- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT02917096
Ruxolitinib Phosphate and Chemotherapy Given Before and After Reduced Intensity Donor Stem Cell Transplant in Treating Patients With Myelofibrosis
Pilot Open-Label Study of Safety and Efficacy of Ruxolitinib Given Peri-Transplant During Reduced Intensity Allogeneic Hematopoietic Cell Transplantation (HCT) in Patients With Myelofibrosis
Study Overview
Status
Conditions
Detailed Description
PRIMARY OBJECTIVES:
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.
Study Type
Enrollment (Actual)
Phase
- Phase 1
Contacts and Locations
Study Locations
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California
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Duarte, California, United States, 91010
- City of Hope Medical Center
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Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Description
Inclusion Criteria:
- Primary or secondary myelofibrosis intermediate or high risk by Dynamic International Prognostic Scoring System (DIPSS) in chronic or accelerated phase
- 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 should not have any uncontrolled illnesses including ongoing or active infection
- 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
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: N/A
- Interventional Model: Single Group Assignment
- Masking: None (Open Label)
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Experimental: 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. |
Correlative studies
Correlative studies
Given IV
Other Names:
Given IV
Other Names:
Given IV and PO
Other Names:
Given IV
Other Names:
Given PO
Other Names:
Given PO
Other Names:
Given PO
Other Names:
Undergo allogeneic HCT
Other Names:
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What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Maximum tolerated dose of ruxolitinib phosphate, defined as less than or equal to 1 of 6 dose limiting toxicities, graded according to the Bearman criteria and the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03
Time Frame: Up to 45 days post stem cell infusion
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Will be summarized in terms of type (organ affected, or laboratory determination) severity, time of onset, duration, probable associates with the study treatment and reversibility or outcome.
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Up to 45 days post stem cell infusion
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Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Engraftment (recovery of granulopoiesis and megakaryopoiesis)
Time Frame: Up to 100 days post stem cell infusion
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Defined as absolute neutrophil count >= 0.5 x 10^3/ul sustained for 3 consecutive lab values on different days with no subsequent decline, and platelets >= 20 K/ul independent of platelet transfusion support.
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Up to 100 days post stem cell infusion
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Cumulative incidence of acute graft-versus-host disease (aGVHD), graded and staged according to the Consensus Grading
Time Frame: Up to 100 days post stem cell infusion
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Will be calculated using the Gray method with prior death or relapse considered competing events.
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Up to 100 days post stem cell infusion
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Cumulative incidence of chronic GVHD, graded and staged according to the Consensus Grading
Time Frame: Up to 100 days post stem cell infusion
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Will be calculated using the Gray method with prior death or relapse considered competing events.
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Up to 100 days post stem cell infusion
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Incidence of infections
Time Frame: Up to 100 days post stem cell infusion
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Will be reported by site of disease, date of onset, severity and resolution, if any.
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Up to 100 days post stem cell infusion
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Overall survival
Time Frame: From the day of stem cell infusion until death, or last follow-up, whichever occurs first, assessed for up to 2 years
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Will be calculated using the Kaplan-Meier method.
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From the day of stem cell infusion until death, or last follow-up, whichever occurs first, assessed for up to 2 years
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Progression-free survival
Time Frame: From the day of stem cell infusion to the date of death, disease relapse/progression, or last follow-up, whichever occurs first, assessed for up to 2 years
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Will be calculated using the Kaplan-Meier method.
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From the day of stem cell infusion to the date of death, disease relapse/progression, or last follow-up, whichever occurs first, assessed for up to 2 years
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Cumulative incidence of relapse/progression
Time Frame: Up to 2 years
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Will be calculated as a competing risk using the Gray method.
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Up to 2 years
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Non-relapse mortality, defined as death occurring in a patient from causes other than relapse or progression
Time Frame: Up to 2 years
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Will be calculated as a competing risk using the Gray method.
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Up to 2 years
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Collaborators and Investigators
Sponsor
Collaborators
Investigators
- Principal Investigator: Haris Ali, City of Hope Medical Center
Publications and helpful links
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Estimated)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
- Bone Marrow Diseases
- Hematologic Diseases
- Myeloproliferative Disorders
- Primary Myelofibrosis
- Physiological Effects of Drugs
- Molecular Mechanisms of Pharmacological Action
- Anti-Infective Agents
- Antiviral Agents
- Enzyme Inhibitors
- Antimetabolites, Antineoplastic
- Antimetabolites
- Antineoplastic Agents
- Immunosuppressive Agents
- Immunologic Factors
- Antineoplastic Agents, Alkylating
- Alkylating Agents
- Myeloablative Agonists
- Anti-Bacterial Agents
- Antibiotics, Antineoplastic
- Antifungal Agents
- Calcineurin Inhibitors
- Melphalan
- Fludarabine
- Fludarabine phosphate
- Tacrolimus
- Sirolimus
- Mechlorethamine
- Nitrogen Mustard Compounds
- Vidarabine
Other Study ID Numbers
- 16337 (Other Identifier: City of Hope Medical Center)
- NCI-2016-01400 (Registry Identifier: CTRP (Clinical Trial Reporting Program))
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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