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

This study is currently recruiting participants. (see Contacts and Locations)
Verified May 2014 by Novartis
Sponsor:
Collaborator:
Incyte Corporation
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )
ClinicalTrials.gov Identifier:
NCT01730248
First received: November 12, 2012
Last updated: May 21, 2014
Last verified: May 2014
  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:


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 for the first 12 cycles, then every 12 weeks thereafter

  • Laboratory test values including Imaging (electrocardiograms (ECGs), abdominal MRI/CT, ECHO/MUGA [ Time Frame: Days 2, 5, 8, 11, 18, 22 of cycle 1, weekly in cycle 2, then on every cycle visit thereafter ( every 28 days until cycle 12, then every 12 weeks thereafter) ] [ 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) performed at baseline, cycle 4, day 1, cycle 7 day 1, cycle 12 day 28, then every 24 weeks thereafter, and end of treatment. 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. Hematology is performed at baseline and days 2, 5, 8, 11, 15, 18, 22 of cycle 1, weekly in cycle 2, then on every cycle visit thereafter (every 28 days until cycle 12, then every 12 weeks thereafter).

  • 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: January 2016
Estimated Primary Completion Date: January 2016 (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, then cycles 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
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, then cycles 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
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
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

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 Recruiting
Herston, Queensland, Australia, 4029
Australia, Victoria
Novartis Investigative Site Recruiting
Melbourne, Victoria, Australia, 3002
Australia
Novartis Investigative Site Withdrawn
Camperdown, Australia, NSW 2050
Austria
Novartis Investigative Site Recruiting
Vienna, Austria, A-1090
France
Novartis Investigative Site Recruiting
Paris, France, 75010
Germany
Novartis Investigative Site Recruiting
Berlin, Germany, 13353
Novartis Investigative Site Recruiting
Rostock, Germany, 18057
Israel
Novartis Investigative Site Recruiting
Jerusalem, Israel, 91120
Novartis Investigative Site Recruiting
Ramat Gan, Israel, 52621
Italy
Novartis Investigative Site Recruiting
Firenze, FI, Italy, 50134
Novartis Investigative Site 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 Recruiting
Edgbaston, Birmingham, United Kingdom, B15 2WB
Novartis Investigative Site Recruiting
London, United Kingdom, SE1 9RT
Novartis Investigative Site Recruiting
London, United Kingdom, NW1 2BU
Novartis Investigative Site Withdrawn
Oxford, United Kingdom, OX3 7LJ
Sponsors and Collaborators
Novartis Pharmaceuticals
Incyte Corporation
Investigators
Study Director: Novartis Pharmaceuticals 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: May 21, 2014
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 July 23, 2014