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

Study Overview
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Brief Summary
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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.

Official Title
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A Phase Ib, Open-label, Multi-center, Two-arm, Dose-finding Study to Assess Safety and Efficacy of the Oral Combination or INC424 (INC424) and BKM120 in Patients With Primary Myelofibrosis (PMF), Postpolycythemia Vera-myelofibrosis (PPV-MF), or Post-essential Thrombocythemia-myelofibrosis (PET-MF)

Conditions
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Myelofibrosis

Intervention / Treatment
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* Drug: INC424
* Drug: BKM120


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: JAK Inhibitor Naive<br>Two treatment periods applicable to all patients; Treatment Period (6 cycles / 28 days per cycle) and Extension Period ( 6 or more cycles of 28 days, with visits every 28days for 6 cycles and then visits every 12 weeks) 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 | Drug: INC424<br>* 5 mg tablets administered orally twice daily<br>Drug: BKM120<br>* 10 mg and 50 mg hard gelatin capsules administered orally once daily<br>|
| Experimental: Prior JAK Inhibitor<br>Two treatment periods applicable to all patients; Treatment Period (6 cycles / 28 days per cycle) and Extension Period (6 or more cycles of 28 days, with visits every 28 days for 6 cycles then visits every 12 weeks) following the treatment period dependent on patient continued eligibility. Two Study Phases: Dose Escalation Phase to determine MTD / RPIID & an Expansion Phase | Drug: INC424<br>* 5 mg tablets administered orally twice daily<br>Drug: BKM120<br>* 10 mg and 50 mg hard gelatin capsules administered orally once daily<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of dose limiting toxicities | The incidence of dose limiting toxicities will be analyzed to establish the maximum tolerated dose. To assess the maximum tolerated dose, labs and adverse events are monitored. | baseline, when the maximum tolerated dose is established. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Frequency of adverse events | Adverse Events are monitored at each study visit and 30 days post last dose of study drug | after each cohort is enrolled at baseline until the maximum tolerated dose is established | 
| Frequency of serious adverse events | Serious Adverse events monitored at each study visit and 30 days post last dose of study drug | after each cohort is enrolled at baseline until the maximum tolerated dose is established | 
| Abnormalities in vital signs | cycle = 28 days | baseline, days 2, 8, 15, 22 of cycle 1, day 1 and 15 at Cycle 2, Day 1 from cycle 3 to 12, day 28 on Cycle 12 and every 12 weeks from Week 60 to 96 and at End of treatment | 
| Laboratory test values including Imaging (electrocardiograms (ECGs), abdominal MRI/CT, ECHO/MUGA | ECGs are performed baseline, days 2, 8, 15, 22 of cycle 1 then day 1 from Cycle 2 to cycle 12, and at cycle 12 day 28 and every 12 weeks and end of treatment. Magnetic resonance imaging (MRI) or Cat Scan (CT) performed at baseline, cycle 4 day 1, cycle 7 day 1, cycle 12 day 28, then every 24 weeks , and end of treatment if not done in past 12 weeks. Echocardiography (ECHO) or Multiple Gated Acquisition (MUGA) is performed at baseline and then every 4 cycles until cycle 12, then every 24 weeks therafter or as clinically indicated until Week 96. Hematology is performed at baseline and days 2, 5, 8, 11, 15, 18, 22, 25 of cycle 1, weekly in cycle 2, then on every scheduled visit (D1 of Cycle 3 to 12, at Cycle 12 Day 28 ,then every 12 weeks) and end of treatment. | Day 1, 2, 5, 8, 11, 18, 22, 25 of cycle 1, weekly in cycle 2, then at every scheduled visit including End of treatment visit | 
| Maximum plasma concentration (Cmax) | To characterize the pharmacokinetics (PK) of INC424 alone or in combination with BKM120 | pre-dose, 0.5, 1, 1.5, 2, 4, 6, 8 hours on days 1, 2, and 8 | 
| Maximum plasma concentration time (Tmax) | To characterize the pharmacokinetics (PK) of INC424 alone or in combination with BKM120 | pre-dose, 0.5, 1, 1.5, 2, 4, 6, 8 hours on days 1, 2, and 8 | 
| Area under the plasma concentration time curve (AUC) | To characterize the pharmacokinetics (PK) of INC424 alone or in combination with BKM120 | pre-dose, 0.5, 1, 1.5, 2, 4, 6, 8 hours on days 1, 2, and 8 | 
| Maximum plasma concentration (Cmax) | To characterize the pharmacokinetics (PK) of BKM120 alone or in combination with INC424 | pre-dose, 0.5, 1, 1.5, 2, 4, 6, 8, 24 hours on days 2 and 8 | 
| Maximum plasma concentration time (Tmax) | To characterize the pharmacokinetics (PK) of BKM120 alone or in combination with INC424 | pre-dose, 0.5, 1, 1.5, 2, 4, 6, 8, 24 hours on days 2 and 8 | 
| Area under the plasma concentration time curve (AUC) | To characterize the pharmacokinetics (PK) of BKM120 alone or in combination with INC424 | pre-dose, 0.5, 1, 1.5, 2, 4, 6, 8, 24 hours on days 2 and 8 | 
| Duration of adverse events | Adverse Events are monitored at each study visit and 30 days post last dose of study drug | after each cohort is enrolled at baseline until the maximum tolerated dose is established | 
| Severity of adverse events | Adverse Events are monitored at each study visit and 30 days post last dose of study drug | after each cohort is enrolled at baseline until the maximum tolerated dose is established | 
| Severity of serious adverse events | Serious Adverse events monitored at each study visit and 30 days post last dose of study drug | after each cohort is enrolled at baseline until the maximum tolerated dose is established | 
| Duration of serious adverse events | Adverse Events are monitored at each study visit and 30 days post last dose of study drug | after each cohort is enrolled at baseline until the maximum tolerated dose is established | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Myelofibrosis,, PMF,, PPV-MF,, PET-MF,, Primary Myelofibrosis,, Post-polycythemia vera myelofibrosis,, Post-essential thrombocythemia myelofibrosis