Ruxolitinib Phosphate and Chemotherapy Given Before and After Reduced Intensity Donor Stem Cell Transplant in Treating Patients With Myelofibrosis
NCT ID: NCT02917096
Last Updated: 2023-12-12
Study Results
The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.
Basic Information
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COMPLETED
PHASE1
18 participants
INTERVENTIONAL
2016-11-13
2023-08-31
Brief Summary
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Detailed Description
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I. Among the dose levels tested, to determine the maximum tolerated dose (MTD) and recommended phase II dose (RP2D) of ruxolitinib phosphate (ruxolitinib), when given as part of reduced intensity allogeneic hematopoietic cell transplant (HCT), in patients with myelofibrosis.
II. To determine if the addition of ruxolitinib is safe by evaluation of toxicities including: type, frequency, severity, attribution, time course and duration.
SECONDARY OBJECTIVES:
I. To characterize and evaluate hematologic recovery, donor cell engraftment and immune reconstitution by cell count and flow cytometry of lymphocyte subsets.
II. To estimate the cumulative incidence of acute graft-versus-host disease (aGVHD) and non-relapse mortality (NRM) at 100-days post transplant.
III. To estimate the cumulative incidence of chronic GVHD at 1- and 2-years post transplant.
IV. To estimate the probabilities of overall and progression-free survival (OS/PFS) at 1- and 2-years post transplant.
V. To characterize changes in aGVHD biomarkers (Reg-3 alpha, soluble tumor necrosis factor receptor I \[sTNF RI\], IL2R alpha), janus associated kinases (JAK)-regulated pro-inflammatory cytokines (i.e. IL-6, TNF alpha, CRP, beta 2microglobulin) and STAT3 phosphorylation (downstream of JAK signaling) over time and by aGVHD status/grade.
OUTLINE: This is a dose-escalation study of ruxolitinib phosphate.
PREPARATIVE REGIMEN: Patients receive fludarabine phosphate intravenously (IV) on days -9 to -5, melphalan IV over 20 minutes on day -4, and ruxolitinib phosphate orally (PO) twice daily (BID) on days -3 to 30 with a taper for 2-3 weeks in the absence of disease progression or unacceptable toxicity.
GVHD PROPHYLAXIS: Patients receive tacrolimus IV continuously beginning on day -3 and convert to PO daily when the patient is able to tolerate and absorb oral medications. Patients also receive sirolimus PO daily beginning on day -3. Treatment continues in the absence of GVHD.
STEM CELL TRANSPLANT: Patients undergo allogeneic HCT on day 0.
After completion of study treatment, patients are followed up for 2 years.
Conditions
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Study Design
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NA
SINGLE_GROUP
TREATMENT
NONE
Study Groups
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Treatment (ruxolitinib phosphate, chemotherapy,allogeneic HCT)
PREPARATIVE REGIMEN: Patients receive fludarabine phosphate IV on days -9 to -5, melphalan IV over 20 minutes on day -4, and ruxolitinib phosphate PO BID on days -3 to 30 with a taper for 2-3 weeks in the absence of disease progression or unacceptable toxicity. Patients being treated with ruxolitinib phosphate prior to allogeneic HCT as standard therapy may continue receiving ruxolitinib phosphate.
GVHD PROPHYLAXIS: Patients receive tacrolimus IV continuously beginning on day -3 and convert to PO daily when the patient is able to tolerate and absorb oral medications. Patients also receive sirolimus PO daily beginning on day -3. Treatment continues in the absence of GVHD.
STEM CELL TRANSPLANT: Patients undergo allogeneic HCT on day 0.
Allogeneic Hematopoietic Stem Cell Transplantation
Undergo allogeneic HCT
Fludarabine
Given IV
Fludarabine Phosphate
Given IV
Laboratory Biomarker Analysis
Correlative studies
Melphalan
Given IV
Pharmacological Study
Correlative studies
Ruxolitinib
Given PO
Ruxolitinib Phosphate
Given PO
Sirolimus
Given PO
Tacrolimus
Given IV and PO
Interventions
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Allogeneic Hematopoietic Stem Cell Transplantation
Undergo allogeneic HCT
Fludarabine
Given IV
Fludarabine Phosphate
Given IV
Laboratory Biomarker Analysis
Correlative studies
Melphalan
Given IV
Pharmacological Study
Correlative studies
Ruxolitinib
Given PO
Ruxolitinib Phosphate
Given PO
Sirolimus
Given PO
Tacrolimus
Given IV and PO
Other Intervention Names
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Eligibility Criteria
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Inclusion Criteria
* Performance status of \>= 70% on the Karnofsky scale
* The effects of chemotherapy, ruxolitinib on the developing fetus are unknown; for this reasonWomen of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control or abstinence) prior to study entry and for 1 year following transplant as per City of Hope standard operating procedure (SOP) for allogeneic transplantation; should a woman become pregnant or suspect that she is pregnant while participating on the trial, she should inform her treating physician immediately
* Bone marrow and peripheral blood studies must be available for confirmation of diagnosis; cytogenetics, flow cytometry, and molecular studies (such as JAK-2, MPL and CALR mutational status) will be obtained as per standard practice
* Bone marrow aspirates/biopsies should be performed within 30 +/- 3 days from registration to confirm disease remission status
* All candidates for this study must have a human leukocyte antigen (HLA) (A, B, C, DR) identical siblings who is willing to donate bone marrow for primed blood stem cells or an 8/8 allele-matched unrelated donor
* All ABO blood group combinations of the donor/recipient are acceptable since even major ABO compatibilities can be dealt with by various techniques (red cell exchange or plasma exchange)
* A cardiac evaluation with an electrocardiogram showing no ischemic changes or abnormal rhythm and an ejection fraction of 50% established by multi-gated acquisition scan (MUGA) or echocardiogram
* Patients must have creatinine of less than or equal to 1.5 mg/dL or creatinine clearance \> 60 ml/min
* A bilirubin of up to 2.0 mg/dL, excluding patients with Gilbert's disease
* Patients should also have a serum glutamic oxaloacetic transaminase (SGOT) and serum glutamate pyruvate transaminase (SGPT) less than 5 times the upper limit of normal
* Pulmonary function test including diffusion capacity of the lung for carbon monoxide (DLCO) will be performed; forced expiratory volume in 1 second (FEV1) and DLCO should be greater than 50% of predicted normal value
* All subjects must have the ability to understand and the willingness to sign a written informed consent that has been approved by the City of Hope Institutional Review Board (COH IRB); the patient, a family member and transplant staff physician (physician, nurse, social worker) will meet at least once prior to the subject signing consent; during this meeting all pertinent information with respect to risks and benefits to donor and recipient will be presented; alternative treatment modalities will be discussed; the risks are explained in detail in the enclosed consent form
* Prior therapy with hydroxyurea, interferon, anagrelide, ruxolitinib, hypomethylating agents, revlimid, thalidomide, steroids, other JAK inhibitors is allowed; for acute myeloid leukemia (AML) patients who are back in chronic phase myeloproliferative neoplasm (MPN), prior induction therapy is allowed
Exclusion Criteria
* Patients may not be receiving any other investigational agents, or concurrent biological, chemotherapy, or radiation therapy
* History of allergic reactions attributed to compounds of similar chemical or biologic composition to ruxolitinib
* Pregnant women are excluded from this study because ruxolitinib is an agent with the potential for teratogenic or abortifacient effects; because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with ruxolitinib, breastfeeding should be discontinued if the mother is treated with ruxolitinib
* Patients with active 2nd malignancies other than myelofibrosis, AML, excised skin cancer, early stage cervical and prostate cancer
* Previous allogeneic hematopoietic stem cell transplantation
* Any psychiatric, social or compliance issues that, in the treating physician opinion, will interfere with completion of the transplant treatment and follow up
* Patients who have been treated with chemotherapy or radiation within two weeks of planned study enrollment; this does not include hydroxyurea, which may be continued until start of conditioning therapy; ruxolitinib may be continued at principal investigator's discretion during conditioning
* Non-compliance; defined as any subject, who in the opinion of the investigator, may not be able to comply with the safety monitoring requirements of the study
18 Years
75 Years
ALL
No
Sponsors
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National Cancer Institute (NCI)
NIH
City of Hope Medical Center
OTHER
Responsible Party
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Principal Investigators
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Haris Ali
Role: PRINCIPAL_INVESTIGATOR
City of Hope Medical Center
Locations
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City of Hope Medical Center
Duarte, California, United States
Countries
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References
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Ali H, Tsai NC, Synold T, Mokhtari S, Tsia W, Palmer J, Stiller T, Al Malki M, Aldoss I, Salhotra A, Rahmanuddin S, Pullarkat V, Cai JL, Stein A, Forman SJ, Marcucci G, Mei M, Snyder DS, Nakamura R. Peritransplantation ruxolitinib administration is safe and effective in patients with myelofibrosis: a pilot open-label study. Blood Adv. 2022 Mar 8;6(5):1444-1453. doi: 10.1182/bloodadvances.2021005035.
Other Identifiers
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NCI-2016-01400
Identifier Type: REGISTRY
Identifier Source: secondary_id
16337
Identifier Type: OTHER
Identifier Source: secondary_id
16337
Identifier Type: -
Identifier Source: org_study_id