Neoplasms

Blood and Lymph Conditions

All Conditions

Heart and Blood Diseases

Rare Diseases

Polycythemia Vera

Polycythemia

Primary Myelofibrosis

Thrombocytosis

Thrombocythemia, Essential

Myeloproliferative Disorders

Bone Marrow Diseases

Hematologic Diseases

Bone Marrow Neoplasms

Hematologic Neoplasms

Blood Platelet Disorders

Hemostatic Disorders

Blood Coagulation Disorders

Hemorrhagic Disorders

Essential Thrombocythemia

Chronic Myeloproliferative Disorders

Central Nervous System Depressants

All Drugs and Chemicals

Other Dietary Supplements

Benzocaine

Tannic Acid

All participants received oral ruxolitinib. Patients began treatment with either 10 mg twice a day (bid), 15 mg bid, 25 mg bid, 50 mg bid, 25 mg once a day (qd), 50 mg qd, 100 mg qd, or 200 mg qd, depending on the time period when they entered the study. The doses were titrated based on efficacy and safety to a maximum of 25 mg bid for patients who entered the study after sufficient dosing information had been obtained to define the maximum dose for patients in the study. Patients could continue receiving treatment indefinitely if receiving benefit at a dose that continues to maintain benefit but does not exceed a maximum dose of 25 mg BID.

5 and 25 mg tablets with a daily dosing range from 10 to 200 mg qd or bid.

Ruxolitinib

Srdan Verstovsek, MD, PhD

Ayalew Tefferi, MD

To determine the safety, tolerability and effectiveness of ruxolitinib (INCB018424), administered orally to patients with Primary Myelofibrosis (PMF), Post Polycythemia Vera Myelofibrosis (PPV-MF) and Essential Thrombocythemia Myelofibrosis (PET-MF).

This is a multicenter, open-label, non-randomized, dose escalation study of ruxolitinib, a small molecule Janus kinase (JAK) inhibitor, administered orally to patients with PMF, PPEV-MF or PET-MF. The study is comprised of 3 parts:

Part 1: Dose escalation and determination of maximum tolerated dose (complete).

Part 2: Exploration of alternative dosing schedules (complete).

Part 3: Further evaluation of selected dose regimens, including additional response measures to explore effect of ruxolitinib on symptoms and other parameters including daily physical activity and long-term survival (ongoing).

Open Label Ruxolitinib (INCB018424) in Patients With Myelofibrosis and Post Polycythemia Vera/Essential Thrombocythemia Myelofibrosis

A Phase 1/2, Open-Label Study of the JAK2 Inhibitor INCB018424 Administered Orally to Patients With Primary Myelofibrosis (PMF) and Post Polycythemia Vera/Essential Thrombocythemia Myelofibrosis (Post-PV/ET)

Treatment-Emergent AEs are events occurring after first drug administration or worsened from baseline.

Treatment-Related AEs are those with a definite, probable, possible or missing causality.

A serious AE is a medical occurrence that results in death, is life-threatening, requires inpatient hospitalization or prolongation of hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect or is a medical event requiring intervention to prevent 1 of the above.

A severe or life-threatening AE is based on intensity, according to National Cancer Institute-Common Toxicity Criteria for Adverse Effects (NCI-CTCAE) v3.0.

Clinical improvement was defined according to the International Working Group Myelofibrosis Research and Treatment criteria, and required 1 of the following:

1. A ≥ 2 g/dL increase in Hemoglobin level or becoming transfusion independent;
2. Either a ≥ 50% reduction in palpable splenomegaly if spleen was ≥ 10 cm at Baseline or a spleen palpable at \> 5 cm at Baseline becomes not palpable;
3. A ≥ 100% increase in platelet count and an absolute platelet count of ≥ 50,000 x 10\^9/L or
4. A ≥ 100% increase in absolute neutrophil count (ANC) and an ANC of ≥ 0.5 x 10\^9/L.

For each visit, patients who had a missing value at the visit, dropped out of the study due to any reasons prior to the visit or had non-palpable spleen at baseline and then became palpable at the time of the visit were all considered as having not achieved the ≥ 50% reduction in spleen palpation length.

Spleen volume was assessed in a subgroup of 27 patients using magnetic resonance imaging (MRI) scans (or computed tomography (CT) scans in patients who were not candidates for MRI) of the abdomen in order to allow objective measurement of spleen volume using standard estimation techniques.

For each visit, patients who had a missing value at the visit or dropped out of the study due to any reason prior to the visit were considered as not having achieved the ≥35% reduction in spleen volume.

Symptoms of myelofibrosis were assessed using a modified Myelofibrosis Symptom Assessment Form (MFSAF). Abdominal discomfort, itching, muscle or bone pain, and night sweats are prominent and troubling symptoms in patients with MF. Therefore, the MFSAF-derived responses for these symptoms were analyzed as a total symptom score. Each symptom was assessed on a scale from 0 (absent), 1 (most favorable) to 10 (worst). The total symptom score is a sum of the individual scores and ranges from 0-40. A higher score indicates worse symptoms hence a negative change from baseline indicates improvement.

Health-related Quality of Life was assessed using the Global Health Status/Quality of Life Scale of the European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30). This scale ranges from 0 to 100, with higher scores indicating higher quality of life.

The ECOG performance status measures patients' functional status on the following scale:

* 0=Fully active, no restrictions;
* 1=Restricted in physically strenuous activity but ambulatory, able to carry out light work;
* 2=Ambulatory and capable of all selfcare, unable to carry out any work activities; Up and about \> 50% of waking hours;
* 3=Limited selfcare, confined to bed or chair more than 50% of waking hours;
* 4=Completely disabled. Totally confined to bed or chair;
* 5=Dead.

Data reported indicate the number of participants with a change from Baseline score of -2, -1, 0 and 1.

Incyte Corporation

Participants received an initial dose of Ruxolitinib 10 mg twice a day (bid). Participants could continue in the study on their prescribed regimen indefinitely if receiving benefit with dose adjustments for safety and efficacy to a maximum of 25 mg bid.

10 mg Bid

Participants received an initial dose of Ruxolitinib 15 mg twice a day (bid). Participants could continue in the study on their prescribed regimen indefinitely if receiving benefit with dose adjustments for safety and efficacy to a maximum of 25 mg bid.

15 mg Bid

Participants received an initial dose of Ruxolitinib 25 mg twice a day (bid). Participants could continue in the study on their prescribed regimen indefinitely if receiving benefit with dose adjustments for safety and efficacy.

25 mg Bid

Participants received an initial dose of Ruxolitinib 50 mg twice a day (bid). Participants could continue in the study on their prescribed regimen indefinitely if receiving benefit with dose adjustments for safety and efficacy.

50 mg Bid

Participants received an initial dose of Ruxolitinib 25, 50, 100 or 200 mg once a day (qd). Participants could continue in the study on their prescribed regimen indefinitely if receiving benefit with dose adjustments for safety and efficacy. Since the numbers of patients in 3 of the qd treatment groups were small, the 4 qd doses were combined to allow meaningful comparisons against the bid treatment groups.

All QD

Participants received an initial dose of Ruxolitinib 25 mg once a day (qd). Participants could continue in the study on their prescribed regimen indefinitely with dose adjustments for safety and efficacy.

25 mg qd

Participants received an initial dose of Ruxolitinib 50 mg once a day (qd). Participants could continue in the study on their prescribed regimen indefinitely if receiving benefit with dose adjustments for safety and efficacy.

50 mg qd

Participants received an initial dose of Ruxolitinib 100 mg once a day (qd). Participants could continue in the study on their prescribed regimen indefinitely if receiving benefit with dose adjustments for safety and efficacy.

100 mg qd

Participants received an initial dose of Ruxolitinib 200 mg once a day (qd). Participants could continue in the study on their prescribed regimen indefinitely if receiving benefit with dose adjustments for safety and efficacy.

200 mg qd

Total

Age, Continuous

Sex: Female, Male

Asian

Black or African American

White

Other

Race/Ethnicity, Customized

Primary myelofibrosis

Post-polycythemia vera-myelofibrosis

Post-essential thrombocythemia-myelofibrosis

Disease sub-type

Body Mass Index (BMI)

Palpable spleen length below the costal margin

Negative

Positive

Unknown

JAK2V617F is a mutation in the pseudokinase domain of Janus Kinase 2 (JAK2) (at amino acid 617, valine to phenylalanine) that results in constitutive activation of JAK2. Mutation status was determined using a validated assay on bone marrow as well as peripheral blood.

JAK2 V617F mutation status

The Eastern Cooperative Oncology Group (ECOG) performance status measures patients' functional status on the following scale: 0=Fully active, no restrictions 1=Restricted in physically strenuous activity but ambulatory, able to carry out light work; 2=Ambulatory and capable of all selfcare, unable to carry out any work activities; Up and about \> 50% of waking hours; 3=Limited selfcare, confined to bed or chair more than 50% of waking hours; 4=Completely disabled. Totally confined to bed or chair; 5=Dead.

Eastern Cooperative Oncology Group Performance Status

Study Director

Any Treatment-Emergent Adverse Event

Treatment-Related Adverse Events

Serious Adverse Events

Severe or Life-threatening Adverse Events

Study Drug Interrupted Due to Adverse Events

Discontinued Study Drug Due to Adverse Events

Study Drug Reduced Due to Adverse Events

Safety population included all patients who received at least 1 dose of study medication.

Number of Participants With Adverse Events (AEs)

12 Weeks [N=25, 34, 42, 5, 32]

24 Weeks [N=21, 31, 40, 4, 29]

36 Weeks [N=18, 30, 36, 4, 25]

48 Weeks [N=17, 28, 36, 3, 23]

60 Weeks [N=15, 21, 33, 2, 21]

The intent-to-treat population included all patients who received at least 1 dose of study medication and had at least 1 follow-up assessment for safety and efficacy. N = the number of patients who had clinical response assessed during the time interval.

Percentage of Participants With Clinical Improvement (CI) Over Time

Week 4 [N=27, 34, 37, 4, 36]

Week 8 [N=27, 34, 37, 4, 36]

Week 12 [N=27, 34, 37, 4, 36]

Week 24 [N=26, 34, 37, 4, 36]

Week 36 [N=26, 34, 37, 4, 36]

Week 48 [N=26, 33, 37, 4, 36]

Week 60 [N=25, 27, 37, 4, 36]

Intent to treat population. A total of 16 patients had either a splenectomy prior to study entry, missing Baseline spleen values or had spleen lengths reported as 0 cm and were excluded.

Percentage of Participants Achieving ≥ 50% Reduction From Baseline in Spleen Palpation Length Over Time

Week 4 [N= 2, 25]

Week 12 [N= 2, 25]

Week 24 [N= 2, 25]

Week 48 [N= 2, 20]

Patients with at least 1 Spleen-Volume Measurement. Patients who had not reached the visit were excluded from the analysis. In addition, at Week 48, 5 patients who did not have MRI measurement due to a protocol amendment were considered as not evaluable and were excluded from the analysis.

Percentage of Participants With ≥ 35% Reduction From Baseline in Spleen Volume Over Time

Intent-to-treat population for whom data was available. The MFSAF was implemented by protocol amendment while the study was ongoing. Hence data are available for only approximately 50% of enrolled patients. This analysis includes patients with a Baseline total symptom score ≥ 0; 8 patients were excluded because they had a Baseline score = 0.

Change From Baseline in Myelofibrosis Total Symptom Score at Week 24

The safety population included all subjects who received at least 1 dose of study medication, and for whom data was available at both time points. The EORTC QLQ C30 was implemented by protocol amendment and as a result this data are available for only approximately 50% of the enrolled patients.

Change From Baseline to Week 24 in Health-Related Quality of Life

Week 4 [n=139]

Week 8 [n=137]

Week 12 [n=129]

Week 24 [n=115]

Week 36 [n=104]

Week 48 [n=99]

Week 60 [n=83]

All participants received ruxolitinib at varying initial dose and regimen. Participants could continue in the study on their prescribed regimen indefinitely if receiving benefit with dose adjustments for safety and efficacy.

All Participants

Intent-to-treat population for patients who had reached each time point and for whom data was available.

Spots Global Cancer Trial Database for Open Label Ruxolitinib (INCB018424) in Patients With Myelofibrosis and Post Polycythemia Vera/Essential Thrombocythemia Myelofibrosis

Trial Identification

Conditions

Interventions

Study Description

Keywords

Eligibility

Locations

Contact Details

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