Overview

This trial is active, not recruiting.

Condition myelofibrosis
Treatments inc424, bkm120
Phase phase 1
Target PI3K
Sponsor Novartis Pharmaceuticals
Collaborator Incyte Corporation
Start date December 2012
End date December 2018
Trial size 63 participants
Trial identifier NCT01730248, CINC424A2104

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.

United States No locations recruiting
Other Countries No locations recruiting

Study Design

Allocation non-randomized
Endpoint classification safety study
Intervention model parallel assignment
Masking open label
Primary purpose treatment
Arm
(Experimental)
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
inc424
5 mg tablets administered orally twice daily
bkm120
10 mg and 50 mg hard gelatin capsules administered orally once daily
(Experimental)
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
inc424
5 mg tablets administered orally twice daily
bkm120
10 mg and 50 mg hard gelatin capsules administered orally once daily

Primary Outcomes

Measure
Incidence of dose limiting toxicities
time frame: baseline, when the maximum tolerated dose is established.

Secondary Outcomes

Measure
Frequency of adverse events
time frame: after each cohort is enrolled at baseline until the maximum tolerated dose is established
Frequency of serious adverse events
time frame: after each cohort is enrolled at baseline until the maximum tolerated dose is established
Abnormalities in vital signs
time frame: 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
time frame: 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)
time frame: pre-dose, 0.5, 1, 1.5, 2, 4, 6, 8 hours on days 1, 2, and 8
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
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
Maximum plasma concentration (Cmax)
time frame: pre-dose, 0.5, 1, 1.5, 2, 4, 6, 8, 24 hours on days 2 and 8
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
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
Duration of adverse events
time frame: after each cohort is enrolled at baseline until the maximum tolerated dose is established
Severity of adverse events
time frame: after each cohort is enrolled at baseline until the maximum tolerated dose is established
Severity of serious adverse events
time frame: after each cohort is enrolled at baseline until the maximum tolerated dose is established
Duration of serious adverse events
time frame: after each cohort is enrolled at baseline until the maximum tolerated dose is established

Eligibility Criteria

Male or female participants at least 18 years old.

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

Additional Information

Official title 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)
Trial information was received from ClinicalTrials.gov and was last updated in August 2016.
Information provided to ClinicalTrials.gov by Novartis.