Overview

This trial is active, not recruiting.

Conditions primary myelofibrosis, thrombocythemia, essential, thrombocytosis, myeloproliferative disorders, bone marrow diseases, hematologic diseases, blood coagulation disorders, blood platelet disorders, hemorrhagic disorders
Treatments lde225, inc424
Phase phase 1/phase 2
Target SMO
Sponsor Novartis Pharmaceuticals
Start date May 2013
End date December 2016
Trial size 50 participants
Trial identifier NCT01787552, 2012-004023-20, CLDE225X2116

Summary

The purpose of this phase Ib/II clinical trial is 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.

United States No locations recruiting
Other Countries No locations recruiting

Study Design

Endpoint classification safety/efficacy study
Intervention model single group assignment
Masking open label
Primary purpose treatment
Arm
(Experimental)
LDE225 and INC424 in combination
lde225
inc424

Primary Outcomes

Measure
Phase Ib: Dose Limiting Toxicities (DLTs)
time frame: 6 weeks (42 days)
Proportion of patients achieving >= 35% reduction in spleen volume
time frame: Baseline, Week 24, Week 48

Secondary Outcomes

Measure
Phase Ib: Safety of LDE225 in combination with INC424 in myelofibrosis patients
time frame: study start, up to and including 30 days after last dose
Phase Ib: Plasma pharmacokinetics (PK) parameters
time frame: Week 1 Day 1, Week 1 Day 2, Week 3 Day 1 and then every 2 weeks until Week 9 Day 1, Week 9 Day 2, Week 13 Day 1 and then every 4 weeks until Week 49 Day 1
Phase II: Proportion of patients experiencing improvement in bone marrow fibrosis by at least one grade
time frame: Baseline, Week 24, Week 48
Phase II: Safety of LDE225 and INC424
time frame: Study start, up to and including 30 days after last dose
Phase II: Change in total symptom score
time frame: Baseline, Week 24, Week 48
Phase ll: Change in JAK2V617F allele burden
time frame: Baseline, Week 24, Week 48
Phase ll: Change in cytokine levels
time frame: Baseline, Week 24, Week 48
Phase II: Plasma pharmacokinetics (PK) parameters
time frame: Week 1 Day 1, Week 1 Day 2, Week 3 Day 1 and then every 2 weeks until Week 9 Day 1, Week 9 Day 2, Week 13 Day 1 and then every 4 weeks until Week 49 Day 1 Day 1
Phase II: Plasma pharmacokinetics (PK) parameters
time frame: Week 1 Day 1 and then every 2 weeks until Week 9 Day 1, then every 4 weeks until Week 49 Day 1
Phase II: Proportion of patients having >= 50% reduction in total symptom score
time frame: Baseline, Week 24, Week 48
Phase II: Change in EORTC QLQ-C30 scores
time frame: Baseline, Week 24, Week 48

Eligibility Criteria

Male or female participants at least 18 years old.

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.

Additional Information

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
Description The purpose of this phase Ib/II clinical trial is 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. Adult patients, aged ≥ 18 years, with myelofibrosis that meet intermediate or high risk prognostic criteria and exhibit palpable splenomegaly ≥ 5 cm below the left costal margin that have not been previously treated with a JAK or Smo inhibitor will be eligible for this study. Approximately 36 patients will participate in the Phase Ib dose escalation and safety expansion part of the study. Dose escalation will be dependent on the available toxicity information (including adverse events that are not DLTs), PK, PD, and efficacy information, as well as the recommendations from the Bayesian Logistic Regression Model (BLRM). In the Phase II part of the study approximately 46 patients will be enrolled: 18 patients will be enrolled into Stage 1, if following an interim analysis the minimum number of responders are observed, 28 additional patients will be enrolled into stage 2. If less than the minimum number of responders are observed in Stage 1 then further enrollment will be halted. Approximately 82 patients will be enrolled in the entire study.
Trial information was received from ClinicalTrials.gov and was last updated in June 2016.
Information provided to ClinicalTrials.gov by Novartis.