Randomized, open label, multicenter phase III study of Efficacy and Safety in POlycythemia vera subjects who are resistant to or intolerant of hydroxyurea: JAK iNhibitor INC424 tablets verSus bEst available care

1. Subjects 18 years of age or older.
2. Subjects must be diagnosed with PV for at least 24 weeks prior to Screening according to
the 2008 World Health Organization criteria (Table 2 in Tefferi and Vardiman 2008;
Appendix 1).
3. Subjects must have a treatment history for PV that meets the definition of resistance or
intolerance to hydroxyurea (HU) by exhibiting at least one of the following five criteria
(modified from Barosi et al 2009A, Appendix 2):
* HU Resistance, defined after 12 weeks into a course of HU therapy at a dose of at least
2 grams/day OR at the subject*s maximally tolerated dose if that dose is less than 2
grams/day:
a. Need for phlebotomy to keep hematocrit < 45%, OR
b. Platelet count > 400 x 109/L AND white blood cell count > 10 x 109/L, OR
c. Failure to reduce splenomegaly extending greater than 10 cm below the costal
margin by more than 50%, as measured by palpation.
* HU Intolerance:
a. Absolute neutrophil count < 1.0 x 109/L OR platelet count < 100 x 109/L OR
hemoglobin < 100 g/L (i.e. 10 g/dL) at the lowest dose of HU required to achieve a response (with response modified from Barosi et al 2009B: hematocrit < 45%
without phlebotomy AND/OR all of the following three items: platelet count
* 400 x 109/L, white blood cell count * 10 x 109/L, and non-palpable spleen), OR
b. Presence of leg ulcers or other unacceptable HU-related non-hematological
toxicities (such as mucocutaneous manifestations, gastrointestinal symptoms,
pneumonitis or fever at any dose of HU), defined as
- CTCAE version 3.0 Grade 3-4, OR
- more than 1 week of CTCAE version 3.0 Grade 2, OR
- permanent discontinuation of HU, OR
- interruption of HU until toxicity resolved, OR
- hospitalization due to HU toxicity.
4. Subjects must have required
a. at least 2 phlebotomies within the 24 weeks prior to Screening, AND
b. at least one phlebotomy within the 16 weeks prior to Screening, AND
c. the most distant and the most recent phlebotomy within the 24 weeks prior to
Screening must be at least 4 weeks apart
OR subjects will be considered to have met this criterion if they have required a
phlebotomy within the 16 weeks prior to Screening AND they exhibit a hematocrit
> 45% at Screening
5. Subjects with splenomegaly, defined as
a. Spleen palpable below the costal margin, provided that MRI (or CT in applicable
subjects) spleen assessment during Screening confirms that the spleen is enlarged,
defined with a volume of * 450 cm3, OR
b. Spleen non palpable below the costal margin due to body habitus (e.g., in obese
subjects), provided that MRI (or CT in applicable subjects) spleen assessment during
Screening confirms that the spleen is enlarged, defined with a volume of * 450 cm3
6. Subjects with ANC * 1.5 x 109/L and PLT * 100 x 109/L at Screening.
7. Subjects with peripheral blood blast count of 0% at Screening.
8. Subjects with an ECOG performance status of 0, 1 or 2 (Appendix 5) at Screening and
Baseline.
9. Subjects on a therapeutic regimen for PV must have been on a stable dose and schedule
for at least 2 weeks prior to Screening and no less than 4 weeks prior to randomization
(Study Day 1).

1. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female
after conception (confirmed by a positive hCG laboratory test ;> 5 mIU/mL) and until the
termination of gestation.
2. Women of child-bearing potential, defined as all women physiologically capable of
becoming pregnant, including women whose career, lifestyle, or sexual orientation
precludes intercourse with a male partner and women whose partners have been sterilized
by vasectomy or other means, UNLESS they are using two birth control methods. The two
methods can be a double barrier method or a barrier method plus a hormonal method.
(Appendix 3).
* Reliable contraception should be maintained throughout the study and for 5-half lives
of study drug after study treatment discontinuation.
* Women are considered post-menopausal and not of child bearing potential if they
have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical
profile (e.g. age appropriate, history of vasomotor symptoms) or six months of
spontaneous amenorrhea with serum FSH levels > 40 mIU/mL [for US only: and
estradiol < 20 pg/mL] or have had surgical bilateral oophorectomy (with or without
hysterectomy) at least six weeks ago. In the case of oophorectomy alone, only when
the reproductive status of the woman has been confirmed by follow up hormone level
assessment is she considered not of child bearing potential.
* Sexually active males must use a condom during intercourse while taking the drug
and for five half-lives after stopping treatment and should not father a child in this
period. A condom is required to be used also by vasectomized men in order to prevent
delivery of the drug via seminal fluid.
3. Subjects with inadequate liver or renal function at Screening as demonstrated by:
a. Encephalopathy Grade 2 or more as per Child-Pugh System. (Appendix 12)
b. Known hepatocellular disease (for example, hepatitis B or C, cirrhosis or other
hepatocellular disease)
c. Direct bilirubin * 2 X upper limit of laboratory normal (ULN).
d. Alanine aminotransferase (ALT) > 2.5x ULN.
e. MDRD-eGFR < 30 mL/min/1.73m2 or on dialysis.
4. Subjects with impairment of gastrointestinal (GI) function or GI disease that may
significantly alter the absorption of oral INC424 (e.g., ulcerative diseases, uncontrolled
nausea, vomiting, diarrhea, malabsorption syndrome, small bowel resection).
5. Subjects with clinically significant bacterial, fungal, parasitic or viral infection which
requires therapy:
* Subjects with acute bacterial infections requiring antibiotic use should delay
screening/enrollment until the course of antibiotic therapy has been completed.
* Subjects with known active hepatitis A, B or C at Screening or with known HIV
positivity.
6. Subjects with diagnosed primary immunodeficiency syndromes such as X-Linked
Agammaglobulinemia and Common Variable Immune Deficiency.
7. Subjects with an active malignancy over the previous 5 years except treated cervical
intraepithelial neoplasia, basal cell carcinoma of the skin, or squamous cell carcinoma of
the skin, with no evidence for recurrence in the past 3 years.
8. Subjects with clinically significant cardiac disease (NYHA Class III or IV; Appendix 6).
9. Subjects receiving PEG-IFN-alpha-2a within 5 weeks of Screening or having a prior
history of 32P therapy.
10. Subjects being treated concurrently with a potent systemic inhibitor of CYP3A4 at the
time of Screening (ketoconazole, clarithromycin, itraconazole, nefazodone or
telithromycin, see Appendix 13).
11. Subjects being treated concurrently with any prohibited medications (see Section 5.1.11
for specific prohibited medications and the associated timeframe over which they are
prohibited).
12. Subjects who have previously received treatment with a JAK inhibitor.
13. Subjects being treated concurrently with any investigational agent or prior participation in
an investigational study within 30 days prior to the first dose of study drug or within 5-
half lives of the investigational product, whichever is longer.
14. Subjects who are unable to comprehend or are unwilling to sign an informed consent form
(ICF).
15. Subjects with active alcohol or drug addiction that would interfere with their ability to
comply with the study requirements.
16. Subjects with an uncontrolled intercurrent illness or any concurrent condition that, in the
investigator*s opinion, would jeopardize the safety of the subject or compliance with the
protocol.