Clinical trial NCT01790295: Ruxolitinib Prior to Transplant in Patients With Myelofibrosis
Official title: 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: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Primary Myelofibrosis
Post Polycythemia Vera Myelofibrosis
Post Essential Thrombocythemia Myelofibrosis
Keywords: Myelofibrosis
Stem cell transplant
Ruxolitinib
Lead sponsor: Icahn School of Medicine at Mount Sinai
Sponsor class: OTHER
Collaborators: name: Myeloproliferative Disorders-Research Consortium
name: National Cancer Institute (NCI)
name: Incyte Corporation
name: Novartis
First posted: 2013-02-13
Enrollment: 21
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

Eligibility criteria: 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

Primary outcomes:
measure: Percent of Participants With 100-day Survival Without Graft Failure
timeFrame: Day 100-post allogeneic stem cell transplantation
Secondary outcomes:
measure: Time to Neutrophil Recovery
timeFrame: up to 4 years
measure: Platelet Recovery
timeFrame: up to 4 years
measure: Percent of Participants With Non-relapse Mortality (NRM)
timeFrame: 100 days
measure: Percent of Participants With Non-relapse Mortality (NRM)
timeFrame: 1-year post transplant
measure: Percent of Participants With Graft Versus Host Disease (GvHD)
timeFrame: 1-year post transplant
measure: Chimerism Studies
timeFrame: 30 days post transplant
measure: Chimerism Studies
timeFrame: 60 days post transplant
measure: Chimerism Studies
timeFrame: 100 days post transplant
measure: Number of Participants With Remission Status According to IWG-MRT Criteria
timeFrame: Day 100 post transplant
measure: Number of Participants With Remission Status at 6 Months Post Transplant
timeFrame: 6 months post transplant
measure: Number of Participants With Remission Status at 12 Months Post Transplant
timeFrame: 12 months post transplant
measure: Number of Participants With Relapse/Progression (Defined as Per IWG-MRT Criteria)
timeFrame: 1-year post transplant
measure: Number of Participants With Progression-free Survival
timeFrame: 1-year post transplant
measure: Number of Overall Survival
timeFrame: 1-year post transplant
measure: Mean Change in the Brief Fatigue Inventory Score
timeFrame: baseline and 48 months
measure: Expression Profiling and Measurements of Cytokines Prior to Start of Ruxolitinib, Prior to Start of Chemotherapy for Conditioning
timeFrame: 30 days post transplant
measure: Expression Profiling and Measurements of Cytokines Prior to Start of Ruxolitinib, Prior to Start of Chemotherapy for Conditioning
timeFrame: 100 days post transplant
measure: Association of Cytokines Levels With Acute and Chronic GvHD
timeFrame: 30 days post transplant
measure: Association of Cytokines Levels With Acute and Chronic GvHD
timeFrame: 100 days post transplant
Other outcomes:
Locations:
city: Atlanta
country: United States
facility: Emory Hospital
state: Georgia
city: Chicago
country: United States
facility: Northwestern University, Robert h. Lurie Comprehensive Cancer Center
state: Illinois
city: Westwood
country: United States
facility: University of Kansas Cancer Center
state: Kansas
city: New York
country: United States
facility: Icahn School of Medicine at Mount Sinai
state: New York
city: Winston-Salem
country: United States
facility: Wake Forest Baptist Medical Center
state: North Carolina
city: Columbus
country: United States
facility: Ohio State University
state: Ohio
city: Toronto
country: Canada
facility: Princess Margaret Cancer Centre, University of Toronto
city: Oxford
country: United Kingdom
facility: University of Oxford
Study officials:
affiliation: Icahn School of Medicine at Mount Sinai
name: John Mascarenhas, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Toronto
name: Vikas Gupta, MD, FRCP, FRCPath
role: STUDY_CHAIR
affiliation: University of Oxford, John Radcliffe Hospital
name: Adam Mead, MD
role: STUDY_CHAIR
References:
citation: Gupta V, Kosiorek HE, Mead A, Klisovic RB, Galvin JP, Berenzon D, Yacoub A, Viswabandya A, Mesa RA, Goldberg J, Price L, Salama ME, Weinberg RS, Rampal R, Farnoud N, Dueck AC, Mascarenhas JO, Hoffman R. Ruxolitinib Therapy Followed by Reduced-Intensity Conditioning for Hematopoietic Cell Transplantation for Myelofibrosis: Myeloproliferative Disorders Research Consortium 114 Study. Biol Blood Marrow Transplant. 2019 Feb;25(2):256-264. doi: 10.1016/j.bbmt.2018.09.001. Epub 2018 Sep 8.