Ruxolitinib Prior to Transplant in Patients With Myelofibrosis

Phase 2

Terminated

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

Interventions: Drug: Ruxolitinib Pre- Hematopoietic cell transplantation (HCT)

Registration Number: NCT01790295

Lead Sponsor: John Mascarenhas

Brief Summary: 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: 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.

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 21

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Ruxolitinib Pre- Hematopoietic cell transplantation (HCT)	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.

Primary Outcome Measures

Name	Time	Method
Percent of Participants With 100-day Survival Without Graft Failure	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 Outcome Measures

Name	Time	Method
Number of Overall Survival	1-year post transplant
Time to Neutrophil Recovery	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	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)	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.
Number of Participants With Remission Status at 6 Months Post Transplant	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	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)	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
Percent of Participants With Graft Versus Host Disease (GvHD)	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. 1. Maculopapular rash\< 25% body surface area (BSA) 2-3 mg/dl 500-999 ml/day 2. Maculopapular rash 25 - 50% BSA 3.1-6 mg/dl 1000-1500 ml/day 3. Maculopapular rash \> 50% BSA 6.1-15 mg/dl Adult: \>1500 ml/day 4. 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	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	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 Progression-free Survival	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.
Mean Change in the Brief Fatigue Inventory Score	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	100 days post transplant
Association of Cytokines Levels With Acute and Chronic GvHD	100 days post transplant

Trial Locations

Locations (8): Emory Hospital
🇺🇸
Atlanta, Georgia, United States
Northwestern University, Robert h. Lurie Comprehensive Cancer Center
🇺🇸
Chicago, Illinois, United States
University of Kansas Cancer Center
🇺🇸
Westwood, Kansas, United States
Icahn School of Medicine at Mount Sinai
🇺🇸
New York, New York, United States
Wake Forest Baptist Medical Center
🇺🇸
Winston-Salem, North Carolina, United States
Ohio State University
🇺🇸
Columbus, Ohio, United States
Princess Margaret Cancer Centre, University of Toronto
🇨🇦
Toronto, Canada
University of Oxford
🇬🇧
Oxford, United Kingdom
Emory Hospital
🇺🇸Atlanta, Georgia, United States