Back to resultsA Study to Find the Maximum Tolerated Dose of the Experimental Combination of the Drugs INC424 and BKM120 in Patients With Primary or Secondary Myelofibrosis
Primary Purpose
Myelofibrosis
Status
Terminated
Phase
Phase 1
Locations
International
Study Type
Interventional
Intervention
INC424
BKM120
Sponsored by
About this trial
This is an interventional treatment trial for Myelofibrosis focused on measuring Myelofibrosis,, PMF,, PPV-MF,, PET-MF,, Primary Myelofibrosis,, Post-polycythemia vera myelofibrosis,, Post-essential thrombocythemia myelofibrosis
Eligibility 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
Sites / Locations
- Novartis Investigative Site
- Novartis Investigative Site
- Novartis Investigative Site
- Novartis Investigative Site
- Novartis Investigative Site
- Novartis Investigative Site
- Novartis Investigative Site
- Novartis Investigative Site
- Novartis Investigative Site
- Novartis Investigative Site
- Novartis Investigative Site
- Novartis Investigative Site
- Novartis Investigative Site
- Novartis Investigative Site
- Novartis Investigative Site
Arms of the Study
Arm 1
Arm 2
Arm Type
Experimental
Experimental
Arm Label
JAK Inhibitor Naive
Prior JAK Inhibitor
Arm Description
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
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
Outcomes
Primary Outcome Measures
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.
Secondary Outcome Measures
Frequency of adverse events
Adverse Events are monitored at each study visit and 30 days post last dose of study drug
Frequency of serious adverse events
Serious Adverse events monitored at each study visit and 30 days post last dose of study drug
Abnormalities in vital signs
cycle = 28 days
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.
Maximum plasma concentration (Cmax)
To characterize the pharmacokinetics (PK) of INC424 alone or in combination with BKM120
Maximum plasma concentration time (Tmax)
To characterize the pharmacokinetics (PK) of INC424 alone or in combination with BKM120
Area under the plasma concentration time curve (AUC)
To characterize the pharmacokinetics (PK) of INC424 alone or in combination with BKM120
Maximum plasma concentration (Cmax)
To characterize the pharmacokinetics (PK) of BKM120 alone or in combination with INC424
Maximum plasma concentration time (Tmax)
To characterize the pharmacokinetics (PK) of BKM120 alone or in combination with INC424
Area under the plasma concentration time curve (AUC)
To characterize the pharmacokinetics (PK) of BKM120 alone or in combination with INC424
Duration of adverse events
Adverse Events are monitored at each study visit and 30 days post last dose of study drug
Severity of adverse events
Adverse Events are monitored at each study visit and 30 days post last dose of study drug
Severity of serious adverse events
Serious Adverse events monitored at each study visit and 30 days post last dose of study drug
Duration of serious adverse events
Adverse Events are monitored at each study visit and 30 days post last dose of study drug
Full Information
NCT ID
NCT01730248
First Posted
November 12, 2012
Last Updated
December 16, 2020
Sponsor
Novartis Pharmaceuticals
Collaborators
Incyte Corporation
1. Study Identification
Unique Protocol Identification Number
NCT01730248
Brief Title
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
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)
Study Type
Interventional
2. Study Status
Record Verification Date
March 2019
Overall Recruitment Status
Terminated
Why Stopped
Decision by Sponsor to to terminate the study early.
Study Start Date
December 18, 2012 (Actual)
Primary Completion Date
September 28, 2017 (Actual)
Study Completion Date
September 28, 2017 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Novartis Pharmaceuticals
Collaborators
Incyte Corporation
4. Oversight
Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No
5. Study Description
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Myelofibrosis
Keywords
Myelofibrosis,, PMF,, PPV-MF,, PET-MF,, Primary Myelofibrosis,, Post-polycythemia vera myelofibrosis,, Post-essential thrombocythemia myelofibrosis
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
63 (Actual)
8. Arms, Groups, and Interventions
Arm Title
JAK Inhibitor Naive
Arm Type
Experimental
Arm Description
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
Arm Title
Prior JAK Inhibitor
Arm Type
Experimental
Arm Description
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 Type
Drug
Intervention Name(s)
INC424
Intervention Description
5 mg tablets administered orally twice daily
Intervention Type
Drug
Intervention Name(s)
BKM120
Intervention Description
10 mg and 50 mg hard gelatin capsules administered orally once daily
Primary Outcome Measure Information:
Title
Incidence of dose limiting toxicities
Description
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.
Time Frame
baseline, when the maximum tolerated dose is established.
Secondary Outcome Measure Information:
Title
Frequency of adverse events
Description
Adverse Events are monitored at each study visit and 30 days post last dose of study drug
Time Frame
after each cohort is enrolled at baseline until the maximum tolerated dose is established
Title
Frequency of serious adverse events
Description
Serious Adverse events monitored at each study visit and 30 days post last dose of study drug
Time Frame
after each cohort is enrolled at baseline until the maximum tolerated dose is established
Title
Abnormalities in vital signs
Description
cycle = 28 days
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
Title
Laboratory test values including Imaging (electrocardiograms (ECGs), abdominal MRI/CT, ECHO/MUGA
Description
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.
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
Title
Maximum plasma concentration (Cmax)
Description
To characterize the pharmacokinetics (PK) of INC424 alone or in combination with BKM120
Time Frame
pre-dose, 0.5, 1, 1.5, 2, 4, 6, 8 hours on days 1, 2, and 8
Title
Maximum plasma concentration time (Tmax)
Description
To characterize the pharmacokinetics (PK) of INC424 alone or in combination with BKM120
Time Frame
pre-dose, 0.5, 1, 1.5, 2, 4, 6, 8 hours on days 1, 2, and 8
Title
Area under the plasma concentration time curve (AUC)
Description
To characterize the pharmacokinetics (PK) of INC424 alone or in combination with BKM120
Time Frame
pre-dose, 0.5, 1, 1.5, 2, 4, 6, 8 hours on days 1, 2, and 8
Title
Maximum plasma concentration (Cmax)
Description
To characterize the pharmacokinetics (PK) of BKM120 alone or in combination with INC424
Time Frame
pre-dose, 0.5, 1, 1.5, 2, 4, 6, 8, 24 hours on days 2 and 8
Title
Maximum plasma concentration time (Tmax)
Description
To characterize the pharmacokinetics (PK) of BKM120 alone or in combination with INC424
Time Frame
pre-dose, 0.5, 1, 1.5, 2, 4, 6, 8, 24 hours on days 2 and 8
Title
Area under the plasma concentration time curve (AUC)
Description
To characterize the pharmacokinetics (PK) of BKM120 alone or in combination with INC424
Time Frame
pre-dose, 0.5, 1, 1.5, 2, 4, 6, 8, 24 hours on days 2 and 8
Title
Duration of adverse events
Description
Adverse Events are monitored at each study visit and 30 days post last dose of study drug
Time Frame
after each cohort is enrolled at baseline until the maximum tolerated dose is established
Title
Severity of adverse events
Description
Adverse Events are monitored at each study visit and 30 days post last dose of study drug
Time Frame
after each cohort is enrolled at baseline until the maximum tolerated dose is established
Title
Severity of serious adverse events
Description
Serious Adverse events monitored at each study visit and 30 days post last dose of study drug
Time Frame
after each cohort is enrolled at baseline until the maximum tolerated dose is established
Title
Duration of serious adverse events
Description
Adverse Events are monitored at each study visit and 30 days post last dose of study drug
Time Frame
after each cohort is enrolled at baseline until the maximum tolerated dose is established
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility 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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Novartis Pharmaceuticals
Organizational Affiliation
Novartis Pharmaceuticals
Official's Role
Study Director
Facility Information:
Facility Name
Novartis Investigative Site
City
Herston
State/Province
Queensland
ZIP/Postal Code
4029
Country
Australia
Facility Name
Novartis Investigative Site
City
Melbourne
State/Province
Victoria
ZIP/Postal Code
3000
Country
Australia
Facility Name
Novartis Investigative Site
City
Vienna
ZIP/Postal Code
A-1090
Country
Austria
Facility Name
Novartis Investigative Site
City
Paris
ZIP/Postal Code
75010
Country
France
Facility Name
Novartis Investigative Site
City
Berlin
ZIP/Postal Code
13353
Country
Germany
Facility Name
Novartis Investigative Site
City
Rostock
ZIP/Postal Code
18057
Country
Germany
Facility Name
Novartis Investigative Site
City
Jerusalem
ZIP/Postal Code
91120
Country
Israel
Facility Name
Novartis Investigative Site
City
Ramat Gan
ZIP/Postal Code
5265601
Country
Israel
Facility Name
Novartis Investigative Site
City
Firenze
State/Province
FI
ZIP/Postal Code
50134
Country
Italy
Facility Name
Novartis Investigative Site
City
Varese
State/Province
VA
ZIP/Postal Code
21100
Country
Italy
Facility Name
Novartis Investigative Site
City
Singapore
ZIP/Postal Code
169608
Country
Singapore
Facility Name
Novartis Investigative Site
City
Madrid
ZIP/Postal Code
28041
Country
Spain
Facility Name
Novartis Investigative Site
City
Edgbaston
State/Province
Birmingham
ZIP/Postal Code
B15 2WB
Country
United Kingdom
Facility Name
Novartis Investigative Site
City
London
ZIP/Postal Code
NW1 2BU
Country
United Kingdom
Facility Name
Novartis Investigative Site
City
London
ZIP/Postal Code
SE1 9RT
Country
United Kingdom
12. IPD Sharing Statement
Plan to Share IPD
No
Links:
URL
https://www.novctrd.com/ctrdweb/trialresult/trialresults/pdf?trialResultId=17230
Description
Results for INC424A2104 can be found on the Novartis Clinical Trial Results Website
Learn more about this trial
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
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