CSF1R Inhibitor JNJ-40346527 in Treating Participants With Relapsed or Refractory Acute Myeloid Leukemia

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.

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 deoxyribonucleic acid (DNA) from
leukemia participants to determine if there is a genetic signature that predicts
response to JNJ-40346527.

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

5. 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.

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.

OUTLINE:

Participants receive FMS inhibitor JNJ-40346527 orally (PO) twice a day (BID) on days 1-28.
Courses 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.

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

4. Sufficient and viable bone marrow aspirate or peripheral blood collection to use for
the ex vivo sensitivity assay

5. Eastern Cooperative Oncology Group (ECOG) performance status 0 to 2.

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.

8. Must be able to take oral medications.

9. Adequate organ function as defined by the following:

1. Serum creatinine =< 2 x the upper limit of normal (ULN), or glomerular filtration
rate > 20 ml/hour (h) as calculated by Cockcroft-Gault formula.

2. Serum potassium, magnesium, and calcium (corrected for albumin) within
institutional normal limits or can be corrected with supplementation.

3. Total serum bilirubin =< 2.5 x ULN.

4. Serum aspartate transaminase (AST) and/or alanine transaminase (ALT) =< 2.5 x
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 principal investigator (PI) prior to enrollment.

4. Clinically significant graft versus host disease (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-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 polymerase chain reaction (PCR), or
chronic hepatitis B (patients positive for hepatitis B core antibody who are receiving
intravenous immunoglobulin (IVIG) are eligible if hepatitis B [HepB] polymerase chain
reaction [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).