Evaluation of Ruxolitinib in Combination With PU-H71 for Treatment of Myelofibrosis

This is a multicenter 2-part, Phase 1b study designed to assess the safety, tolerability, PK
and preliminary efficacy of PU-H71 (dihydrochloride salt) in subjects taking concomitant
ruxolitinib. The first part (Dose Escalation) will employ a standard 3+3 dose escalation
design to determine MTD. The second part of the study (Dose Confirmation) will confirm the
RP2D in an expanded population.

Up to 30 subjects who have active disease despite having received a minimum of 6 months of
ruxolitinib therapy (including last 2 months at a daily dose of ≥5 mg twice daily and no more
than one dose reduction 2-8 weeks prior to the baseline visit)stable dose will be enrolled to
evaluate the safety, PK, and MTD of IV PU-H71 administered in combination ruxolitinib. Four
ascending dose levels are planned. The planned dose levels of PU-H71 are 225 mg/m2, 300
mg/m2, 400 mg/m2, and 600 mg/m2. Additional dosing cohorts may be added at the discretion of
the Safety Review Committee (SRC).

Following a 28-day screening period, eligible subjects will receive PU-H71 once weekly
intravenously for three consecutive weeks, followed by one week off on a 28-day cycle (D1,
D8, D15, every 28 days). Ruxolitinib will be administered twice daily per the package insert
at the stable dose the subject had been receiving prior to enrolling in the study.

Subjects will have pk samples taken and ECGs performed at various time points throughout the
study. Subjects will have safety evaluations including physical examinations, vital signs,
laboratory assessments, and AE reporting. If deemed necessary, additional safety measurements
will be performed at the discretion of the Investigator or the SRC.

Subjects will be treated until disease progression, DLT, death, or study termination.

At each dose level, a 3+3 dose escalation design will be employed. If none of the initial 3
subjects in the cohort experience a DLT within the first cycle, a new cohort of 3 subjects
will be treated at the next higher dose level. If 1 of the 3 subjects in a cohort experiences
a DLT, then 3 additional subjects will be treated at the same dose level as described under
Dose Limiting Toxicities.

Once the MTD has been determined in the dose escalation portion of the study, up to 15
patients may be enrolled for further evaluation of safety, PK, and preliminary clinical
activity in a dose confirmation phase.

A safety review committee (SRC) will assess the safety, tolerability, and available PK
information collected for each dose level, decide whether to proceed to the next cohort, and
determine the dose for the cohort.

Inclusion Criteria:

1. Subject has a confirmed diagnosis of myelofibrosis, including PMF, post-PV MF, and
post-ET MF.

2. Subject has been receiving ruxolitinib therapy for intermediate or high-risk
myelofibrosis for >6 months prior to enrollment with no more than 1 dose reduction of
ruxolitinib in the 2-8 weeks prior to enrollment and a stable daily dose ≥5 mg twice
daily (BID) >2 months prior to enrollment.

3. Subject has MF with evidence of persistent disease despite ruxolitinib monotherapy
treatment, consisting of:

1. Persistent or worsening disease-related symptoms, including but not limited to
fatigue, pruritus, night sweats, early satiety, and other symptoms as determined
by a MPN-SAF TSS score of >20 points; AND

2. Documented splenomegaly of at least 5 cm below the costal margin as measured on
inspiration by physical exam.

4. Subject has an Eastern Cooperative Oncology Group performance status of 0-2.

5. Acceptable pre-study organ function during screening defined as:

1. Absolute neutrophil count (ANC) ≥ 1000/uL

2. Hemoglobin (hgb) ≥ 8.0 g/dL (may be supported with transfusion)

3. Platelets (plt) ≥ 75,000/uL

4. AST/SGOT and ALT/SGPT ≤2 x Upper Limit of Normal (ULN)

5. Direct serum bilirubin ≤ 1.5 x ULN

6. Creatinine clearance >50 mL/min/1.73 m2 based on Cockcroft Gault equation.

Exclusion Criteria:

1. Subject has known active liver disease, including viral hepatitis or cirrhosis.

2. Subject has known or suspected HIV or other active infections requiring acute or
chronic treatment with systemic antibiotics. Conditions requiring topical antibiotics
are acceptable.

3. Subject has a QTcF > 480 ms (corrected) in the screening or baseline ECG.

4. Subject has left ventricular ejection fraction (LVEF) ≤ 50%, or below institution's
lower limit of normal (whichever is lower) by echocardiogram (ECHO) or multigated
acquisition (MUGA) scan.

5. Subject has a history (or family history) of long QT syndrome.

6. Subject has coronary artery disease with an ischemic event within 6 months prior to
enrollment.

7. Subject has a permanent cardiac pacemaker.

8. Subject has history of a second primary malignancy within the past 2 year except for
the following (if appropriately treated and considered cured): stage I endometrial,
surgically treated cervical or prostate carcinoma, and non-melanoma skin cancer.

9. Subject has significant uncontrolled medical condition within 6 months prior to
enrollment, as determined by the investigator.

10. Subject has concurrent participation in any interventional studies within 14 days of
first dose of study drug.

11. Subject has uncontrolled diabetes mellitus, in the judgment of the Principal
Investigator.

12. Subject has an active ocular condition that in the opinion of the investigator may
alter visual acuity during the course of the study (i.e., ocular inflammatory disease
etc.) or a history or anticipation of major ocular surgery (including cataract
extraction, intraocular surgery, etc.) during the study.