Ruxolitinib Prior to Transplant in Patients With Myelofibrosis

NCT ID: NCT01790295

Last Updated: 2019-03-20

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE2
• Total Enrollment: 21 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2013-11-30
• Study Completion Date: 2017-10-26

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.

Conditions

Primary Myelofibrosis; Post Polycythemia Vera Myelofibrosis; Post Essential Thrombocythemia Myelofibrosis

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Ruxolitinib Pre- Hematopoietic cell transplantation (HCT)

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.

Group Type: EXPERIMENTAL

Ruxolitinib Pre- Hematopoietic cell transplantation (HCT)

Intervention Type: DRUG

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.

Interventions

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.

Intervention Type: DRUG

Other Intervention Names

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

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

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 70 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Myeloproliferative Disorders-Research Consortium

NETWORK

Sponsor Role: collaborator

National Cancer Institute (NCI)

NIH

Sponsor Role: collaborator

Incyte Corporation

INDUSTRY

Sponsor Role: collaborator

Novartis

INDUSTRY

Sponsor Role: collaborator

John Mascarenhas

OTHER

Sponsor Role: lead

Responsible Party

John Mascarenhas

Associate Professor

Responsibility Role: SPONSOR_INVESTIGATOR

Principal Investigators

John Mascarenhas, MD

Role: PRINCIPAL_INVESTIGATOR

Icahn School of Medicine at Mount Sinai

Vikas Gupta, MD, FRCP, FRCPath

Role: STUDY_CHAIR

University of Toronto

Adam Mead, MD

Role: STUDY_CHAIR

University of Oxford, John Radcliffe Hospital

Locations

Emory Hospital

Atlanta, Georgia, United States

Northwestern University, Robert h. Lurie Comprehensive Cancer Center

Chicago, Illinois, United States

University of Kansas Cancer Center

Westwood, Kansas, United States

Icahn School of Medicine at Mount Sinai

New York, New York, United States

Wake Forest Baptist Medical Center

Winston-Salem, North Carolina, United States

Ohio State University

Columbus, Ohio, United States

Princess Margaret Cancer Centre, University of Toronto

Toronto, , Canada

University of Oxford

Oxford, , United Kingdom

Countries

United States; Canada; United Kingdom

References

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.

Reference Type: DERIVED

PMID: 30205231 (View on PubMed)

Provided Documents

Document Type: Study Protocol, Statistical Analysis Plan, and Informed Consent Form

View Document

Other Identifiers

MPD-RC 114

Identifier Type: -

Identifier Source: secondary_id

GCO 12-1809

Identifier Type: -

Identifier Source: org_study_id