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 - Full Text View

Purpose

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.

Condition	Intervention	Phase
Myelofibrosis	Drug: INC424 Drug: BKM120	Phase 1

Study Type:	Interventional
Study Design:	Allocation: Non-Randomized Endpoint Classification: Safety Study Intervention Model: Parallel Assignment Masking: Open Label Primary Purpose: Treatment
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)

Resource links provided by NLM:

Genetics Home Reference related topics: essential thrombocythemia polycythemia vera primary myelofibrosis

U.S. FDA Resources

Further study details as provided by Novartis:

Primary Outcome Measures:

Incidence of dose limiting toxicities [ Time Frame: baseline, when the maximum tolerated dose is established. ] [ Designated as safety issue: Yes ]
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 Outcome Measures:

Frequency of adverse events [ Time Frame: after each cohort is enrolled at baseline until the maximum tolerated dose is established ] [ Designated as safety issue: Yes ]
Adverse Events are monitored at each study visit and 30 days post last dose of study drug
Frequency of serious adverse events [ Time Frame: after each cohort is enrolled at baseline until the maximum tolerated dose is established ] [ Designated as safety issue: Yes ]
Serious Adverse events monitored at each study visit and 30 days post last dose of study drug
Abnormalities in vital signs [ Time Frame: baseline, days 2, 8, 15, 22 of cycle 1, day 1 of every additional cycle ] [ Designated as safety issue: Yes ]
cycle = 28 days
Laboratory test values including Imaging (electrocardiograms (ECGs), abdominal MRI/CT, ECHO/MUGA [ Time Frame: Days 2, 5, 8, 11, 18, 22 and then weekly for every other cycle after ] [ Designated as safety issue: Yes ]
ECGs are performed baseline, days 2, 8, 15, 22 of cycle 1 then day 1 of every additional cycle. Magnetic resonance imaging (MRI) or Cat Scan (CT) and Echocardiography (ECHO) or Multiple Gated Acquisition (MUGA) is performed at baseline and then every 3 cycles until the end of treatment. . Hematology is performed at baseline and days 2, 5, 8, 11, 15, 18, 22 and then weekly in subsequent cycles.
Maximum plasma concentration (Cmax) [ Time Frame: pre-dose, 0.5, 1, 1.5, 2, 4, 6, 8 hours on days 1, 2, and 8 ] [ Designated as safety issue: No ]
To characterize the pharmacokinetics (PK) of INC424 alone or in combination with BKM120
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 ] [ Designated as safety issue: No ]
To characterize the pharmacokinetics (PK) of INC424 alone or in combination with BKM120
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 ] [ Designated as safety issue: No ]
To characterize the pharmacokinetics (PK) of INC424 alone or in combination with BKM120
Maximum plasma concentration (Cmax) [ Time Frame: pre-dose, 0.5, 1, 1.5, 2, 4, 6, 8, 24 hours on days 2 and 8 ] [ Designated as safety issue: No ]
To characterize the pharmacokinetics (PK) of BKM120 alone or in combination with INC424
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 ] [ Designated as safety issue: No ]
To characterize the pharmacokinetics (PK) of BKM120 alone or in combination with INC424
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 ] [ Designated as safety issue: No ]
To characterize the pharmacokinetics (PK) of BKM120 alone or in combination with INC424
Duration of adverse events [ Time Frame: after each cohort is enrolled at baseline until the maximum tolerated dose is established ] [ Designated as safety issue: Yes ]
Adverse Events are monitored at each study visit and 30 days post last dose of study drug
Severity of adverse events [ Time Frame: after each cohort is enrolled at baseline until the maximum tolerated dose is established ] [ Designated as safety issue: Yes ]
Adverse Events are monitored at each study visit and 30 days post last dose of study drug
Duration of serious adverse events [ Time Frame: after each cohort is enrolled at baseline until the maximum tolerated dose is established ] [ Designated as safety issue: Yes ]
Serious Adverse events monitored at each study visit and 30 days post last dose of study drug
Severity of serious adverse events [ Time Frame: after each cohort is enrolled at baseline until the maximum tolerated dose is established ] [ Designated as safety issue: Yes ]
Serious Adverse events monitored at each study visit and 30 days post last dose of study drug

Estimated Enrollment:	62
Study Start Date:	December 2012
Estimated Study Completion Date:	June 2015
Estimated Primary Completion Date:	June 2015 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Experimental: JAK Inhibitor Naive Two treatment periods applicable to all patients; Treatment Period (6 cycles / 28 days per cycle) and Extension Period (6 cycles of 28 days) 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 5 mg tablets administered orally twice daily Drug: BKM120 10 mg and 50 mg hard gelatin capsules administered orally once daily
Experimental: Prior JAK Inhibitor Two treatment periods applicable to all patients; Treatment Period (6 cycles / 28 days per cycle) and Extension Period (6 cycles of 28 days) following the treatment period dependent on patient continued eligibility. Two Study Phases: Dose Escalation Phase to determine MTD / RPIID & an Expansion Phase	Drug: INC424 5 mg tablets administered orally twice daily Drug: BKM120 10 mg and 50 mg hard gelatin capsules administered orally once daily

Eligibility

Ages Eligible for Study:	18 Years and older
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

Criteria

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

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT01730248

Contacts

Contact: Novartis Pharmaceuticals	+41613241111
Contact: Novartis Pharmaceuticals

Locations

Australia, Queensland
Novartis Investigative Site	Not yet recruiting
Herston, Queensland, Australia, 4029
Australia, Victoria
Novartis Investigative Site	Not yet recruiting
Melbourne, Victoria, Australia, 3002
Australia
Novartis Investigative Site	Not yet recruiting
Camperdown, Australia, NSW 2050
Austria
Novartis Investigative Site	Not yet recruiting
Vienna, Austria, A-1090
France
Novartis Investigative Site	Not yet recruiting
Paris, France, 75010
Germany
Novartis Investigative Site	Recruiting
Berlin, Germany, 13353
Israel
Novartis Investigative Site	Not yet recruiting
Jerusalem, Israel, 91120
Novartis Investigative Site	Not yet recruiting
Ramat Gan, Israel, 52621
Italy
Novartis Investigative Site	Recruiting
Firenze, FI, Italy, 50134
Novartis Investigative Site	Not yet recruiting
Varese, VA, Italy, 21100
Singapore
Novartis Investigative Site	Recruiting
Singapore, Singapore, 169608
Spain
Novartis Investigative Site	Recruiting
Madrid, Spain, 28041
United Kingdom
Novartis Investigative Site	Not yet recruiting
Edgbaston, Birmingham, United Kingdom, B15 2WB
Novartis Investigative Site	Not yet recruiting
London, United Kingdom, SE1 9RT
Novartis Investigative Site	Not yet recruiting
Oxford, United Kingdom, OX3 7LJ

Sponsors and Collaborators

Novartis Pharmaceuticals

Incyte Corporation

Investigators

Study Director:

Novartis Pharmaceuticals

More Information

No publications provided

Responsible Party:	Novartis ( Novartis Pharmaceuticals )
ClinicalTrials.gov Identifier:	NCT01730248 History of Changes
Other Study ID Numbers:	CINC424A2104
Study First Received:	November 12, 2012
Last Updated:	April 1, 2013
Health Authority:	Australia: Department of Health and Ageing Therapeutic Goods Administration Austria: Ethikkommission France: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis) Germany: Federal Institute for Drugs and Medical Devices Israel: Ministry of Health Italy: The Italian Medicines Agency Singapore: Health Sciences Authority Spain: Agencia Española de Medicamentos y Productos Sanitarios United Kingdom: Medicines and Healthcare Products Regulatory Agency

Keywords provided by Novartis:

Myelofibrosis,
PMF,
PPV-MF,
PET-MF,

Primary Myelofibrosis,
Post-polycythemia vera myelofibrosis,
Post-essential thrombocythemia myelofibrosis

Additional relevant MeSH terms:

Primary Myelofibrosis
Thrombocythemia, Essential
Thrombocytosis
Myeloproliferative Disorders
Bone Marrow Diseases

Hematologic Diseases
Blood Coagulation Disorders
Blood Platelet Disorders
Hemorrhagic Disorders

ClinicalTrials.gov processed this record on May 16, 2013