Ruxolitinib in Combination With Autotransplant

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

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.

Study Overview

• Status: Withdrawn
• Conditions: Myelofibrosis; MF
• Intervention / Treatment: Drug: RUXOLITINIB / INC 424; Drug: Filgrastim; Drug: Busulfan

Detailed Description

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.

• Study Type: Interventional
• Phase: Not Applicable

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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:

  1. Red cell transfusion dependency
  2. unfavorable Karyotype
  3. platelet count <100 x 109/L
  4. symptomatic splenomegaly
  5. PB blasts > 1%
  6. Blasts in PB <20% prior to study enrollment
  7. 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
  8. 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):

  1. Adequate renal function - creatinine <2 x ULN
  2. 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
  3. Adequate hematopoietic function - Platelet ≥50 x 109/L (without transfusion) and ANC ≥1.0 x 109/L
  4. LVEF >40% (MUGA or echocardiogram)
  5. 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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NA
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Ruxolitinib / INC 424; 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; 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).; Other Names: Jakafi®; RUX; Drug: Filgrastim; Peripheral blood stem cells (PBSC) will be mobilized with filgrastim 10 mcg/kg/day IV; Other Names: Neupogen®; Drug: Busulfan; 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; Other Names: Busulfex®

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Marina Kremyanskaya
• Collaborators: Incyte Corporation

Study record dates

Study Major Dates

• Study Start: May 1, 2015
• Primary Completion (Actual): August 1, 2016
• Study Completion (Actual): August 1, 2016

Study Registration Dates

• First Submitted: May 28, 2015
• First Submitted That Met QC Criteria: June 9, 2015
• First Posted (Estimate): June 12, 2015

Study Record Updates

• Last Update Posted (Estimate): August 12, 2016
• Last Update Submitted That Met QC Criteria: August 11, 2016
• Last Verified: August 1, 2016

More Information

Terms related to this study

• Keywords: Myelofibrosis; Autologous stem cell transplant; RUXOLITINIB
• Additional Relevant MeSH Terms: Bone Marrow Diseases; Hematologic Diseases; Myeloproliferative Disorders; Primary Myelofibrosis; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Busulfan
• Other Study ID Numbers: GCO 14-2106