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)
Overview
- Phase
- Phase 1
- Status
- Terminated
- Sponsor
- Novartis Pharmaceuticals
- Enrollment
- 63
- Locations
- 1
- Primary Endpoint
- Incidence of dose limiting toxicities
Overview
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.
Study Design
- Study Type
- Interventional
- Allocation
- Non Randomized
- Intervention Model
- Parallel
- Primary Purpose
- Treatment
- Masking
- None
Eligibility Criteria
- Ages
- 18 Years to — (Adult, Older Adult)
- Sex
- All
- Accepts 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
Arms & Interventions
JAK Inhibitor Naive
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
Intervention: INC424 (Drug)
JAK Inhibitor Naive
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
Intervention: BKM120 (Drug)
Prior JAK Inhibitor
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
Intervention: INC424 (Drug)
Prior JAK Inhibitor
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
Intervention: BKM120 (Drug)
Outcomes
Primary Outcomes
Incidence of dose limiting toxicities
Time Frame: 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 Outcomes
- Severity of serious adverse events(after each cohort is enrolled at baseline until the maximum tolerated dose is established)
- 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)
- Maximum plasma concentration time (Tmax)(pre-dose, 0.5, 1, 1.5, 2, 4, 6, 8, 24 hours on days 2 and 8)
- Duration of serious adverse events(after each cohort is enrolled at baseline until the maximum tolerated dose is established)
- Area under the plasma concentration time curve (AUC)(pre-dose, 0.5, 1, 1.5, 2, 4, 6, 8, 24 hours on days 2 and 8)
- Maximum plasma concentration (Cmax)(pre-dose, 0.5, 1, 1.5, 2, 4, 6, 8, 24 hours on days 2 and 8)
- Frequency of adverse events(after each cohort is enrolled at baseline until the maximum tolerated dose is established)
- Frequency of serious adverse events(after each cohort is enrolled at baseline until the maximum tolerated dose is established)
- 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)
- Duration of adverse events(after each cohort is enrolled at baseline until the maximum tolerated dose is established)
- Severity of adverse events(after each cohort is enrolled at baseline until the maximum tolerated dose is established)