Ruxolitinib Phosphate, Tacrolimus and Sirolimus in Preventing Acute Graft-versus-Host Disease During Reduced Intensity Donor Hematopoietic Cell Transplant in 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 (ruxolitinib phosphate), when given in
combination with tacrolimus and sirolimus (TAC/SIR) as acute graft-versus-host disease
(aGVHD) prophylaxis as part of reduced intensity allogeneic hematopoietic cell transplant
(HCT), in patients with myelofibrosis or other related myeloid neoplasm with marrow
fibrosis.

SECONDARY OBJECTIVES:

I. To determine if the addition of ruxolitinib, to the standard aGVHD prophylactic regimen
of TAC/SIR, is safe by evaluation of toxicities including: type, frequency, severity,
attribution, time course and duration.

II. To estimate the cumulative incidence of 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 characterize and evaluate hematologic recovery, donor cell engraftment and immune
reconstitution by cell count and flow cytometry of lymphocyte subsets.

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

VI. To characterize changes in aGVHD biomarkers (regenerating islet-derived 3-alpha
[Reg-3alpha], soluble tumor necrosis factor receptor I [sTNF RI], interleukin 2 receptor
alpha [IL2Ralpha]), Janus-associated kinase (JAK)-regulated pro-inflammatory cytokines (i.e.
interleukin [IL]-6, tumor necrosis factor [TNF] alpha, C-reactive protein [CRP], beta 2
microglobulin) and signal transducer and activator of transcription 3 (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 and melphalan IV over 20 minutes on day -4. Beginning greater than 48 hours after
completion of melphalan, patients undergo peripheral blood stem cell or bone marrow
transplant according to standard guidelines on day 0.

GVHD PROPHYLAXIS: Patients receive ruxolitinib phosphate orally (PO) twice daily (BID) on
days -3 to 30 tapered to day 60, tacrolimus IV continuously or PO BID on days -3 to 100 ,
and sirolimus PO once daily (QD) on day -3 to 100. Treatment continues in the absence of
disease progression or unacceptable toxicity.

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

Inclusion Criteria:

- Primary or secondary myelofibrosis intermediate or high risk by Dynamic International
Prognostic Scoring System 26 (DIPSS26) in chronic or accelerated phase

- Transformed acute myeloid leukemia (AML) with marrow fibrosis is allowed, if AML is
in complete remission after induction therapy

- Patients with a 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,
myeloproliferative leukemia [MPL] and calreticulin [CALR] mutational status) will be
obtained as per standard practice

- Bone marrow aspirates/biopsies should be performed within 23 ± 7 days from
registration to confirm disease remission status

- All candidates for this study must have a 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 diffusing 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 City of Hope (COH)
Institutional Review Board (IRB); the patient, a family member and transplant staff
physician (physician, nurse, and 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 AML
patients who are back in chronic phase MPN, prior induction chemotherapy is allowed

- DONOR: Donor evaluation and eligibility will be assessed as per current City of Hope
SOP

Exclusion Criteria:

- Patients should not have any uncontrolled illness 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 opinion,
will interfere with 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 or ruxolitinib, which may
be continued until start of conditioning therapy

- 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