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Clinical Trial Details — Status: Terminated

Administrative data

NCT number NCT01790295
Other study ID # GCO 12-1809
Secondary ID MPD-RC 114
Status Terminated
Phase Phase 2
First received
Last updated
Start date November 2013
Est. completion date October 26, 2017

Study information

Verified date February 2019
Source Icahn School of Medicine at Mount Sinai
Contact n/a
Is FDA regulated No
Health authority
Study type Interventional

Clinical Trial 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.


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 information / eligibility

Status Terminated
Enrollment 21
Est. completion date October 26, 2017
Est. primary completion date October 26, 2017
Accepts healthy volunteers No
Gender All
Age group 18 Years to 70 Years
Eligibility 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


Related Conditions & MeSH terms


Intervention

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.

Locations

Country Name City State
Canada Princess Margaret Cancer Centre, University of Toronto Toronto
United Kingdom University of Oxford Oxford
United States Emory Hospital Atlanta Georgia
United States Northwestern University, Robert h. Lurie Comprehensive Cancer Center Chicago Illinois
United States Ohio State University Columbus Ohio
United States Icahn School of Medicine at Mount Sinai New York New York
United States University of Kansas Cancer Center Westwood Kansas
United States Wake Forest Baptist Medical Center Winston-Salem North Carolina

Sponsors (5)

Lead Sponsor Collaborator
John Mascarenhas Incyte Corporation, Myeloproliferative Disorders-Research Consortium, National Cancer Institute (NCI), Novartis

Countries where clinical trial is conducted

United States,  Canada,  United Kingdom, 

Outcome

Type Measure Description Time frame Safety issue
Primary Percent of Participants With 100-day Survival Without Graft Failure 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. Day 100-post allogeneic stem cell transplantation
Secondary Time to Neutrophil Recovery Neutrophil recovery will be defined as first of the three consecutive days with neutrophil count =0.5 x 109/l. up to 4 years
Secondary Platelet Recovery 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. up to 4 years
Secondary Percent of Participants With Non-relapse Mortality (NRM) 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. 100 days
Secondary Percent of Participants With Non-relapse Mortality (NRM) 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. 1-year post transplant
Secondary Percent of Participants With Graft Versus Host Disease (GvHD) 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 -
1-year post transplant
Secondary Chimerism Studies Will check percentage of donor versus recipient blood cells to determine efficacy of donor engraftment 30 days post transplant
Secondary Chimerism Studies Will check percentage of donor versus recipient blood cells to determine efficacy of donor engraftment 60 days post transplant
Secondary Chimerism Studies Will check percentage of donor versus recipient blood cells to determine efficacy of donor engraftment 100 days post transplant
Secondary Number of Participants With Remission Status According to IWG-MRT Criteria 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
Day 100 post transplant
Secondary Number of Participants With Remission Status at 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
6 months post transplant
Secondary Number of Participants With Remission Status at 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
12 months post transplant
Secondary Number of Participants With Relapse/Progression (Defined as Per IWG-MRT Criteria) Relapse/progression defined as:
Peripheral blood: Hemoglobin =100 g/L and
1-year post transplant
Secondary Number of Participants With Progression-free Survival 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. 1-year post transplant
Secondary Number of Overall Survival 1-year post transplant
Secondary Mean Change in the Brief Fatigue Inventory Score 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. baseline and 48 months
Secondary Expression Profiling and Measurements of Cytokines Prior to Start of Ruxolitinib, Prior to Start of Chemotherapy for Conditioning 30 days post transplant
Secondary Expression Profiling and Measurements of Cytokines Prior to Start of Ruxolitinib, Prior to Start of Chemotherapy for Conditioning 100 days post transplant
Secondary Association of Cytokines Levels With Acute and Chronic GvHD 30 days post transplant
Secondary Association of Cytokines Levels With Acute and Chronic GvHD 100 days post transplant
See also
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Terminated NCT02091752 - A Phase II Study of Re-treatment of Myelofibrosis Patients With Ruxolitinib/Jakavi After Treatment Interruption Due to Loss of Response and/or Adverse Event (ReTreatment Trial) Phase 2
Completed NCT01445769 - Alternative Dosing Strategy of Ruxolitinib in Patients With Myelofibrosis Phase 2
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Unknown status NCT01298934 - LBH589 (Panobinostat) for the Treatment of Myelofibrosis Phase 1/Phase 2
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Active, not recruiting NCT02530619 - Alisertib in Treating Patients With Myelofibrosis or Relapsed or Refractory Acute Megakaryoblastic Leukemia N/A
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Completed NCT01731951 - Imetelstat Sodium in Treating Participants With Primary or Secondary Myelofibrosis Phase 2
Completed NCT01371617 - A Phase 2 Study With IPI-926 in Patients With Myelofibrosis Phase 2
Active, not recruiting NCT02251821 - JAK Inhibitor Before Donor Stem Cell Transplant in Treating Patients With Primary or Secondary Myelofibrosis Phase 2
Active, not recruiting NCT04446650 - A Study of Fedratinib in Japanese Subjects With DIPSS (Dynamic International Prognostic Scoring System)- Intermediate or High-risk Primary Myelofibrosis (PMF), Post-polycythemia Vera Myelofibrosis (Post-PV MF), or Post-essential Thrombocythemia Myelofibrosis (Post-ET MF) Phase 1/Phase 2
Completed NCT01981850 - A Phase 2 Study of RO7490677 In Participants With Myelofibrosis Phase 2
Withdrawn NCT04283526 - Study of Select Combinations in Adults With Myelofibrosis Phase 1
Withdrawn NCT02584777 - A Phase II Non-Controlled, Open-Label, Efficacy, Safety, Pharmacokinetic, and Pharmacodynamic Study of Pacritinib in Myelofibrosis Phase 2
Recruiting NCT05364762 - Adding Itacitinib to Cyclophosphamide and Tacrolimus for the Prevention of Graft Versus Host Disease in Patients Undergoing Hematopoietic Stem Cell Transplants Phase 2

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