NCT01787552

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.

Trial Health

98
On Track

Trial Health Score

Automated assessment based on enrollment pace, timeline, and geographic reach

Enrollment
50

participants targeted

Target at P50-P75 for phase_1

Timeline
Completed

Started May 2013

Longer than P75 for phase_1

Geographic Reach
11 countries

18 active sites

Status
completed

Health score is calculated from publicly available data and should be used for screening purposes only.

Trial Relationships

Click on a node to explore related trials.

Study Timeline

Key milestones and dates

First Submitted

Initial submission to the registry

February 6, 2013

Completed
2 days until next milestone

First Posted

Study publicly available on registry

February 8, 2013

Completed
3 months until next milestone

Study Start

First participant enrolled

May 8, 2013

Completed
4.9 years until next milestone

Primary Completion

Last participant's last visit for primary outcome

April 10, 2018

Completed
Same day until next milestone

Study Completion

Last participant's last visit for all outcomes

April 10, 2018

Completed
2 years until next milestone

Results Posted

Study results publicly available

April 15, 2020

Completed
Last Updated

April 15, 2020

Status Verified

April 1, 2020

Enrollment Period

4.9 years

First QC Date

February 6, 2013

Results QC Date

April 8, 2019

Last Update Submit

April 3, 2020

Conditions

Primary MyelofibrosisThrombocytosisEssential ThrombocythemiaPolycythemia VeraMyeloproliferative DisordersBone Marrow DiseasesHematologic DiseasesBlood Coagulation DisordersBlood Platelet DisordersHemorrhagic Disorders

Keywords

Dose escalationMaximum Tolerated DoseMTDSafety ExpansionSafetyEfficacyMyelofibrosisPost-polycythemia vera myelofbrosis (Post PV-PMF)Post essential thrombocythemia myelofibrosis (Post ET-MF)Primary myelofibrosis (PMF)Intermediate risk myelofibrosisHigh risk myelofibrosisCombination TreatmentHedgehog Signaling PathwaySmoothened inhibitorJAK inhibitor

Outcome Measures

Primary Outcomes (2)

  • Number of Participants With Dose Limiting Toxicities (DLTs) (Phase 1b)

    A dose-limiting toxicity (DLT) was defined as an adverse event or abnormal laboratory value assessed as unrelated to disease progression, inter-current illness, or concomitant medications that met certain criteria as defined in the protocol.

    6 weeks (42 days)

  • Percentage of Patients Achieving >= 35% Reduction in Spleen Volume in Phase Ib Expansion and Phase II Stage 1

    Reduction in spleen volume as measured by magnetic resonance imaging/Cat Scan (MRI/CT) in Phase Ib expansion and Phase II Stage 1 patients

    Week 24 and Week 48

Secondary Outcomes (14)

  • Phase Ib and Phase II: LDE225: Plasma Pharmacokinetics (PK) Parameter: Area Under the Curve(AUC0-24h)

    0, 0.5, 1. 1.5, 2, 4, 6, 8 hrs on Week 1 Day 1 & Week 9 Day 1

  • Phase Ib and Phase II: INC424: PK Parameters: Area Under the Curve for AUC0-12h, AUCinf & AUClast

    0, 0.5, 1. 1.5, 2, 4, 6, 8 hrs on Week 1 Day 1 & Week 9 Day 1

  • Phase Ib and Phase II: LDE225 & INC424: PK Parameter: Maximum Plasma Concentration (Cmax)

    0, 0.5, 1. 1.5, 2, 4, 6, 8 hrs on Week 1 Day 1 & Week 9 Day 1

  • Phase Ib and Phase II: LDE225 & INC424: Plasma PK Parameter: Time to Maximum Plasma Concentration (Tmax)

    0, 0.5, 1. 1.5, 2, 4, 6, 8 hrs on Week 1 Day 1 & Week 9 Day 1

  • Phase Ib and Phase II: LDE225 & INC424:: Plasma Pharmacokinetics (PK) Parameters: Area Under the Curve(CL/F)

    0, 0.5, 1. 1.5, 2, 4, 6, 8 hrs on Week 1 Day 1 & Week 9 Day 1

  • +9 more secondary outcomes

Study Arms (1)

LDE225 + INC424

EXPERIMENTAL

LDE225 and INC424 in combination

Drug: LDE225Drug: INC424

Interventions

LDE225DRUG
LDE225 + INC424
INC424DRUG
LDE225 + INC424

Eligibility Criteria

Age18 Years+
Sexall
Healthy VolunteersNo
Age GroupsAdult (18-64), Older Adult (65+)

You may qualify if:

  • 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).

You may not qualify if:

  • 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.

Contact the study team to confirm eligibility.

Sponsors & Collaborators

Study Sites (18)

Novartis Investigative Site

Camperdown, New South Wales, NSW, Australia

Location

Novartis Investigative Site

Woolloongabba, Queensland, 4102, Australia

Location

Novartis Investigative Site

Leuven, 3000, Belgium

Location

Novartis Investigative Site

Toronto, Ontario, M5G 2M9, Canada

Location

Novartis Investigative Site

Montreal, Quebec, H3T 1E2, Canada

Location

Novartis Investigative Site

Roskilde, 4000, Denmark

Location

Novartis Investigative Site

Marseille, 13273, France

Location

Novartis Investigative Site

Aachen, 52074, Germany

Location

Novartis Investigative Site

Magdeburg, 39120, Germany

Location

Novartis Investigative Site

Galway, Ireland

Location

Novartis Investigative Site

Florence, FI, 50134, Italy

Location

Novartis Investigative Site

Reggio Calabria, RC, 89124, Italy

Location

Novartis Investigative Site

Amsterdam, 1081 HV, Netherlands

Location

Novartis Investigative Site

Rotterdam, 3015 GD, Netherlands

Location

Novartis Investigative Site

Barcelona, Catalonia, 08036, Spain

Location

Novartis Investigative Site

Madrid, 28034, Spain

Location

Novartis Investigative Site

Glasgow, Scotland, G12 0YN, United Kingdom

Location

Novartis Investigative Site

London, SE1 9RT, United Kingdom

Location

Related Publications (1)

  • 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.

    PMID: 32634234DERIVED

MeSH Terms

Conditions

Primary MyelofibrosisThrombocytosisThrombocythemia, EssentialPolycythemia VeraMyeloproliferative DisordersBone Marrow DiseasesHematologic DiseasesBlood Coagulation DisordersBlood Platelet DisordersHemorrhagic Disorders

Interventions

sonidegibruxolitinib

Condition Hierarchy (Ancestors)

Hemic and Lymphatic DiseasesBone Marrow NeoplasmsHematologic NeoplasmsNeoplasms by SiteNeoplasms

Limitations and Caveats

Please refer to detailed description regarding reason for early termination of study.

Results Point of Contact

Title
Study Director
Organization
Novartis Pharmaceuticals
Novartis.email@novartis.com
862-778-8300

Study Officials

  • Novartis Pharmaceuticals

    Novartis Pharmaceuticals

    STUDY DIRECTOR

Publication Agreements

PI is Sponsor Employee
No
Restriction Type
OTHER
Restrictive Agreement
Yes

Study Design

Study Type
interventional
Phase
phase 1
Allocation
NA
Masking
NONE
Purpose
TREATMENT
Intervention Model
SINGLE GROUP
Sponsor Type
INDUSTRY
Responsible Party
SPONSOR

Study Record Dates

First Submitted

February 6, 2013

First Posted

February 8, 2013

Study Start

May 8, 2013

Primary Completion

April 10, 2018

Study Completion

April 10, 2018

Last Updated

April 15, 2020

Results First Posted

April 15, 2020

Record last verified: 2020-04

Data Sharing

IPD Sharing
Will share

Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent expert panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations. This trial data is currently available according to the process described on www.clinicalstudydatarequest.com.

Shared Documents
STUDY PROTOCOL, SAP

Locations

IT(2)NL(2)GB(2)ES(2)FR(1)CA(2)AU(2)IE(1)DE(2)BE(1)DK(1)