYP 
Cytochrome P450 
CyTOF 
Cytometry by Time of Flight 
DFS 
Disease-free survival 
DLT 
Dose limiting toxicity 
DOB 
Date of birth 
DSMB 
Data and Safety Monitoring Board 
DSMC 
Data and Safety Monitoring Committee 
DSMP 
Data and Safety Monitoring Plan 
ECG, EKG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic Case Report Form 
eCRIS 
Electronic Clinical Research Information System 
EDC 
Electronic data capture 
EDTA 
Ethylenediaminetetraacetic acid 
EOT 
End of treatment 
eq 
Equivalent 
FACS 
Fluorescence-activated cell sorting 
FCBP 
Female of childbearing potential 


 
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FDA 
United States Food and Drug Administration 
GCP 
Good Clinical Practice 
GMP 
Good Manufacturing Practice 
GVHD 
Graft versus host disease 
HBeAg 
Hepatitis B “e” antigen 
HBV 
Hepatitis B virus 
HCT 
Hematocrit 
HCV 
Hepatitis C virus 
HGB 
Hemoglobin 
HIPPA 
Health Insurance Portability and Accountability Act 
HIV 
Human immunodeficiency virus 
HSCT 
Hematopoietic stem cell transplant 
IB 
Investigator’s brochure 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IDE 
Investigational device exemption 
IL 
Interleukin 
IND 
Investigational new drug application 
INR 
International normalized ratio 
IP 
Investigational product 
IRB 
Institutional Review Board 
IWG 
International Working Group 
IV 
Intravenous 
JMD 
Juxtamembrane domain 
LDH 
Lactate dehydrogenase 
LFT 
Liver function test 
M2 
mono-oxygenated metabolite 
M7 
mono-oxygenated metabolite 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
Magnetic resonance imaging 
MRN 
Medical record number 
MTD 
Maximum tolerated dose 
N/A 
Not applicable 
NCI 
National Cancer Institute 
NHL 
Non-Hodgkin’s lymphoma 
OHRP 
Office for Human Research Protections 
OHSU 
Oregon Health & Science University 
ORR 
Overall response rate 
PCR 
Polymerase chain reaction 
PD 
Progressive Disease 
PET 
Postitron emission tomography 
PD 
Pharmacodynamic 
P-gp 
P-glycoprotein 
PHI 
Protected health information 
PI 
Principle Investigator 
PK 
Pharmacokinetics 
PO 
Per os (by mouth, orally) 
PR 
Partial remission 
PTT 
Partial Thromboplastin Time 
QD 
Per day 
QOL 
Quality of Life 
RBC 
Red blood cell (count) 


 
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RP2D 
Recommended Phase II Dose 
RNA 
Ribonucleic acid 
RNAseq 
RNA sequencing 
RNI 
Reportable new information 
RT 
Radiation therapy 
SAE 
Serious adverse event 
SD 
Stable disease 
SD 
Standard deviation 
SGOT 
Serum glutamic oxaloacetic transaminase 
SGPT 
Serum glutamic pyruvic transaminase 
t½  
Apparent elimination half-life 
TAMS 
Tumor-associated macrophages 
TSMP 
Trial Specific Monitoring Plan 
UA 
Urinalysis 
ULN 
Upper limit of normal 
UP 
Unanticipated problem 
WBC 
White blood cell (count) 
 


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PI: Elie Traer 
 
activated kinase (MEK), and Wiskot-Aldrich syndrome protein (WASP) (Figure 2. CSF-1R 
signaling.Figure 2).8,10   
  
“CSF-1R is a member of the platelet-derived growth factor (PDGF) receptor family and is closely 
related to stem-cell factor receptor (c-Kit) and fms-related tyrosine kinase-3 (FLT-3)/Flk2. CSF-
1R is expressed primarily by cells of the macrophage lineage, including monocytes, 
inflammatory and resident tissue macrophages, dendritic cells, and osteoclasts.  The CSF-
1/CSF-1R pathway regulates the migration, differentiation, and survival of macrophage 
precursors.8”a 
 
1.2.1 CSF-1/CSF-1R SIGNALING AND CANCER 
 
Continuous inflammation in the tumor microenvironment is a hallmark of cancer and is 
characterized by the presence of immune cells that interact with tumor cells to influence the 
initiation, growth, and metastasis of tumors.  Specifically, tumor-associated macrophages 
(TAMs), are often prominent immune cells that orchestrate various factors in the tumor 
microenvironment, and the CSF-1/CSF-1R pathway is shown to regulate the migration, 
differentiation, and controls the recruitment, differentiation, and survival of TAMs.  
 
“TAMs are generally characterized as being either “classical” M1 macrophages or “alternative” 
M2 macrophages (Figure 3).  Classical M1-macrophages are those that interact with T helper 1 
[TH1] cells) and are involved in efficient antigen presentation and pathogen killing. Alternatively, 
M2 macrophages interact with T helper 2 [TH2] cells and demonstrate high phagocytotic and 
anti-inflammatory activity.11  In the tumor microenvironment, M1-like TAMs secrete high 
amounts of pro-inflammatory cytokines and are thought to promote anti-tumor immunity.  In 
contrast, M2-like TAMs produce low amounts of pro-inflammatory cytokines and higher amounts 
of the anti-inflammatory cytokine IL-10.  As such, M2-like TAMs are thought to promote tumor 
progression by contributing to the resolution of inflammation, stimulating tumor angiogenesis, 
and suppressing the activity of cytotoxic T cells.11 
 
The precise roles played by the M1- and M2-like TAM phenotypes during tumor progression and 
in response to anti-tumor therapies are the subject of intense investigations.  However, it 
appears that M1-like TAMs are pre-dominantly present in pre-malignant and early stages of 
Figure 3. Polarization of tumor 
associated macrophages.  
Cancer cell metabolism, aging, and 
apoptosis generate signals to attract 
monocytes from the blood circulation 
and drive them toward macrophage 
differentiation into “classical” M1-like 
and “alternative” M2-like macrophages 
within the tumor microenvironment. 
The CSF-1/CSF-1R pathway is 
involved in the chemotaxis of 
monocytes into the tumor stroma and 
the differentiation into immuno-
suppressive and tumor-promoting M2-
like TAMs.1 


 
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tumor development, whereas in locally advanced and invasive tumors the presence of 
inflammatory cytokines, including CSF-1 and metabolic signals (lactic acid and hypoxia), 
promote TAM polarization toward the M2-like phenotype.1  These M2-like TAMs overexpress 
CSF-1R and may be highly dependent on CSF-1; their presence in various solid12 and 
hematologic13 malignancies is of prognostic relevance and correlates with poor survival. 
 
Targeting and depleting TAMs is emerging as an attractive paradigm for novel anti-tumor 
therapies.14  The CSF-1/CSF-1R pathway is a particularly attractive molecular target to 
selectively inhibit the recruitment, activation, polarization, and survival of immunosuppressive 
TAMs.  Multiple clinical drug candidates that target CSF-1R intrinsic tyrosine kinase activity, or 
interfere with CSF-1 binding, receptor dimerization, or receptor signaling, are currently 
undergoing clinical development.” a  However, there are no clear biomarkers to identify 
responsive patients since CSF-1R inhibitors don’t directly target cancer cells. Data from an ex 
vivo drug screening platform has found that 20-25% of AML patient samples (leukemia cells and 
associated surrounding cells) are sensitive to CSF-1R inhibitors15. This assay may be a useful 
biomarker to predict sensitivity to CSF-1R inhibitors. Further study of the sensitive AML patient 
samples has suggested that CSF-1R indirectly targets supportive cells within the marrow 
microenvironment, which leads to subsequent loss of pro-growth signals to the leukemia cells. 
This is similar to the mechanism in tenosynovial giant cell tumors, where CSF-1R inhibits the 
expansion of associated monocytes to reduce tumor size (see Figure 4). Initial studies have 
suggested that a subset of CD14 monocytes is likely the target for CSF-1R. That being said, 
pre-clinical research has not revealed a direct relationship between just the number of CD14 
cells and ex vivo sensitivity. Data suggests that CD14 monocytes can be activated to secrete 
paracrine signals to support AML cell growth, but CD14 cells are not necessarily activated in 
every AML sample, when means there is not a perfect correlation. One of the exploratory goals 
of the clinical trial will be to more accurately characterize the CD14 supportive cells (using 
CyTOF) that predict CSF-1R sensitivity. Until the mechanism is better understood, the ex vivo 
sensitivity assay has worked reliably in the lab for many years, and will be used to stratify 
patients into sensitive and non-sensitive arms to test for response to CSF-1R inhibitors.  
 
 
Figure 4. Model of CSF-1R signaling in tenosynovial giant cell tumor (TGCT) and 
proposed model for AML. In TGCT the tumor cells themselves synthesize and secrete CSF-1 
which stimulates growth and expansion of infiltrating monocytes. In AML, we propose that 
supportive cells expressing CSF-1R are stimulated by CSF-1, perhaps through an autocrine 
pathway, and then secrete other cytokines and growth signals for AML cells. Inhibition of CSF-
1R signaling leads to a reduction in supportive paracrine growth signals and AML cell growth. 
 
1.3 
OVERVIEW OF JNJ-40346527 
 


 
A Phase 2 study of the CSF-1R inhibitor, JNJ-40346527, in relapsed/refractory acute myeloid leukemia  
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Please refer to investigator brochure for detailed information.a  
 
JNJ-40346527 is a potent orally available, small-molecule inhibitor of CSF-1R tyrosine kinase 
activity that is in clinical development for the treatment of diseases in which macrophages play 
an important causative role, such as (i) in amplifying chronic inflammation and promoting tissue 
remodeling in inflammatory diseases or (ii) in stimulating cell growth and in providing 
suppression of immune-surveillance mechanisms such as those in the microenvironment of 
some tumors. 
 
1.3.1 MECHANISM OF ACTION FOR JNJ-40346527 
 
“JNJ-40346527 is a selective inhibitor of CSF-1R tyrosine kinase that is capable of inhibiting 
monocyte and macrophage responses to CSF-1.  In vitro kinase assays show that only  
CSF-1R tyrosine kinase was inhibited >50% at 0.01 μM, whereas other kinases (e.g., FMS-like 
tyrosine kinase 3 (FLT3), JAK2) were not inhibited at similar concentrations.” 
 
1.3.2 PRE-CLINICAL EXPERIENCE 
 
In vivo, JNJ-40346527 demonstrates robust CSF-1R-specific pharmacodynamic (PD) activity in 
mice and rats, and possesses the ability to reduce macrophage recruitment and differentiation 
in animal models of inflammatory disease and malignant tumors.a 
 
“In mice, the intravenous (IV) administration of recombinant CSF-1 induced c-fos mRNA 
expression in splenic macrophages.  Treatment with JNJ-40346527 at 3 and 10 mg/kg 
administered 6 hours before IV administration of CSF-1 inhibited c-fos mRNA expression by 
75% and 100%, respectively”.a 
 
“Inhibition of ex vivo CSF-1-mediated CSF-1R phosphorylation of blood cells obtained from 
healthy rats and from rats with streptococcal cell wall (SCW)-induced arthritis was investigated 
as a PD biomarker of JNJ-40346527 activity.  The IC50 for JNJ-40346527 inhibition of CSF-1-
induced CSF-1R phosphorylation ex vivo in blood cells from healthy rats was 20 ng/mL and in 
blood cells from arthritic rats was 21 ng/mL.” a 
 
1.3.2.1 Pharmacokinetics and metabolism 
 
The pharmacokinetics of JNJ-40346527 has been evaluated in rodents (mice and rat), canine 
and primate models. a “In all four species tested, single-dose PO administration of JNJ-
40346527 was associated with rapid absorption (tmax = 1 to 3.3 hours).” a  No sex-related 
differences in JNJ-40346527 exposure were observed. 
 
“JNJ-40346527 is highly bound to plasma proteins and liver microsomes and is partitioned into 
red blood cells.  The elimination of JNJ-40346527 is slow with a plasma half-life ranging from a 
minimum of 7 hours (in rats) to a maximum of 32 hours (in dogs).  Following a single IV 
administration, extensive distribution outside of plasma is detected with the highest JNJ-
40346527 concentrations measured in kidney followed by muscle, liver, lung, spleen, heart, and 
brain.  
 
JNJ-40346527 is a substrate of CYP450 and is primarily metabolized through oxidative 
biotransformation catalyzed by CYP3A4 leading to the formation of carboxymetabolites.  Minor 
                                              
 
a JNJ-40346527 IB 4th ed - Janssen Confidential Information 


 
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pathways are catalyzed by CYP2C8 and CYP2C9 leading to monooxygenated metabolites. 
Excretion of JNJ-40346527 and its metabolites occurred primarily via feces.” a 
 
1.3.2.2 Preclinical toxicities 
 
“JNJ-40346527 was evaluated at 10 mg/kg in rats after 3 months of dosing and 25 mg/kg in 
dogs after 9 months of dosing.  In general, pathology findings were mild and reversible after the 
1 month recovery period.  Relevant toxicities observed with JNJ-40346527 across the species 
that are considered potentially related to the mode-of-action of CSF-1R inhibition are 
summarized in Table 1”.a 
 
Table 1. Summary of preclinical toxicities associated with CSF-1R inhibitiona 
Hematopoietic system: 
• 
Bone marrow hypocellularity with decreased erythropoiesis and 
increased accumulation of adipose tissue;  
• 
Peripheral blood changes with decreased lymphocytes and 
increased neutrophil counts 
Kidney:  • 
Nephropathy and increased glomerular thickness;  
• 
Urinary calcium decrease 
Liver: • 
Transaminase (AST and ALT) elevations 
Blood vessels: • 
Fibrinoid necrosis 
Connective tissue: • 
Mucinous accumulation 
Bone: • 
Increased thickness of the epiphyseal plate in the femur 
Spleen:  • 
Accumulation of congestion and pigment laden macrophages 
Testicles: • 
Bilateral degeneration 
Skin: • 
Sensitizing potential 
Eyes: • 
Severe irritant 
1.3.3 CLINICAL STUDIES OF JNJ-40346527 
 
“Clinical information on the PK/PD, safety, and efficacy of JNJ-40346527 are available for 178 
participants that enrolled into 3 completed clinical studies conducted in distinct populations:  
 
• 
Phase 1 Study 40346527EDI1001 in healthy volunteers (n = 94) 
• 
Phase 2a Study 40346527ARA2001 in subjects with active rheumatoid arthritis (n = 63) 
• 
Phase 1/2 Study 40346527HKL1001 in subjects with Hodgkin’s lymphoma (n = 21)” a 
 
1.3.3.1 Pharmacokinetics in Humans 
 
“The pharmacokinetic characteristics of JNJ-40346527 were assessed in all 3 clinical studies 
conducted so far.  Across studies the following main PK characteristics of JNJ-40346527 
following multiple daily oral regimen were observed: 
 
• 
Rapid absorption following oral administration 
• 
Dose proportional increase of Cmax (following QD dosing) and AUC (QD and BID dosing) 
• 
Mean terminal half-life (t½ ) of ~140 hours 
• 
Dose-related systemic accumulation 
• 
Steady state level reached by ~21 days of dosing 
• 
No apparent sex related differences in PK characteristics 
• 
No impact of food on PK characteristics” a 
 
1.3.3.2 Metabolism in Humans 
 


 
A Phase 2 study of the CSF-1R inhibitor, JNJ-40346527, in relapsed/refractory acute myeloid leukemia  
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“The major JNJ-40346527 metabolite in humans, M7, is generated by mono oxygenation.  The 
formation of M7 is due largely to the CYP2C subfamily, specifically CYP2C8, and CYP2C19. M7 
was found to be slightly (<2-fold) more potent than JNJ-40346527 in an in vitro CSF-1R kinase 
assay.  The formation of the other metabolite M2 is largely due to CYP3A4.  Radiolabeled 
studies have not been conducted in humans, however in animals 14C-JNJ-40346527 was highly 
bound (≥99%) to plasma proteins in all species tested.  After 25 mg/kg oral administration of 
14C-JNJ-40346527 to male rats and male dogs, radioactivity was excreted primarily in feces.” a 
 
1.3.3.3 Drug Interactions 
 
JNJ-40346527 is a reversible inhibitor of primarily CYP3A4 and CYP2C8 and to a lesser extent 
of several other CYP isoforms (i.e., CYPs 2B6, 2C9, 2C19, and 2D6) in vitro.  JNJ-40346527 
increased the plasma exposure of midazolam (by ~65%) in a clinical Phase 1 study, suggesting 
a weak inhibition of CYP3A4 at clinically relevant doses.  
 
1.3.3.4 Safety in Humans 
 
JNJ-40346527 was generally well tolerated by (i) healthy volunteers, (ii) subjects with active RA, 
and (iii) subjects with relapsed or refractory HL.  The most frequent JNJ-40346527 treatment-
emergent adverse events (AEs) are shown in Table 2. a 
 
Table 2. Summary of JNJ-40346527 treatment emergent adverse eventsa 
Organ system 
Treatment emergent AEs 
Gastrointestinal: • diarrhea, 
• nausea, 
• vomiting 
• constipation, 
• abdominal pain,  
• gastroesophageal reflux 
Hematologic:  • anemia, 
• decrease in WBC (neutrophils, monocytes, lymphocytes), 
• reticulocytes 
Hepatic:  • AST and ALT increase 
Pulmonary:  • dyspnea 
Constitutional 
symptoms:  
• pyrexia, 
• headache, 
• back pain 
Laboratory changes:  • increase in creatinine kinase and lactate dehydrogenase 
 
1.3.3.5 Efficacy in Humans 
 
“The preliminary efficacy of JNJ-40346527 was evaluated in participants with active rheumatoid 
arthritis in Study 40346527ARA2001.  No consistent evidence of efficacy was observed in 
subjects with RA receiving JNJ-40346527 compared with subjects receiving the placebo. 
 
In study 40346527HKL1001, limited efficacy was observed for JNJ-40346527 evaluated in 
participants with relapsed or refractory Hodgkin’s lymphoma.  One out of 20 evaluable subjects 
(5.0%) demonstrated complete response.  An additional 11 subjects (55.0%) experienced stable 
disease, while 8 subjects (40.0%) had progressive disease.” a 
 


 
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1.3.4 SMALL MOLECULAR KINASE INHIBITOR SCREEN 
 
The kinase inhibitor screen is an ex vivo drug screening platform that facilitates functional 
evaluation of small molecule inhibitors on primary patient samples.15  In this assay, a library of 
small-molecule inhibitors is plated in 384-well format in 7-point concentration series.  Primary 
AML patient specimens are cultured on the assay plates (10,000 cells/well) for 3 days, after 
which drug sensitivity is assessed by a tetrazolium-based viability assay.  A probit dose-
response curve is generated for each drug, and IC50 values are computed based on the probit 
models.  Effective selection of drugs for patients using this assay has been achieved in 
numerous n-of-1 studies and within the context of ongoing phase 1b (NCT02779283) and phase 
2 (NCT01620216) trials for newly diagnosed and relapsed/refractory AML, respectively.   
 
1.4 
RATIONALE 
 
CSF-1R inhibitors have caused growth inhibition in 20-25% of AML samples screened with the 
ex vivo assay (in revision). In particular, treatment with the CSF-1R inhibitor JNJ-28312141 has 
resulted in a sensitivity rate of ~37% (as defined by a sensitivity cutoff of ≤ 40 nM). Response to 
CSF-1R inhibition does not correlate with intrinsic CSF-1R expression in leukemia cells, but 
rather appears to be related to CSF-1R expression in a subpopulation of supportive cells that 
provides paracrine growth signals. Our underlying hypothesis is that JNJ-40346527 targets a 
subpopulation of supportive cells, which leads to interruption of paracrine survival signals to 
leukemia cells, and subsequent leukemia cell death. This is similar to the mechanism of action 
of JNJ-40346527 in tenosynovial giant cell tumor; however, in tenosynovial giant-cell tumors the 
malignant cell secretes CSF-1, which recruits non-malignant CSF-1R+ monocytes and 
histiocytes. In our model, the non-malignant CSF-1R+ population is supporting malignant 
leukemia cell survival by an unknown paracrine signal and this signal is turned off after CSF-1R 
inhibition. 
 
We hypothesize that the CSF-1R inhibitor JNJ-40346527 will be effective in treating a subset of 
AML patients, and that given the absence of genetic or other markers, we can select sensitive 
patients using our ex vivo functional screen.  
 
1.4.1 DOSE RATIONALE 
 
Results of study 40346527HKL1001, investigating JNJ-40346527 in patients with relapsed or 
refractory Hodgkin’s lymphoma found optimal inhibition of phosphorylated CSF-1R at 150 mg 
twice a day.16  In this study, participants will receive JNJ-40346527 at 150 mg PO twice daily in 
continuous 28-day cycles.  
 
1.5 
POTENTIAL RISKS AND BENEFITS 
 
1.5.1 KNOWN POTENTIAL RISKS  
 
Available clinical safety data suggest that JNJ-40346527 is likely to be safe and well tolerated. 
Based on the mechanism of CSF-1R inhibition, however, there is a risk that JNJ-40346527 may 
induce side effects when administered as single agent (or in combination with other agents) that 
have not been observed yet and that may be of severe intensity. Toxicities reported with other 
CSF-1R targeting small molecules or antibodies that have not yet been reported with JNJ-
40346527 include: 
1. FPA008, a small-molecule CSF-1R inhibitor. Phase 1 study data collected following 
participant exposure to FPA008 was associated with AEs of eyelid edema, facial swelling, 


 
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pruritus, and blurred vision.17 
2. PLX3397, a small-molecule CSF-1R inhibitor. In a Phase 2 study conducted with the 
PLX3397, cases of hair depigmentation and liver toxicity were observed.18 
3. Emactuzumab, a CSF-1R inhibiting antibody. Investigators of a Phase 1 study noted that 
Emactuzumab was associated with cases of lupus erythematosus and cases of cutaneous 
toxicities, including; erythema, pruritus, dermatitis and facial edema were reported.19 
 
1.5.2 KNOWN POTENTIAL BENEFITS 
 
Given the lack of treatment options for treating relapse or refractory AML, the current study may 
provide access to a new treatment approach not previously available. It cannot, however, be 
guaranteed that participants in this study will directly benefit from treatment during participation, 
as the clinical trial is designed to provide information about the safety and effectiveness of the 
investigational approach. 
 
1.6 
CORRELATIVE STUDIES BACKGROUND 
 
The goals of the correlative studies are twofold:  
 
1. Identify the biomarkers that correlate with clinical response, and  
2. Identify the effect of JNJ-40346527 on leukemia cells and the immune microenvironment 
and potential drug combinations for future trials.  
 
The information from the second goal will be important to understand what cells are targeted by 
CSF-1R inhibition, and identify additional targets for combination trials. For example, removing 
supportive paracrine CD14+ cells from the leukemia microenvironment may uncover novel 
kinase inhibitor sensitivities in the leukemia cells that were masked by paracrine survival signals 
(Figure 4). Alternatively, CSF-1R inhibition may enhance expression of immune checkpoint 
proteins such as PD1 or PDL1 in the leukemia microenvironment, facilitating use of immune 
checkpoint inhibitors in AML.  
 
Figure 5. CSF-1R is expressed in non-malignant CD14+ cells.  
CSF-1R is expressed in non-malignant CD14+ cells, which correlates with ex vivo sensitivity to GW-
2580, a highly specific CSF-1R inhibitor. AML samples were analyzed for cells that express CD14 
and CSF-1R (CD115) by CyTOF. Samples with A) CD14+ CSF-1R+ and B) CD14+ CSF-1R- 
populations are shown. C) Ex vivo sensitivity and correlation with CSF-1R+ cells is shown, 


 
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Specific cell populations in the leukemia immune microenvironment will also likely be modulated 
by JNJ-40346527, such as T-cell and NK cell populations, which could potentially enhance 
antibody-dependent cellular cytotoxicity of targeted antibodies such as talacotuzumab 
(CSL362/JNJ-56022473). Understanding which patients are most likely to respond to JNJ-
40346527 treatment, and how the leukemia cells and their immune microenvironment are 
affected by treatment, will be critical to develop effective combinations in the future. 


 
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2. OBJECTIVES 
 
2.1 
PRIMARY OBJECTIVES 
 
Evaluate preliminary efficacy of JNJ-40346527 in participants with relapsed/refractory AML, 
assessed by best objective response rate (>PR).   
 
2.2 
SECONDARY OBJECTIVES 
 
1. Assess the safety of JNJ-40346527 in participants with relapsed or refractory AML.  
2. Assess the duration of disease response associated with JNJ-40346527.  
3. Overall incidence of treatment-related and non-treatment related toxicity. 
4. Duration of response. 
5. 12-month event-free survival. 
6. 12-month overall survival. 
 
2.3 
EXPLORATORY OBJECTIVES 
 
1. Evaluate the pharmacokinetics of JNJ-40346527 and effective inhibition of CSF-1R in marrow 
aspirates using plasma inhibitory assays, with established CSF-1R-sensitive cell lines. 
2. Identify the effect of JNJ-40346527 on leukemia cells and the immune microenvironment. 
3. Identify and quantify the specific subpopulation of cells that express CSF-1R in participants 
and correlate these with clinical response to JNJ-40346527. 
4. Analyze the frequency of mutations using genomic DNA from leukemia participants to 
determine if there is a genetic signature that predicts response to JNJ-40346527.  
5. Using RNA sequencing (RNAseq), identify an expression signature in CSF-1R+ cells that 
predicts patient response.  
6. Evaluate the effect of JNJ-40346527 on immune cell populations (cytotoxic T cells, etc.) and 
phospho-signaling proteins by CyTOF analysis in pre- and post-treatment samples in order to 
identify biomarkers that predict patient response and prioritize potential combination strategies 
for future clinical trials. 
7. Determine how leukemia cells change in response to CSF-1R inhibition by assessing cells 
collected pre- and post-treatment using an ex vivo sensitivity to a panel of small molecule 
inhibitors to determine what new drug sensitivities may emerge in AML cells after CSF-1R 
inhibition. 


 
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3. STUDY DESIGN AND ENDPOINTS 
 
3.1 
DESCRIPTION OF THE STUDY DESIGN 
 
Refer to Section 10, STATISTICAL CONSIDERATIONS for additional information regarding 
statistical methods used in this study. 
 
This is a Phase 2, Simon 2-stage minimax design to determine clinical efficacy of JNJ-40346527 
in relapsed/refractory AML. Participants must meet the inclusion criteria, have none of the 
exclusion criteria, and have provided written informed consent before the conduct of any 
screening tests not performed routinely in their treatment. 
 
 
 
 
 
 
 
 
 
 
 
 
Results from preclinical studies suggest that responsive patients may be selected by using an ex 
vivo assay with JNJ-40346527. Eligible participants will be divided into two treatment arms based 
on an ex vivo sensitivity of AML cells derived from either bone marrow aspirates or peripheral 
blood (if inaspirable and >20% circulating blasts).  Participants with an ex vivo IC50 that is ≤20% 
of the median IC50 (to be determined with preclinical testing) will be considered sensitive to JNJ-
40346527 (termed “assay positive”), whereas those with an IC50 >20% of the median IC50 will be 
considered insensitive (termed “assay negative”) for purposes of assignment. This threshold is 
set prior to the study start and does not change. This will result in 2 study arms: 1) Assay positive 
and 2) Assay negative (Figure 6). Patients that screen fail (for example indeterminate assay 
results or insufficient sample) will not be included in the study. Patients can rescreen per provider 
discretion. 
 
For each arm, 7 participants will be enrolled in the first stage. If there is at least 1 response 
among the first 7 participants, the study will proceed to the second stage, in which an additional 
7 participants will be enrolled. The treatment is considered promising if there are at least 3 
responses among 14 participants. The best objective response and exact confidence intervals 
will be estimated using the binomial distribution for each arm. 
 
We anticipate that ex vivo sensitivity will predict participants’ response and that only the assay 
positive arm will continue to enroll in stage 2. The expected total enrollment of both Arms would 
be 21 participants in this case. If no participant responds in either treatment arm, the enrollment 
will end with 14 patients. If >1 out of 7 eligible participants respond to JNJ-40346527 in both the 
assay positive and assay negative arms, then both arms will continue to stage 2. In this case, 
the maximum enrollment would be 28 participants. 
 
This study has a stopping rule for both futility (a lack of efficacy) and safety. No response 
among the first 7 patients is defined as futility and will halt each either arm of the study.  


 
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Likewise, excess toxicity will suspend enrollment if the lower 90% confidence interval for Grade 
3 or higher treatment-related toxicity exceeds 30% (considered acceptable dose-limiting toxicity 
(DLT) incidence).  
 
3.2 
STUDY ENDPOINTS 
 
3.2.1 PRIMARY ENDPOINT 
 
Endpoint 
Start  
End  
1. Best objective response rate. 
 
First dose of 
JNJ-40346527 
Over 3 cycles 
 
3.2.2 SECONDARY ENDPOINT(S) 
 
Endpoint 
Start  
End  
1. Overall incidence of treatment-
related and non-treatment related 
toxicity.. 
First dose 
of JNJ-
40346527 
 
30 days after last dose of study agent 
2. Duration of response. For patients 
that achieve >PR, how long do they 
maintain this 
response before 
progression. 
 
3. Event-free survival at 12-months 
12 months from first dose 
4. Overall survival at 12-months 
Death (or date of last contact) 
 


 
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4. STUDY ENROLLMENT AND WITHDRAWAL 
 
4.1 
PARTICIPANT INCLUSION CRITERIA 
 
To be eligible to participate in this study, an individual must meet all of the following criteria: 
 
1. Ability to understand and the willingness to sign a written informed consent document. 
2. Age ≥18 years at time of informed consent.  Both men and women and members of all races 
and ethnic groups will be included.  
3. Morphologically documented relapsed/refractory AML as defined by World Health 
organization (WHO) criteria after at least 1 prior therapy for AML with the exception of 
hydroxyurea, and not felt to have curative treatment options per treating physician, or the 
patients themselves are unwilling to consider curative treatment options.  
4. Sufficient and viable bone marrow aspirate or peripheral blood collection to use for the ex 
vivo sensitivity assay. 
5. ECOG performance status 0 to 2 (Refer to Appendix A) 
6. Women must not be pregnant or breastfeeding. Women of childbearing potential must have 
a negative serum or urine pregnancy test within 14 days prior to start of study drug 
administration. 
7. Participants must agree to use an adequate method contraception (see Appendix C). 
8. Must be able to take oral medications. 
9. Adequate organ function as defined by the following: 
a. Serum creatinine ≤2× the upper limit of normal (ULN), or glomerular filtration rate 
>20ml/min as calculated by Cockgroft-Gault formula. 
b. Serum potassium, magnesium, and calcium (corrected for albumin) within institutional 
normal limits or can be corrected with supplementation. 
c. Total serum bilirubin ≤2.5× ULN. 
d. Serum aspartate transaminase (AST) and/or alanine transaminase (ALT) ≤2.5× ULN. 
 
4.2 
PARTICIPANT EXCLUSION CRITERIA 
 
An individual who meets any of the following criteria will be excluded from participation in this 
study: 
 
1. Diagnosis of acute promyelocytic leukemia (APL, or AML M3 subtype) 
2. Active central nervous system involvement with AML 
3. Concurrent active malignancy with expected survival of less than 1 year. For example, 
candidates with treated skin cancers, prostate cancer, breast cancer, etc. without metastatic 
disease are candidates for therapy since their expected survival exceeds that of relapsed or 
refractory AML. All subjects with concurrent malignancies will be reviewed by the PI prior to 
enrollment. 
4. Clinically significant GVHD or active GVHD requiring initiation or escalation of treatment 
within 28 day screening period. 


 
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5. Clinically significant coagulation abnormality, such as disseminated intravascular 
coagulation. 
6. Participants who are currently receiving any other investigational agents. 
7. Previous treatment with CSF-1R kinase inhibitor or CSF-1R blocking antibody. 
8. Known clinically significant liver disease defined as 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. 
9. Untreated HIV or active hepatitis C detectable by PCR, or chronic hepatitis B (patients 
positive for hepatitis B core antibody who are receiving IVIG are eligible if HepB PCR is 
negative). 
10. Known history of cerebrovascular accident, myocardial infarction, or intracranial hemorrhage 
within 2 months of enrollment. 
11. Clinically significant surgery within 2 weeks of enrollment.  
12. Per PI discretion, active infection that is not well controlled by antibacterial or antiviral 
therapy. 
13. Cancer-directed therapy within 2 weeks prior to starting treatment, with the exception of 
hydroxyurea, which is allowed to control white blood cell count. Hydroxyurea will weaned as 
soon as clinically feasible. 
14. Unwillingness to receive infusion of blood products. 
15. Drugs that affect the CYP3A4 systems are allowed and essential for cancer patients, 
including anti-fungals but should be used with caution.  
16. Patients with uncontrolled white blood cell count (defined as >50 K/cu mm  not controlled 
with hydrea). 
 
4.3 
STRATEGIES FOR RECRUITMENT AND RETENTION 
 
Participants for this study will be recruited from within the hematology and oncology practices 
participating research sites. Participants may be identified and referred to this study by their 
primary treating physician from the outside community. Participants may also initiate contact 
with the investigator through information of this study posted on the clinicaltrials.gov website. 
 
4.3.1 ACCRUAL ESTIMATES 
 
The number of participants to be accrued is driven by the study primary objective. An estimated 
28 participants across OHSU and 2 participating sites will be recruited over a 24 month period. 
 
No OHSU Knight Cancer Institute study will focus on any particular gender, racial or ethnic 
subset. No participant 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. Gender-
nonconforming and gender-fluid individuals as members of the general population will also be 
recruited. 
The projected gender, racial, and ethnic composition of the study will represent that of the state 
of Oregon (Table 3).  


 
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Table 3. Projected accrual for present study based on Oregon population demographics 
Ethnic Category 
Sex/Gender 
Females 
Males 
Total 
  
n 
% 
n 
% 
n 
% 
Hispanic or Latino 
2 
6.4 
2 
6.3 
4 
12.7 
Not Hispanic or Latino 
11 
38.7 
11 
37.9 
21 
76.6 
Ethnic Category: Total of all participants* 
 13 
  
13 
  
  
100* 
  
Racial Category 
  
American Indian or Alaskan Native 
1 
3.9 
1 
3.9 
2 
7.8 
Asian 
1 
2.2 
1 
2.2 
1 
4.4 
Black or African American 
0 
1.1 
0 
1.0 
1 
2.1 
Native Hawaiian or other Pacific Islander 
0 
0.2 
0 
0.2 
0 
0.4 
White 
12 
44.2 
12 
43.4 
25 
87.6 
Two or more races 
1 
1.9 
1 
1.8 
1 
3.7 
  
Racial Category: Total of all participants* 
15 
50.5 
15 
49.5 
  
100 
Source: Adapted from U.S. Census Bureau, 2010. 
*Totals may not equal 100 due to rounding. 
 
4.3.2 INCLUSION OF CHILDREN 
 
This protocol does not include children because no dosing or adverse event data are currently 
available on the use of this study agent in this way in persons <18 years of age; therefore, 
children are excluded from this study. 
 
4.4 
REGISTRATION PROCEDURES 
 
4.4.1 PARTICIPANT REGISTRATION 
 
4.4.1.1 OHSU Registration 
 
This is a Phase II trial and there is no randomization.  
 
Participants will be required to give written informed consent to participate in the study before 
any screening tests or evaluations are conducted that are not part of standard care. 
 
Registration from all consented participants must be entered into the OHSU electronic Clinical 
Research Management System (CRMS, e.g., eCRIS). At a minimum, registration of OHSU 
participants will include: 
• 
A completed Participant Registration Form 
• 
A completed Eligibility Checklist signed by the Investigator 
• 
Signed copies of the most recently IRB-approved, informed consent form and HIPAA 


 
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authorization 
 
4.4.2 MULTICENTER REGISTRATION 
 
The OHSU coordinating center study team will manage the participant registration process. 
Investigators, or study team designee, at participating sites will identify eligible participants and 
send source documents that support eligibility to OHSU for review and verification before the 
participating site may enroll and treat the participant.  
 
The OHSU coordinating center team is responsible for verifying completeness of documents, 
entering registration information into the Knight CRMS, and assigning a study number/identifier 
for each individual participant.  The OHSU coordinating center will send an email to the 
participating site to indicate whether or not a participant is eligible and will assign a participant 
number/identifier.   
 
Registration at participating research site will include a minimum of the following: 
• 
A completed Participant Enrollment Form 
• 
A completed Eligibility Checklist signed by the Investigator 
• 
De-identified source documentation of eligibility 
• 
Signed copies of the most recently local IRB-approved, informed consent form and HIPAA 
authorization. 
 
Each participating research site is expected to maintain a screening log of all participants who 
are approached for the study.  The log documents an explanation for exclusion due to screen 
failure.  This log should be submitted to the OHSU coordinating center on a regular basis. 
Participating sites are required to retain, in a confidential manner, sufficient information on each 
participant so that the participant may be contacted should the need arise 
 
 
4.5 
PARTICIPANT SCREENING AND ENROLLMENT 
 
In order to participate in this study, signed informed consent must be obtained from the 
participant or the participant's legally acceptable representative.  The current Institutional 
Review Board (IRB) approved informed consent must be signed and dated by each participant 
prior to undergoing any study procedures or before any prohibited medications are withheld 
from the participant in order to participate in this study.  
 
This study consists of a 28 day screening period.  Screening will begin once the participant has 
provided written informed consent to participate in the study and ends on Day 0 of the study.  All 
screening and baseline evaluations will be performed during the screening phase.  Eligible 
participant assignment to one of two treatment arms, assay positive or assay negative, based 
on results from ex vivo screening assay will occur no later than 14 days prior to starting 
treatment with study agent. Samples will be collected from study eligible participants no later 
than 14 days prior to initiating treatment with study agent.  Day 1 of the clinical trial will be when 
participants are started on JNJ-40346527.  Total accrual of all participants is anticipated to take 
a total of 24 months. 
 
4.6 
PARTICIPANT WITHDRAWAL OR DISCONTINUATION 
 
Participants are free to withdraw consent and discontinue participation in the study at any time 
and without prejudice to further treatment. If a participant no longer wants to receive 
investigational product, but is willing to come for follow-up appointments, the participant’s 


 
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request should be honored, if possible. The following are examples demonstrating why a 
participant’s treatment might be discontinued. 
• 
Toxicity precludes further study treatment.  
• 
There is a need for any treatment not allowed by the protocol.  
• 
The participant fails to meet the criteria for study treatment.  
• 
Disease recurrence or progression. 
• 
Investigator’s discretion.  
 
No further participant contact should be made if the participant withdraws consent for 
participation in the study. Information about the reason(s) for discontinuation and collection of 
any new or ongoing adverse events (AEs) should be collected at the time the participant 
withdraws consent.  
 
For all other reasons for discontinuation from the study treatment phase, the participant should 
return to the clinic for the end of treatment (EOT) visit according to Section 7. 
 
4.6.1 HANDLING PARTICIPANT WITHDRAWAL AND DISCONTINUATION 
 
Participants that discontinue the first cycle without experiencing a DLT may be replaced. 
Participants may be replaced if they voluntarily withdraw from the protocol, or if the participant is 
taken off study per the PI’s discretion for reasons such as continued noncompliance. Per 45 
CFR 46, the reasons for withdrawal, if known, will be recorded.  
 
4.7 
OFF-STUDY CRITERIA 
 
Criteria that can take a participant off-study include: 
• 
Participant requests to be withdrawn from study without further follow-up, 
• 
Completed study follow-up period, 
• 
Death, 
• 
Screen failure 
 
4.7.1 SCREEN FAILURE 
 
Any participant that has signed the consent form (for either screening or study participation) but 
does not meet the study eligibility criteria, or meets study eligibility criteria but terminates the 
participation prior to receiving study treatment, will be considered a screen failure. The reason 
for screen failure should be captured in the database for each participant failing to meet the 
eligibility criteria.  
 
4.8 
STUDY DISCONTINUATION 
 
This study may be temporarily suspended or prematurely terminated if there is sufficient 
reasonable cause. Written notification, documenting the reason for study suspension or 
termination, will be provided by the suspending or terminating party to Manufacturer, Sponsor, 
local IRB or other regulatory agency. If the study is prematurely terminated or suspended, the 
Investigator will promptly inform the IRB and will provide the reason(s) for the termination or 
suspension. 
 
Reasons for terminating the study may include the following: 
• 
Incidence or severity of adverse events, in this or other studies, indicates a potential 
health hazard to participants. 


 
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• 
Interim futility analysis demonstrates that the primary endpoint is unlikely to be met. 
• 
Data that are not sufficiently complete and/or evaluable. 
• 
Investigator(s) do not adhere to the study protocol, or applicable regulatory guidelines in 
conducting the study.  
• 
Participant enrollment is unsatisfactory.  
• 
Submission of knowingly false information from the study site to Sponsor or regulatory 
authorities. 
• 
Upon instruction by local or other regulatory, or oversight authority.    
 
Study may resume once concerns about safety, protocol compliance, data quality are 
addressed and satisfy the Sponsor, IRB and/or FDA. 
 


 
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5. INVESTIGATIONAL PRODUCT 
 
A list of the adverse events and potential risks associated with the investigational or other 
agents administered in this study can be found in Section 9.4. 
 
5.1 
JNJ-40346527 
 
“JNJ-40346527 is a selective inhibitor of CSF-1R tyrosine kinase, with an IC50 of 0.0032 μM. In 
tissue culture, concentrations of JNJ-40346527 <10 nM are capable of inhibiting monocyte and 
macrophage responses to CSF-1. JNJ-40346527 is a hydrochloride salt and has a molecular 
weight of 498.06 and a molecular formula of C27H35N5O2●HCl. Refer to investigator brochure for 
additional details.” a  
 
5.1.1 ACQUISITION 
 
JNJ-40346527 will be supplied by Manufacturer to the drug distributor Biologics, and prepared 
by OHSU research pharmacy per manufacturer instructions. Following submission and approval 
of the required regulatory documents, a supply of JNJ-40346527 may be ordered from Janssen 
by completing a Drug Request Form.  
 
Allow 4 business days for shipment of drug from receipt of the Drug Request Form. Drug is 
protocol specific, but not patient specific. There will be no weekend or holiday delivery of drugs. 
 
5.1.1.1 Re-Supply 
 
Drug re-supply request form should be submitted electronically to Biologics no less than 4 
business days before the expected delivery date.  Deliveries will be made Tuesday through 
Friday. When assessing need for resupply, the institution should keep in mind that shipments 
may take 4 business days from time of receipt request.  JNJ-40346527 is not patient specific. 
The investigator or designated study staff is responsible for verifying with research pharmacy 
the existing stock of study agent to assure optimal use of available drug. 
 
5.1.2 FORMULATION, APPEARANCE, PACKAGING AND LABELING  
“JNJ-40346527 drug substance is a white to off-white powder. The active JNJ-40346527 is 
available as free-base equivalent (eq.) 50 mg and 150 mg hard gelatin capsules. Both capsules 
are  sized 00 opaque capsule. Qualitatively, the hard gelatin capsule contains JNJ-40346527, 
Microcrystalline Cellulose (filler), Lactose Monohydrate (filler), Hydroxypropyl Methylcellulose 
(binder), Crospovidone (disintegrant).”  
 
All packages containing investigational product will have the following, or similar, language: 
“Caution: New Drug—Limited by Federal law to investigational use.” 
 
5.1.3 PRODUCT STORAGE AND STABILITY 
 
JNJ-40346527 capsules should be stored at room temperature, 15°C to 30°C (59°F to 86°F). 
 
 
5.1.4 COMPATIBILITY 
 
“JNJ-40346527 is a reversible inhibitor of primarily CYP3A4 and CYP2C8 and to a lesser extent 
of several other CYP isoforms (ie, CYPs 2B6, 2C9, 2C19, and 2D6) in vitro. JNJ-40346527 
increased the plasma exposure of midazolam (by ~65%) in a clinical Phase 1 study, suggesting 


 
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a weak inhibition of CYP3A4 at clinically relevant doses.  
 
JNJ-40346527 is an inhibitor of P-gp mediated transport of digoxin in vitro but was not a 
substrate for P-gp in vitro. Care should be taken if JNJ-40346527 is to be administered with     
P-gp substrates, especially those with narrow therapeutic index. The clinical impact of co-
administration of JNJ-40346527 with known inhibitors and inducers of CYP3A4/5, CYP2C8, or 
CYP2C19 are not fully understood. An increase or decrease of the systemic exposures of JNJ-
40346527 and its active metabolites has to be anticipated” a 
 
5.1.4.1 Solubility 
 
Very lightly soluble in: 0.1 N HCl, 0.1 N NaOH 
 
Practically insoluble in: H2O, Citrate/HCl buffer (pH 2-4), Citrate/NaOH buffer (pH 6), Borate/HCl 
buffer (pH 8), Borate/NaOH buffer (pH 10), simulated intestinal fluid, 20% hydroxypropyl-β-
cyclodextrin.  
 
5.1.5 HANDLING 
 
JNJ-40346527 must be dispensed only by the investigator or assigned designee, (e.g., study 
pharmacist, research nursing staff) to ensure the proper number of capsules are made available 
to the participants to satisfy dosing requirements for the study.  The containers provided to the 
participant 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. 
 
5.1.6 PREPARATION 
 
JNJ-40346527 is packaged as hard gelatin capsules. No additional preparation is required.  
 
5.1.7 ADMINISTRATION 
 
JNJ-40346527 will be supplied by Janssen Research & Development, LLC. or its designee in 
the form of 50 mg and 150 mg hard gelatin capsules as individual participant supply packaged 
in bottles. JNJ-40346527 is to be taken orally, twice daily. JNJ-40346527 must be taken as 
follows:  
 
• 
Participants should be instructed to take the JNJ-40346527 capsules with a large glass of 
water (~250ml) at the same time each day.  
• 
Participants should be instructed to swallow the JNJ-40346527 capsules whole and not to 
chew, crush or open them.  
• 
JNJ-40346527 can be taken without regard to meals, preferably right after breakfast and 
dinner. Anti-acids may affect absorption, suggest adding to use them only 2 hours or more 
before or after any doses of study drug. 
• 
Regardless, dietary habits around the time of dosing should be as consistent as possible 
throughout the study, and in particular during those periods when samples are being taken 
for PK analysis.  
• 
If vomiting occurs during the course of treatment, no re-dosing of the participant is allowed 
before the next scheduled dose.  
• 
Any doses that are missed (not taken within 6 hours of the intended time) should be skipped 
and should not be replaced or made up on a subsequent day.  


 
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• 
Participants must avoid consumption of grapefruit, grapefruit hybrids, pummelos, star-fruit, 
Seville oranges or products containing the juice of each during the entire study and 
preferably 7 days before the first dose of study medication, due to potential CYP3A4   
interaction with the study medication. Orange juice is allowed.  
• 
Due to potential interactions with JNJ-40346527, no herbal or dietary supplements are 
permitted, including St. John’s Wort without provider consultation.  
• 
Multivitamins are allowed.  
• 
Refer to Appendix C for tables of prohibited medications and medications to be used with 
caution in association with administration of JNJ-40346527.   
• 
If a subject is taking frequent antacids, e.g. always take JNJ-40346527 with food, ie, within 
approximately 30 minutes after breakfast in the morning and within approximately 30 
minutes after their evening meal. 
 
5.1.8 SPECIAL CONSIDERATIONS FOR ADMINISTRATION  
 
5.1.8.1 Participant self-administration 
 
JNJ-40346527 may be self-administered by participant. Specific instructions for at-home 
administration of JNJ-40346527 must be given to participant by physician or other designated 
healthcare provider.  
 
5.1.8.2 Participant Medical Diary    
 
Participants are required to keep a medical diary to record ingestion of study agent (e.g., 
frequency, volume of water per ingestion, as well as duration between meals).  
 
5.1.9 ACCOUNTABILITY 
 
The Investigator, or a responsible party designated by the Investigator, 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).   
 
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 or other oversight bodies. 
 
The Investigator or designee will collect and retain all used, unused, and partially used 
containers of study medication until full accounting has been completed. The Investigator or 
designee must maintain records that document: 
• Investigational product delivery to the study site. 
• The inventory at the site. 
• Use by each participant including pill/unit counts from each supply dispensed. 
• Return of investigational product to the Investigator or designee. 
• Destruction or return of investigational product for final disposal. 
 
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 
participants. 


 
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The investigational product must be used only in accordance with the protocol. The Investigator 
will also maintain records adequately documenting that the participants 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 
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 Manufacturer. 
 
5.1.10 DESTRUCTION AND RETURN 
 
At the end of the study, or earlier upon approval from study management, unused supplies of 
JNJ-40346527 should be destroyed according to institutional policies. Drug supplies will be 
counted and reconciled in full at the site with all monitoring procedures complete before 
destruction. Destruction will be documented in the Drug Accountability Record Form. 
 


 
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6. TREATMENT PLAN 
 
6.1 
DOSAGE AND ADMINISTRATION 
 
JNJ-40346527 will be administered at a fixed dose of 150 mg PO twice daily in continuous 28 
day cycles (defined as a single treatment cycle).  Treatment will be administered on an out-
patient basis.  Reported adverse events and potential risks are described in Section 9.  
Appropriate dose modifications are described in Section 6.2.  No investigational or commercial 
agents or therapies other than those described below may be administered with the intent to 
treat the participant's malignancy. 
 
6.2 
DOSING DELAYS AND MODIFICATIONS 
 
6.2.1 DEFINITION OF DOSE-LIMITING TOXICITY (DLT) 
 
A DLT is defined as an adverse event or abnormal laboratory value assessed as unrelated to 
disease, disease progression, inter-current illness, or concomitant medications.  A DLT requires 
a definite, probable or possible adverse experience to be related to the investigational product. 
Toxicities will be assessed using the National Cancer Institute Common Terminology Criteria for 
Adverse Events (NCI CTCAE v5).  
Safety will be assessed by evaluating the incidence of DLTs that exceeds the expected 
toxicities associated with JNJ-40346527. That is, DLTs are defined as any ≥ Grade 3 treatment 
related toxicity according to CTCAE v5.0.  The following expected adverse events are excluded: 
 
• 
Grade 3 and 4 prolonged hematologic toxicities 
• 
Grade 3 AST levels (i.e., >5 to 20 x ULN) 
• 
Grade 3 Creatinine kinase (CK) levels (i.e., >3.0 baseline; >3.0 - 6.0 x ULN) 
 
A DLT will also be defined as: 
 
(1) An ANC that fails to recover to >0.5 Gi/L within 42 days from the start of therapy in the 
absence of active leukemia or myelodysplasia; and, 
(2) A platelet count that fails to recover to >20 Gi/L within 42 days from the start of therapy in 
the absence of active leukemia or myelodysplasia or that is associated with clinically significant 
bleeding that requires transfusion of red cells or platelets. 
 
6.2.1.1 Duration of DLT assessment 
 
The DLT evaluation period will begin with the first dose of JNJ-40346527 and be continuously 
assessed throughout the study.  
 
6.2.2 DOSE DELAYS 
 
Treatment may be delayed for up to 28 days from the end of a previous 28-day cycle for SAEs 
described in Table 4.  In case of a treatment delay subsequent study assessment days will be 
adjusted accordingly.   
Regimen Description 
Agent 
Premedication; 
Precautions 
Dose 
Route 
Cycle Length 
JNJ-40346527 
 
150 mg, b.i.d PO 
28 Days 


 
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6.2.3 DOSE ESCALATION 
 
No dose escalation is allowed. JNJ-40342527 will be administered at a fixed dose of 150mg 
twice daily.  
 
6.2.4 DOSE DE-ESCALATION 
 
Dose reductions are allowable per PI discretion. If treatment-related toxicities are observed that 
based on the investigator’s best clinical judgement require a dose reduction, the dose of 
JNJ-40346527 can be reduced to 100 mg PO BID. The dose of JNJ-40346527 can be reduced 
only once. In case of another episode of treatment-related toxicity which based on the 
investigator’s best clinical judgement requires a dose reduction, the study treatment with 
JNJ-40346527 needs to be discontinued. 
 
6.2.5 GENERAL DOSE DELAY GUIDELINES 
 
Dose delays will be made as indicated in Table 4. The descriptions and grading scales found in 
the revised CTCAE v5 will be utilized for dose delays.  
 
 
Table 4. Dose delay guidelines and management of next dose forJNJ-40346527 
Non-hematologic 
≤Grade 1 
No dose modification. 
Grade 2 
No dose modification.  
Grades 3-4 and clinically 
significant* 
Dose modification per PI discretion. 
Hematologic 
All grades 
Dose modification per PI discretion. 
 
*For non-hematologic grade 3 and 4 AEs, JNJ-40346527 will be held until toxicity 
resolves to grade <2. Once grade <2, JNJ-40346527 will be restarted at 50 mg BID, 
then increased to 100 mg BID, and finally to 150 mg BID if subject was felt to be 
deriving clinical benefit and would like to continue on study. This dose escalation 
regimen will be reviewed by the treating physician and medical monitor. 
 
6.3 
TREATMENT PERIOD AND MAINTENANCE 
 
Participants will receive JNJ-40346527 at 150 mg PO twice daily in continuous 28-day cycles.  
Initial response will be assessed by bone marrow biopsy after cycles 1-3 and then every 3 
months thereafter. Further study assessments will be performed as outlined in the Section 7.10, 
Schedule of Events .  
 
Treatment with JNJ-40346527 will continue until disease progression or stopping rules are 
triggered as a result of either excess toxicity or lack of efficacy (refer to Section 10.2.4 ).  
 
Disease progression will be defined as any patient with response > PR who then loses PR 
based upon the original pre-treatment marrow sample (PR defined as > 50% decrease in 
marrow blasts to 5-25% of marrow). For example, a patient with 30% blasts on pre-treatment 


 
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marrow who achieved CR with 4% blasts and then was found to have 6% blasts with continued 
hematologic recovery on subsequent marrow (PR) would remain on trial until subsequent 
marrow blasts were >15%, or with loss of hematologic response. Patients with stable disease 
who continue to receive clinical benefit per PI review may remain on study drug. 
 
If a participant achieves a complete remission (CR) and is deemed a candidate for allogeneic 
stem-cell transplant, JNJ-40346527 should be discontinued 7 days before initiation of the 
conditioning regimen. Treatment with JNJ-40346527 may be resumed 30-100 days after the 
transplant if patients has a relapse of their disease, no active GVHD, and after review by the PI.  
 
6.4 
CONCOMITANT MEDICATION AND SUPPORTIVE CARE GUIDELINES 
 
Supportive measures for optimal medical care are to be given throughout the study as indicated 
by the treating physician’s assessment of the participant’s medical need and institutional and 
general medical guidelines for the care of participants undergoing treatment of AML. 
 
Medications required to treat AEs, manage cancer symptoms, concurrent diseases and 
supportive care agents, such as pain medications, anti-emetics and anti-diarrheals are allowed in 
general. The participant must be told to notify the investigational site about any new medications 
begun after the start of the study treatment. All medications (other than investigational products) 
and significant non-drug therapies (including vitamins, herbal medications, physical therapy and 
blood transfusions) administered during the study must be listed on the CRF.  
 
6.4.1 BLOOD PRODUCTS 
 
All blood products are to be irradiated and leukocyte-reduced according to institution guidelines. 
Additionally, cytomegalovirus (CMV)-negative participants should receive CMV-negative blood 
products according to institution guidelines.  
 
Medications that inhibit Platelet Function and Anticoagulants: Caution should be exercised if 
patients are required to take medications that inhibit platelet function or anticoagulants.  
Participants enrolled in this study should not take concomitant medications which durably inhibit 
platelet function unless medically necessary and caution should be used if anticoagulation is 
required. For such medications, a wash-out period of 7 days is required prior to starting kinase 
inhibitor therapy. Agents that inhibit platelet function transiently or inhibit coagulation by other 
mechanisms are restricted; however, if anticoagulation is required while on study this must first 
be reviewed with the pharmacist and the study PI. 
 
Medications that directly and durably inhibit platelet function include: Aspirin or aspirin-
containing combinations, clopidogrel, dipyridamole, tirofiban, epoprostenol, eptifibatide, 
cilostazol, abciximab, ticlopidine. 
 
Medications that directly and durably inhibit anticoagulation include: Warfarin, heparin/low 
molecular weight heparin [e.g., danaparoid, dalteparin, tinzaparin, enoxaparin] exceptions are 
low-dose warfarin for prophylaxis to prevent catheter thrombosis and heparin for flushes of IV 
lines. 
 
6.4.2 INFECTION PROPHYLAXIS 
 
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to institutional guidelines.  
**Note, certain antibiotics may have interactions with specific inhibitors and thus this must be 
reviewed closely prior to study enrollment and while on study.**  
 
Possible prophylaxis includes use of prophylaxis for HSV infection with acyclovir or valacyclovir; 
levofloxacin for bacterial prophylaxis, as long as patient is not febrile.  
 
The azole isavuconazole can likely be used concurrently with the study drug without dose 
adjustments. However if other azoles are prescribed such asposaconazole, fluconazole,or 
voriconazole, caution must be used as prophylaxis and may require measurement of drug levels 
to monitor dose. Potential interaction of antifungals should be reviewed with an oncology 
pharmacist and the study PI.  
 
6.4.3 TREATMENT OF FEVER AND NEUTROPENIA 
 
Neutropenic fever (defined as ANC <0.500/mm3 or 1.000/mm3 and known to be falling and 
temperature ≥38.0ºC) will be treated per institution guidelines.  
 
6.4.4 CYTOCHROME (CYP) INHIBITION 
 
“JNJ-40346527 is a reversible inhibitor of primarily CYP3A4 and CYP2C8 and to a lesser extent 
of several other CYP isoforms (i.e., CYPs 2B6, 2C9, 2C19, and 2D6) in vitro. JNJ-40346527 
increased the plasma exposure of midazolam (by ~65%) in a clinical Phase 1 study, suggesting 
a weak inhibition of CYP3A4 at clinically relevant doses. The clinical impact of co-administration 
of JNJ-40346527 with known inhibitors and inducers of CYP3A4/5, CYP2C8, or CYP2C19 are 
not fully understood. An increase or decrease of the systemic exposures of JNJ-40346527 and 
its active metabolites has to be anticipated.” a 
 
“Drugs that induce CYP3A4 activity may decrease JNJ-40346527 plasma concentrations. For 
participant in which CYP3A4 inducers are indicated, alternative agents with less enzyme 
induction potential should be used (Refer to Appendix B for detailed list of agents). 
 
JNJ-40346527 is a substrate of CYP450 and is primarily metabolized through oxidative 
biotransformation catalyzed by CYP3A4 leading to the formation of carboxymetabolites. Minor 
pathways are catalyzed by CYP2C8 and CYP2C9 leading to monooxygenated metabolites.  
Concomitant use of JNJ-40346527 and drugs that inhibit CYP3A4 may increase exposure to 
certain kinase inhibitors. Caution is warranted when administering JNJ-40346527 to participants 
taking drugs that are highly dependent on CYP3A4 for metabolism and have a narrow 
therapeutic index.  Systemic exposures to these medications could be increased while receiving 
JNJ-40346527.  
 
Additionally, strong to moderate CYP3A4 inhibitors (e.g. ketoconazole, itraconazole, 
erythromycin, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, 
telithromycin) may significantly increase concentrations of JNJ-40346527 and should be used 
with caution when administered concurrently with JNJ-40346527.” a 
 
6.4.5 P-GLYCOPROTEINS (P-GP) 
 
“JNJ-40346527 is an inhibitor of P-gp mediated transport of digoxin in vitro but was not a 
substrate for P-gp in vitro. Care should be taken if JNJ-40346527 is to be administered with P-


 
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gp substrates” especially those with narrow therapeutic index (e.g., digoxin) and consultation 
with oncology pharmacist and Investigator is required (Refer to Appendix B for detailed list of 
agents).  
 
6.4.6 GASTROINTESTINAL  
 
Anti-emetics, anti-diarrheal agents and acid suppressive therapies should not be taken 2 hours 
before or after study drug (e.g., antacids, H2 blockers, and proton pump inhibitors) will be 
prescribed per institutional guidelines.  
 
Study participants may receive anti-emetic therapy as needed during their treatment which may 
include ondansetron, prochlorperazine, haloperidol and lorazepam.   
 
The use of anti-diarrheals will be administered per investigator’s discretion. First line agents 
such as loperamide and tincture of opium, and/or octreotide can be utilized. 
 
Nonclinical data demonstrates that JNJ-40346527 was not affected by the concomitant intake of 
medications inducing a pronounced and long-lasting reduction of gastric acid production such 
as proton-pump inhibitors or histamine H2 receptor antagonists. The use of acid reducing 
agents will be per investigators discretion.  
 
6.5 
PRECAUTIONARY MEDICATIONS, TREATMENTS, AND PROCEDURES 
 
6.5.1 GENERAL PRECAUTIONS 
 
JNJ-40346527 is an investigational drug. All subjects receiving JNJ-40346527 should be closely 
monitored according to the relevant clinical study protocol.  While there has not been increased 
incidence of infection-related AEs observed, investigators should be vigilant for serious 
infections since JNJ-40346527 may impact subject’s ability to fight infection via a reduction in 
macrophage function. 
 
6.5.2 ANTIGENICITY AND MUTAGENICITY 
 
There is no information on the risk of antibody formation against JNJ-40346527. JNJ-40346527 
is not considered genotoxic based on the currently available in vitro and in vivo data. 
 
6.5.3 IMPAIRMENT OF FERTILITY AND PREGNANCY 
 
Since no fertility studies have been performed to date; it is possible that JNJ-40346527 may 
elicit embryofetal toxicity. JNJ-40346527 can only be administered in female and male subjects 
who practice effective birth control methods (refer to Appendix C) for 120 days after their last 
dose. For males no sperm donation should be allow either during the study or within 120 days 
after last dose.  
 
6.5.4 USE IN RENAL/HEPATIC DYSFUNCTION/FAILURE 
 
Clinical studies in subjects with renal/hepatic impairment have not been performed to date; 
therefore, those subjects should be excluded from participation in studies of JNJ-40346527. 
 
6.5.5 OVERDOSAGE AND ABUSE POTENTIAL 
 
Information regarding overdosage and abuse of JNJ-40346527 is not available to date. General 


 
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supportive measures should be taken as appropriate. 
 
6.5.6 CONTRAINDICATIONS 
 
There are no contraindications identified at this time for JNJ-40346527. 
 
6.6 
PROHIBITED MEDICATIONS, TREATMENTS, AND PROCEDURES  
 
No AML-directed concomitant therapy or investigational therapy is allowed during the study. 
Use of alternative medications (herbal or botanical for anticancer purposes) is not permitted 
during the study.  


 
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7. STUDY PROCEDURES/EVALUATIONS AND SCHEDULE  
 
7.1 
STUDY SPECIFIC PROCEDURES 
 
7.1.1 MEDICAL HISTORY  
 
A medical history will be obtained by the investigator or qualified designee. In addition to 
collecting information on demographics, the medical history will include all active conditions, and 
any prior conditions that are considered to be clinically significant by the PI. Details regarding 
the participant’s AML will be recorded separately and not listed as medical history. 
 
7.1.2 DISEASE ASSESSMENT 
 
The investigator or qualified designee will obtain prior and current details regarding the 
participant’s AML. 
 
7.1.3 MEDICATION HISTORY  
 
A complete medication history will be acquired concurrent with medical history.  
 
7.1.4 PHYSICAL EXAMINATION  
 
Physical exams must be performed by a medically qualified individual such as a licensed 
physician, Physician’s Assistant or advanced Registered Nurse Practitioner as local law permits. 
The physical exam at baseline should include a complete physical exam per institutional 
standards. All other physical exams after baseline will include an evaluation of any AEs, or any 
previously reported symptoms, or prior physical examination findings. 
 
As part of screening/baseline visit, physical examination is to be conducted within 14 days prior 
to start of treatment. All physical examinations will also include: 
 
7.1.4.1 Vital signs  
Vitals to be collected include BP, HR, and temperature. As part of screening/baseline visit, vitals 
should be obtained within 10 days prior to first dose of study agent. Vitals will also be obtained 
during treatment.  
 
Significant findings that were present prior to the signature of the informed consent must be 
included in the Medical History eCRF page. Significant new findings that begin or worsen after 
informed consent must be recorded on the Adverse Event eCRF page.  
 
7.1.4.2 Height and weight  
 
Height is only required as part of screening.  
 
7.1.4.3 Performance status  
 
Performance status will be determined for all participants at screening and at select times during 
treatment as per assessment schedule in Section 7.10. Refer to Appendix B for performance 
criteria. 
 


 
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7.1.5 ELECTROCARDIOGRAM (ECG)  
 
A standard of care ECG will be performed within 28 days prior to initiating treatment. Refer to 
schedule in Section 7.10.  
 
7.1.6 MEDICAL DIARY 
 
Participants that self-administer JNJ-40346527 are required to maintain a medical diary to 
assess compliance. Participants will receive instruction on how to administer JNJ-40346527 
from a physician, clinical research nurse, or other designated, qualified healthcare provider. 
Participants will be provided with a medical diary and are required to record the date, dose, and 
the time of each oral dose.   
 
7.1.7 ADVERSE EVENTS  
 
Toxicities and adverse experiences will be assessed at each visit using the CTCAE v5.0. Safety 
will be monitored by assessing physical examination, vital signs, body weight, performance 
status, as well as hematology, and chemistry as indicated in Section 7.10. 
 
7.2 
LABORATORY PROCEDURES AND EVALUATIONS 
 
7.2.1 HEMATOLOGY 
 
Hematologic profiling will be collected per institutional standards, and may include evaluation of 
hematocrit, hemoglobin, platelets, white blood cells with differential (basophils, eosinophils, 
lymphocytes, monocytes, neutrophils), and absolute lymphocyte count. 
 
7.2.2 COAGULATION PANEL 
 
INR, prothrombin time, and PTT. 
 
7.2.3 BIOCHEMISTRY 
 
Blood chemistry will be collected per institutional standards and may include the following: 
Creatinine, BUN, total bilirubin, Alkaline Phosphatase, serum electrolytes, magnesium, calcium, 
and potassium, phosphorous, as well as lactate dehydrogenase and uric acid. Testing for HCV 
B or C will only take place during screening  
 
7.2.4 URINALYSIS 
 
Glucose, protein, hemoglobin (blood), bilirubin, ketones, pH, and specific gravity. A microscopic 
exam should be performed for 2+ (~0.5 to 1.5 g/24 hours) or higher hemoglobin or protein 
levels. 
 
 
7.2.5 BONE MARROW EXAM 
 
Bone marrow aspirate must be collected at the visits outlined in the Section 7.10, Schedule of 
Events (Cycle 1 Day 29, Cycle 2 Day 29, Cycle 3 Day 29, and every 3 months following Cycle 3 
Day 29. Additional bone marrow evaluations may occur if clinically indicated at the discretion of 


 
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the investigator (e.g., at the time of suspected disease progression or disease remission.) 
 
Bone Marrow Aspirate will be collected to assess: 
• 
Hematopathology review  
• 
myeloid:erythroid ratio per standard of care 
• 
Cellularity (%) 
• 
blast quantification per standard of care. 
• 
Cytogenetics will be performed as standard of care.  
• 
Pharmacokinetic assay described in Section 7.3.1. (5-8ml in sodium heparin) 
• 
Flow cytometry: as standard of care per institutional standards and exploratory analysis 
described in Section 7.3.2.  
 
7.2.6 SKIN PUNCH BIOPSY 
 
Data analysis from next generation sequencing can be greatly simplified by comparison of a 
patient’s tumor sequence with germline sequence. The comparison facilitates identification of 
mutations that are unique to the tumor and not inherited sequence polymorphisms. The 
currently recognized method for obtaining germline sequence (espoused by The Cancer 
Genome Atlas project) is through the sequencing of DNA from skin fibroblasts that are obtained 
from a 3.5mm skin punch biopsy. Skin biopsies will be collected during the standard of care 
bone marrow procedure once during the study. The skin punch biopsy can be collected at any 
bone marrow collection time point. This procedure replaces the normal skin incision made to 
access the bone and does not require any additional sterilization or anesthetic.  
 
Briefly, the procedure will be performed with a skin punch. The skin biopsy will be placed in 
saline or on moist gauze and transported to the research lab. One half of the biopsy will be used 
for genomic DNA extraction using standard tissue extraction protocols/kits. The remaining half 
will be snap-frozen and stored at -80ºC.  
 
7.2.7 BLOOD COLLECTION 
 
Blood will be collected at time points outlined in the Section 7.10, Schedule of Events . 
 
Peripheral Blood (2.0 mL in EDTA tube) will be collected for hematologic profiling. 
 
Peripheral Blood (10ml) collected in sodium heparin-coated tubes or sodium citrate tubes will be 
used for evaluation of serum biochemistry and coagulation, respectively.  
 
Peripheral Blood (10-40 ml) collected in  EDTA coated tubes will be used for genetic studies 
described in Section 7.3.3 and 7.3.4. 
 
7.2.8 PREGNANCY TEST  
 
A serum (β-HCG) or urine pregnancy test is required during screening for all persons of 
childbearing potential within 14 days of initiating study drug. If the urine pregnancy test is 
positive, a serum pregnancy test must be performed per institutional standards. Pregnancy tests 
(serum and/or urine tests) should be repeated, if required, per institutional guidelines. 
 
 


 
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7.3 
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES 
 
The two overarching aims of the proposed exploratory studies are to: (i) evaluate the 
pharmacokinetics of JNJ-40346527 and effective inhibition of CSF-1R in marrow aspirates using 
plasma inhibitory assays with established CSF-1R-sensitive cell lines, and (ii) identify the effect 
of JNJ-40346527 on leukemia cells and the immune microenvironment. 
 
7.3.1 EVALUATE THE PHARMACOKINETICS OF JNJ-40346527 AND EFFECTIVE 
INHIBITION OF CSF-1R 
 
Plasma inhibitory assays using GDM-1 cells (very sensitive to CSF-1R inhibitors) will be 
performed with bone marrow aspirates before treatment (no later than 14 days prior to start of 
treatment) and after 28 days to estimate the effective CSF-1R inhibition by JNJ-40346527 in 
plasma derived from the marrow.  The goal is to evaluate how well JNJ-40346527 inhibits CSF-
1R within the marrow microenvironment.  
 
7.3.2 IDENTIFY AND QUANTIFY THE SPECIFIC SUBPOPULATION OF CELLS THAT 
EXPRESS CSF-1R IN SUBJECTS AND CORRELATE WITH CLINICAL RESPONSE 
TO JNJ-40346527.  
 
Bone marrow aspirates or peripheral blood will be collected from subjects and analyzed for ex 
vivo sensitivity to JNJ-40346527 prior to entry. The samples will also be analyzed for CSF-1R 
expression using FACS analysis using the CLIA-certified clinical flow lab at OHSU. In addition to 
CSF-1R expression, the samples will be analyzed for standard immunophenotypic markers to 
identify the subpopulation that most highly expresses CSF-1R.  
 
Preliminary data suggests that CSF-1R is expressed on a subset of CD14+ cells (a monocytic 
marker). This data supports our hypothesis that CSF-1R inhibition is not directly affecting the 
leukemia cells, but rather is targeting a smaller supportive cell population, as shown in Figure 4. 
Evaluation of pure CD14+ populations in AML samples is somewhat limited since a subset of 
AML samples express CD14+ on blasts; however, there is still a trend towards sensitivity to 
CSF-1R inhibition in samples that have higher expression of CSF-1R on non-leukemic CD14+ 
cells.  
 
CSF-1R expression will be correlated with CD14 and standard immunophenotypic flow markers 
in the clinical flow lab (Table 5) to determine the specific population(s) that express CSF-1R and 
are likely to be a target of JNJ-40346527. CSF-1R expression in specific hematopoietic lineages 
will be correlated with ex vivo sensitivity to JNJ-40346527 and clinical response.  
 
The goal of this aim is to identify the specific subpopulation of cells that expresses CSF-1R, and 
if a quantitative analysis of this population can be used to predict clinical response to CSF-1R 
inhibition.  
 
Table 5. Clinical flow cytometry antibodies tested with CSF-1R in CLIA-certified lab. 
CD1a 
CD2 
sCD3 
cCD3 
CD4 
CD5 
CD7 
CD8 
CD10 
CD11b 
CD13 
CD14 
CD15 
CD16 
CD19 
CD20 
CD22 
CD33 
CD34 
CD38 
CD45 
CD56 
CD58 
CD64 
TdT 
CD103 
CD23 
CD25 
CSF-1R 
 
 
 
 
An identical FACS analysis will also be performed on bone marrow biopsies after one month of 
therapy to assess the expression of CSF-1R and CD14+ cells after JNJ-40346527 treatment in 


 
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both clinical responders and non-responders. This will establish if there is a reduction only in the 
CSF-1R-expressing population, or if other lineages are also affected. For example, it may be 
that JNJ-40346527 only affects CD14+ cells that express CSF-1R, or JNJ-40346527 may shrink 
the entire population of CD14+ cells. The relative proportion of leukemia cells, B-cells, and T-
cells will also be evaluated after treatment.  
 
Since this work will be done in a CLIA-certified clinical lab using standard flow procedures and 
equipment, it would provide a companion diagnostic that could be rapidly incorporated into 
standard flow protocols for larger trials. 
 
7.3.3 ASSESSING A GENETIC SIGNATURE THAT PREDICTS RESPONSE TO JNJ-
40346527. 
 
Genomic DNA from leukemia patients will be analyzed for frequent leukemia mutations to 
determine if there is a genetic signature that predicts response to JNJ-40346527.  The 
GeneTrails Hematologic Malignancies Gene Panel developed at OHSU’s Knight Diagnostic 
Laboratory covers 76 genes that are frequently mutated in both lymphoid and myeloid leukemia, 
and is run as a CLIA-approved (CLIA#38D2018256), standard-of-care test on leukemia patients 
(Refer to D). Additional sites will use their in-house leukemia panel per standard of care. 
Redacted source documentation from sites will be sent to OHSU for genetic marker analysis. 
 
Sequencing data from participants who have clinically responded to JNJ-40346527 will be 
compared to that from non-responders, to determine if there are genetic markers of clinical 
response. The goal is to identify a potential genetic subtype of AML that predicts clinical 
response to JNJ-40346527, either alone or in combination with the quantitative and qualitative 
analysis of CSF-1R+ cells. 
 
Additionally, coded and de-identified DNA samples will be stored in the Druker Lab (OHSU) for 
further retrospective analyses, including targeted sequencing, whole-exome sequencing, or 
methylation analysis. Samples will be stored indefinitely. Access to samples will be limited to 
study staff.   
 
7.3.4 TRANSCRIPTOME ANALYSIS TO IDENTIFY POTENTIAL QUALITATIVE 
DIFFERENCES IN CSF-1R+ CELLS THAT PREDICT PATIENT RESPONSE. 
 
RNAseq will also be performed on leukemia samples from expression signature in CSF-1R+ 
cells that predicts patient response. We hypothesize that there may be a qualitative difference in 
CSF-1R+ CD14+ and CSF-1R- CD14+ cells that results in clinical sensitivity to CSF-1R inhibitors. 
This difference may not be detected by the CyTOF approach outlined above, as that requires 
using candidate phospho-protein and cytokines. RNAseq offers an unbiased way to analyze the 
functional difference between these cells.  
 
CSF-1R+ CD14+ and CSF-1R- CD14+ cells will be isolated with magnetic antibody sorting. Since 
not every subject will have sufficient cells for RNAseq, we will review the FACS analysis of 
patients at screening to identify subjects that are likely to have sufficient numbers of CD14+ and 
CSF-1R+ cells. Our preliminary data has found that CSF-1R+ cells account for about 1-3% of 
the total number of cells. 40 ml of peripheral blood will be collected from subjects with a total 
peripheral blood WBC>10. This WBC typically correlates with a yield of ~100 million cells after 
Ficoll separation, which will subsequently allow for collection of >1 million CSF-1R+ CD14+ cells 
to process for RNA. This peripheral blood sample will be collected on day 1 prior to JNJ-


 
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40346527 treatment. 
 
Collectively, these studies are aimed at identifying a genetic or expression signature of CSF-1R+ 
cells that predicts clinical response to JNJ-40346527, as well as uncovering potential 
mechanisms of resistance/adaptation. 
 
7.3.5 MASS CYTOMETRY EVALUATION OF JNJ-40346527 EFFECT ON PHOSPHO-
SIGNALING PROTEINS IN IMMUNE CELL POPULATIONS  
 
This exploratory study will utilize mass cytometry (cytometry by Time of Flight, CyTOF) to evaluate 
the effect that JNJ-40346527 has on intracellular phospho-signaling of proteins within immune 
cell populations (i.e., cytotoxic T cells, etc.) in pre- and post-treatment samples. These studies 
are intended to identify biomarkers that predict patient response and prioritize potential 
combination strategies for future clinical trials.  
 
Bone marrow aspirates and blood samples will be collected and purified by Ficoll gradient. The 
cells will be fixed and labeled with antibodies coupled to heavy metal isotopes for CyTOF using 
established protocols. Cells expressing CSF-1R will be evaluated by CyTOF to look at 
downstream signaling pathways such as phospho-STAT3/5, phospho-Akt, phospho-MAPK, 
phospho-p38 and phospho-S6. As a positive control, we will use the GDM-1 cell line, which has 
an activating mutation in CSF-1R and responds robustly to CSF-1R inhibition in vitro. Antibodies 
to identify relevant subpopulations of monocytes, lymphocytes, and leukemia cells will be used to 
analyze phospho-signaling in CSF-1R+ cells, CD14+ cells, and leukemia cells (Table 6). 
 
Table 6. Antibody panel for analysis of kinase signaling and cytokine analysis by CyTOF. 
CSF-1R 
CD14 
pSTAT3 
pSTAT5 
pMAPK 
pS6 
pP38 
pAkt 
EGF 
FGF2 
HGF 
SDF1 
VEGF 
IL-6 
IL-1 
MCP1 
MCP2 
CXCL1 
IL-8 
IL-10 
RANTES 
TGF 
MIP1b 
G-CSF 
IL3 
MIP1a 
GCSF-1 
 
 
 
 
 
 
To examine the secreted proteins from the supportive cells, we will pretreat samples with a 
Golgi trap (brefeldin A) to retain secreted proteins in the cells for intracellular staining. A 
selection of signaling molecules known to impact leukemia cell survival will also be evaluated, 
including a focus on the CSF-1R+ and CD14+ cells. Particularly, we will investigate the 
expression of the ligand CSF-1, which may act in an autocrine manner to expand supportive 
CSF-1R+ cells ().  
 
Bone marrow aspirates will be tested at screening and after one cycle of therapy to evaluate 
signaling in CSF-1R+ CD14+ cells, CSF-1R- CD14+ cells, immune cell populations, and leukemia 
cells both before and after treatment. Responsive versus non-responsive subjects will be 
compared to determine if there is a qualitative difference in CSF-1R+ cells that predicts clinical 
response to JNJ-40346527, and if this population either disappears or is functionally altered by 
JNJ-40346527 treatment. The goal is to determine if there is a qualitative signature of CSF-1R+ 
cells that predicts clinical response to JNJ-40346527 that can be used to identify sensitive 
patients or immunotherapeutic targets in future clinical trials. 
 


 
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In addition to identifying a biomarker, we predict that CSF-1R inhibition will alter the leukemic 
immune microenvironment as well. This will be evaluated by CyTOF analysis pre- and post-
treatment for each patient. Our CyTOF panels cover immune checkpoint proteins, B- and T-cell 
populations, NK populations, and leukemia surface antigens in addition to the 
microenvironmental proteins outlined (Table 6; Error! Reference source not found.). JNJ-
40346527 may potentially increase expression of checkpoint proteins, alter specific immune 
populations such as NK cells, or increase expression of leukemia cell antigens that can be 
targeted with antibody-directed immunotherapies (CD123, CD33, etc.). The goal is to identify 
promising combinations for future immunotherapy clinical trials. 
 
7.3.6 SCREENING EX VIVO SENSITIVITY TO SMALL MOLECULE INHIBITORS 
FOLLOWING CSF-1R INHIBITION.  
 
Ex vivo sensitivity to a panel of small molecules will be performed on bone marrow samples pre- 
and post-treatment to determine how leukemia cells change in response to CSF-1R inhibition. 
Participants with an ex vivo IC50 that is ≤20% of the median IC50 (to be determined with preclinical 
testing) will be considered sensitive to JNJ-40346527 (termed “assay positive”), whereas those 
with an IC50 >20% of the median IC50 will be considered insensitive (termed “assay negative”).   
 
Figure 7. Evaluation of cells expressing CSF-1R and CD14 by CyTOF using viSNE clustering.  
The AML sample 15-00880 was stained with 35 distinct markers and analyzed by CyTOF.  Cell 
populations expressing CSF-1R (CD115+) were identified, and the gating map is shown in panel A. 
The cell populations that express B) CD115 or C) CD14 are shown by viSNE cluster analysis 
displayed as intensity maps for CD115 and CD14, respectively. D) The relative fold enrichments of 16 
surface markers frequently found in AML show the fold increase compared to all live events for each 
of the populations defined in panel A. We propose to use antibodies that interrogate kinase signaling, 
immune cell populations, and cytokines (Table 6) to obtain functional information about CSF-1R+ cell 
populations in AML. 


 
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The ex vivo drug screening platform contains ~175 small-molecules inhibitors, including 
numerous kinase inhibitors. Changes in sensitivity of bone marrow aspirates pre- and post-
treatment (day 29) will be evaluated. Preliminary data suggests that CSF-1R inhibition affects 
secretion of paracrine survival signals from supportive cells in the microenvironment, which will 
lead to leukemia cell death. Removing paracrine survival signals may also reveal sensitivities to 
other small molecules that were previously obscured by paracrine survival signals. The goal of 
these studies is to identify novel drugs that could be used in combination, or sequentially, with 
JNJ-40346527.  
 
7.4 
SCREENING ASSESSMENTS 
 
Toxicities which occur prior to the start of treatment will not be subject to analysis. Consent must 
be obtained before initiation of any clinical screening procedure that is performed solely for the 
purpose of determining eligibility for this research study. Evaluations performed as part of 
routine care before informed consent can be utilized as screening evaluations if done within the 
defined time period.  
 
Screening assessments will occur over a 28-day period prior to start of treatment with study 
agent. Participants will be evaluated for medical history, physical examination, vital signs, 
ECOG performance status, chest X-ray, concomitant medications, blood sampling for laboratory 
tests, ECG evaluation, bone marrow biopsy aspiration/biopsy.  
 
Ex vivo sensitivity analysis of AML cells from either bone marrow aspirate or peripheral blood 
will be completed no later than 7 days prior to initiating treatment. Peripheral blood may be used 
in place of bone marrow if participant cannot be aspirated or patient has undergone bone 
marrow biopsy within the last 10 days prior to desired screening date and blast cells comprise 
≥20% of circulating nucleated cells. 
 
7.4.1 INFORMATION TO BE COLLECTED ON SCREENING FAILURES 
  
A participant who signed an informed consent form but failed to be started on treatment for any 
reason will be considered a screen failure. Those found not to be eligible after signing the main 
study consent will be considered screening failures, and data will be handled in the same 
manner. The demographic information and informed consent.  No other data will be entered into 
the clinical database for individuals who are screen failures. 
 
7.5 
ASSESSMENTS DURING TREATMENT 
 
Visits will occur on Day 1 of every cycle.  Additional visits in cycles 1 and 2 are listed in the 
schedule of assessments. Under certain circumstances (e.g., clinic holiday, inclement weather) 
Day 1 may be delayed by not more than 3 days, or occur earlier than scheduled by not more 
than 3 days during Cycle 2 and subsequent cycles.  Specific on-study assessments are listed in 
the Section 7.10, Schedule of Events .   
 
Initial response to JNJ-40346527 will be assessed by bone marrow biopsy after cycles 1-3 and 
every 3 months thereafter. Tumor response will be evaluated per International Working Group 
(IWG) criteria for AML (refer to Section 8). All studies must be obtained ± 7 day of stated time 
point.   
 
7.6 
END OF TREATMENT VISIT 
 


 
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Participants will be followed until death.  Participants will be evaluated for end of treatment 
within  ± 7 days after stopping JNJ-40346527. End of treatment assessments are listed in the 
Section 7.10, Schedule of Events . If participants do not reach the end of treatment due to 
transition to hospice or death, an end of treatment visit will not be conducted. 
 
7.7 
FOLLOW-UP 
 
Participants will be followed every 6 months until death.  Participants removed from protocol 
therapy for unacceptable AE(s) will be followed until resolution or stabilization of the AE. 
 
7.8 
EARLY TERMINATION VISIT 
 
Study assessments for an early termination visit will mirror the end of treatment visit.  A 
standard of care treatment plan will be formulated as soon as possible for those participants that 
withdraw from the study abruptly for any reason.  Participants will be encouraged to return for 
the follow-up visit. 
 
7.9 
UNSCHEDULED VISITS 
 
Section 7.10, Schedule of Events lists the mandatory data collected at each time point for the 
clinical trial but it is expected that additional tests/procedures or visits may occur as standard of 
care, which is entirely at the discretion of the investigator. Most participants will have additional 
laboratory studies and clinical evaluations outside of this schedule as part of their standard of 
care. The labs or studies outlined in the schedule of events may be completed within 7 days of 
the target week (i.e., 7 days before or 7 days after).  Every effort will be made to adhere to this 
schedule as close as possible.  This is the minimum schedule of laboratory studies and follow-
up visits required for the study.  
 
 


 
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7.10 
SCHEDULE OF EVENTS  
 
 
Screening 
Period 
Treatment Period* (C1D29=C2D1) 
End of 
Treatment† 
Follow-up‡ 
Cycle 
C1 
C1 
C1 
C1 
C2 
C2 
C3+ 
 
 
Days -28 to -1 
Day 
+1 
Day 
+8 
Day 
+15 
Day 
+22 
Day 
+1* 
Day 
+15 
Day 
+1 
 
 
JNJ-40346527A 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
Inclusion/exclusion 
X 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
Concomitant 
MedicationsB 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Physical ExamC 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
ECG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Chest X-rayD 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HematologyE 
X 
X 
X 
X 
X 
X 
 
X 
 
 
Biochemistry 
X 
X 
X 
X 
X 
X 
 
X 
 
 
Coagulation Panel 
X 
X 
X 
X 
X 
X 
 
X 
 
 
Urinalysis 
X 
 
 
 
 
X 
 
X 
 
 
Pregnancy testF 
X 
X 
 
 
 
X 
 
X 
 
 
Bone MarrowG 
XH 
 
 
 
 
XH 
 
 
X 
 
Flow cytometry 
X 
 
 
X 
 
X 
 
 
 
 
Cytogenetics 
X 
 
 
 
 
 
 
 
 
 
GeneTrails 
X 
 
 
 
 
 
 
 
 
 
Skin Punch BiopsyI 
XI 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AEJ 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 


 
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Ex vivo screening 
X 
 
X 
X 
 
X 
 
 
 
FACS 
X 
 
 
X 
 
X 
 
 
 
RNAseq 
X 
X 
 
X 
 
X 
 
 
 
Research Blood 
SamplesK 
X 
X 
X 
X 
X 
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 otherw ise specified. 
Treatment cycles are 28 days; how ever the treatment cycle interval may be increased due to toxicity according to the dose modification guidelines 
provided in Section 6.2.. If the interval is increased, all procedures except imaging should be performed based on the new  dosing schedule.  
** In general, the w indow  for each visit is ± 7 days unless otherw ise noted. 
*** Point of care CBC w ill be run every 2 w eeks during Cycle 2. Once a cycle in subsequent cycles (Cycle 3+). 
† Study treatment w ill end upon evidence of disease progression as defined by IWG for AML. Refer to Section 8 for additional details. 
‡ Participants w ill be follow ed until death. Participants may be contacted by phone, and survival status w ill be collected and documented  
A JNJ-40346527 (150 mg) is administered PO tw ice daily. 
B For concomitant medications – enter new  medications started during the trial through the EOT visit. Record all medications taken for grade 3 and 4 
SAEs as defined in Section 9.6. 
C Full physical exam at screening visit. Direct physical exam for all other visits. All physical exams w ill include assessing w eight, vital signs, and 
ECOG performance status. Height w ill be measured at screening visit only. 
D Chest X-ray at screening w ill be performed w ithin 28 days prior to the first dose of trial treatment. Scans performed as part of routine clinical 
management are acceptable for use as the screening image if they are of diagnostic quality and performed w ithin 28 days prior to the first dose of trial 
treatment. 
E After Cycle 1, pre-dose lab samples can be collected up to 72 hours prior to the scheduled time point. Hematology and biochemistry tests should be 
collected pre-dose on Day 1 of every 28 day cycle. Testing for HCV B or C w ill only take place during screening. 
F For w omen of reproductive potential, a urine pregnancy test should be performed w ithin 14 days prior to first dose of trial treatment. If urine 
pregnancy results cannot be confirmed as negative, a serum pregnancy test performed by the local study site laboratory w ill be required. Pregnancy 
tests (serum and/or urine tests) should be repeated, if required, per institutional guidelines. 
G Peripheral blood may be used in place of bone marrow  and blast cells comprise ≥20% of circulating nucleated cells. 
H Standard of care bone marrow  exams are done at screening and Day 29 for Cycles 1-3, and every 3 months for subsequent cycles.  
I  Skin punch biopsy w ill be collected once anytime during the study.  
J AEs and laboratory safety measurements w ill be graded per NCI CTCAE version 5.0.  All AEs, w hether gradable by CTCAE or not, w ill also be 
evaluated for seriousness. Record grade 3 and 4AEs occurring w ithin 30 days after the last dose of trial treatment. Report grade 3 and 4 hem and 
non-hem SAEs (related and unrelated to trial treatment) occurring up until 90 days after the last dose of trial treatment, or the start of new  anti-cancer 
treatment, w hichever comes first. Afterw ards, report only SAEs that are related to trial treatment. 
K Research blood samples w ill be draw n during standard of care lab draw . 


 
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8. EFFICACY MEASURES 
 
8.1 
DEFINITION OF EFFICACY MEASURES 
 
Assessment of clinical response will be made according to IWG criteria.20  The major criteria for 
judging response will include physical examination and examination of blood and bone marrow. 
Relevant laboratory studies that are abnormal prior to study will be repeated according to the 
study schedule to document the degree of maximal response.  
 
8.1.1 EVALUABLE FOR TOXICITY 
 
All participants who have received at least 1 dose of study agent will be evaluable for toxicity 
from the time of their first treatment with JNJ-40346527. 
 
8.1.2 EVALUABLE FOR OBJECTIVE RESPONSE 
 
Only those participants who have completed at least 1 cycle of study agent will be evaluable. 
 
8.2 
RESPONSE CRITERIA FOR AML 
 
The objective response rate will be defined as >PR, including cytogenetic and molecular 
responses when applicable, and will be determined at the end of each cycle. 
 
Complete Remission (CR)*: • Bone marrow blasts < 5%;  
• Absence of blasts with Auer rods;  
• Absence of extramedullary disease;  
• Absolute neutrophil count >1 x 109/L (1000/µL);  
• Platelet count > 100 x 109/L (100,000/µL);  
• Independence of red cell transfusions 
Morphologic CR: • Bone marrow blasts <5%;  
• Absence of blasts with Auer rods;  
• Absence of extramedullary disease;  
• No hematologic recovery required 
Partial Remission • Relevant in the setting of phase 1 and 2 clinical trials only; 
• All hematologic criteria of CR;  
• Decrease of bone marrow blast percentage to 5% to 25%;  
• Decrease of pretreatment bone marrow blast percentage by 
at least 50% 
Cytogenetic Complete 
Remission (CRc): 
• Reversion to a normal karyotype at the time of morphologic 
CR in cases with an abnormal karyotype at the time of 
diagnosis; based on the evaluation of 20 metaphase cells 
from bone marrow. 
Molecular CR (CRm): • Molecular studies are negative (i.e., normal molecular 
markers in persons with previously abnormal molecular 
studies (e.g. c-KIT, NPM1, FLT3). 


 
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8.2.1 OUTCOME MEASURES IN AML 
 
Outcome 
Definition 
Response 
Category 
Point of 
Measurement 
Overall 
survival 
Defined for all patients of a trial; measured 
from the date of entry into a study to the date 
of death from any cause; patients not known 
to have died at last follow-up are censored on 
the date they were last known to be alive. 
All patients 
Trial entry 
Event-free 
survival 
Defined for all patients of a trial; measured 
from the date of entry into a study to the date 
of relapse from PR or CR or CRi, or death 
from any cause; patients not known to have 
any of these events are censored on the date 
they were last examined. 
All patients 
Trial entry 
 
 
 
 
 
CR with incomplete 
recovery (CRi): 
 
Stable disease (SD) 
 
Progressive disease (PD) 
• All CR criteria except for residual neutropenia (< 1 x 109/L 
[1000/µL), or thrombocytopenia (< 100 X 109/L [100,000/µL). 
 
Not fulfilling either PR or PD criteria and clinical stability 
 
Increase in blasts by >50% 
 
Definitions of response criteria are amended from Cheson et al.20 
 
*All criteria need to be fulfilled; marrow  evaluation should be based on a count of 200 nucleated cells in an aspirate 
w ith spicules; if ambiguous, consider repeat exam after 5 to 7 days; flow  cytometric evaluation may help to 
distinguish betw een persistent leukemia and regenerating normal marrow ; a marrow  biopsy should be performed 
in cases of dry tap, or if no spicules are obtained; no minimum duration of response required. 


 
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9. SAFETY 
 
9.1 
SPECIFICATION OF SAFETY PARAMETERS 
 
As the sponsor of the Study, INSTITUTION and PRINCIPAL INVESTIGATOR shall be solely 
responsible for complying, within the required timelines, any safety reporting obligation to 
competent Health Authorities, IRB/ECs and any participating (co or sub) investigators, as 
defined in applicable laws and regulations 
 
The Investigator is responsible for monitoring the safety of participants who have enrolled in the 
study. Safety assessments will be based on medical review of adverse events and the results of 
safety evaluations at specified time points as described in Section 7.10, Schedule of Events. 
Any clinically significant adverse events persisting at the end of treatment visit will be followed 
by the Investigator until resolution/stabilization or death, whichever comes first. 
 
Management of Safety Data 
This Study has been designated as an interventional study.  As such, all adverse events for 
Janssen Medicinal Products regardless of causality and special situations excluding those from 
subjects not exposed to a Janssen Medicinal Product and product quality complaints with or 
without an adverse event as described in this section will be reported from the time a subject 
has started study drug until completion of the subject’s last study-related procedure (which may 
include contact for follow-up safety).  Serious adverse events will be reported for 30 days after 
the last dose of study drug. 
 
For the purposes of this study, the Janssen medicinal product is: JNJ-40346527  
 
 
9.2 
DEFINITIONS 
 
9.2.1 ADVERSE EVENT (AE) 
 
An adverse event is defined as any undesirable physical, psychological or behavioral effect 
experienced by a participant during their participation in an investigational study, in conjunction 
with the use of the investigational product, whether or not considered intervention-related (21 
CFR 312.32 (a)). In general, this includes signs or symptoms experienced by the participant 
from the time subject has started study drug to completion of the study.   
 
AEs may include, but are not limited to: 
• 
Subjective or objective symptoms spontaneously offered by the participant and/or 
observed by the Investigator or medical staff.  
• 
Clinically significant laboratory abnormalities.  
• 
A significant worsening of the participant’s condition from study entry.  
• 
Disease signs and symptoms and/or laboratory abnormalities existing prior to the use of 
the study treatment that resolve but then recur after treatment.  
• 
Disease signs and symptoms and/or laboratory abnormalities existing prior to the use of 
the study treatment which increase in frequency, intensity, or a change in quality after 
treatment.  
 
9.2.2 SERIOUS ADVERSE EVENT (SAE) 
 


 
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An AE or suspected adverse reaction is considered "serious" if, in the view of either the 
Investigator, it results in any of the following outcomes: 
  
• 
Death,  
• 
A life-threatening adverse event,  
• 
In-patient hospitalization or prolongation of existing hospitalization,  
• 
A persistent or significant incapacity or substantial disruption of the ability to conduct normal 
life functions, or 
• 
A congenital anomaly/birth defect.  
 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical judgment, 
they may jeopardize the participant and/or participant may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition. 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 in-patient hospitalization, or 
• 
The development of drug dependency or drug abuse.  
 
Hospitalization 
 
For reports of hospitalization, it is the sign, symptom or diagnosis which led to the 
hospitalization that is the serious event for which details must be provided. 
 
Any event requiring hospitalization or prolongation of hospitalization that occurs during the study 
must be reported as a serious adverse event, except hospitalizations for the following: 
 
• 
Hospitalizations not intended to treat an acute illness or adverse event (e.g., social reasons 
such as pending placement in long-term care facility) 
• 
Surgery or procedure planned before entry into the study. [Note: Hospitalizations that were 
planned before the start of data collection and where the underlying condition for which the 
hospitalization was planned has not worsened will not be considered serious adverse events. 
Any adverse event that results in a prolongation of the originally planned hospitalization is to 
be reported as a new serious adverse event. 
• 
For convenience, the investigator may choose to hospitalize the subject for the duration of the 
treatment period. 
 
Life-Threatening Conditions 
 
Disease progression should not be recorded as an adverse event or serious adverse event 
term; instead, signs and symptoms of clinical sequelae resulting from disease progression/lack 
of efficacy will be reported if they fulfill the serious adverse event definition 
 
9.2.3 UNANTICIPATED PROBLEMS (UP) 
 
The Office for Human Research Protections (OHRP) considers UPs involving risks to 
participants or others to include, in general, any incident, experience, or outcome that meets all 
of the following criteria: 
 


 
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1. Unexpected in terms of nature, severity, or frequency given (a) the research procedures that 
are described in the protocol-related documents, such as the IRB-approved research 
protocol and informed consent document; and (b) the characteristics of the participant 
population being studied; 
2. Related or possibly related to participation in the research (“possibly related” means there is 
a reasonable possibility that the incident, experience, or outcome may have been caused by 
the procedures involved in the research); and 
3. Suggests that the research places participants or others at a greater risk of harm (including 
physical, psychological, economic, or social harm) than previously known or recognized. 
 
This study will use the OHRP definition of UP. 
 
9.2.4 SEVERITY OF EVENT 
 
The Investigator will grade the severity of each AE using, when applicable, the current version 
of the CTCAE v5.0. In the event of an AE for which no grading scale exists, the Investigator will 
classify the AE as defined below:  
 
• Mild (grade 1) – An event that is usually transient in nature and generally not interfering with 
normal activities 
• Moderate (grade 2) – An event that is sufficiently discomforting to interfere with normal 
activities 
• Severe (grade 3) – An event that is incapacitating with inability to work or do usual activity, 
or inability to work or perform normal daily activity 
• Life-threatening/debilitating (grade 4) – An event that puts the participant at immediate or 
potential risk of death, requires hospitalization, or which drastically impacts a participant’s 
well-being 
• Fatal (grade 5) 
 
9.2.5 ASSESSMENT OF CAUSALITY RELATIONSHIP TO STUDY AGENT  
 
For all collected AEs, the clinician who examines and evaluates the participant will determine 
the AE’s causality based on temporal relationship and his/her clinical judgment. The degree of 
certainty about causality will be graded using the categories below. 
 
• Definite – The AE is clearly related to the study treatment. 
• Probable – The AE is likely related to the study treatment. 
• Possible – The AE may be related to the study treatment.  
• Unlikely – The AE is doubtfully related to the study treatment. 
• Unrelated –The AE is clearly NOT related to the study treatment. 
 
9.3 
EXPECTEDNESS 
 
Dr. Elie Traer will be responsible for determining whether an AE is expected or unexpected. An 
AE will be considered unexpected if the nature, severity, or frequency of the event is not 
consistent with the risk information previously described for the study agent. The coordinating 
center will submit reports to Janssen as outlined in the section 9.6.2. 
 
9.4 
ADVERSE EVENT LIST(S)  
 


 
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9.4.1 ADVERSE EVENT LIST FOR JNJ-40346527 
 
Detailed information about the risks and expected AEs of JNJ-40346527 may be found in the 
current edition of the manufacturer’s IB. a The most frequently reported AEs (occurring in ≥20% 
of participants) by preferred term were pyrexia (11 [52.4%]), nausea (7 [33.3%]), headache (7 
[33.3%]), vomiting (6 [28.6%]), and anemia (5 [23.8%]). Severe (CTCAE Grade 3) AEs were 
reported in 7 (33%) participants and included anemia, lymphopenia, gastric obstruction, 
peripheral edema, abnormal hepatic function, increased lipase, and hypoalbuminemia.  A single 
subject experienced a CTCAE Grade 4 dyspnea. 
 
 
9.5 
ADVERSE EVENT ASSESSMENT AND FOLLOW-UP 
 
The occurrence of an UP, AE or SAE may come to the attention of study personnel during study 
visits and interviews of a study participant presenting for medical care, or upon review by a 
study monitor. All adverse events and special situations, whether serious or non-serious, related 
or not related, following exposure to a Janssen medicinal product are to be documented by the 
investigator and recorded in the CRF and in the subject’s source records. Investigators must 
record in the CRF their opinion concerning the relationship of the adverse event to a Janssen 
medicinal product. Information to be collected includes event description, time of onset, 
clinician’s assessment of severity, seriousness, expectedness, relationship to study product 
(assessed only by those with the training and authority to make a diagnosis), and date of 
resolution/stabilization of the event. All AEs occurring while on study must be documented 
appropriately regardless of relationship. All AEs will be followed to adequate resolution. 
 
Any medical condition that is present at the time that the participant is screened will be 
considered as baseline and not reported as an AE. However, if the study participant’s condition 
deteriorates at any time during the study, it will be recorded as an AE.  
 
Changes in the severity of an AE will be documented to allow an assessment of the duration of 
the event at each level of severity to be performed. AEs characterized as intermittent require 
documentation of onset and duration of each episode. 
 
At each study visit, the Investigator will inquire about the occurrence of AE/SAEs since the last 
visit. Events will be followed for outcome information until resolution or stabilization.  
 
The Investigator will record all reportable events with start dates occurring any time after the 
subject has started study drug until completion of the subject’s last study-related procedure 
(which may include contact for follow-up safety). Serious adverse events will be reported for 30 
days after the last dose of study drug or until the participant receives alternative therapy for 
his/her AML, whichever occurs first. Any SAE that occurs after treatment with alternative 
therapy will be reported only if the Investigator or current treating physician has assessed the 
SAE as related to the study treatment. Adverse events will be evaluated using the current 
version of the CTCAE v5.0. 
  
An adverse event as described in this section will be reported from the time a subject has 
started study drug until completion of the subject’s last study-related procedure (which may 
include contact for follow-up safety).  Serious adverse events will be reported for 30 days after 
the last dose of study drug. 


 
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9.6 
REPORTING PROCEDURES 
 
9.6.1 OHSU IRB REPORTING OF UNANTICIPATED PROBLEMS AND ADVERSE EVENTS 
 
Unanticipated Problems and AEs will be reported to OHSU IRB according to the policies, 
procedures and guidelines posted on the OHSU IRB web site. 
 
Events that must be reported by the Investigator to the IRB are detailed in the OHSU IRB 
Investigator Guidance: Prompt Reporting Requirements (HRP-801). At a minimum, events 
requiring reporting to the IRB include: 
• 
Any new or increased risk related to the research, including AEs or IND safety reports 
that require a change to the protocol or consent,  
• 
Publications identifying new risks,  
• 
Data Safety Monitoring Board/Committee letters recommending changes or discussing 
new risks 
• 
Unanticipated adverse device effect 
• 
Unauthorized disclosure of confidential participant information 
 
9.6.2 CENTRAL REPORTING OF ADVERSE EVENTS FOR MULTICENTER STUDIES  
 
A participating site must report an SAE 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, as well as any other study-related documentation requested by the OHSU 
study team. 
 
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 (DSMP). 
The PI 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. 
 
9.6.3 SAE REPORTING  
 
The Sponsor is required to report SAEs with the provided Janssen SAE form. Adverse events to 
be reported include any UPs (i.e., not listed in the package insert) and any SAEs with a 
suspected association to the investigational product. 
 
9.6.4 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. All events reported to the FDA will 
also be reported to Janssen Research and Development, LLC as provided in the Research 
Agreement within 24 hours the investigator becomes aware of the SAE. This information should 


 
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be transmitted to Janssen via the Janssen Serious Adverse Event Report Form via secure email 
to IIS-BIO-VIRO-GCO@its.jnj.com. 
 
 
Special Reporting Situations  
Safety events of interest for a Janssen medicinal product that require expediting reporting 
and/or safety evaluation include, but are not limited to: 
• 
Drug exposure during pregnancy (maternal and paternal) 
• 
Overdose of a Janssen medicinal product  
• 
Exposure to a Janssen medicinal product from breastfeeding  
• 
Suspected abuse/misuse of a Janssen medicinal product 
• 
Inadvertent or accidental exposure to a Janssen medicinal product  
• 
Medication error involving a Janssen medicinal product (with or without patient 
exposure to the Janssen medicinal product, e.g., name confusion) 
• 
Suspected transmission of any infectious agent via administration of a medicinal 
product 
 
These safety events may not meet the definition of an adverse event; however, from a 
COMPANY perspective, they are treated in the same manner as adverse events. Special 
situations should be recorded on the Adverse Event page of the CRF. 
 
Any special situation that meets the criteria of a serious adverse event should be recorded on a 
Serious Adverse Event Report Form and be reported to the COMPANY within 24 hours of 
becoming aware of the event. 
 
Product Quality Complaint (PQC) 
A product quality compliant is defined as any suspicion of a product defect related to a 
potential quality issue during manufacturing, packaging, release testing, stability 
monitoring, dose preparation, storage or distribution of the product, or delivery system.  
Not all PQCs involve a subject.  Lot and batch numbers are of high significance and 
need to be collected whenever available. 
 
Examples of PQC include but not limited to: 
• 
Functional Problem: e.g., altered delivery rate in a controlled release product 
• 
Physical Defect:  e.g. abnormal odor, broken or crushed tablets/capsules 
• 
Suspected Contamination 
• 
Suspected Counterfeit 
 
PQC Reporting 
 
A PQC may have an impact on the safety and efficacy of the product. Timely, accurate, and 
complete reporting and analysis of PQC information from studies are crucial for the protection of 
patients, investigators, and the COMPANY, and are mandated by regulatory agencies 
worldwide. The COMPANY has established procedures in conformity with regulatory 
requirements worldwide to ensure appropriate reporting of PQC information. Lot and/or Batch 
#s shall be collected or any reports failure of expected pharmacological action (i.e., lack of 
effect). The product should be quarantined immediately and if possible, take a picture. 
 


 
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All initial PQCs involving a Janssen medicinal product under study must be reported to the 
COMPANY by the PRINCIPAL INVESTIGATOR within 24 hours after being made aware of 
the event. The Janssen contact will provide additional information/form to be completed. 
 
If the defect for a Janssen medicinal product under study is combined with either a serious 
adverse event or non-serious adverse event, the PRINCIPAL INVESTIGATOR must report the 
PQC to the COMPANY according to the serious adverse event reporting timelines.  A sample of 
the suspected product should be maintained for further investigation if requested by the 
COMPANY. 
 
9.6.5 REPORTING OF PREGNANCY 
 
All initial reports of pregnancy must be reported to the COMPANY by the PRINCIPAL 
INVESTIGATOR within 24 hours of becoming aware of the event using the Serious Adverse 
Event Form. Abnormal pregnancy outcomes (e.g. spontaneous abortion, fetal death, stillbirth, 
congenital anomaly, ectopic pregnancy) are considered serious adverse events and must be 
reported using the Serious Adverse Event Form.  
 
Any subject who becomes pregnant during the study must be promptly withdrawn from the study 
and discontinue further study treatment. 
 
No fertility studies have been performed to date. However, JNJ-40346527 may elicit embryofetal 
toxicity. JNJ-40346527 can only be administered in female and male subjects who practice 
effective birth control methods. Because the effect of the Janssen medicinal product on sperm is 
unknown, pregnancies in partners of male subjects exposed to a Janssen medicinal product will 
be reported by the PRINCIPAL INVESTIGATOR within 24 hours of their knowledge of the 
event using the Serious Adverse Event Form.  Depending on local legislation this may require 
prior consent of the partner. 
 
Follow-up information regarding the outcome of the pregnancy and any postnatal sequelae in 
the infant will be required. 
 
9.7 
STUDY STOPPING RULES 
 
The overall study will be paused, and appropriate authorities (e.g., IRB, Knight Data and Safety 
Monitoring Committee) notified if the following events occur: 
• 
Life-threatening grade 4 toxicity attributable to protocol therapy that is unmanageable, or 
unexpected [detail specific events as appropriate]. 
• 
Death suspected to be related to JNJ-40346527. 
• 
As indicated by statistical stopping rules in Section 10.2.4. 
 


 
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10. STATISTICAL CONSIDERATIONS 
 
Refer to Section 3.1, Description of the Study Design for a detailed description of the study 
design and endpoints.   
 
10.1 
ANALYSIS POPULATIONS  
Most common analysis populations are described below: 
 
Analysis Population 
Definition 
Endpoint 
Intent to Treat (ITT) 
Those who consent and are 
registered for the trial 
regardless of actual receipt of 
screening or treatment 
Used to report accrual 
Evaluable for Safety 
Those who received at least 
one dose of JNJ 40346527 
Incidence of DLT and SAE 
Evaluable for Response 
 
Those who received at least 
one cycle of JNJ 40346527 
and have response 
measurements 
Best objective response 
Evaluable for Overall Survival 
and Event-Free Survival 
Those who received at least 
one dose of JNJ 40346527 
and have survival information 
Overall survival 
  
 
10.2 
DESCRIPTION OF STATISTICAL METHODS 
 
 
10.2.1 ANALYSIS OF PRIMARY ENDPOINT(S) 
 
A Simon 2-stage minimax design will be used to determine best objective response. For each 
arm, we will enroll 7 patients in the first stage. If there is at least 1 response among the first 7 
patients, we will proceed to the second stage and enroll an additional 7 patients. The treatment 
is considered promising if we have at least 3 responses among 14 patients. We will estimate the 
best objective response and exact confidence interval using the binomial distribution for each 
arm separately. 
 
Response assessment will be based on best objective response rates within the first 2 cycles of 
study drug, including CR, CR with inadequate bone marrow recovery, partial response, stable 
disease, or progressive disease as defined by Cheson et al.20 
 
10.2.2 ANALYSIS OF THE SECONDARY ENDPOINT(S)  
 
For the secondary endpoints, we will estimate the incidence of the overall incidence of 
treatment-related and non-treatment related toxicityand the exact confidence interval. In 
addition, each toxicity event will be tabulated and summarized by severity and major organ site 
according to the CTCAE v5.0. Time-to-event analysis (e.g., Kaplan-Meier and cumulative 
incidence curves) will be used to evaluate event-free and overall survival. 
 


 
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10.2.3 ANALYSIS OF THE EXPLORATORY ENDPOINT(S)  
 
10.2.3.1 
Transcriptome analysis to identify potential qualitative differences in CSF-1R+ cells 
that predict patient response 
 
For statistical analysis, we will need >5 responders and non-responders. We anticipate this will 
be feasible with 14 participants enrolling on the assay positive arm (not all will respond in vivo, 
and the non-responders can be used for comparison). In addition, we will also collect samples 
from the 7 patients enrolling on the assay negative arm who are likely to be non-responders. 
 
If sufficient participants initially respond to JNJ-40346527 but later develop resistance, we will 
also collect these resistant samples to be analyzed by RNAseq as a separate comparison 
group. This may provide insight into how patients develop resistance to JNJ-40346527. 
 
10.2.4 INTERIM ANALYSIS AND STOPPING RULES 
 
This study will consist of 2 stopping rules: one for futility (lack of efficacy) and another for excess 
toxicity.  
 
For futility, we will follow the stopping rule based on the Simon’s 2-stage design with the 
minimax criteria. Specifically, if there is no response among the first 7 patients after receiving 2 
cycles of study agent, the arm will not proceed to the second stage. 
 
For excess toxicity, we will suspend enrollment if the lower 90% confidence interval for Grade 3 
or higher treatment-related toxicity exceeds 30% (considered acceptable dose-limiting toxicity 
(DLT) incidence). We will then conduct a comprehensive toxicity evaluation and consult with the 
Knight Cancer Institute’s Data and Safety Monitoring Committee for guidance on possible 
modifications of the protocol, including termination of one or more of the arms, dose 
modification, and/or changes in eligibility criteria 
 
10.2.4.1 
Safety Stopping Rule 
 
Temporarily suspend the trial if the number of patients with DLT is equal to or greater than the 
number shown below: 
 
N 4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
20 
DLT 3 
4 
4 
5 
5 
5 
6 
6 
7 
7 
7 
8 
8 
9 
9 
9 
10 
 


 
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The safety boundary is also show in Figure 4. Toxicity stopping rule.Figure 4.  
 
10.3 
SAMPLE SIZE, POWER, ACCRUAL RATE AND STUDY DURATION 
 
10.3.1 SAMPLE SIZE AND POWER 
 
The sample size for each group was derived according to the 2-stage design with minimax 
criteria using the following parameter settings: 1) 80% power; 2) 5% significance level; 3) 
historical response rate of 5% (poor response), and 4) desired response rate of 30% (promising 
response).21 The sample size and power analyses were conducted using PASS 14 software 
(http://www.ncss.com/software/pass/). Based on the expected accrual rate of 14 participants per 
year, we anticipate this trial to take 36 months (24 months of accrual and 12 month of minimum 
follow-up). 
 
10.4 
HANDLING OF MISSING DATA 
 
Missing data will not be imputed. Whenever possible, the analysis will be conducted using all 
available data. Missing data will be reported in the descriptive summary, and it will be noted if 
some subjects are excluded from the analysis due to missing data. 
 
0
1
2
3
4
5
6
7
8
9
10
11
12
4
5
6
7
8
9
10 11 12 13 14 15 16 17 18 19 20
Patients with DLT
Total Number of Patients
Toxicity Stopping Rule
Figure 4. Toxicity 
stopping rule.  
If the number of 
patients with DLT is 
on the boundary or 
exceeds the 
boundary, suspend 
the trial due to safety. 
 
 
 
 
 
 
 


 
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11. CLINICAL MONITORING 
 
11.1 
OHSU KNIGHT CANCER INSTITUTE DATA & SAFETY MONITORING PLAN 
 
This study is under the oversight of the Knight Cancer Institute’s DSMC as described in the 
Knight institutional DSMP.  The Knight DSMP outlines the elements required to ensure the 
safety of clinical trial participants, the accuracy and integrity of the data and the appropriate 
modification of cancer-related clinical trials for which significant benefits or risks have been 
discovered or when the clinical trial cannot be successfully concluded.  The Knight DSMP also 
describes the methods and procedures for ensuring adequate oversight of cancer-related 
research at OHSU. 
 
As described in the Knight DSMP, regardless of a trial’s risk level and any specific Knight 
oversight in place, the Investigator is singularly responsible for overseeing every aspect of the 
design, conduct, and final analysis of his/her investigation. 
 
The Knight DSMC will review and monitor study progress, toxicity, safety and other data from 
this study. Information that raises any questions about participant safety or protocol 
performance will be addressed by the Investigator, statistician and study team. Should any 
major concerns arise, the Knight DSMC may recommend corrective action and determine 
whether or not to suspend the study. 
 
The Knight DSMC will review each protocol every 6 months, but may occur more often, if 
required, to review toxicity and accrual data (please refer to Knight DSMP for additional details 
on audit frequency). The Knight DSMC will review accrual, toxicity, response and reporting 
information. Information to be provided to the DSMC may include: participant accrual; treatment 
regimen information; AEs and SAEs reported by category; summary of any deaths on study; 
audit results; and a summary provided by the study team. Other information (e.g. laboratory 
values) will be provided upon request.  
 
11.2 
CLINICAL DATA & SAFETY MONITORING 
 
Monitoring visits will be performed during the study to ensure that the rights and well-being of 
human participants are protected, that the reported trial data are accurate, and that the conduct 
of the trial is in compliance with the protocol, GCP, and applicable regulatory requirements.  
 
Details of monitoring activities, including designation of assigned monitoring entities, scope of 
monitoring visits, timing, frequency, duration of visits, and visit reporting, will be included in a 
separate TSMP that is reviewed and approved by the Knight DSMC and IRB according to the 
DSMP v5.1. 
 
The Investigator agrees that the monitor will be permitted to conduct monitoring visits at 
appropriate intervals. The Investigator agrees to provide all relevant information and 
documentation as requested by the monitor, including access to all original study documents 
and source data, including access to electronic medical records and/or source documents if 
necessary. 
 
The monitor will conduct source data review and verification as outlined in the TSMP, and 
following each visit will generate a report summarizing the visit findings. 


 
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Regardless of monitoring entity, the Sponsor is ultimately, singularly responsible for overseeing 
every aspect of the design, conduct, and final analysis of the investigation. 
 
If at any time Investigator noncompliance is discovered at OHSU, the Sponsor shall promptly 
either secure compliance or end the Investigator’s participation in the study. 
 
Independent audits may be conducted by the Knight DSMC to verify that the rights and well-
being of human participants are protected, that the reported trial data are accurate, that the 
conduct of the trial is in compliance with the protocol and applicable regulatory requirements, 
that monitoring practices are adequate and in compliance with the monitoring plan, and that 
evidence of ongoing investigator oversight is present. 
 
11.3 
QUALITY ASSURANCE & QUALITY CONTROL 
 
The investigational site will provide direct access to all trial related source data/documents, and 
reports for the purpose of monitoring by the monitor and/or sponsor, and auditing by the Knight 
DSMC and/or regulatory authorities.  
 
Quality assurance (QA) auditing activities will occur as detailed in the Knight DSMP. All 
discrepancies, queries, deviations, observations, and findings will be compiled into a final audit 
report along with a Corrective and Preventative Action Plan. 
 
The Sponsor-investigator, or study monitor, will verify that the clinical trial is conducted and data 
are generated, documented (recorded), and reported in compliance with the protocol, GCP, and 
the applicable regulatory requirements (e.g., Good Laboratory Practices (GLP), Good 
Manufacturing Practices (GMP)). 
 


 
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12. DATA HANDLING AND MANAGEMENT RESPONSIBILITIES 
 
12.1 
SOURCE DATA/DOCUMENTS 
 
The Investigator is responsible for ensuring the accuracy, completeness, legibility, and 
timeliness of the data reported. All source documents should be completed in a neat, legible 
manner to ensure accurate interpretation of data. The Investigator will maintain adequate case 
histories of study participants, including accurate CRFs, and source documentation. 
 
12.2 
PARTICIPANT & DATA CONFIDENTIALITY 
 
The information obtained during the conduct of this clinical study is confidential, and unless 
otherwise noted, disclosure to third parties is prohibited. Information contained within this study 
will be maintained in accordance with applicable laws protecting participant privacy, including 
the provisions of the Health Insurance Portability and Accountability Act (HIPAA). 
 
Participant confidentiality is strictly held in trust by the participating Investigator(s) and study 
team. This confidentiality is extended to cover testing of biological samples and genetic tests in 
addition to the clinical information relating to participants. Therefore, the study protocol, 
documentation, data, and all other information generated will be held in strict confidence. No 
information concerning the study or the data will be released to any unauthorized third party 
without prior written approval of the sponsor. 
 
The study monitor, other authorized representatives of the sponsor, representatives of the IRB 
or manufacturer supplying study product may inspect all documents and records required to be 
maintained by the Investigator, including but not limited to, medical records (office, clinic, or 
hospital) and pharmacy records for the participants in this study. The clinical study site will 
permit access to such records.  
 
Upon enrollment, participants will be assigned a code that will be used instead of their name, 
medical record number or other personally identifying information. Electronic files for data 
analysis will contain only the participant code. Codes will not contain any part of the 18 HIPAA 
identifiers (e.g., initials, DOB, MRN). The key associating the codes and the participants’ 
personally identifying information will be restricted to the Investigator and study staff. The key 
will be kept secure on a restricted OHSU network drive   in a limited access folder. 
 
The study participant’s contact information will be securely stored at each clinical site for internal 
use during the study. At the end of the study, all records will continue to be kept in a secure 
location for as long a period as dictated by local IRB and institutional regulations. Study 
participant research data, which is for purposes of statistical analysis and scientific reporting, 
will be transmitted to and stored within the Knight Cancer Institute per OHSU’s Information 
Security Directives. Individual participants and their research data will be identified by a unique 
study identification number. The study data entry and study management systems used by 
clinical sites and by Knight Cancer Institute research staff will be secured and password 
protected per OHSU’s Information Security Directives. At the end of the study, all study 
databases will be de-identified and archived within the Knight Cancer Institute. 
 
12.3 
DATA COLLECTION & STORAGE: PRIVACY, CONFIDENTIALITY & SECURITY  
 


 
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Data collection is the responsibility of the clinical trial staff at the site under the supervision of 
the site Investigator. The Investigator is responsible for ensuring the accuracy, completeness, 
legibility, and timeliness of the data reported. Standard institutional practices will be followed as 
described in the OHSU’s Information Security Directives to maintain the confidentiality and 
security of data collected in this study. Study staff will be trained with regard to these 
procedures. 
 
Loss of participant confidentiality is a risk of participation. Efforts will be made to keep study 
participant identities confidential except as required by law. Participants’ samples will be 
identified by code only and stored in OHSU protocol #4422. Specifically, each consenting 
participant will be assigned a unique coded identifier consisting of numbers. This identifier will 
be associated with the participant throughout the duration of their participation in the trial. The 
coded identifier will also be used to identify any participant specific samples. 
 
Basic accrual tracking information (demographic, consent, visit information) will be captured in 
OHSU’s electronic clinical information research system (eCRIS), hosted on OHSU secure 
servers and managed by OHSU’s information technology group at their data center in downtown 
Portland, Oregon. Any additional printed documents containing participant identifiers, such as 
those from the medical record to confirm eligibility, will be filed in binders and kept in a locked, 
secure location. 
 
Study outcome data will be captured in electronic case report forms (eCRFs) using an electronic 
data capture (EDC) system, REDCap Cloud. The REDCap Cloud EDC is a web-hosted 
application hosted by nPhase (located in Encinitas, CA), and is an approved EDC system that 
has been reviewed by OHSU Security.  To further preserve confidentiality, PHI in the EDC 
system will be limited to just demographics, birth date and visit dates. The web-accessible EDC 
system is password protected and encrypted with role-based security, and administered by 
designated informatics staff within OHSU or Knight Cancer Institute. All users of the database 
are assigned a unique ID, username, and password and must complete training appropriate to 
their role before they are authorized to enter, access, and store data in the database.  
 
Data from correlative studies will be entered into the RedCap Cloud EDC system by study 
personnel at OHSU. All other electronic data extracts will be stored only on OHSU computers 
and restricted drives, limited only to study investigators and staff with authorization to access 
the data. Quality assurance will be conducted as outlined in Section 11.3, Quality Assurance & 
Quality Control. 
 
12.3.1 FUTURE USE OF STORED SPECIMENS 
 
Each participant who signs consent will be assigned a unique coded identifier consisting of 
numbers. This identifier will be associated with the participant throughout the duration of their 
participation in the trial. The coded identifier will be used to identify any participant specific 
samples. Blood and bone marrow samples collected for the purposes of this protocol will be 
stored under OHSU protocol #4422 until they can be analyzed in the Druker Laboratory. 
 
12.4 
MAINTENANCE OF RECORDS 
 
Records and documents pertaining to the conduct of this study, source documents, consent 
forms, laboratory test results and medication inventory records, must be retained by the 


 
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Investigator for a period of 2 years following the date a marketing application is approved for the 
drug for the indication for which it is being investigated; or, if no application is to be filed or if the 
application is not approved for such indicate, until 2 years after the investigation is discontinued 
and FDA is notified. No records will be destroyed without the written consent of the Sponsor, if 
applicable. It is the responsibility of the sponsor to inform the Investigator when these 
documents no longer need to be retained. 
 
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 or another investigator at 
OHSU. Records must be maintained according to institutional or FDA requirements.  
 
12.5 
PUBLICATION AND DATA SHARING POLICY 
 
This study will comply with the NIH Public Access Policy, which ensures that the public has 
access to the published results of NIH funded research. It requires scientists to submit final 
peer-reviewed journal manuscripts that arise from NIH funds to the digital archive PubMed 
Central upon acceptance for publication.  
 
This study will adhere to the requirements set forth by the ICMJE and FDAAA that requires all 
clinical trials to be registered in a public trials registry (e.g., ClinicalTrials.gov) prior to participant 
enrollment.  
 
12.6 
DELIVERY OF PROGRESS REPORTS TO STUDY FUNDER 
 
Upon the request of Janssen Research & Development, LLC, the Institution will submit oral or 
written reports on the progress of the Study as provided by this protocol. Within one hundred 
twenty (120) days following the completion or termination of the study, Institution will furnish 
Janssen Research & Development, LLC with a final report detailing the results of this study. 
 


 
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13. ETHICS/PROTECTION OF HUMAN PARTICIPANTS 
 
13.1 
ETHICAL STANDARD 
 
The Investigator will ensure that this study is conducted in full conformity with Regulations for 
the Protection of Human Participants of Research codified in 45 CFR Part 46, 21 CFR Part 50, 
21 CFR Part 56, 21 CFR 312 (for IND studies), 21 CFR 812 (for IDE studies), and/or the ICH 
E6. 
 
13.2 
INSTITUTIONAL REVIEW BOARD 
 
The protocol, informed consent form(s), recruitment materials, and all participant materials will 
be submitted to the IRB for review and approval. Approval of both the protocol and the consent 
form must be obtained before any participant is enrolled. Any amendment to the protocol will 
require review and approval by the IRB before the changes are implemented to the study. All 
changes to the consent form will be IRB approved; a determination will be made regarding 
whether previously consented participants need to be re-consented. 
 
13.3 
INFORMED CONSENT 
 
Written informed consent will be obtained from all participants, or the legally authorized 
representative of the participant, participating in this trial, as stated in the Informed Consent 
section of 21 CFR Part 50. If a participant’s signature cannot be obtained, and for all 
participants under the age of 18, the Investigator must ensure that the informed consent is 
signed by the participant’s legally authorized representative. Documentation of the consent 
process and a copy of the signed consent shall be maintained in the participant’s medical 
record.  
 
13.3.1 CONSENT PROCEDURES AND DOCUMENTATION 
 
Informed consent is a process that is initiated prior to the individual’s agreement to participate in 
the study and continues throughout the individual’s study participation. Extensive discussion of 
risks and possible benefits of participation will be provided to the participants and their families 
as appropriate. Consent forms will be IRB-approved and the participant will be asked to read 
and review the document. The Investigator will explain the research study to the participant and 
answer any questions that may arise. All participants will receive a verbal explanation in terms 
suited to their comprehension of the purposes, procedures, and potential risks/benefits of the 
study, alternatives to participation, and of their rights as research participants. Participants will 
have the opportunity to carefully review the written consent form and ask questions prior to 
signing. The participants should have the opportunity to discuss the study with their surrogates 
or think about it prior to agreeing to participate. The participant will sign the informed consent 
document prior to any procedures being done specifically for the study. The participants may 
withdraw consent at any time throughout the course of the trial. A copy of the informed consent 
document will be given to the participants for their records. The rights and welfare of the 
participants will be protected by emphasizing to them that the quality of their medical care will 
not be adversely affected if they decline to participate in this study. 
 
13.4 
PROTOCOL REVIEW 
 


 
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The protocol and informed consent form for this study must be reviewed and approved in writing 
by the OHSU Knight Cancer Institute’s Clinical Research Review Committee (CRRC) and the 
appropriate IRB prior to any participant being consented on this study.   
 
13.5 
CHANGES TO PROTOCOL  
 
Any modification of this protocol must be documented in the form of a protocol revision or 
amendment submitted by the Investigator and 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 participant.  In that event, the Investigator must notify the IRB and 
Sponsor within 5 business days after the implementation.  


 
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14. REFERENCES 
 
1. 
Bronte V, Murray PJ. Understanding local macrophage phenotypes in disease: 
modulating macrophage function to treat cancer. Nature medicine. 2015;21(2):117. 
2. 
Howlader N NA, Krapcho M, Miller D, Bishop K, Kosary CL, Yu M, Ruhl J, Tatalovich Z, 
Mariotto A, Lewis DR, Chen HS, Feuer EJ, Cronin KA SEER Cancer Statistics Review, 
1975-2014. National Cancer Institute. 2017. 
3. 
Ramos RN, Mo CC, Karp EJ, Hourigan SC. Current Approaches in the Treatment of 
Relapsed and Refractory Acute Myeloid Leukemia. Journal of Clinical Medicine. 
2015;4(4). 
4. 
Walter RB, Othus M, Burnett AK, et al. Resistance prediction in AML: analysis of 4601 
patients from MRC/NCRI, HOVON/SAKK, SWOG and MD Anderson Cancer Center. 
Leukemia. 2015;29(2):312-320. 
5. 
Bose P, Vachhani P, Cortes JE. Treatment of Relapsed/Refractory Acute Myeloid 
Leukemia. Current Treatment Options in Oncology. 2017;18(3):17. 
6. 
Döhner H, Weisdorf DJ, Bloomfield CD. Acute myeloid leukemia. New England Journal 
of Medicine. 2015;373(12):1136-1152. 
7. 
Pemmaraju N, Kantarjian H, Garcia-Manero G, et al. Improving outcomes for patients 
with acute myeloid leukemia in first relapse: A single center experience. American 
Journal of Hematology. 2015;90(1):27-30. 
8. 
Chitu V, Stanley ER. Colony-stimulating factor-1 in immunity and inflammation. Current 
opinion in immunology. 2006;18(1):39-48. 
9. 
Yu W, Chen J, Xiong Y, Pixley FJ, Yeung Y-G, Stanley ER. Macrophage proliferation is 
regulated through CSF-1 receptor tyrosines 544, 559, and 807. Journal of Biological 
Chemistry. 2012;287(17):13694-13704. 
10. 
Stanley ER, Chitu V. CSF-1 receptor signaling in myeloid cells. Cold Spring Harbor 
perspectives in biology. 2014;6(6):a021857. 
11. 
Liddiard K, Taylor PR. Understanding local macrophage phenotypes in disease: shape-
shifting macrophages. Nature medicine. 2015;21(2):119. 
12. 
Zhang Q-w, Liu L, Gong C-y, et al. Prognostic significance of tumor-associated 
macrophages in solid tumor: a meta-analysis of the literature. PloS one. 
2012;7(12):e50946. 
13. 
Pedersen MB, Danielsen AV, Hamilton-Dutoit SJ, et al. High intratumoral macrophage 
content is an adverse prognostic feature in anaplastic large cell lymphoma. 
Histopathology. 2014;65(4):490-500. 
14. 
Jinushi M, Komohara Y. Tumor-associated macrophages as an emerging target against 
tumors: Creating a new path from bench to bedside. Biochimica et Biophysica Acta 
(BBA)-Reviews on Cancer. 2015;1855(2):123-130. 
15. 
Tyner JW, Yang WF, Bankhead A, et al. Kinase Pathway Dependence in Primary 
Human Leukemias Determined by Rapid Inhibitor Screening. Cancer Research. 
2013;73(1):285-296. 
16. 
von Tresckow B, Morschhauser F, Ribrag V, et al. An Open-Label, Multicenter, Phase 
I/II Study of JNJ-40346527, a CSF-1R Inhibitor, in Patients with Relapsed or Refractory 
Hodgkin Lymphoma. Clinical Cancer Research. 2015;21(8):1843-1850. 
17. 
Zhou L, Sikorski R, Rogers S, et al. A Phase 1 Study of FPA008, an Anti-Colony 
Stimulating Factor 1 Receptor (anti-CSF-1R) Antibody in Patients with Rheumatoid 
Arthritis (RA): Preliminary Results. American College fo Rheumatology Annual Meeting. 
2015;#2749. 
18. 
Moskowitz CH, Younes A, de Vos S, et al. CSF-1R Inhibition by PLX3397 in Patients 


 
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with Relapsed or Refractory Hodgkin Lymphoma: Results From a Phase 2 Single Agent 
Clinical Trial. Blood. 2012;120(21):1638-1638. 
19. 
Cassier PA, Italiano A, Gomez-Roca CA, et al. CSF-1R inhibition with emactuzumab in 
locally advanced diffuse-type tenosynovial giant cell tumours of the soft tissue: a dose-
escalation and dose-expansion phase 1 study. The Lancet Oncology. 2015;16(8):949-
956. 
20. 
Cheson BD, Bennett JM, Kopecky KJ, et al. Revised recommendations of the 
international working group for diagnosis, standardization of response criteria, treatment 
outcomes, and reporting standards for therapeutic trials in acute myeloid leukemia. 
Journal of clinical oncology. 2003;21(24):4642-4649. 
21. 
Wason JM, Mander AP. Minimizing the maximum expected sample size in two-stage 
Phase II clinical trials with continuous outcomes. J Biopharm Stat. 2012;22(4):836-852. 
 


 
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15. APPENDICES 


 
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APPENDIX A: PERFORMANCE STATUS CRITERIA 
 
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: SUMMARY OF CAUTIONARY MEDICATIONS 
 
 
Summary of Cautionary Medications 
Category 
Drug Name 
Strong 
CYP3A4/5 
inhibitors  
Voriconazole, Boceprevir, clarithromycin, cobicistat, conivaptan, 
danoprevir/ritonavir, eltegravir/ritonavir, grapefruit juice, 
indinavir/ritonavir, itraconazole, ketoconazole, lopinavir/ritonavir, 
mibefradil, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, 
saquinavir/ritonavir, telaprevir, telithromycin, tipranavir/ritonavir, 
troleandomycin, voriconazole  
Strong 
CYP3A4/5 
inducers  
Avasimibe2,3, carbamazepine, mitotane, nafcillin, nevirapine, 
oxcarbazepine, phenobarbital, phenytoin, primidone, rifabutin, rifampin 
(rifampicin)3, St. John's wort (hypericum perforatum)3  
CYP3A4/5 
substrates with 
NTI1  
Terfenadine, Alfentanil, apixaban (doses >2.5 mg only), aprepitant, 
astemizole, cisapride, cyclosporine, diergotamine, dihydroergotamine, 
ergotamine, fentanyl, lovastatin, nicardipine, nisoldipine, pimozide, 
quinidine, rivaroxaban, simvastatin, sirolimus, tacrolimus, terfenadine, 
thioridazine  
Pgp inducers 
Aliskiren, colchicine, dabigatran, digoxin, everolimus, fexofenadine, 
loperamide, marovirac, posaconazole, ranolazine, saxigliptan, sirolimus, 
sitagliptin, and tolvaptan 
 
 
1 NTI = narrow  therapeutic index drugs w hose exposure-response indicates that increases in their exposure levels 
by the concomitant use of potent inhibitors may lead to serious safety concerns (e.g., Torsades de Pointes).  
2 Herbal product  
3 P-gp inducer  


 
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APPENDIX C: CONTRACEPTION 
 
For men and women contraception should be in place during study and for a minimum of 120 
days since the last dose of study drug for both men and women,  
 
For Males Subjects Participating in the Study: 
The following methods have been determined to be more than 99% effective (failure rate less 
than 1% per year, when used consistently and correctly) (Trussell, 2004), by the male subject and 
his partner and are permitted under this protocol: 
 
• 
Complete abstinence from sexual intercourse 
• 
Double barrier methods 
o Condom with spermicide in conjunction with use of an intrauterine device (IUD) 
o Condom with spermicide in conjunction with use of a diaphragm 
• 
Oral, injectable, or implanted contraceptives 
• 
Tubal ligation or vasectomy (surgical sterilization) 
• 
Avoid sperm donation within the treatment period and 120 days after the last study drug 
dose 
 
 
For Female Subjects Participating in the Study: 
The following methods have been determined to be more than 99% effective (failure rate less 
than 1% per year, when used consistently and correctly) (Trussell, 2004), by the female subject 
and her partner and are permitted under this protocol: 
 
• 
Complete abstinence from sexual intercourse 
• 
Double barrier methods 
o Condom with spermicide in conjunction with use of an IUD 
o Condom with spermicide in conjunction with use of a diaphragm 
• 
Tubal ligation or vasectomy (surgical sterilization) 
• 
Oral, injectable, or implanted contraceptives 
 
Subjects >55 y/o and without menses for at least 3 years are considered in menopause. 


 
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APPENDIX D: HEMATOLOGICAL MALIGNANCY GENE PANEL 
 
Gene Categories 
Kinase 
ABL1,  
ATM,  
BRAF,  
CCND1,  
CDKN2A,  
JAK1,  
JAK2,  
JAK3, 
STAT3  
Transcription  
BCOR 
BCL6 
CEBPA  
CREBBP 
ETV6 
EP300 
FOXO1 
GATA1 
GATA2 
MEF2B 
MLL 
MLL2 
MYC 
1D3 
IKZF1 
PAX5 
PHF6 
PRDM1 
RUNX1 
STAT3  
TDF3 
WT1  
Epigenetic 
ASXL1 
DNMT3A 
EZH2 KDM6A/UTX 
PTEN 
SUZ12 
TET  
RAS  
HRAS 
KRAS 
NRAS 
Adaptor 
CBL 
CBL-B 
MYD88 
Phosphatase 
PTPN11 
Ubiquitin 
BIRC3 
FBXW7 
TNFAIP3 
TNFRSF14 
Receptor Tyrosine Kinase 
FLT3 
KIT  
 
Receptor 
CSF3R 
GNA13 
IL7R 
MPL 
NOTCH1 
NOTCH2 
Splicing 
SF3B1 
SRSF2 
U2AF35 
ZRSR2 
Cohesin-Complex gene 
RAD21 
SMC1A 
SMC3 
STAG2  
Other 
CALR 
CARD11 
CD79A 
BCL2 
FAM5C 
HNRNPK 
IDH1 
IDH2 
NPM1