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Ruxolitinib Prior to Transplant in Patients With Myelofibrosis

Primary Purpose

Primary Myelofibrosis, Post Polycythemia Vera Myelofibrosis, Post Essential Thrombocythemia Myelofibrosis

Status

Terminated

Phase

Phase 2

Locations

International

Study Type

Interventional

Intervention

Ruxolitinib Pre- Hematopoietic cell transplantation (HCT)

About this trial

This is an interventional treatment trial for Primary Myelofibrosis focused on measuring Myelofibrosis, Stem cell transplant, Ruxolitinib

Eligibility Criteria

18 Years - 70 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

Emory Hospital
Northwestern University, Robert h. Lurie Comprehensive Cancer Center
University of Kansas Cancer Center
Icahn School of Medicine at Mount Sinai
Wake Forest Baptist Medical Center
Ohio State University
Princess Margaret Cancer Centre, University of Toronto
University of Oxford

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Ruxolitinib Pre- Hematopoietic cell transplantation (HCT)

Arm Description

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.

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

Time to Neutrophil Recovery

Neutrophil recovery will be defined as first of the three consecutive days with neutrophil count ≥0.5 x 109/l.

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.

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.

Percent of Participants With Non-relapse Mortality (NRM)

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 -

Chimerism Studies

Will check percentage of donor versus recipient blood cells to determine efficacy of donor engraftment

Chimerism Studies

Will check percentage of donor versus recipient blood cells to determine efficacy of donor engraftment

Chimerism Studies

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

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 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 <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

Number of Participants With Relapse/Progression (Defined as Per IWG-MRT Criteria)

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

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.

Number of Overall Survival

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.

Expression Profiling and Measurements of Cytokines Prior to Start of Ruxolitinib, Prior to Start of Chemotherapy for Conditioning

Association of Cytokines Levels With Acute and Chronic GvHD

Full Information

NCT ID

NCT01790295

First Posted

February 8, 2013

Last Updated

February 28, 2019

Sponsor

John Mascarenhas

Collaborators

Myeloproliferative Disorders-Research Consortium, National Cancer Institute (NCI), Incyte Corporation, Novartis

1. Study Identification

Unique Protocol Identification Number

NCT01790295

Brief Title

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

2. Study Status

Record Verification Date

February 2019

Overall Recruitment Status

Terminated

Study Start Date

November 2013 (undefined)

Primary Completion Date

October 26, 2017 (Actual)

Study Completion Date

October 26, 2017 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor-Investigator

Name of the Sponsor

John Mascarenhas

Collaborators

Myeloproliferative Disorders-Research Consortium, National Cancer Institute (NCI), Incyte Corporation, Novartis

4. Oversight

Data Monitoring Committee

Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Primary Myelofibrosis, Post Polycythemia Vera Myelofibrosis, Post Essential Thrombocythemia Myelofibrosis

Keywords

Myelofibrosis, Stem cell transplant, Ruxolitinib

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

N/A

Enrollment

21 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Ruxolitinib Pre- Hematopoietic cell transplantation (HCT)

Arm Type

Experimental

Arm Description

Intervention Type

Drug

Intervention Name(s)

Ruxolitinib Pre- Hematopoietic cell transplantation (HCT)

Other Intervention Name(s)

Ruxolitinib \Pre- Hematopoietic cell transplantation (HCT), INC424

Intervention Description

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.

Primary Outcome Measure Information:

Title

Percent of Participants With 100-day Survival Without Graft Failure

Description

Time Frame

Day 100-post allogeneic stem cell transplantation

Secondary Outcome Measure Information:

Title

Time to Neutrophil Recovery

Description

Neutrophil recovery will be defined as first of the three consecutive days with neutrophil count ≥0.5 x 109/l.

Time Frame

up to 4 years

Title

Platelet Recovery

Description

Time Frame

up to 4 years

Title

Percent of Participants With Non-relapse Mortality (NRM)

Description

Time Frame

100 days

Title

Percent of Participants With Non-relapse Mortality (NRM)

Description

Time Frame

1-year post transplant

Title

Percent of Participants With Graft Versus Host Disease (GvHD)

Description

Time Frame

1-year post transplant

Title

Chimerism Studies

Description

Will check percentage of donor versus recipient blood cells to determine efficacy of donor engraftment

Time Frame

30 days post transplant

Title

Chimerism Studies

Description

Will check percentage of donor versus recipient blood cells to determine efficacy of donor engraftment

Time Frame

60 days post transplant

Title

Chimerism Studies

Description

Will check percentage of donor versus recipient blood cells to determine efficacy of donor engraftment

Time Frame

100 days post transplant

Title

Number of Participants With Remission Status According to IWG-MRT Criteria

Description

Time Frame

Day 100 post transplant

Title

Number of Participants With Remission Status at 6 Months Post Transplant

Description

Time Frame

6 months post transplant

Title

Number of Participants With Remission Status at 12 Months Post Transplant

Description

Time Frame

12 months post transplant

Title

Number of Participants With Relapse/Progression (Defined as Per IWG-MRT Criteria)

Description

Time Frame

1-year post transplant

Title

Number of Participants With Progression-free Survival

Description

Time Frame

1-year post transplant

Title

Number of Overall Survival

Time Frame

1-year post transplant

Title

Mean Change in the Brief Fatigue Inventory Score

Description

Time Frame

baseline and 48 months

Title

Expression Profiling and Measurements of Cytokines Prior to Start of Ruxolitinib, Prior to Start of Chemotherapy for Conditioning

Time Frame

30 days post transplant

Title

Expression Profiling and Measurements of Cytokines Prior to Start of Ruxolitinib, Prior to Start of Chemotherapy for Conditioning

Time Frame

100 days post transplant

Title

Association of Cytokines Levels With Acute and Chronic GvHD

Time Frame

30 days post transplant

Title

Association of Cytokines Levels With Acute and Chronic GvHD

Time Frame

100 days post transplant

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

70 Years

Accepts Healthy Volunteers

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 Red cell transfusion dependency Unfavorable Karyotype 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

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

John Mascarenhas, MD

Organizational Affiliation

Icahn School of Medicine at Mount Sinai

Official's Role

Principal Investigator

First Name & Middle Initial & Last Name & Degree

Vikas Gupta, MD, FRCP, FRCPath

Organizational Affiliation

University of Toronto

Official's Role

Study Chair

First Name & Middle Initial & Last Name & Degree

Adam Mead, MD

Organizational Affiliation

University of Oxford, John Radcliffe Hospital

Official's Role

Study Chair

Facility Information:

Facility Name

Emory Hospital

City

Atlanta

State/Province

Georgia

ZIP/Postal Code

30322

Country

United States

Facility Name

Northwestern University, Robert h. Lurie Comprehensive Cancer Center

City

Chicago

State/Province

Illinois

ZIP/Postal Code

60611

Country

United States

Facility Name

University of Kansas Cancer Center

City

Westwood

State/Province

Kansas

ZIP/Postal Code

66205

Country

United States

Facility Name

Icahn School of Medicine at Mount Sinai

City

New York

State/Province

New York

ZIP/Postal Code

10029

Country

United States

Facility Name

Wake Forest Baptist Medical Center

City

Winston-Salem

State/Province

North Carolina

ZIP/Postal Code

27103

Country

United States

Facility Name

Ohio State University

City

Columbus

State/Province

Ohio

ZIP/Postal Code

43210

Country

United States

Facility Name

Princess Margaret Cancer Centre, University of Toronto

City

Toronto

ZIP/Postal Code

M5G 2M9

Country

Canada

Facility Name

University of Oxford

City

Oxford

ZIP/Postal Code

OX3 9DS

Country

United Kingdom

12. IPD Sharing Statement

Citations:

PubMed Identifier

30205231

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.

Results Reference

derived

Links:

URL

http://www.mpdrc.org

Description

Related Info

Learn more about this trial

Ruxolitinib Prior to Transplant in Patients With Myelofibrosis

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