Ruxolitinib Prior to Transplant in Patients With Myelofibrosis

Overview

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.

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

Study Type

  • Study Type: Interventional
  • Study Design
    • Allocation: N/A
    • Intervention Model: Single Group Assignment
    • Primary Purpose: Treatment
    • Masking: None (Open Label)
  • Study Primary Completion Date: October 26, 2017

Detailed Description

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.

Interventions

  • Drug: Ruxolitinib Pre- Hematopoietic cell transplantation (HCT)
    • 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.

Arms, Groups and Cohorts

  • Experimental: Ruxolitinib Pre- Hematopoietic cell transplantation (HCT)
    • 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.

Clinical Trial Outcome Measures

Primary Measures

  • Percent of Participants With 100-day Survival Without Graft Failure
    • Time Frame: Day 100-post allogeneic stem cell transplantation
    • 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.

Secondary Measures

  • Time to Neutrophil Recovery
    • Time Frame: up to 4 years
    • Neutrophil recovery will be defined as first of the three consecutive days with neutrophil count ≥0.5 x 109/l.
  • Platelet Recovery
    • Time Frame: up to 4 years
    • 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.
  • Percent of Participants With Non-relapse Mortality (NRM)
    • Time Frame: 100 days
    • 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.
  • Percent of Participants With Non-relapse Mortality (NRM)
    • Time Frame: 1-year post transplant
    • 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.
  • Percent of Participants With Graft Versus Host Disease (GvHD)
    • Time Frame: 1-year post transplant
    • 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 –
  • Chimerism Studies
    • Time Frame: 30 days post transplant
    • Will check percentage of donor versus recipient blood cells to determine efficacy of donor engraftment
  • Chimerism Studies
    • Time Frame: 60 days post transplant
    • Will check percentage of donor versus recipient blood cells to determine efficacy of donor engraftment
  • Chimerism Studies
    • Time Frame: 100 days post transplant
    • Will check percentage of donor versus recipient blood cells to determine efficacy of donor engraftment
  • Number of Participants With Remission Status According to IWG-MRT Criteria
    • Time Frame: Day 100 post transplant
    • 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)
  • Number of Participants With Remission Status at 6 Months Post Transplant
    • Time Frame: 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
  • Number of Participants With Remission Status at 12 Months Post Transplant
    • Time Frame: 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
  • Number of Participants With Relapse/Progression (Defined as Per IWG-MRT Criteria)
    • Time Frame: 1-year post transplant
    • 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
  • Number of Participants With Progression-free Survival
    • Time Frame: 1-year post transplant
    • 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.
  • Number of Overall Survival
    • Time Frame: 1-year post transplant
  • Mean Change in the Brief Fatigue Inventory Score
    • Time Frame: baseline and 48 months
    • 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.
  • Expression Profiling and Measurements of Cytokines Prior to Start of Ruxolitinib, Prior to Start of Chemotherapy for Conditioning
    • Time Frame: 30 days post transplant
  • Expression Profiling and Measurements of Cytokines Prior to Start of Ruxolitinib, Prior to Start of Chemotherapy for Conditioning
    • Time Frame: 100 days post transplant
  • Association of Cytokines Levels With Acute and Chronic GvHD
    • Time Frame: 30 days post transplant
  • Association of Cytokines Levels With Acute and Chronic GvHD
    • Time Frame: 100 days post transplant

Participating in This Clinical Trial

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 1. Red cell transfusion dependency 2. Unfavorable Karyotype 3. 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

Gender Eligibility: All

Minimum Age: 18 Years

Maximum Age: 70 Years

Are Healthy Volunteers Accepted: No

Investigator Details

  • Lead Sponsor
    • John Mascarenhas
  • Collaborator
    • Myeloproliferative Disorders-Research Consortium
  • Provider of Information About this Clinical Study
    • Sponsor-Investigator: John Mascarenhas, Associate Professor – Icahn School of Medicine at Mount Sinai
  • Overall Official(s)
    • John Mascarenhas, MD, Principal Investigator, Icahn School of Medicine at Mount Sinai
    • Vikas Gupta, MD, FRCP, FRCPath, Study Chair, University of Toronto
    • Adam Mead, MD, Study Chair, University of Oxford, John Radcliffe Hospital

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