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

Sponsor

Novartis Pharmaceuticals (Industry)

Overall Status

Terminated

CT.gov ID

NCT01730248

Collaborator

Incyte Corporation (Industry)

Enrollment

Locations

Arms

57.3

Actual Duration (Months)

4.2

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

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.

Condition or Disease	Intervention/Treatment	Phase
Myelofibrosis	Drug: INC424 Drug: BKM120	Phase 1

Study Design

Study Type:

Interventional

Actual Enrollment :

63 participants

Allocation:

Non-Randomized

Intervention Model:

Parallel Assignment

Masking:

None (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)

Actual Study Start Date :

Dec 18, 2012

Actual Primary Completion Date :

Sep 28, 2017

Actual Study Completion Date :

Sep 28, 2017

Arms and Interventions

Arm	Intervention/Treatment
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	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 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	Drug: INC424 5 mg tablets administered orally twice daily Drug: BKM120 10 mg and 50 mg hard gelatin capsules administered orally once daily

Arm

Intervention/Treatment

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

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 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

Drug: INC424

5 mg tablets administered orally twice daily

Drug: BKM120

10 mg and 50 mg hard gelatin capsules administered orally once daily

Outcome Measures

Primary Outcome Measures

Incidence of dose limiting toxicities [baseline, when the maximum tolerated dose is established.]
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 [after each cohort is enrolled at baseline until the maximum tolerated dose is established]
Adverse Events are monitored at each study visit and 30 days post last dose of study drug
Frequency of serious adverse events [after each cohort is enrolled at baseline until the maximum tolerated dose is established]
Serious Adverse events monitored at each study visit and 30 days post last dose of study drug
Abnormalities in vital signs [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]
cycle = 28 days
Laboratory test values including Imaging (electrocardiograms (ECGs), abdominal MRI/CT, ECHO/MUGA [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]
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) [pre-dose, 0.5, 1, 1.5, 2, 4, 6, 8 hours on days 1, 2, and 8]
To characterize the pharmacokinetics (PK) of INC424 alone or in combination with BKM120
Maximum plasma concentration time (Tmax) [pre-dose, 0.5, 1, 1.5, 2, 4, 6, 8 hours on days 1, 2, and 8]
To characterize the pharmacokinetics (PK) of INC424 alone or in combination with BKM120
Area under the plasma concentration time curve (AUC) [pre-dose, 0.5, 1, 1.5, 2, 4, 6, 8 hours on days 1, 2, and 8]
To characterize the pharmacokinetics (PK) of INC424 alone or in combination with BKM120
Maximum plasma concentration (Cmax) [pre-dose, 0.5, 1, 1.5, 2, 4, 6, 8, 24 hours on days 2 and 8]
To characterize the pharmacokinetics (PK) of BKM120 alone or in combination with INC424
Maximum plasma concentration time (Tmax) [pre-dose, 0.5, 1, 1.5, 2, 4, 6, 8, 24 hours on days 2 and 8]
To characterize the pharmacokinetics (PK) of BKM120 alone or in combination with INC424
Area under the plasma concentration time curve (AUC) [pre-dose, 0.5, 1, 1.5, 2, 4, 6, 8, 24 hours on days 2 and 8]
To characterize the pharmacokinetics (PK) of BKM120 alone or in combination with INC424
Duration of adverse events [after each cohort is enrolled at baseline until the maximum tolerated dose is established]
Adverse Events are monitored at each study visit and 30 days post last dose of study drug
Severity of adverse events [after each cohort is enrolled at baseline until the maximum tolerated dose is established]
Adverse Events are monitored at each study visit and 30 days post last dose of study drug
Severity of serious adverse events [after each cohort is enrolled at baseline until the maximum tolerated dose is established]
Serious Adverse events monitored at each study visit and 30 days post last dose of study drug
Duration of serious adverse events [after each cohort is enrolled at baseline until the maximum tolerated dose is established]
Adverse Events are monitored at each study visit and 30 days post last dose of study drug

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

Locations

	Site	City	State	Country	Postal Code
1	Novartis Investigative Site	Herston	Queensland	Australia	4029
2	Novartis Investigative Site	Melbourne	Victoria	Australia	3000
3	Novartis Investigative Site	Vienna		Austria	A-1090
4	Novartis Investigative Site	Paris		France	75010
5	Novartis Investigative Site	Berlin		Germany	13353
6	Novartis Investigative Site	Rostock		Germany	18057
7	Novartis Investigative Site	Jerusalem		Israel	91120
8	Novartis Investigative Site	Ramat Gan		Israel	5265601
9	Novartis Investigative Site	Firenze	FI	Italy	50134
10	Novartis Investigative Site	Varese	VA	Italy	21100
11	Novartis Investigative Site	Singapore		Singapore	169608
12	Novartis Investigative Site	Madrid		Spain	28041
13	Novartis Investigative Site	Edgbaston	Birmingham	United Kingdom	B15 2WB
14	Novartis Investigative Site	London		United Kingdom	NW1 2BU
15	Novartis Investigative Site	London		United Kingdom	SE1 9RT