Ruxolitinib for Adult T-Cell Leukemia

Background:

- Adult T-cell leukemia is a lymphoproliferative disorder characterized by the presence of
CD4/CD25 expressing T cells (IL-2R alpha expressing) in the peripheral blood, in
lymphoid and other tissues.

- In smoldering and chronic ATL the HTLV-1 encoded protein, Tax constitutively activates
interleukin-2 (IL-2), IL-9 and IL-15 autocrine/paracrine systems that in turn activate
the Janus kinase (JAK)-1/3/STAT5 pathways.

- Ruxolitinib a therapeutic agent inhibits cytokine mediated JAK1/2 activation and ex vivo
proliferation of malignant T cells from patients with ATL.

- Ruxolitinib is a potent orally bioavailable JAK1/2 inhibitor.

Primary Objective:

- To determine the maximum tolerated dose and clinical response rate for ruxolitinib given

at doses of 30, 40 or 50 mg orally twice daily in patients with smoldering, chronic and

biologically indolent acute or lymphomatous subtype of ATL

Eligibility

- Patients greater than or equal to 18 years old with pathologically confirmed adult
T-cell leukemia: smoldering or chronic or previously treated lymphomatous or acute
subtypes with clinically indolent behavior indicated by lack of significant symptoms and
treatment free interval of greater than 6 months.

- Patients must have measurable or evaluable disease. Patients with > 10% of their PBMCs
having the characteristic abnormal (i.e., CD3dim, CD4 plus CD25 plus expressing) FACS
profile for circulating ATL cells will be considered to have measurable disease.

- Patients with symptomatic leukemic meningitis, bony or GI tract involvement, serum
calcium or LDH > 1.5 times the upper limit of normal will be excluded. However patients
that have both ATL and another HTLV-1 associated disease such as tropical spastic
paraparesis (HAM/TSP) will be included.

- No prior treatment with another JAK inhibitor; patients previously treated in this
protocol

at the lower dose are eligible to restart treatment at the higher dose levels.

Design

- This is a pilot open-label, trial of oral ruxolitinib that will enroll 27 to 33 patients
with

smoldering or chronic or clinically indolent ATL. Groups of 3 to 6 newly enrolled or

reenrolled patients will begin treatment at a dose of 30 mg orally given twice daily. If

this dose is tolerated without exceeding the criteria for dose limiting toxicity (DLT)

during the first cycle of treatment, the tolerability of treatment at 40 mg and then 50 mg

twice daily will be evaluated.

- INCLUSION CRITERIA:

NOTE: After approval and activation of Amendment D, patients who have failed this protocol
treatment previously at the initial dose level may be eligible for re-enrollment and
retreatment if they otherwise meet eligibility criteria.

- Patients greater than or equal to 18 years old with pathologically confirmed adult T-
cell leukemia: smoldering or chronic, or previously treated lymphomatous or acute
subtypes with clinically indolent behavior indicated by lack of significant symptoms
and treatment free interval of greater than 6 monthsare eligible for treatment in the
dose escalation and expansion cohorts.

- Patients must have serum antibodies directed to HTLV-1.

- Patients must have measurable or evaluable disease. Patients with > 10% of the PBMCs
having the characteristic abnormal (i.e., CD3dim, CD4 plus CD25 plus expressing) FACS
profile for circulating ATL cells will be considered to have evaluable disease.

- Patients must have adequate physiologic parameters:

- Absolute granulocyte count greater than or equal to 500 K/microL, platelet count
greater than or equal to 75,000 K/microL and hemoglobin greater than or equal to 10
g/dL.

- Bilirubin and creatinine less than or equal to 1.5 times institutional ULN.

- AST, ALT less than or equal to 3.0 times institutional ULN.

- Karnofsky Performance Score greater than or equal to 70% or ECOG less than or equal 1.

- Patients must be able to understand and sign Informed Consent Form.

EXCLUSION CRITERIA:

- Patients with symptomatic leukemic meningitis, bony or GI tract involvement, serum
calcium or LDH > 1.5 times the upper limit of normal will be excluded. However,
patients that have both ATL and another HTLV-1 associated disease such as tropical
spastic paraparesis (HAM/TSP) will be included.

- Patients who have received high doses of systemic corticosteroids for the treatment of
their ATL within 4 weeks prior to the start of therapy.

- Patients who have received any cytotoxic therapy, immunotherapy, antitumor vaccines or
monoclonal antibodies in the 4 weeks prior to the start of the study.

- Life expectancy of less than 3 months.

- Documented active bacterial infections, HTLV-II infection, or hepatitis B or C as
follows:

- A positive hepatitis B serology indicative of previous immunization (i.e., HBsAb
positive and HBc Ab negative), or a fully resolved acute hepatitis B infection is
not an exclusion criterion.

- Patients with an indolent chronic hepatitis B infection (normal ALT, AST, albumin
and no radiographic or biopsy evidence of cirrhosis) may be eligible.

- Patients with active hepatitis C are excluded. Patients positive for hepatitis C
virus (HCV) antibody are eligible only if polymerase chain reaction (PCR) is
negative for HCV RNA.

- Patients who have untreated human immunodeficiency virus (HIV) are not eligible for
this study because by definition they have a defective immune response and are at much
higher risk for opportunistic infections due to immune disregulation by both HTLV-1
and HTLVIII (HIV) viruses. Patients on HIV therapy with undetectable viral loads as
measured by HIV RNA quantitative real time PCR may be eligible.

- Inability or refusal to practice effective contraception during therapy. Men and women
of childbearing potential must use an effective method of birth control or abstinence
during treatment and for 4 months after completion of the treatment.

- Patient has significant and/or uncontrolled cardiac, renal, hepatic or other systemic
disorders or significant psychological conditions at baseline visit that in the
investigator s judgment would jeopardize subject enrollment or compliance with the
study procedures.

- Patients with an absolute requirement for a medication that is a strong inhibitor of
P450 CYP3A4 are not eligible.