Ruxolitinib Phosphate and Chemotherapy Given Before and After Reduced Intensity Donor Stem Cell Transplant in Treating Patients With Myelofibrosis

PRIMARY OBJECTIVES:

I. Among the dose levels tested, to determine the maximum tolerated dose (MTD) and
recommended phase II dose (RP2D) of ruxolitinib phosphate (ruxolitinib), when given as part
of reduced intensity allogeneic hematopoietic cell transplant (HCT), in patients with
myelofibrosis.

II. To determine if the addition of ruxolitinib is safe by evaluation of toxicities
including: type, frequency, severity, attribution, time course and duration.

SECONDARY OBJECTIVES:

I. To characterize and evaluate hematologic recovery, donor cell engraftment and immune
reconstitution by cell count and flow cytometry of lymphocyte subsets.

II. To estimate the cumulative incidence of acute graft-versus-host disease (aGVHD) and
non-relapse mortality (NRM) at 100-days post transplant.

III. To estimate the cumulative incidence of chronic GVHD at 1- and 2-years post transplant.

IV. To estimate the probabilities of overall and progression-free survival (OS/PFS) at 1- and
2-years post transplant.

V. To characterize changes in aGVHD biomarkers (Reg-3 alpha, soluble tumor necrosis factor
receptor I [sTNF RI], IL2R alpha), janus associated kinases (JAK)-regulated pro-inflammatory
cytokines (i.e. IL-6, TNF alpha, CRP, beta 2microglobulin) and STAT3 phosphorylation
(downstream of JAK signaling) over time and by aGVHD status/grade.

OUTLINE: This is a dose-escalation study of ruxolitinib phosphate.

PREPARATIVE REGIMEN: Patients receive fludarabine phosphate intravenously (IV) on days -9 to
-5, melphalan IV over 20 minutes on day -4, and ruxolitinib phosphate orally (PO) twice daily
(BID) on days -3 to 30 with a taper for 2-3 weeks in the absence of disease progression or
unacceptable toxicity.

GVHD PROPHYLAXIS: Patients receive tacrolimus IV continuously beginning on day -3 and convert
to PO daily when the patient is able to tolerate and absorb oral medications. Patients also
receive sirolimus PO daily beginning on day -3. Treatment continues in the absence of GVHD.

STEM CELL TRANSPLANT: Patients undergo allogeneic HCT on day 0.

After completion of study treatment, patients are followed up for 2 years.

Inclusion Criteria:

- Primary or secondary myelofibrosis intermediate or high risk by Dynamic International
Prognostic Scoring System (DIPSS) in chronic or accelerated phase

- Performance status of >= 70% on the Karnofsky scale

- Women of child-bearing potential and men must agree to use adequate contraception
(hormonal or barrier method of birth control or abstinence) prior to study entry and
for 1 year following transplant as per City of Hope standard operating procedure (SOP)
for allogeneic transplantation; should a woman become pregnant or suspect that she is
pregnant while participating on the trial, she should inform her treating physician
immediately

- Bone marrow and peripheral blood studies must be available for confirmation of
diagnosis; cytogenetics, flow cytometry, and molecular studies (such as JAK-2, MPL and
CALR mutational status) will be obtained as per standard practice

- Bone marrow aspirates/biopsies should be performed within 30 +/- 3 days from
registration to confirm disease remission status

- All candidates for this study must have an human leukocyte antigen (HLA) (A, B, C, DR)
identical siblings who is willing to donate bone marrow or primed blood stem cells or
an 8/8 allele-matched unrelated donor

- All ABO blood group combinations of the donor/recipient are acceptable since even
major ABO compatibilities can be dealt with by various techniques (red cell exchange
or plasma exchange)

- A cardiac evaluation with an electrocardiogram showing no ischemic changes or abnormal
rhythm and an ejection fraction of 50% established by multi-gated acquisition scan
(MUGA) or echocardiogram

- Patients must have creatinine of less than or equal to 1.5 mg/dL or creatinine
clearance > 60 ml/min

- A bilirubin of up to 2.0 mg/dL, excluding patients with Gilbert's disease

- Patients should also have a serum glutamic oxaloacetic transaminase (SGOT) and serum
glutamate pyruvate transaminase (SGPT) less than 5 times the upper limit of normal

- Pulmonary function test including diffusion capacity of the lung for carbon monoxide
(DLCO) will be performed; forced expiratory volume in 1 second (FEV1) and DLCO should
be greater than 50% of predicted normal value

- All subjects must have the ability to understand and the willingness to sign a written
informed consent that has been approved by the COH institutional review board (IRB);
the patient, a family member and transplant staff physician (physician, nurse, social
worker) will meet at least once prior to the subject signing consent; during this
meeting all pertinent information with respect to risks and benefits to donor and
recipient will be presented; alternative treatment modalities will be discussed; the
risks are explained in detail in the enclosed consent form

- Prior therapy with hydroxyurea, interferon, anagrelide, ruxolitinib, hypomethylating
agents, revlimid, thalidomide, steroids, other JAK inhibitors is allowed; for acute
myeloid leukemia (AML) patients who are back in chronic phase myeloproliferative
neoplasm (MPN), prior induction therapy is allowed

Exclusion Criteria:

- Patients should not have any uncontrolled illnesses including ongoing or active
infection

- Patients may not be receiving any other investigational agents, or concurrent
biological, chemotherapy, or radiation therapy

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to ruxolitinib

- Pregnant women are excluded from this study; breastfeeding should be discontinued if
the mother is treated with ruxolitinib

- Patients with active 2nd malignancies other than myelofibrosis, AML, excised skin
cancer, early stage cervical and prostate cancer

- Previous allogeneic hematopoietic stem cell transplantation

- Any psychiatric, social or compliance issues that, in the treating physician's
opinion, will interfere with the completion of the transplant treatment and follow up

- Patients who have been treated with chemotherapy or radiation within two weeks of
planned study enrollment; this does not include hydroxyurea, which may be continued
until start of conditioning therapy; ruxolitinib may be continued at principal
investigator's discretion during conditioning

- Non-compliance; defined as any subject, who in the opinion of the investigator, may
not be able to comply with the safety monitoring requirements of the study