Ruxolitinib Prior to Transplant in Patients With Myelofibrosis

Study Overview
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Brief Summary
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The purpose of this study is to find out if giving the study drug Ruxolitinib (INC424) prior to a combination of other chemotherapeutic drugs (Fludarabine and Busulfan) before infusing another person's hematopoietic stem cells (bone marrow transplantation) will be successful in people who have advanced primary myelofibrosis (PMF), post-polycythemia vera myelofibrosis (PPV-MF) or post-essential thrombocythemia myelofibrosis (PET-MF), collectively known as myelofibrosis (MF). MF is a disorder in which bone marrow tissue develops in abnormal sites because the bone marrow itself undergoes fibrosis or scarring. This study plans to evaluate whether adding the drug Ruxolitinib will further aid in reducing pre-transplant spleen size, improve physical performance levels and reduce adverse events (side effects) related to the transplant. Ruxolitinib is a drug that is approved by the FDA for the treatment of patients with advanced forms of myelofibrosis. Using Ruxolitinib prior to stem cell transplantation is experimental.

Detailed Description
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A two- stage Simon Phase II study will be conducted in each of two groups of patients: related and unrelated donor transplants. In each donor transplant group, the first stage of this design will include 11 patients evaluated for death or graft failure by 100 days post-transplant. In each stratum, we will enroll additional patients (up to 20%) of stratum total to take into account exclusions due to donor failure (such as donor deemed unsuitable for stem cell donation due to medical or other reasons) only. Those patients who have toxicities related to Ruxolitinib and not been able to reach HCT due to these toxicities will be included in the estimation of overall failure rates. Only those patients who are excluded based on donor related issues without any regimen related complications will be excluded from the estimation of failure rates. However, all data on these patients will be reported.

Official Title
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Exploring the Potential of Dual Kinase JAK 1/2 Inhibitor Ruxolitinib (INC424) With Reduced Intensity Allogeneic Hematopoietic Cell Transplantation in Patients With Myelofibrosis

Conditions
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Primary Myelofibrosis, Post Polycythemia Vera Myelofibrosis, Post Essential Thrombocythemia Myelofibrosis

Intervention / Treatment
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* Drug: Ruxolitinib Pre- Hematopoietic cell transplantation (HCT)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Documented diagnosis of primary myelofibrosis according to WHO criteria or post PV myelofibrosis or post ET myelofibrosis as per IWG-MRT criteria Age 18-70 years Intermediate-2/ high-risk disease as per Dynamic IPSS (DIPSS) criteria OR Intermediate-1 risk disease with one of the following additional unfavorable features known to impact the survival adversely Red cell transfusion dependency Unfavorable Karyotype Platelet count <100 x 109/l Blasts in the PB and BM ≤10% prior to study enrollment Availability of a suitable matched related (6/6 or 5/6) or unrelated donor (10/10 or 9/10 antigen or allele matched). Able to give informed written consent ECOG Performance status of 0-2. Life expectancy >3 months Off all MF-directed therapy including investigational agents for at least 2 weeks prior to study enrollment and recovered from all toxicities* Adequate organ function Adequate renal function - creatinine <1.5 x IULN Adequate hepatic function - AST/ALT <2.5 x IULN, Total Bilirubin <1.5 x IULN Adequate hematopoietic function - Platelet ≥50 x 109/l and ANC ≥1.0 x 109/l LVEF >40% (MUGA or echocardiogram) Normal per Institutional standard Adequate pulmonary function with DLCO >50% A patient who has been on stable dose of Ruxolitinib and has received ruxolitinib ≤6 months prior to the study entry will be considered potentially eligible for the study with the caveat that there is no evidence of loss of response (>5cm increase in spleen size from the nadir). Exclusion Criteria: Any previous JAK2 inhibitor treatment prior to study enrollment, with the exception of Ruxolitinib Hypersensitivity to JAK inhibitor Clinical or laboratory evidence of cirrhosis Prior allogeneic transplant for any hematopoietic disorder >20% blast in the PB or BM prior to HCT or had leukemic transformation (>20% blasts in PB or BM any time prior to HCT) Syngeneic donor Cord Blood transplant Active uncontrolled infection H/o another malignancy within 5-years of date of HCT except h/o basal cell or squamous cell carcinoma of skin or PV or ET Known HIV positive Pregnancy at the time of BMT Any other concurrent illness which in investigator's opinion puts the patient at excessive risk of treatment related toxicities Unable to give informed consent Active infection with hepatitis A,B or C virus Subjects who require therapy with a strong CYP3A4 inhibitor prior to enrollment to this study

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ruxolitinib Pre- Hematopoietic cell transplantation (HCT)<br>Ruxolitinib (INC424) tablets will be started 62 days (day -67) prior to start of conditioning chemotherapy. The starting dose of Ruxolitinib will be determined according to baseline platelet count and will be modified according to platelet count at follow-up. The drug will be given in the maximum tolerated dose as defined in the protocol for 56 days, followed by 4 days of taper, and will be stopped completely at the planned start of conditioning therapy (starting on day -5) i.e. 5 days prior to stem cell infusion. The drug will be supplied as 5 mg tablets. | Drug: Ruxolitinib Pre- Hematopoietic cell transplantation (HCT)<br>* Ruxolitinib (INC424) tablets will be started 60 days (day -65) prior to start of conditioning chemotherapy. The starting dose of Ruxolitinib will be determined according to baseline platelet count and will be modified according to platelet count at follow-up. The drug will be given in the maximum tolerated dose as defined in the protocol for 56 days, followed by 4 days of taper, and will be stopped completely at the planned start of conditioning therapy (starting on day -5) i.e. 5 days prior to stem cell infusion. The drug will be supplied as 5 mg tablets.<br>* Other names: INC424;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent of Participants With 100-day Survival Without Graft Failure | The feasibility of combining Ruxolitinib (INC424) with a Reduced intensity conditioning (RIC) regimen likely to produce success post transplantation, success being defined as patient being alive, and without graft failure at day 100-post allogeneic stem cell transplantation (in patients who receive (a) related donor transplant and in those who receive (b) an unrelated donor transplant. | Day 100-post allogeneic stem cell transplantation | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Neutrophil Recovery | Neutrophil recovery will be defined as first of the three consecutive days with neutrophil count ≥0.5 x 109/l. | up to 4 years | 
| Platelet Recovery | Platelet recovery will be defined as first of the 7 days with platelet count ≥20 x 109/l, without platelet transfusion support and both maintained for 30 days without transfusion support or myeloid cytokine support. | up to 4 years | 
| Percent of Participants With Non-relapse Mortality (NRM) | NRM will be defined as death in first 30 days due to any cause, and subsequently death due to any cause without the recurrence or progression of myelofibrosis. Cumulative incidence of NRM will be calculated taking relapse/progression as competing event. | 100 days | 
| Percent of Participants With Non-relapse Mortality (NRM) | NRM will be defined as death in first 30 days due to any cause, and subsequently death due to any cause without the recurrence or progression of myelofibrosis. Cumulative incidence of NRM will be calculated taking relapse/progression as competing event. | 1-year post transplant | 
| Percent of Participants With Graft Versus Host Disease (GvHD) | Acute and chronic GvHD. GvHD is a potentially serious complication of allogeneic stem cell transplantation. Stage Skin Liver (bilirubin) Gut (stool output/day) 0 No GVHD rash < 2 mg/dl < 500 ml/day or persistent nausea. Maculopapular rash< 25% body surface area (BSA) 2-3 mg/dl 500-999 ml/day Maculopapular rash 25 - 50% BSA 3.1-6 mg/dl 1000-1500 ml/day Maculopapular rash > 50% BSA 6.1-15 mg/dl Adult: >1500 ml/day Generalized erythroderma plus bullous formation >15 mg/dl Severe abdominal pain with or without ileus Grade I Stage 1-2 None None II Stage 3 or Stage 1 or Stage 1 III - Stage 2-3 or Stage 2-4 IV Stage 4 or Stage 4 - | 1-year post transplant | 
| Chimerism Studies | Will check percentage of donor versus recipient blood cells to determine efficacy of donor engraftment | 30 days post transplant | 
| Chimerism Studies | Will check percentage of donor versus recipient blood cells to determine efficacy of donor engraftment | 60 days post transplant | 
| Chimerism Studies | Will check percentage of donor versus recipient blood cells to determine efficacy of donor engraftment | 100 days post transplant | 
| Number of Participants With Remission Status According to IWG-MRT Criteria | Remission status according to International Working Group for Myelofibrosis Research and Treatment (IWG-MRT) criteria Remission defined as: Bone marrow:* Age-adjusted normocellularity; <5% blasts; ≤grade 1 MF and Peripheral blood: Hemoglobin ≥100 g/L and <UNL; neutrophil count ≥ 1 × 109/L and <UNL; Platelet count ≥100 × 109/L and <UNL; <2% immature myeloid cells and Clinical: Resolution of disease symptoms; spleen and liver not palpable; no evidence of extramedullary hematopoiesis (EMH) | Day 100 post transplant | 
| Number of Participants With Remission Status at 6 Months Post Transplant | Remission defined as: Bone marrow:* Age-adjusted normocellularity; <5% blasts; ≤grade 1 MF† and Peripheral blood: Hemoglobin ≥100 g/L and <UNL; neutrophil count ≥ 1 × 109/L and <UNL; Platelet count ≥100 × 109/L and <UNL; <2% immature myeloid cells‡ and Clinical: Resolution of disease symptoms; spleen and liver not palpable; no evidence of EMH | 6 months post transplant | 
| Number of Participants With Remission Status at 12 Months Post Transplant | Remission defined as: Bone marrow:* Age-adjusted normocellularity; <5% blasts; ≤grade 1 MF† and Peripheral blood: Hemoglobin ≥100 g/L and <UNL; neutrophil count ≥ 1 × 109/L and <UNL; Platelet count ≥100 × 109/L and <UNL; <2% immature myeloid cells‡ and Clinical: Resolution of disease symptoms; spleen and liver not palpable; no evidence of EMH | 12 months post transplant | 
| Number of Participants With Relapse/Progression (Defined as Per IWG-MRT Criteria) | Relapse/progression defined as: Peripheral blood: Hemoglobin ≥100 g/L and <UNL; neutrophil count ≥1 × 109/L and <UNL; platelet count ≥100 × 109/L and <UNL; <2% immature myeloid cells‡ and Clinical: Resolution of disease symptoms; spleen and liver not palpable; no evidence of EMH or Bone marrow:* Age-adjusted normocellularity; <5% blasts; ≤grade 1 MF†, and peripheral blood: Hemoglobin ≥85 but <100 g/L and <UNL; neutrophil count ≥1 × 109/L and <UNL; platelet count ≥50, but <100 × 109/L and <UNL; <2% immature myeloid cells‡ and Clinical: Resolution of disease symptoms; spleen and liver not palpable; no evidence of EMH | 1-year post transplant | 
| Number of Participants With Progression-free Survival | Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions. | 1-year post transplant | 
| Number of Overall Survival |  | 1-year post transplant | 
| Mean Change in the Brief Fatigue Inventory Score | Mean change in the Brief Fatigue Inventory score (BFI) from baseline to 48 months to assess impact of allogeneic stem cell transplant on myelofibrosis associated symptoms and overall quality of life. The BFI is a 9 item scored from 0 (no fatigue) -10 (as bad as you can imagine), items are averaged with total score from 0-10, with higher score indicating more fatigue. | baseline and 48 months | 
| Expression Profiling and Measurements of Cytokines Prior to Start of Ruxolitinib, Prior to Start of Chemotherapy for Conditioning |  | 30 days post transplant | 
| Expression Profiling and Measurements of Cytokines Prior to Start of Ruxolitinib, Prior to Start of Chemotherapy for Conditioning |  | 100 days post transplant | 
| Association of Cytokines Levels With Acute and Chronic GvHD |  | 30 days post transplant | 
| Association of Cytokines Levels With Acute and Chronic GvHD |  | 100 days post transplant | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Myelofibrosis, Stem cell transplant, Ruxolitinib