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Myeloproliferative Disorders

Polycythemia Vera

Polycythemia

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Primary Myelofibrosis

Bone Marrow Diseases

Thrombocytosis

Thrombocythemia, Essential

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All Drugs and Chemicals

Janus Kinase Inhibitors

LDE225

INC424

Novartis Pharmaceuticals

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.

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

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

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.

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.

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

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

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 \[mass x time x volume-1\].

Cmax: Maximum observed plasma concentration after drug administration \[mass x volume-

1\].

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

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: Change in Pharmacodynamic Biomarkers: JAK2V617F allele burden

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

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.

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.

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

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

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

Participants who took a combination of LDE225 400mg and INC424 10mg in the dose escalation phase

LDE225 400 mg + INC424 10 mg

Participants who took a combination of LDED225 400mg and INC424 15mg in the dose escalation phase

LDE225 400 mg + INC424 15 mg

Participants who took a combination of LDED225 400mg and INC424 20mg in the dose escalation phase

LDE225 400 mg + INC424 20 mg

Participants who took a combination of LDED225 400mg and INC424 20mg in the dose expansion phase

LDE225 400 mg + INC424 20 mg (Dose Expansion)

All Patients

Participants who took a combination of LDE225 400mg and INC424 10mg in the dose escalation phase.

LDE225 400mg + INC424 10 mg (Dose Escalation Phase)

LDE225 400mg + INC424 15 mg (Dose Escalation Phase)

Participants who took a combination of LDE225 400mg and INC424 20mg in the dose escalation phase.

LDE225 400mg + INC424 20mg (Dose Escalation Phase)

LDED225 400mg + INC424 20mg (Dose Expansion Phase)

Total

Age, Continuous

Sex: Female, Male

Race (NIH/OMB)

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

Study Director

LDE225 400mg + INC424 10mg (Dose Escalation Phase)

LDE225 400mg + INC424 15mg (Dose Escalation Phase)

Safety Analysis Set (SAS) included all participants in Phase Ib \& Phase II who received at least 1 dose of LDE225 and/or INC424 \& had at least 1 valid post-baseline safety assessment. DLT was measured in the Phase Ib dose escalation \& expansion phase, as part of the primary outcome. All participants in the safety set were considered for toxicities.

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

Week 24

Week 48

The Full Analysis Set (FAS) comprised all subjects in Phase Ib and Phase II who received at least one dose of LDE225 and/or INC424. The data disclosed includes only participants from Phase Ib dose expansion phase and Ph II Stage 1. This data does not include dose escalation Phase Ib participants.

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

LDE225 (Week 1, Day 1) (n=6,10,4,24)

LDE225 (Week 9, Day 1) (n=6,6,4,14)

The Pharmacokinetic Analysis set (PAS) consisted of all subjects in Phase Ib and Phase II who received at least one (full or partial) dose of LDE225 and/or INC424 and provided at least one evaluable PK blood sample for LDE225 and/or INC424.

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

AUC0-12h: Wk1 Day 1 (n=8,10,5,25)

AUC0-12h: Wk 9 Day 1 (n=8,9,4,20)

AUCinf: Wk1 Day 1 (n=7,9,4,16)

AUCinf: Wk 9 Day 1 (n=8,9,3,15)

AUClast: Wk1 Day 1 (n=8,10,5,26)

AUClast: Wk 9 Day 1 (n=8,9,4,20)

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

LDE225 (Week 1, Day 1) (n=6,10,5,26)

LDE225 (Week 9, Day 1) (n=8,8,5,20)

INC424 (Week 1, Day 1) (n=8,10,5,27)

INC424 (Week 9, Day 1) (n=8,9,4,20)

The pharmacokinetic analysis set (PAS) consisted of all subjects in Phase Ib and Phase II who received at least one (full or partial) dose of LDE225 and/or INC424 and provided at least one evaluable PK blood sample for LDE225 and/or INC424.

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

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

LDE225 (Week 1, Day 1) (n=5,5,1,12)

INC424 (Week 1, Day 1) (n=7,9,4,16)

INC424 (Week 9, Day 1) (n=0,0,0,0)

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

Baseline, grade 0 (n=0,0,0,1)

Baseline, grade 1 (n=0,1,0,4)

Baseline, grade 2 (n=4,6,3,8)

Baseline, grade 3 (n=3,3,0,8)

Baseline, missing grade (n=1,0,2,6)

Week 25 Day 1, grade 1 (n=1,1,0,1)

Week 25 Day 1, grade 2 (n=0,3,2,7)

Week 25 Day 1, grade 3 (n=5,4,1,5)

Week 25 Day 1, missing grade (n=2,2,2,14)

Week 49 Day 1, grade 0 (n=0,0,0,1)

Week 49, Day 1 grade 1 (n=0,0,0,1)

Week 49 Day 1, grade 2 (n=0,1,1,2)

Week 49 Day 1, grade 3 (n=2,2,2,3)

Week 49 Day 1, missing grade (n=6,7,2,20)

The Full Analysis Set (FAS) comprised all subjects in Phase Ib and Phase II who received at least one dose of LDE225 and/or INC424.

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

Baseline

Week 25 Day 1 (n=7,6,5,21)

Week 49 Day 1 (n=4,3,4,13)

The Biomarker Analysis Set (BAS) consisted of all subjects in Phase Ib and Phase II who received at least one (full or partial) dose of LDE225 and/or INC424 and provided at least one evaluable biomarker sample.

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

AFP: Week 25 Day 1 (Wk 25 D1) (n=7,8,5,22)

AFP: Week 49 Day 1 (WK25 D1) (n=4,3,4,14)

APOA-1: Week 25 Day 1 (n=7,8,5,22)

APOA-1: Week 49 Day 1 (n=4,3,4,14)

B2M: Week 25 Day 1 (n=7,8,5,22)

B2M: Week 49 Day 1 (n=4,3,4,14)

BDNF: Week 25 Day 1 (n=7,8,5,22)

BDNF: Week 49 Day 1 (n=4,3,4,14)

C Reactive Protein: Week 25 Day 1 (n=7,8,5,22)

C Reactive Protein: Week 49 Day 1 (n=4,3,4,14)

Carcinoembryyonic Antigen: Wk 25 D1 (n=7,8,5,22)

Carcinoembryyonic Antigen: Wk 49 D1 (n=4,3,4,14)

Cluster of. Diff 40: Wk 25 D1 (n=7,7,5,0)

Cluster of. Diff 40: Wk 49 D1 (n=4,2,0,0)

Eotaxin1: Wk 25 D1 (n=7,8,5,22)

Eotaxin1: Wk 49 D1 (n=4,3,4,14)

ICAM1: Wk 25 D1 (n=7,8,5,22)

ICAM1: Wk 49 D1 (n=4,3,4,14)

IL10: Wk 25 D1 (n=7,8,5,22)

IL10: Wk 49 D1 (n=4,3,4,14)

IL18: Wk 25 D1 (n=7,8,5,22)

IL18: Wk 49 D1 (n=4,3,4,14)

IL1B: Wk 25 D1 (n=7,8,5,22)

IL1B: Wk 49 D1 (n=4,3,4,14)

IL1RN: Wk 25 D1 (n=7,8,5,22)

IL1RN: Wk 49 D1 (n=4,3,4,14)

IL6: Wk 25 D1 (n=7,8,5,22)

IL6: Wk 49 D1 (n=4,3,4,14)

IL8: Wk 25 D1 (n=7,8,5,22)

IL8: Wk 49 D1 (n=4,3,4,14)

Insulin: Wk 25 D1 (n=7,8,5,22)

Insulin: Wk 49 D1 (n=4,3,4,14)

LEP: Wk 25 D1 (n=7,8,5,22)

LEP: Wk 49 D1 (n=4,3,4,14)

Macro. Inflam. Prot-1 Beta: Wk 25 D1 (n=7,8,5,22)

Macro. Inflam. Prot-1 Beta: Wk 49 D1 (n=4,3,4,14)

Macro.-derived Chemokine: Wk 25 D1 (n=7,8,5,22)

Macro.-derived Chemokine: Wk 49 D1 (n=4,3,4,14)

MPO: Wk 25 D1 (n=7,8,5,22)

MPO: Wk 49 D1 (n=4,3,4,14)

Myoglobin: Wk 25 D1 (n=7,8,5,22)

Myoglobin: Wk 49 D1 (n=4,3,4,14)

Plasmin. Activ. Inhibitor 1: Wk 25 D1 (n=7,8,5,22)

Plasmin. Activ. Inhibitor 1: Wk 49 D1 (n=4,3,4,14)

RANTES: Wk 25 D1 (n=7,8,5,22)

RANTES: Wk 49 D1 (n=4,3,4,14)

Thyroxine binding globulin Wk 25 D1 (n=7,8,5,22)

Thyroxine binding globulin: Wk 49 D1 (n=4,3,4,14)

TNFA: Wk 25 D1 (n=7,8,5,22)

TNFA: Wk 49 D1 (n=4,3,4,14)

TNFRT 2: Wk 25 D1 (n=7,8,5,22)

TNFRT 2: Wk 49 D1 (n=4,3,4,14)

VCAM1: Wk 25 D1 (n=7,8,5,22)

VCAM1: Wk 49 D1 (n=4,3,4,14)

VEGF: Wk. 25 D1 (n=7,8,5,22)

VEGF: Wks. 49 D1 (n=4,3,4,14)

VWF: Wk. 25 D1 (n=7,8,5,22)

VWF: Wk. 49 D1 (n=4,3,4,14)

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

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

Week 25 (n = 6, 7, 5, 19)

Week 49 (n = 4, 5, 4, 10)

Participants who took a combination of LDE225 400mg and INC424 15mg in the dose escalation phase.

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

Glob. Health Status/Qol: Wk 25 (n=6,7,5,19)

Glob. Health Status/Qol: Wk 49(n=4,4,4,10)

Phys. Func: Wk 25 (n=6,7,5,19)

Phys. Func: Wk 49 (n=4,4,4,10)

Role Func: Wk 25 (n=6,7,5,19)

Role Func: Wk 49 (n=4,4,4,10)

Emo. Func: Wk 25 (n=6,7,5,19)

Emo. Func: Wk 49 (n=4,4,4,10)

Cog. Func: Wk 25 (n=6,7,5,19

Cog. Func: Wk 49 (n=4,4,4,10)

Soc. Func: Wk 25 (n=6,7,4,19)

Soc. Func: Wk 49 (n=3,4,4,10)

Fatigue: Wk 25 (n=6,7,5,19)

Fatigue: Wk 49 (n=4,4,4,10)

Naus & Vom: Wk 25 (n=6,7,5,19)

Naus & Vom: Wk 49 (n=4,4,4,10)

Pain: Wk 25 (n=6,7,5,18)

Pain: Wk 49 (n=4,4,4,10)

Dyspnoea: Wk 25 (n=6,7,5,19)

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

Spots Global Cancer Trial Database for high risk myelofibrosis