Ruxolitinib in Treating Patients With Hypereosinophilic Syndrome or Primary Eosinophilic Disorders

PRIMARY OBJECTIVES:

I. To determine the overall hematologic response rate to ruxolitinib in patients with
hypereosinophilic syndrome and primary eosinophilic disorders.

SECONDARY OBJECTIVES:

I. To determine safety profile of ruxolitinib in patients with hypereosinophilic syndrome and
primary eosinophilic disorders.

II. To determine the proportion of patients on corticosteroids who are able to become
corticosteroid-independent and/or reduce the dose by >= 50%.

III. To evaluate the duration of response (DoR). IV. To evaluate the time-to-response (TTR).
V. To evaluate progression-free survival (PFS) and overall survival.

EXPLORATORY OBJECTIVES:

I. To evaluate the ability of ruxolitinib to elicit morphologic and cytogenetic/molecular
remissions in patients with baseline clonal abnormalities.

II. To assess whether hematologic responses correlate with certain types of mutations on
myeloid mutation panel testing and/or by flow immunophenotyping of T-cells in patients with
lymphocyte-variant hypereosinophilia.

III. To determine whether improvement in organ damage is observed in patients with baseline
organ dysfunction.

IV. To determine whether improvement in symptoms is observed based on a modified
Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF).

V. To evaluate biologic correlates of response including ribonucleic acid (RNA) sequencing
(RNAseq) and JAK-STAT activation status (JAK2 and/or STAT3 phosphorylation) of eosinophils
from whole blood and/or marrow.

OUTLINE:

Patients receive ruxolitinib orally (PO) twice daily (BID) on days 1-28. Treatment repeats
for up to 6 cycles in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 4-6 weeks and every 6 months
for up to 3 years.

Inclusion Criteria:

- Subject with idiopathic hypereosinophilic syndrome must meet the following:

- Has as at least 2 readings with an absolute eosinophil count >= 1,500/mm^3 in the
preceding 3 months prior to starting ruxolitinib (one reading must be during the
screening period).

- Dependent, intolerant or refractory to corticosteroids OR has relapsed/refractory
disease to other therapy besides corticosteroids.

- Symptomatic from his/her disease OR has one or more signs of organ damage
(assessed by the investigator as possibly-related to eosinophilia or
biopsy-proven). This can include skin, lung, cardiac, central nervous system,
liver, or gastrointestinal (GI) involvement, or evidence of symptomatic hepatic
or splenic enlargement.

- Subject with lymphocyte-variant hypereosinophilia must meet the following

- Has at least 2 readings with an absolute eosinophil count >= 1,500/mm^3 in the
preceding 3 months prior to starting ruxolitinib (one reading must be during the
screening period).

- Dependent, intolerant or refractory to corticosteroids* OR has
relapsed/refractory disease to other therapy besides corticosteroids.

- Symptomatic from his/her disease OR has one or more signs of organ damage
(assessed by the investigator as possibly-related to eosinophilia or
biopsy-proven). This can include skin, lung, cardiac, central nervous system,
liver, or GI involvement, or evidence of symptomatic hepatic or splenic
enlargement

- Has abnormal T-lymphocyte immuno-phenotype by flow cytometry.

- Subject with chronic eosinophilic leukemia, not otherwise specified (CEL,NOS) must
meet the following

- Has at least 2 readings with an absolute eosinophil count >= 500/mm^3 in the
preceding 3 months prior to starting ruxolitinib (one reading must be during the
screening period).

- Newly-diagnosed OR receiving corticosteroids OR has relapsed/refractory disease
to any therapy besides corticosteroids.

- Has increased blasts in the blood or bone marrow (> 5% and < 20%), and/or a
clonal cytogenetic or molecular abnormality

- Subjects with JAK2 mutations are included within this group.

- Subject with JAK2-rearranged eosinophilic neoplasm must meet the following

- Has at least 2 readings with an absolute eosinophil count >= 500/mm^3 in the
preceding 3 months prior to starting ruxolitinib (one reading must be during the
screening period).

- Newly-diagnosed OR receiving corticosteroids OR has relapsed/refractory disease
to any therapy besides corticosteroids.

- This group includes subjects with PCM1-JAK2, BCR-JAK2, ETV6-JAK2 or other
JAK2 rearrangements.

- If receiving corticosteroids, must be a stable dose for >= 28 days prior to Day 1
(unstable dosing not eligible).

- Eastern Cooperative Oncology Group (ECOG) performance status =< 3.

- Willing and able to review and execute informed consent (legally-authorized consent
acceptable).

Exclusion Criteria:

- Active life-threatening complication(s) from underlying eosinophilic disease (i.e.,
leukostasis; acute thromboembolic disease including central nervous system (CNS)
involvement; severe pulmonary or cardiac dysfunction). Stabilization of acute,
life-threatening eosinophil-related co-morbidities will allow enrollment of the
patient.

- World Health Organization (WHO)-defined myeloid neoplasm associated with eosinophilia
other than CEL NOS and JAK2 rearranged neoplasms (e.g., myelodysplastic syndrome
(MDS); myeloproliferative neoplasms (MPN); MDS/MPN overlap disorders; and systemic
mastocytosis (SM).

- Reactive hypereosinophilia due to connective tissue disease, sarcoidosis or
eosinophilic granulomatosis with polyangiitis.

- Organ-restricted ?tissue? eosinophilia with the absence of peripheral eosinophilia in
the blood.

- Invasive malignancy over the previous 2 years except treated early stage carcinomas of
the skin, completely resected intraepithelial carcinoma of the cervix, and completely
resected papillary thyroid and follicular thyroid cancers.

- Myeloid or lymphoid neoplasm with eosinophilia and abnormalities of PDGFRA, PDGFRB or
FGFR1.

- Anticipated to receive a hematopoietic stem cell transplant within the first 6 months
of treatment on trial.

- Major surgery within 4 weeks prior to entering the study.

- Life expectancy of < 6 months.

- Known diagnosis of human immunodeficiency virus (HIV).

- Known diagnosis of chronic active hepatitis B or C (viral testing is not required).
Subjects with a known history of hepatitis B and/or C are allowed on trial if at the
time of enrollment, the virus is not active and undetected (testing required if there
is a known history), and such patients are not actively receiving antiviral treatment
specific for hepatitis B and/or C.

- Clinically serious infections requiring ongoing antibiotic therapy.

- Parasitic infection diagnosed within 24 weeks prior to enrollment.

- Platelet count =< 25 x 10^9/L at baseline.

- Alanine aminotransferase (ALT)/serum glutamate pyruvate transaminase (SGPT) > 4 x
upper limit of normal (ULN) or direct bilirubin > 4 x ULN (if considered to be
unrelated to the underlying eosinophilic disorder).

- End-stage renal function (creatinine clearance [CrCl] < 15 mL/min or glomerular
filtration rate [GFR] < 15 mL/min) regardless of whether hemodialysis is required.

- Use of investigational or commercial therapies with the intent to treat the underlying
eosinophilic disorder within 28 days of study start, including interferon; imatinib;
alemtuzumab; cyclosporine; methotrexate; mepolizumab; benralizumab; or other antibody
therapies.

- Use of hydroxyurea within 7 days of study start.

- Prior therapy with ruxolitinib or other JAK inhibitors.

- Previous allergic reactions to JAK inhibitors or excipients.

- Unwilling to commit to abstinence from heterosexual contact or agree to use and comply
with highly effective contraception, 28 days prior to starting study drug, during the
treatment period and for 12 weeks after discontinuation of study treatment.

- Females of childbearing potential who have a positive pregnancy test (urine or serum)
during screening period.