Ruxolitinib in Combination With Autotransplant

Study Overview
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Brief Summary
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To determine the safety of the approach of giving RUXOLITINIB before and after an autologous stem cell transplant, as measured by graft failure or death.

Detailed Description
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This is a pilot, single arm, single center study with no stratification to assess the safety (measured by graft failure or death) and feasibility (measured by adequacy of stem cell collection) of combining ruxolitinib with autologous Hematopoeitic Stem Cell Transplantation (HSCT) in patients with advanced myelofibrosis (MF). Patients will receive a short course of ruxolitinib prior to and during mobilization of HSCT with Filgrastim. Conditioning for the autologous HSCT will consist of Bulsulfan. Post-transplant patients will receive ruxolitinib maintenance.

Official Title
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Ruxolitinib in Combination With High Dose Therapy and Autologous Stem Cell Transplantation for Myelofibrosis

Conditions
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Myelofibrosis, MF

Intervention / Treatment
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* Drug: RUXOLITINIB / INC 424
* Drug: Filgrastim
* Drug: Busulfan


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically documented diagnosis of MF (idiopathic or post PV/ET) Age 18-75 years Intermediate-2/ high-risk disease as per Dynamic IPSS (DIPSS) criteria or Intermediate-1 risk disease with one of the following features within one year from screening: Red cell transfusion dependency unfavorable Karyotype platelet count <100 x 109/L symptomatic splenomegaly PB blasts > 1% Blasts in PB <20% prior to study enrollment No available suitable matched related (6/6 or 5/6) or unrelated donor (8/8 or 7/8 allele matched) or unwilling or unable to pursue allogeneic stem cell transplant WBC <50,000/ml at screening Able to give informed written consent ECOG Performance status of 0-2 Life expectancy >6 months Off all myelofibrosis-related investigational or standard agents (except for ruxolitinib) for at least 4 weeks prior to study enrollment and recovered from all toxicities. If patient is already on ruxolitinib for a minimum of 16 weeks prior to study enrollment, patient can proceed to mobilization and collection Adequate organ function defined as the following (*unless clearly disease related): Adequate renal function - creatinine <2 x ULN Adequate hepatic function - AST/ALT <3 x ULN, Total Bilirubin <3 x ULN, exception is elevated indirect bilirubin attributed to Gilbert's syndrome or hemolysis Adequate hematopoietic function - Platelet ≥50 x 109/L (without transfusion) and ANC ≥1.0 x 109/L LVEF >40% (MUGA or echocardiogram) Adequate pulmonary function with DLCO >40% Exclusion Criteria: Hypersensitivity to JAK inhibitor Clinical evidence of cirrhosis Leukemic transformation (>20% blasts in PB or BM any time prior to HCT) Platelet count <50 x 109/L Active uncontrolled infection History of another malignancy within 5-years of date of HCT except history of basal cell or squamous cell carcinoma of skin or PV or ET Known HIV positive Woman of childbearing potential unwilling or unable to use adequate contraception Pregnant or nursing females Known active infection with hepatitis A, B or C virus

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 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 / INC 424<br>Ruxolitinib, Jakafi ®, will be given orally at standard dose daily for 16 weeks pre ASCT and up to 3 months post-ASCT for 10 patients (allowing for 2 additional screen failures). Patients will restart ruxolitinib at 100 days after the ASCT as long as their platelet count is at least 50 x103. For patients whose platelet count is below 50 x103 at day 100, ruxolitinib should be restarted once platelet count reaches 50 x103. The dose of ruxolitinib can be titrated up as per clinical guidelines. PBSC mobilization will include G-CSF 10 mcg/kg/day. HDC for ASCT will consist of IV busulfan 2.0 mg/KBW once daily x 4 for days -5 to -2. | Drug: RUXOLITINIB / INC 424<br>* Administered orally 5-20 mg twice daily x 16 weeks of therapy prior to attempted peripheral blood stem cells (PBSC) collection, during the collection and rest period and 3 months of therapy after high dose chemotherapy (HDC).<br>* Other names: Jakafi®;Drug: Filgrastim<br>* Peripheral blood stem cells (PBSC) will be mobilized with filgrastim 10 mcg/kg/day IV<br>* Other names: Neupogen®;Drug: Busulfan<br>* Conditioning for autologous Hematopoeitic Stem Cell Transplantation (HSCT) will consist of IV busulfan 2.0 mg/KBW once daily x 4 for days -5 to -2<br>* Other names: Busulfex®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety of combining ruxolitinib with autologous HSCT measured by graft failure or death | Safety of this approach as measured by graft failure or death | 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| CD34 cells | Total CD34+ cell dose will be calculated based on results of flow cytometric analysis and patient's weight. | 4 years | 
| The regimen related mortality (RRM) |  | day 100 | 
| The regimen related mortality (RRM) |  | day 365 | 
| Rate of engraftment/graft failure |  | 4 years | 
| Time of engraftment for neutrophils and platelets |  | 4 years | 
| The incidence of serious infectious complications |  | up to 1 year post transplant | 
| Changes in marrow fibrosis score | The myelofibrosis score will be assessed as per the European Consensus Grading published by Thiele Grading Description at 365 days as compared to 180 days | at 180 and 365 days post-transplant | 
| Change in FISH allele | Changes in FISH abnormalities when present will be measured by cytogenetics. | at 365 days post-transplant | 
| Change in JAK allele | Changes in Jak 2 V617F allele burden when present will be measured by quantitative RT-PCR | at 365 days post-transplant | 
| Rate of response | Overall efficacy will be rated on a scale as complete remission, partial remission, clinical improvement, or stable disease | at 6 months post-transplant | 
| Rate of response | Overall efficacy will be rated on a scale as complete remission, partial remission, clinical improvement, or stable disease | at 1 year post-transplant | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Myelofibrosis, RUXOLITINIB, Autologous stem cell transplant