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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/ct2/show/NCT01730248




Registration number
NCT01730248
Ethics application status
Date submitted
12/11/2012
Date registered
21/11/2012
Date last updated
19/12/2020

Titles & IDs
Public 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
Scientific 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)
Secondary ID [1] 0 0
CINC424A2104
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Myelofibrosis 0 0
Condition category
Condition code
Musculoskeletal 0 0 0 0
Other muscular and skeletal disorders
Human Genetics and Inherited Disorders 0 0 0 0
Other human genetics and inherited disorders
Cancer 0 0 0 0
Leukaemia - Chronic leukaemia

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - INC424
Treatment: Drugs - BKM120

Experimental: JAK Inhibitor Naive - 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

Experimental: Prior JAK Inhibitor - 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


Treatment: Drugs: INC424
5 mg tablets administered orally twice daily

Treatment: Drugs: BKM120
10 mg and 50 mg hard gelatin capsules administered orally once daily
Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Incidence of dose limiting toxicities
Timepoint [1] 0 0
baseline, when the maximum tolerated dose is established.
Secondary outcome [1] 0 0
Frequency of adverse events
Timepoint [1] 0 0
after each cohort is enrolled at baseline until the maximum tolerated dose is established
Secondary outcome [2] 0 0
Frequency of serious adverse events
Timepoint [2] 0 0
after each cohort is enrolled at baseline until the maximum tolerated dose is established
Secondary outcome [3] 0 0
Abnormalities in vital signs
Timepoint [3] 0 0
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 outcome [4] 0 0
Laboratory test values including Imaging (electrocardiograms (ECGs), abdominal MRI/CT, ECHO/MUGA
Timepoint [4] 0 0
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 outcome [5] 0 0
Maximum plasma concentration (Cmax)
Timepoint [5] 0 0
pre-dose, 0.5, 1, 1.5, 2, 4, 6, 8 hours on days 1, 2, and 8
Secondary outcome [6] 0 0
Maximum plasma concentration time (Tmax)
Timepoint [6] 0 0
pre-dose, 0.5, 1, 1.5, 2, 4, 6, 8 hours on days 1, 2, and 8
Secondary outcome [7] 0 0
Area under the plasma concentration time curve (AUC)
Timepoint [7] 0 0
pre-dose, 0.5, 1, 1.5, 2, 4, 6, 8 hours on days 1, 2, and 8
Secondary outcome [8] 0 0
Maximum plasma concentration (Cmax)
Timepoint [8] 0 0
pre-dose, 0.5, 1, 1.5, 2, 4, 6, 8, 24 hours on days 2 and 8
Secondary outcome [9] 0 0
Maximum plasma concentration time (Tmax)
Timepoint [9] 0 0
pre-dose, 0.5, 1, 1.5, 2, 4, 6, 8, 24 hours on days 2 and 8
Secondary outcome [10] 0 0
Area under the plasma concentration time curve (AUC)
Timepoint [10] 0 0
pre-dose, 0.5, 1, 1.5, 2, 4, 6, 8, 24 hours on days 2 and 8
Secondary outcome [11] 0 0
Duration of adverse events
Timepoint [11] 0 0
after each cohort is enrolled at baseline until the maximum tolerated dose is established
Secondary outcome [12] 0 0
Severity of adverse events
Timepoint [12] 0 0
after each cohort is enrolled at baseline until the maximum tolerated dose is established
Secondary outcome [13] 0 0
Severity of serious adverse events
Timepoint [13] 0 0
after each cohort is enrolled at baseline until the maximum tolerated dose is established
Secondary outcome [14] 0 0
Duration of serious adverse events
Timepoint [14] 0 0
after each cohort is enrolled at baseline until the maximum tolerated dose is established

Eligibility
Key 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
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key 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

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 1
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Terminated
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
18/12/2012
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
28/09/2017
Sample size
Target
Accrual to date
Final
63
Recruitment in Australia
Recruitment state(s)
QLD,VIC
Recruitment hospital [1] 0 0
Novartis Investigative Site - Herston
Recruitment hospital [2] 0 0
Novartis Investigative Site - Melbourne
Recruitment postcode(s) [1] 0 0
4029 - Herston
Recruitment postcode(s) [2] 0 0
3000 - Melbourne
Recruitment outside Australia
Country [1] 0 0
Austria
State/province [1] 0 0
Vienna
Country [2] 0 0
France
State/province [2] 0 0
Paris
Country [3] 0 0
Germany
State/province [3] 0 0
Berlin
Country [4] 0 0
Germany
State/province [4] 0 0
Rostock
Country [5] 0 0
Israel
State/province [5] 0 0
Jerusalem
Country [6] 0 0
Israel
State/province [6] 0 0
Ramat Gan
Country [7] 0 0
Italy
State/province [7] 0 0
FI
Country [8] 0 0
Italy
State/province [8] 0 0
VA
Country [9] 0 0
Singapore
State/province [9] 0 0
Singapore
Country [10] 0 0
Spain
State/province [10] 0 0
Madrid
Country [11] 0 0
United Kingdom
State/province [11] 0 0
Birmingham
Country [12] 0 0
United Kingdom
State/province [12] 0 0
London

Funding & Sponsors
Primary sponsor type
Commercial sector/Industry
Name
Novartis Pharmaceuticals
Address
Country
Other collaborator category [1] 0 0
Commercial sector/Industry
Name [1] 0 0
Incyte Corporation
Address [1] 0 0
Country [1] 0 0

Ethics approval
Ethics application status

Summary
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.
Trial website
https://clinicaltrials.gov/ct2/show/NCT01730248
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
Novartis Pharmaceuticals
Address 0 0
Novartis Pharmaceuticals
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for scientific queries



Summary Results

For IPD and results data, please see https://clinicaltrials.gov/ct2/show/NCT01730248