A Phase Ib/II Dose-finding Study to Assess the Safety and Efficacy of LDE225 + INC424 in Patients With MF

Novartis Pharmaceuticals50 enrolled

Overview

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.

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.

Study Type

INTERVENTIONAL

Allocation

Purpose

TREATMENT

Masking

NONE

Enrollment

Conditions

Primary Myelofibrosis Thrombocytosis Essential Thrombocythemia Polycythemia Vera

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

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.

Locations (18)

Novartis Investigative Site

Camperdown, New South Wales, Australia

Novartis Investigative Site

Woolloongabba, Queensland, Australia

Novartis Investigative Site

Leuven, Belgium

Novartis Investigative Site

Toronto, Ontario, Canada

Novartis Investigative Site

Montreal, Quebec, Canada

Novartis Investigative Site

Roskilde, Denmark

Novartis Investigative Site

Marseille, France

Novartis Investigative Site

Aachen, Germany

Novartis Investigative Site

Magdeburg, Germany

Novartis Investigative Site

Galway, Ireland

...and 8 more locations

Outcomes

Primary Outcomes

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.

Time frame: 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

Time frame: Week 24 and Week 48

Secondary Outcomes

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

Plasma Concentration Time Curve: AUC0-24h: Area under the concentration-time curve from time zero to 24 hours extrapolate from AUClast\[mass x time x volume-1\]