Myelofibrosis
Conditions
Keywords
Myelofibrosis,, PMF,, PPV-MF,, PET-MF,, Primary Myelofibrosis,, Post-polycythemia vera myelofibrosis,, Post-essential thrombocythemia myelofibrosis
Brief summary
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.
Interventions
DRUGINC424
5 mg tablets administered orally twice daily
DRUGBKM120
10 mg and 50 mg hard gelatin capsules administered orally once daily
Sponsors
Incyte Corporation
Novartis Pharmaceuticals
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of dose limiting toxicities | baseline, when the maximum tolerated dose is established. | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Frequency of serious adverse events | after each cohort is enrolled at baseline until the maximum tolerated dose is established | Serious Adverse events monitored at each study visit and 30 days post last dose of study drug |
| Abnormalities in vital signs | 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 | cycle = 28 days |
| Laboratory test values including Imaging (electrocardiograms (ECGs), abdominal MRI/CT, ECHO/MUGA | 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 | 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. |
| Maximum plasma concentration (Cmax) | pre-dose, 0.5, 1, 1.5, 2, 4, 6, 8 hours on days 1, 2, and 8 | To characterize the pharmacokinetics (PK) of INC424 alone or in combination with BKM120 |
| Maximum plasma concentration time (Tmax) | pre-dose, 0.5, 1, 1.5, 2, 4, 6, 8 hours on days 1, 2, and 8 | To characterize the pharmacokinetics (PK) of INC424 alone or in combination with BKM120 |
| Frequency of adverse events | after each cohort is enrolled at baseline until the maximum tolerated dose is established | Adverse Events are monitored at each study visit and 30 days post last dose of study drug |
| Duration of adverse events | after each cohort is enrolled at baseline until the maximum tolerated dose is established | Adverse Events are monitored at each study visit and 30 days post last dose of study drug |
| Severity of adverse events | after each cohort is enrolled at baseline until the maximum tolerated dose is established | Adverse Events are monitored at each study visit and 30 days post last dose of study drug |
| Severity of serious adverse events | after each cohort is enrolled at baseline until the maximum tolerated dose is established | Serious Adverse events monitored at each study visit and 30 days post last dose of study drug |
| Duration of serious adverse events | after each cohort is enrolled at baseline until the maximum tolerated dose is established | Adverse Events are monitored at each study visit and 30 days post last dose of study drug |
| Area under the plasma concentration time curve (AUC) | pre-dose, 0.5, 1, 1.5, 2, 4, 6, 8 hours on days 1, 2, and 8 | To characterize the pharmacokinetics (PK) of INC424 alone or in combination with BKM120 |
Countries
Australia, Austria, France, Germany, Israel, Italy, Singapore, Spain, United Kingdom
Outcome results
None listed