Study of Efficacy and Safety in Polycythemia Vera Subjects Who Are Resistant to or Intolerant of Hydroxyurea: JAK Inhibitor INC424 (INCB018424) Tablets Versus Best Available Care: (The RESPONSE Trial) ((RESPONSE))

• To compare the proportion of subjects randomized to INC424 vs. Best Available Therapy achieving both durable absence of phlebotomy eligibility and durable spleen volume reduction. [ Time Frame: 48 Weeks. ] [ Designated as safety issue: No ]
• To compare the proportion of subjects randomized to INC424 vs. Best Available Therapy achieving complete hematological remission. [ Time Frame: 32 Weeks ] [ Designated as safety issue: No ]
• To determine the proportion of subjects achieving a durable spleen volume reduction [ Time Frame: 48 Weeks ] [ Designated as safety issue: No ]
• To estimate the proportion of subjects achieving a durable complete hematological remission [ Time Frame: 48 Weeks ] [ Designated as safety issue: No ]
• To estimate the proportion of subjects achieving a durable phlebotomy independence [ Time Frame: 48 Weeks ] [ Designated as safety issue: No ]
• To estimate the duration of both the absence of phlebotomy eligibility and reduction in spleen volume [ Time Frame: Through study completion ] [ Designated as safety issue: No ]
• To determine the overall clinicohematologic response rate [ Time Frame: 32 Weeks ] [ Designated as safety issue: No ]
• To estimate the proportion of subjects achieving a durable complete or partial clinicohematologic response [ Time Frame: 48 Weeks ] [ Designated as safety issue: No ]
• To estimate the duration of the overall clinicohematologic response [ Time Frame: Through study completion ] [ Designated as safety issue: No ]
• To estimate the proportion of subjects achieving both durable absence of phlebotomy eligibility and durable spleen volume reduction 48 weeks after the response was initially documented [ Time Frame: Through study completion. ] [ Designated as safety issue: No ]
• Safety and tolerability of INC424 as measured by adverse events, laboratory assessments, physical examination, vital signs, and ECG measurements. [ Time Frame: Through study completion ] [ Designated as safety issue: No ]

• Proportion of subjects achieving complete hematologic remission at Week 32. [ Time Frame: 32 weeks ] [ Designated as safety issue: No ]
• Proportion of all randomized subjects who both achieve the Week 32 primary response endpoint and maintain response for ≥ 48 weeks from the time that response was initially documented. [ Time Frame: At least 80 weeks ] [ Designated as safety issue: No ]

This pivotal phase III trial (CINC424B2301) is designed to compare the efficacy and safety of INC424 to Best Available Therapy (BAT) in subjects with polycythemia vera (PV) who are resistant to or intolerant of hydroxyurea (HU).

• Drug: INC424 tablets
  Starting dose of 10 mg BID with individualized dose titration ranging from 5 mg QD to 25 mg BID based on safety and efficacy
• Other: Best Available Therapy (BAT)
  Best Available Therapy (BAT) will be selected by the investigator for each subject. BAT may not include experimental agents (i.e. those not approved for the treatment of any indication) as well as a limited number of other selected drugs.
  Other Names:

  • BAT:
  • 1. Hydroxyurea
  • 2. IFN/PEG-IFN
  • 3. Pipobroman
  • 4. Anagrelide
  • 5. IMIDs
  • 6. Observation only

• Experimental: INC424 tablets
  Starting dose of 10 mg BID with individualized dose titration ranging from 5 mg QD to 25 mg BID based on safety and efficacy
  Intervention: Drug: INC424 tablets
• Best Available Therapy
  Best Available Therapy (BAT) will be selected by the Investigator for each subject. BAT may not include experimental agents (i.e. those not approved for the treatment of any indication) as well as a limited number of other selected drugs.
  Intervention: Other: Best Available Therapy (BAT)

Inclusion Criteria:

• Subjects diagnosed with PV for at least 24 weeks prior to screening according to the 2008 World Health Organization criteria
• Subjects resistant to or intolerant of hydroxyurea
• Subjects with a phlebotomy requirement
• Subjects with a palpable splenomegaly and a spleen volume of greater than or equal to 450 cubic centimeters
• Subjects with an ECOG performance status of 0, 1 or 2

Exclusion Criteria:

• Women who are pregnant or nursing
• Subjects with inadequate liver or renal function
• Subjects with significant bacterial, fungal, parasitic, or viral infection requiring treatment
• Subjects with an active malignancy within the past 5 years, excluding specific skin cancers
• Subjects with known active hepatitis or HIV positivity
• Subjects who have previously received treatment with a JAK inhibitor
• Subjects being treated with any investigational agent