A Study to Find the Maximum Tolerated Dose of the Experimental Combination of the Drugs INC424 and BKM120 in Patients With Primary or Secondary Myelofibrosis

• Frequency of adverse events [ Time Frame: after each cohort is enrolled at baseline until the maximum tolerated dose is established ] [ Designated as safety issue: Yes ]
  Adverse Events are monitored at each study visit and 30 days post last dose of study drug
• Frequency of serious adverse events [ Time Frame: after each cohort is enrolled at baseline until the maximum tolerated dose is established ] [ Designated as safety issue: Yes ]
  Serious Adverse events monitored at each study visit and 30 days post last dose of study drug
• Abnormalities in vital signs [ Time Frame: baseline, days 2, 8, 15, 22 of cycle 1, day 1 of every additional cycle ] [ Designated as safety issue: Yes ]
  cycle = 28 days
• Laboratory test values including Imaging (electrocardiograms (ECGs), abdominal MRI/CT, ECHO/MUGA [ Time Frame: Days 2, 5, 8, 11, 18, 22 and then weekly for every other cycle after ] [ Designated as safety issue: Yes ]
  ECGs are performed baseline, days 2, 8, 15, 22 of cycle 1 then day 1 of every additional cycle. Magnetic resonance imaging (MRI) or Cat Scan (CT) and Echocardiography (ECHO) or Multiple Gated Acquisition (MUGA) is performed at baseline and then every 3 cycles until the end of treatment. . Hematology is performed at baseline and days 2, 5, 8, 11, 15, 18, 22 and then weekly in subsequent cycles.
• Maximum plasma concentration (Cmax) [ Time Frame: pre-dose, 0.5, 1, 1.5, 2, 4, 6, 8 hours on days 1, 2, and 8 ] [ Designated as safety issue: No ]
  To characterize the pharmacokinetics (PK) of INC424 alone or in combination with BKM120
• Maximum plasma concentration time (Tmax) [ Time Frame: pre-dose, 0.5, 1, 1.5, 2, 4, 6, 8 hours on days 1, 2, and 8 ] [ Designated as safety issue: No ]
  To characterize the pharmacokinetics (PK) of INC424 alone or in combination with BKM120
• Area under the plasma concentration time curve (AUC) [ Time Frame: pre-dose, 0.5, 1, 1.5, 2, 4, 6, 8 hours on days 1, 2, and 8 ] [ Designated as safety issue: No ]
  To characterize the pharmacokinetics (PK) of INC424 alone or in combination with BKM120
• Maximum plasma concentration (Cmax) [ Time Frame: pre-dose, 0.5, 1, 1.5, 2, 4, 6, 8, 24 hours on days 2 and 8 ] [ Designated as safety issue: No ]
  To characterize the pharmacokinetics (PK) of BKM120 alone or in combination with INC424
• Maximum plasma concentration time (Tmax) [ Time Frame: pre-dose, 0.5, 1, 1.5, 2, 4, 6, 8, 24 hours on days 2 and 8 ] [ Designated as safety issue: No ]
  To characterize the pharmacokinetics (PK) of BKM120 alone or in combination with INC424
• Area under the plasma concentration time curve (AUC) [ Time Frame: pre-dose, 0.5, 1, 1.5, 2, 4, 6, 8, 24 hours on days 2 and 8 ] [ Designated as safety issue: No ]
  To characterize the pharmacokinetics (PK) of BKM120 alone or in combination with INC424
• Duration of adverse events [ Time Frame: after each cohort is enrolled at baseline until the maximum tolerated dose is established ] [ Designated as safety issue: Yes ]
  Adverse Events are monitored at each study visit and 30 days post last dose of study drug
• Severity of adverse events [ Time Frame: after each cohort is enrolled at baseline until the maximum tolerated dose is established ] [ Designated as safety issue: Yes ]
  Adverse Events are monitored at each study visit and 30 days post last dose of study drug
• Duration of serious adverse events [ Time Frame: after each cohort is enrolled at baseline until the maximum tolerated dose is established ] [ Designated as safety issue: Yes ]
  Serious Adverse events monitored at each study visit and 30 days post last dose of study drug
• Severity of serious adverse events [ Time Frame: after each cohort is enrolled at baseline until the maximum tolerated dose is established ] [ Designated as safety issue: Yes ]
  Serious Adverse events monitored at each study visit and 30 days post last dose of study drug

The purpose of this phase Ib clinical trial is to evaluate the safety of the combination of INC424 and BKM120 in the myelofibrosis population and to establish the maximum tolerated dose and or the Recommended Phase II dose of the combination guided by the Bayesian dose escalation model. INC424 has shown efficacy in myelofibrosis (MF) and is approved in the US and EU for the treatment of MF. BKM120 is a PI3K inhibitor. Preclinical and early clinical experience support inhibition of the PI3K/mTOR pathway in MF as aberrant activation of the pathway has been observed in MF models and may contribute to the pathogenesis of the disease.

• Drug: INC424
  5 mg tablets administered orally twice daily
• Drug: BKM120
  10 mg and 50 mg hard gelatin capsules administered orally once daily

• Experimental: JAK Inhibitor Naive
  Two treatment periods applicable to all patients; Treatment Period (6 cycles / 28 days per cycle) and Extension Period (6 cycles of 28 days) following the treatment period dependent on patient continued eligibility. Two Study Phases: Dose Escalation Phase to determine maximum tolerated dose (MTD) / Recommended Phase II dose (RPIID) & an Expansion Phase
  Interventions:

  • Drug: INC424
  • Drug: BKM120
• Experimental: Prior JAK Inhibitor

  Two treatment periods applicable to all patients; Treatment Period (6 cycles / 28 days per cycle) and Extension Period (6 cycles of 28 days) following the treatment period dependent on patient continued eligibility.

  Two Study Phases: Dose Escalation Phase to determine MTD / RPIID & an Expansion Phase

  Interventions:

  • Drug: INC424
  • Drug: BKM120

Inclusion Criteria:

• Diagnosed with PMF, PPV-MF or PET-MF irrespective of JAK2 mutation status
• Myelofibrosis patients requiring therapy must be classified as intermediate risk level 1 )1 or more prognostic factors defined by IWG) with at least one criteria other than age
• Must have palpable spleen of at least 5 cm from the costal margin to the point of greatest splenic profusion at Screening
• Must have active symptoms of MF (one symptom score of at least 5 or two symptom scores of at least 3 at Screening) (per MFSSF 0-10)
• PLT counts > or = 75X 10^9/L at Screening or Cycle 1 Day 1 (not with aid of transfusions

Exclusion Criteria:

• Pregnant or nursing women
• WOCBP not using highly effective methods of contraception
• Sexually active males who refuse condom use
• Previous Treatment with one of the following: PI3 K inhibitors and AKT inhibitors; JAK inhibitors that resulted in clinically significant toxicities per the Investigator;
• Patients who have had splenic irradiation within 12 months prior to Screening
• Patients with specific mood disorders
• Any history of bleeding diathesis
• Patients receiving the following treatments / medications:

EIAED within 2 wks. prior to study treatment; medication known to prolong QT interval or induce Torsades de Pointes; treatment with potent systemic systemic inhibitor or systemic inducer of CYP3A4; any use of drug that interferes with coagulation or inhibits PLT function

-current and willing candidates for a stem cell transplantation