Clinical trial NCT01730248: 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
Overall status: TERMINATED
Phase: PHASE1
Conditions: Myelofibrosis
Keywords: Myelofibrosis,
PMF,
PPV-MF,
PET-MF,
Primary Myelofibrosis,
Post-polycythemia vera myelofibrosis,
Post-essential thrombocythemia myelofibrosis
Lead sponsor: Novartis
Sponsor class: INDUSTRY
Collaborators: name: Incyte Corporation
First posted: 2012-11-21
Enrollment: 63
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


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

Primary outcomes:
measure: Incidence of dose limiting toxicities
timeFrame: baseline, when the maximum tolerated dose is established.
Secondary outcomes:
measure: Frequency of adverse events
timeFrame: after each cohort is enrolled at baseline until the maximum tolerated dose is established
measure: Frequency of serious adverse events
timeFrame: after each cohort is enrolled at baseline until the maximum tolerated dose is established
measure: Abnormalities in vital signs
timeFrame: 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
measure: Laboratory test values including Imaging (electrocardiograms (ECGs), abdominal MRI/CT, ECHO/MUGA
timeFrame: 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
measure: Maximum plasma concentration (Cmax)
timeFrame: pre-dose, 0.5, 1, 1.5, 2, 4, 6, 8 hours on days 1, 2, and 8
measure: Maximum plasma concentration time (Tmax)
timeFrame: pre-dose, 0.5, 1, 1.5, 2, 4, 6, 8 hours on days 1, 2, and 8
measure: Area under the plasma concentration time curve (AUC)
timeFrame: pre-dose, 0.5, 1, 1.5, 2, 4, 6, 8 hours on days 1, 2, and 8
measure: Maximum plasma concentration (Cmax)
timeFrame: pre-dose, 0.5, 1, 1.5, 2, 4, 6, 8, 24 hours on days 2 and 8
measure: Maximum plasma concentration time (Tmax)
timeFrame: pre-dose, 0.5, 1, 1.5, 2, 4, 6, 8, 24 hours on days 2 and 8
measure: Area under the plasma concentration time curve (AUC)
timeFrame: pre-dose, 0.5, 1, 1.5, 2, 4, 6, 8, 24 hours on days 2 and 8
measure: Duration of adverse events
timeFrame: after each cohort is enrolled at baseline until the maximum tolerated dose is established
measure: Severity of adverse events
timeFrame: after each cohort is enrolled at baseline until the maximum tolerated dose is established
measure: Severity of serious adverse events
timeFrame: after each cohort is enrolled at baseline until the maximum tolerated dose is established
measure: Duration of serious adverse events
timeFrame: after each cohort is enrolled at baseline until the maximum tolerated dose is established
Other outcomes:
Locations:
city: Herston
country: Australia
facility: Novartis Investigative Site
state: Queensland
city: Melbourne
country: Australia
facility: Novartis Investigative Site
state: Victoria
city: Vienna
country: Austria
facility: Novartis Investigative Site
city: Paris
country: France
facility: Novartis Investigative Site
city: Berlin
country: Germany
facility: Novartis Investigative Site
city: Rostock
country: Germany
facility: Novartis Investigative Site
city: Jerusalem
country: Israel
facility: Novartis Investigative Site
city: Ramat Gan
country: Israel
facility: Novartis Investigative Site
city: Firenze
country: Italy
facility: Novartis Investigative Site
state: FI
city: Varese
country: Italy
facility: Novartis Investigative Site
state: VA
city: Singapore
country: Singapore
facility: Novartis Investigative Site
city: Madrid
country: Spain
facility: Novartis Investigative Site
city: Edgbaston
country: United Kingdom
facility: Novartis Investigative Site
state: Birmingham
city: London
country: United Kingdom
facility: Novartis Investigative Site
city: London
country: United Kingdom
facility: Novartis Investigative Site
Study officials:
affiliation: Novartis Pharmaceuticals
name: Novartis Pharmaceuticals
role: STUDY_DIRECTOR
References: