Controlled Myelofibrosis Study With Oral Janus-associated Kinase (JAK) Inhibitor Treatment-II: The COMFORT-II Trial

• Percentage of Participants With at Least 35% Reduction in Spleen Volume From Baseline at Week 24 [ Time Frame: Baseline, Week 24 ] [ Designated as safety issue: No ]
  The change in spleen volume from baseline to week 24 was measured by magnetic resonance imaging (MRI) (or by computer tomography (CT) for participants unable to undergo MRI) and was calculated only for participants who had an evaluable spleen volume at baseline. The percentage of participants achieving a greater than or equal to 35% reduction in spleen volume from baseline to week 24 was then calculated by treatment group.
• Duration of Maintenance of at Least 35% Reduction in Spleen Volume (DoMSR) From Baseline [ Time Frame: Baseline, every 12 weeks until 25% progression from baseline ] [ Designated as safety issue: No ]
  DoMSR is defined as the interval between the first spleen volume measurement that is >=35% reduction from baseline and the first scan that is no longer = 35% reduction AND that is a >25% increase over nadir. It was evaluated using the Kaplan-Meier estimate for each treatment arm. The analysis was performed only for subjects who achieved greater than 35% reduction in spleen volume.
• Time to First at Least 35% Reduction in Spleen Volume From Baseline by Treatment [ Time Frame: Baseline, every 12 weeks until first 35% reduction in spleen is achieved ] [ Designated as safety issue: No ]
  This is defined as the interval between randomization and date of the first MRI showing a 35% reduction from baseline in spleen volume. The analysis was performed for participants who achieved a 35% reduction in spleen volume.
• Progression Free Survival (PFS) by Treatment [ Time Frame: every three months after EOS until end of extension phase (96 weeks LPLV for the primary endpoint) ] [ Designated as safety issue: No ]
  Defined as the time from the date of randomization/start of treatment to the date of the first documented disease progression including death due to any cause.
• Leukemia-free Survival (LFS) [ Time Frame: every three months after EOS until end of extension phase (96 weeks LPLV for the primary end) ] [ Designated as safety issue: No ]
  Defined as the interval between randomization and the date of the bone marrow blast count of 20% or greater OR the date of the first peripheral blast count of 20% or greater that was subsequently confirmed to have been sustained for at least 8 weeks OR the date of death from any cause, whichever occurs first.LFS was summarized using Kaplan-Meier estimates for each treatment arm. The estimates were supplemented by tables of number of events and probability estimates at several timepoints.
• Overall Survival (OS) by Treatment [ Time Frame: every three months after EOS until end of extension phase (96 weeks LPLV for the primary end) ] [ Designated as safety issue: No ]

  Defined as the interval between randomization and death from any cause. Hazard ratios of OS and the corresponding 95% CIs were estimated using the Cox proportional hazards model stratified by baseline prognostic category. For the comparison of OS between INC424 (INCB018424) and BAT, a stratified 2-sided log-rank test was used.

  Sensitivity analysis was also conducted for OS with the data being censored at the end of the Randomized Phase for those subjects who entered the Extension Phase. Unstratified analyses were also performed by reporting hazard ratios with 95% CIs.

• Percentage of Participants With Bone Marrow Histomorphology at Week 48 [ Time Frame: 48 weeks ] [ Designated as safety issue: No ]
  This was noted as fibrosis density and was tabulated by fibrosis grade at baseline and at week 48 (post-baseline). Descriptive statistics (participant percentages) were used.

This is an open label, randomized study comparing the efficacy and safety of randomized 2:1 INC424/INCB018424 tablets versus best-available therapy, as selected by the investigator. The purpose is to compare the efficacy, safety and tolerability of INC424/INCB018424 given twice daily to the best-available therapy, in subjects with primary myelofibrosis (PMF), post polycythemia vera myelofibrosis (PPV-MF) or post essential thrombocythemia myelofibrosis (PET-MF).

Male or female individuals, aged 18 years or older who have been diagnosed with Myelofibrosis (either Primary Myelofibrosis (PMF) or Post-Polycythemia Vera Myelofibrosis (PPV-MF) or Post-Essential Thrombocythemia Myelofibrosis (PET-MF), were observed to have palpable splenomegaly, were not candidates for stem cell transplantation, and had 2 or more risk factors, thereby placing them in an intermediate-2 or high-risk prognostic group may enroll. Subjects were permitted to have received any or no prior therapy for MF. This is an open label, randomized study comparing the efficacy and safety of INCB018424 tablets versus best-available therapy, as selected by the investigator. The purpose is to compare the efficacy, safety and tolerability of INCB018424 given twice daily to the best-available therapy, in subjects with primary myelofibrosis (PMF), post polycythemia vera myelofibrosis (PPV-MF) or post essential thrombocythemia myelofibrosis (PET-MF).

• Drug: INC424/INCB018424
  Oral 5 mg tablets with packaged as 60-count in high-density polyethylene bottles.
• Drug: Best Available Therapy (BAT)
  Best available investigator-selected therapy (oral or parenteral therapies) was commercially available and was administered according to manufacturer's instructions and investigator discretion. Instructions for prescribing and taking these therapies were found in their respective package inserts.

• Experimental: INC424/INCB018424
  Starting dose of 15 mg BID or 20 mg BID were selected with starting dose based on baseline platelet count. Dose titration ranging from 5 mg BID to a maximum dose of 25 mg BID was permitted during the study based on safety and efficacy. Tablets were to be taken 12 hours apart. Administration instructions were provided at study visits.
  Intervention: Drug: INC424/INCB018424
• Active Comparator: Best Available Therapy (BAT)
  Best-available Investigator-selected therapy included a combination of available agents to treat the disease and/or its symptoms, and was selected by the investigator for each subject. Therapy changed at different times during the treatment phase. No experimental agents (e.g. those not approved for the treatment of any indication) were allowed. BAT also included the option of no treatment.
  Intervention: Drug: Best Available Therapy (BAT)

Inclusion Criteria:

• Subjects must be diagnosed with PMF, PPV-MF or PET-MF according to the 2008 World Health Organization criteria
• Subjects with MF requiring therapy must be classified as high risk OR intermediate risk level 2 according to the prognostic factors defined by the International Working Group
• Subjects with an ECOG performance status of 0, 1, 2 or 3
• Subjects with peripheral blood blast count of < 10%.
• Subjects who have not previously received treatment with a JAK inhibitor

Exclusion Criteria:

• Subjects with a life expectancy of less than 6 months
• Subjects with inadequate bone marrow reserve as demonstrated by specific clinical laboratory counts
• Subjects with any history of platelet counts < 50,000/µL or ANC < 500/µL except during treatment for a myeloproliferative disorder or treatment with cytotoxic therapy for any other reason
• Subjects with inadequate liver or renal function
• Subjects with clinically significant bacterial, fungal, parasitic or viral infection which require therapy
• Subjects with an active malignancy over the previous 5 years except specific skin cancers
• Subjects with severe cardiac conditions
• Subjects who have had splenic irradiation within 12 months