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

Primary Purpose

Primary Myelofibrosis, Thrombocytosis, Essential Thrombocythemia

Status

Completed

Phase

Phase 1

Locations

International

Study Type

Interventional

Intervention

LDE225

INC424

About this trial

This is an interventional treatment trial for Primary Myelofibrosis focused on measuring 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

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

LDE225 + INC424

Arm Description

LDE225 and INC424 in combination

Outcomes

Primary Outcome Measures

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.

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

Secondary Outcome Measures

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]

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

AUC0-12h: Area under the concentration-time curve from time zero to 12 hours extrapolate from AUClast[mass x time x volume-1]. AUCinf: Area under the concentration-time curve from time zero to infinity with extrapolation of the terminal phase [mass x time x volume-1]. AUClast: Area under the concentration-time curve from time zero to the time of last measurable concentration [mass x time x volume-1].

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

Cmax: Maximum observed plasma concentration after drug administration [mass x volume- 1].

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

Tmax: Time to reach Cmax [time]

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

CL/F: Apparent total plasma clearance of drug after oral administration [volume x time-1]

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

The number of patients experiencing improvement in their bone marrow fibrosis by at least one grade and assessment of cellularity.

Phase Ib and Phase ll: Summary of JAK2V617F Allele Burden by Visit and Treatment in Phase Ib and Phase II Stage 1

Phase Ib and Phase ll: Change in Pharmacodynamic Biomarkers: JAK2V617F allele burden

Phase Ib and Phase ll: Summary of Cytokine Levels in Pharmacodynamic for All Collected Biomarkers

Summary of cytokine levels in Pharmacodynamic Biomarkers for all 26 collected at Week 25 Day 1 and Week 49 Day 1

Phase Ib and Phase II: Percentage of Participants With >= 50% Reduction From Baseline in MFSAF Total Symptom Scores

The 7-day modified Myelofibrosis Symptom Assessment Form (MFSAF) v2.0 is a 7-item PRO instrument based on the modified MFSAF v2.0 diary administered at specified visits. The first 6 items assess MF symptom severity at its worst as recalled in the 7 days prior to the clinic visit assessment. The symptoms measured include night sweats, itching, abdominal discomfort, pain under the ribs (left side), early satiety, & bone/muscle pain. The 7th item captures MF-related inactivity in the past 7 days prior to the clinic visit assessment. All 7 items ask subjects to record their answers on an 11-point numeric rating scale (NRS), (0 = Absent, 10 = Worst Imaginable). The first 6 items of the instrument focus on MF symptoms & are summed to create a Total Symptom score.

Phase Ib and Phase II: Change in Total Symptom Score (TSS) From Baseline to Week 25 & Week 49 Using the MFSAF Total Symptom Scores

Phase I and Phase II: Change in EORTC QLQ-C30 Scores From Baseline Compared to Week 24 & Week 48

EORTC QLQ-C30 is the European Organization for Research & Treatment of Cancer, Quality of Life (QoL) Questionnaire & is one of the most widely used & validated instruments to measure health-related QoL in subjects with cancer. The scale includes 5 functional scales (physical functioning, role functioning, emotional functioning, cognitive functioning & social functioning), global health status/QoL & 9 symptom scale/items (fatigue, nausea & vomiting, pain, dyspnea, insomnia, appetite loss, constipation, diarrhea, & financial difficulties). This instrument asks the subject to respond according to the past week, with the exception of the first 5 questions that represent physical functioning & capture the subject's current status. The range of scores for all of the scales is from 0 to 100. For functional & global health status/QoL scales, higher scores indicate better QoL & level of functioning; for symptom scales, higher scores indicate greater level of symptoms or difficulties.

Phase Ib and Phase II: LDE225: PK Parameter: Racc

Racc: Accumulation ratio calculated as AUC0-12h on Week 9 Day 1 divided by AUC0-12h on Week 1 Day 1 [fold]

Phase Ib and Phase II: INC424: PK Parameter: T1/2

T1/2: Elimination half-life associated with the terminal slope (lambda_z) of a semi logarithmic concentration-time curve [time]

Phase Ib and Phase II: INC424: PK Parameter: Vss/F

Vss/F: Apparent volume of distribution at steady state after oral administration [volume]

Full Information

NCT ID

NCT01787552

First Posted

February 6, 2013

Last Updated

April 3, 2020

Sponsor

Novartis Pharmaceuticals

1. Study Identification

Unique Protocol Identification Number

NCT01787552

Brief Title

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

2. Study Status

Record Verification Date

April 2020

Overall Recruitment Status

Completed

Study Start Date

May 8, 2013 (Actual)

Primary Completion Date

April 10, 2018 (Actual)

Study Completion Date

April 10, 2018 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Novartis Pharmaceuticals

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

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

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1, Phase 2

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

N/A

Enrollment

50 (Actual)

8. Arms, Groups, and Interventions

Arm Title

LDE225 + INC424

Arm Type

Experimental

Arm Description

LDE225 and INC424 in combination

Intervention Type

Drug

Intervention Name(s)

LDE225

Intervention Type

Drug

Intervention Name(s)

INC424

Primary Outcome Measure Information:

Title

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

Description

Time Frame

6 weeks (42 days)

Title

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

Description

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 Outcome Measure Information:

Title

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

Description

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]

Time Frame