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

Myelofibrosis Clinical Trial

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)

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT01730248
• Other study ID #: CINC424A2104
• Status: Terminated
• Phase: Phase 1
• Start date: December 18, 2012
• Est. completion date: September 28, 2017

Study information

• Verified date: March 2019
• Source: Novartis
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 63
• Est. completion date: September 28, 2017
• Est. primary completion date: September 28, 2017
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Myelofibrosis
• Primary Myelofibrosis

Intervention

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

Locations

Country	Name	City	State
Australia	Novartis Investigative Site	Herston	Queensland
Australia	Novartis Investigative Site	Melbourne	Victoria
Austria	Novartis Investigative Site	Vienna
France	Novartis Investigative Site	Paris
Germany	Novartis Investigative Site	Berlin
Germany	Novartis Investigative Site	Rostock
Israel	Novartis Investigative Site	Jerusalem
Israel	Novartis Investigative Site	Ramat Gan
Italy	Novartis Investigative Site	Firenze	FI
Italy	Novartis Investigative Site	Varese	VA
Singapore	Novartis Investigative Site	Singapore
Spain	Novartis Investigative Site	Madrid
United Kingdom	Novartis Investigative Site	Edgbaston	Birmingham
United Kingdom	Novartis Investigative Site	London
United Kingdom	Novartis Investigative Site	London

Sponsors (2)

Lead Sponsor	Collaborator
Novartis Pharmaceuticals	Incyte Corporation

Countries where clinical trial is conducted

Australia,  Austria,  France,  Germany,  Israel,  Italy,  Singapore,  Spain,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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

External Links

•   Results for INC424A2104 can be found on the Novartis Clinical Trial Results Website