Phase 2
N=50
A Phase Ib/II Dose-finding Study to Assess the Safety and Efficacy of LDE225 + INC424 in Patients With MF
Primary Myelofibrosis · Thrombocytosis · Essential Thrombocythemia · Polycythemia Vera · Myeloproliferative Disorders
Bottom Line
View on ClinicalTrials.gov: NCT01787552 ↗Enrolled (actual)
50
Serious AEs
52.0%
Results posted
Apr 2020
Primary outcome: Primary: Number of Participants With Dose Limiting Toxicities (DLTs) (Phase 1b) — 0; 2; 0; 1 Participants
Study Design & Population
- Study type
- Interventional
- Phase
- Phase 2
- Interventions
- LDE225 (Drug); INC424 (Drug)
- Age
- Adult, Older Adult · 18+ yrs
- Sex
- All
- Sponsor
- Novartis Pharmaceuticals
- Primary completion
- Apr 2018
Outcome Measures
| Outcome | Result | p-value |
|---|---|---|
| PRIMARY Number of Participants With Dose Limiting Toxicities (DLTs) (Phase 1b) |
0; 2; 0; 1 | — |
| PRIMARY Percentage of Patients Achieving >= 35% Reduction in Spleen Volume in Phase Ib Expansion and Phase II Stage 1 |
44.4; 29.6 | — |
| SECONDARY Phase Ib and Phase II: LDE225: Plasma Pharmacokinetics (PK) Parameter: Area Under the Curve(AUC0-24h) |
2680; 1900; 1090; 2060; 15500; 13000 | — |
| SECONDARY Phase Ib and Phase II: INC424: PK Parameters: Area Under the Curve for AUC0-12h, AUCinf & AUClast |
473; 805; 1130; 1190; 489; 835 | — |
| SECONDARY Phase Ib and Phase II: LDE225 & INC424: PK Parameter: Maximum Plasma Concentration (Cmax) |
311; 221; 161; 251; 879; 720 | — |
| SECONDARY Phase Ib and Phase II: LDE225 & INC424: Plasma PK Parameter: Time to Maximum Plasma Concentration (Tmax) |
3.01; 2.08; 2.00; 2.00; 1.79; 2.00 | — |
| SECONDARY Phase Ib and Phase II: LDE225 & INC424:: Plasma Pharmacokinetics (PK) Parameters: Area Under the Curve(CL/F) |
145; 238; 727; 122; 27.8; 34.5 | — |
| SECONDARY 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 |
3.7; 10.0; 14.8; 50.0; 50.0; 60.0 | — |
| SECONDARY Phase Ib and Phase ll: Summary of JAK2V617F Allele Burden by Visit and Treatment in Phase Ib and Phase II Stage 1 |
84.7; 61.7; 88.3; 55.4; 88.6; 48.0 | — |
| SECONDARY Phase Ib and Phase ll: Summary of Cytokine Levels in Pharmacodynamic for All Collected Biomarkers |
0.75; 0.79; 1.10; 0.49; 0.68; 0.60 | — |
| SECONDARY Phase Ib and Phase II: Percentage of Participants With >= 50% Reduction From Baseline in MFSAF Total Symptom Scores |
50.00; 40.0; 80.0; 33.3; 25.00; 20.0 | — |
| SECONDARY Phase Ib and Phase II: Change in Total Symptom Score (TSS) From Baseline to Week 25 & Week 49 Using the MFSAF Total Symptom Scores |
-18.8; -14.0; -19.4; -6.5; -18.5; -13.6 | — |
| SECONDARY Phase I and Phase II: Change in EORTC QLQ-C30 Scores From Baseline Compared to Week 24 & Week 48 |
-2.8; -2.4; 16.7; 2.6; -2.1; 14.6 | — |
| SECONDARY Phase Ib and Phase II: LDE225: PK Parameter: Racc |
4.60; 7.40; 10.9; 4.75 | — |
| SECONDARY Phase Ib and Phase II: INC424: PK Parameter: T1/2 |
1.81; 2.42; 2.20; 1.99 | — |
| SECONDARY Phase Ib and Phase II: INC424: PK Parameter: Vss/F |
63.7; 67.1; 53.1; 54.5 | — |
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.
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.
Data sourced from ClinicalTrials.gov (NCT01787552). Outcome figures and adverse-event rates are extracted automatically from the registry's posted results and are provided for clinician reference, not as a substitute for the primary publication.