Clinical trial NCT01787552: A Phase Ib/II Dose-finding Study to Assess the Safety and Efficacy of LDE225 + INC424 in Patients With MF
Official title: A Phase Ib/II, Open-label, Multi-center, Dose-finding Study to Assess the Safety and Efficacy of the Oral Combination of LDE225 and INC424 (Ruxolitinib) in Patients With Myelofibrosis
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Primary Myelofibrosis
Thrombocytosis
Essential Thrombocythemia
Polycythemia Vera
Myeloproliferative Disorders
Bone Marrow Diseases
Hematologic Diseases
Blood Coagulation Disorders
Blood Platelet Disorders
Hemorrhagic Disorders
Keywords: Dose escalation
Maximum Tolerated Dose
MTD
Safety Expansion
Safety
Efficacy
Myelofibrosis
Post-polycythemia vera myelofbrosis (Post PV-PMF)
Post essential thrombocythemia myelofibrosis (Post ET-MF)
Primary myelofibrosis (PMF)
Intermediate risk myelofibrosis
High risk myelofibrosis
Combination Treatment
Hedgehog Signaling Pathway
Smoothened inhibitor
JAK inhibitor
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2013-02-08
Enrollment: 50
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: The purpose of this phase Ib/II clinical trial was to: a) evaluate the safety of the co-administration of LDE225 and INC424 in myelofibrosis patients and establish a maximum tolerated dose and/or Recommended Phase II dose of the combination and b) to assess the efficacy of the co-administration of LDE225 and INC424 on spleen volume reduction.

Detailed description: The study is considered to have been completed because the participants completed the study as per study design at the time of trial termination. If participants were already in extension phase until discontinuation criteria were met or alternative setting was available, they were considered as completed. The study was terminated due to one of the compounds being divested.

Eligibility criteria: Inclusion Criteria:

* Diagnosed with PMF per 2008 WHO criteria, post-PV MF or post-ET MF per IWG-MRT criteria.
* Ineligible or unwilling to undergo stem cell transplantion.
* PLT counts \> or = 75X 10\^9/L not reached with the aid of transfusions.
* ECOG performance status ≤ 2.
* Palpable splenomegaly defined as ≥ 5 cm below the left costal margin.
* Intermediate risk level 1 (1 prognostic factor which is not age), Intermediate risk level 2, or high risk.
* Active symptoms of MF as demonstrated by one symptom score of at least 5 (0 to10 point scale) or two symptom scores of at least 3 (0 to 10 point scale) on the MF Symptom Assessment Form (MFSAF).

Exclusion Criteria:

* Previous therapy with JAK or Smoothened inhibitors.
* Patient is currently on medications that interfere with coagulation (including warfarin) or platelet function with the exception of low dose aspirin (up to 100 mg) and LMWH.
* Impairment of GI function or GI disease that may significantly alter the absorption of INC424 or LDE225 (e.g., uncontrolled nausea, vomiting, diarrhea; malabsorption syndrome; small bowel resection).
* Splenic irradiation within 12 months prior to Screening.
* Pregnant or nursing women.
* WOCBP not using highly effective methods of contraception
* Sexually active males who refuse condom use
* Patients who have neuromuscular disorders (e.g. inflammatory myopathies, muscular dystrophy, amyotrophic lateral sclerosis and spinal muscular atrophy) or are on concomitant treatment with drugs that are recognized to cause rhabdomyolysis, such as HMG CoA inhibitors (statins), clofibrate and gemfibrozil. Pravastatin may be used if necessary, with extra caution.

Primary outcomes:
measure: Number of Participants With Dose Limiting Toxicities (DLTs) (Phase 1b)
timeFrame: 6 weeks (42 days)
measure: Percentage of Patients Achieving >= 35% Reduction in Spleen Volume in Phase Ib Expansion and Phase II Stage 1
timeFrame: Week 24 and Week 48
Secondary outcomes:
measure: Phase Ib and Phase II: LDE225: Plasma Pharmacokinetics (PK) Parameter: Area Under the Curve(AUC0-24h)
timeFrame: 0, 0.5, 1. 1.5, 2, 4, 6, 8 hrs on Week 1 Day 1 & Week 9 Day 1
measure: Phase Ib and Phase II: INC424: PK Parameters: Area Under the Curve for AUC0-12h, AUCinf & AUClast
timeFrame: 0, 0.5, 1. 1.5, 2, 4, 6, 8 hrs on Week 1 Day 1 & Week 9 Day 1
measure: Phase Ib and Phase II: LDE225 & INC424: PK Parameter: Maximum Plasma Concentration (Cmax)
timeFrame: 0, 0.5, 1. 1.5, 2, 4, 6, 8 hrs on Week 1 Day 1 & Week 9 Day 1
measure: Phase Ib and Phase II: LDE225 & INC424: Plasma PK Parameter: Time to Maximum Plasma Concentration (Tmax)
timeFrame: 0, 0.5, 1. 1.5, 2, 4, 6, 8 hrs on Week 1 Day 1 & Week 9 Day 1
measure: Phase Ib and Phase II: LDE225 & INC424:: Plasma Pharmacokinetics (PK) Parameters: Area Under the Curve(CL/F)
timeFrame: 0, 0.5, 1. 1.5, 2, 4, 6, 8 hrs on Week 1 Day 1 & Week 9 Day 1
measure: Phase Ib and Phase II: Percentage of Participants With Fibrosis Grade Assessed by Bone Marrow Histomorphology, by Time and Treatment in Phase Ib and Phase II Stage 1
timeFrame: Baseline, Week 25 Day 1 (Week 24), Week 49 Day 1 (Week 48)
measure: Phase Ib and Phase ll: Summary of JAK2V617F Allele Burden by Visit and Treatment in Phase Ib and Phase II Stage 1
timeFrame: Baseline, Week 25 Day 1 (Week 24), Week 49 Day 1 (Week 48)
measure: Phase Ib and Phase ll: Summary of Cytokine Levels in Pharmacodynamic for All Collected Biomarkers
timeFrame: Baseline, Week 25 Day 1 (Week 24), Week 49 Day 1 (Week 48)
measure: Phase Ib and Phase II: Percentage of Participants With >= 50% Reduction From Baseline in MFSAF Total Symptom Scores
timeFrame: Week 24, Week 48
measure: Phase Ib and Phase II: Change in Total Symptom Score (TSS) From Baseline to Week 25 & Week 49 Using the MFSAF Total Symptom Scores
timeFrame: Baseline, Week 25, Week 49
measure: Phase I and Phase II: Change in EORTC QLQ-C30 Scores From Baseline Compared to Week 24 & Week 48
timeFrame: Week 24, Week 48
measure: Phase Ib and Phase II: LDE225: PK Parameter: Racc
timeFrame: 0, 0.5, 1. 1.5, 2, 4, 6, 8 hrs on Week 9 Day 1
measure: Phase Ib and Phase II: INC424: PK Parameter: T1/2
timeFrame: 0, 0.5, 1. 1.5, 2, 4, 6, 8 hrs on Week 1 Day 1
measure: Phase Ib and Phase II: INC424: PK Parameter: Vss/F
timeFrame: 0, 0.5, 1. 1.5, 2, 4, 6, 8 hrs on Week 1 Day 1
Other outcomes:
Locations:
city: Camperdown
country: Australia
facility: Novartis Investigative Site
state: New South Wales
city: Woolloongabba
country: Australia
facility: Novartis Investigative Site
state: Queensland
city: Leuven
country: Belgium
facility: Novartis Investigative Site
city: Toronto
country: Canada
facility: Novartis Investigative Site
state: Ontario
city: Montreal
country: Canada
facility: Novartis Investigative Site
state: Quebec
city: Roskilde
country: Denmark
facility: Novartis Investigative Site
city: Marseille
country: France
facility: Novartis Investigative Site
city: Aachen
country: Germany
facility: Novartis Investigative Site
city: Magdeburg
country: Germany
facility: Novartis Investigative Site
city: Galway
country: Ireland
facility: Novartis Investigative Site
city: Firenze
country: Italy
facility: Novartis Investigative Site
state: FI
city: Reggio Calabria
country: Italy
facility: Novartis Investigative Site
state: RC
city: Amsterdam
country: Netherlands
facility: Novartis Investigative Site
city: Rotterdam
country: Netherlands
facility: Novartis Investigative Site
city: Barcelona
country: Spain
facility: Novartis Investigative Site
state: Catalunya
city: Madrid
country: Spain
facility: Novartis Investigative Site
city: Glasgow
country: United Kingdom
facility: Novartis Investigative Site
state: Scotland
city: London
country: United Kingdom
facility: Novartis Investigative Site
Study officials:
affiliation: Novartis Pharmaceuticals
name: Novartis Pharmaceuticals
role: STUDY_DIRECTOR
References:
citation: Gupta V, Wolleschak D, Hasselbalch H, Vannucchi AM, Koschmieder S, Cervantes F, Li Y, Dong T, Wroclawska M, Bharathy S, Harrison C. Safety and efficacy of the combination of sonidegib and ruxolitinib in myelofibrosis: a phase 1b/2 dose-finding study. Blood Adv. 2020 Jul 14;4(13):3063-3071. doi: 10.1182/bloodadvances.2019001212.