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Ruxolitinib Phosphate and Chemotherapy Given Before and After Reduced Intensity Donor Stem Cell Transplant in Treating Patients With Myelofibrosis

Primary Purpose

Primary Myelofibrosis, Secondary Myelofibrosis

Status
Active
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
Allogeneic Hematopoietic Stem Cell Transplantation
Fludarabine
Fludarabine Phosphate
Laboratory Biomarker Analysis
Melphalan
Pharmacological Study
Ruxolitinib
Ruxolitinib Phosphate
Sirolimus
Tacrolimus
Sponsored by
City of Hope Medical Center
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Primary Myelofibrosis

Eligibility Criteria

18 Years - 75 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • City of Hope Medical Center

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Treatment (ruxolitinib phosphate, chemotherapy,allogeneic HCT)

Arm Description

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.

Outcomes

Primary Outcome Measures

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
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.

Secondary Outcome Measures

Engraftment (recovery of granulopoiesis and megakaryopoiesis)
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.
Cumulative incidence of acute graft-versus-host disease (aGVHD), graded and staged according to the Consensus Grading
Will be calculated using the Gray method with prior death or relapse considered competing events.
Cumulative incidence of chronic GVHD, graded and staged according to the Consensus Grading
Will be calculated using the Gray method with prior death or relapse considered competing events.
Incidence of infections
Will be reported by site of disease, date of onset, severity and resolution, if any.
Overall survival
Will be calculated using the Kaplan-Meier method.
Progression-free survival
Will be calculated using the Kaplan-Meier method.
Cumulative incidence of relapse/progression
Will be calculated as a competing risk using the Gray method.
Non-relapse mortality, defined as death occurring in a patient from causes other than relapse or progression
Will be calculated as a competing risk using the Gray method.

Full Information

First Posted
September 26, 2016
Last Updated
December 8, 2022
Sponsor
City of Hope Medical Center
Collaborators
National Cancer Institute (NCI)
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1. Study Identification

Unique Protocol Identification Number
NCT02917096
Brief Title
Ruxolitinib Phosphate and Chemotherapy Given Before and After Reduced Intensity Donor Stem Cell Transplant in Treating Patients With Myelofibrosis
Official Title
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 Type
Interventional

2. Study Status

Record Verification Date
December 2022
Overall Recruitment Status
Active, not recruiting
Study Start Date
November 13, 2016 (Actual)
Primary Completion Date
April 16, 2020 (Actual)
Study Completion Date
November 16, 2023 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
City of Hope Medical Center
Collaborators
National Cancer Institute (NCI)

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
This pilot clinical trial studies the side effects and best dose of ruxolitinib phosphate when given together with chemotherapy before and after a donor stem cell transplant in treating patients with myelofibrosis. Ruxolitinib phosphate may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as fludarabine phosphate and melphalan, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving ruxolitinib phosphate together with chemotherapy before and after a donor stem cell transplant may help stop the growth of cells in the bone marrow, including normal blood-forming cells (stem cells) and cancer cells. It may also stop the patient's immune system from rejecting the donor's stem cells. When the healthy stem cells from a donor are infused into the patient they may help the patient's bone marrow make stem cells, red blood cells, white blood cells, and platelets. The donated stem cells may also replace the patient?s immune cells and help destroy any remaining cancer cells.
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.

6. Conditions and Keywords

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

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
18 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Treatment (ruxolitinib phosphate, chemotherapy,allogeneic HCT)
Arm Type
Experimental
Arm Description
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.
Intervention Type
Procedure
Intervention Name(s)
Allogeneic Hematopoietic Stem Cell Transplantation
Other Intervention Name(s)
Allogeneic Hematopoietic Cell Transplantation, Allogeneic Stem Cell Transplantation, HSC, HSCT
Intervention Description
Undergo allogeneic HCT
Intervention Type
Drug
Intervention Name(s)
Fludarabine
Other Intervention Name(s)
Fluradosa
Intervention Description
Given IV
Intervention Type
Drug
Intervention Name(s)
Fludarabine Phosphate
Other Intervention Name(s)
2-F-ara-AMP, 9H-Purin-6-amine, 2-fluoro-9-(5-O-phosphono-.beta.-D-arabinofuranosyl)-, Beneflur, Fludara, SH T 586
Intervention Description
Given IV
Intervention Type
Other
Intervention Name(s)
Laboratory Biomarker Analysis
Intervention Description
Correlative studies
Intervention Type
Drug
Intervention Name(s)
Melphalan
Other Intervention Name(s)
Alanine Nitrogen Mustard, CB-3025, L-PAM, L-Phenylalanine Mustard, L-sarcolysin, L-Sarcolysin Phenylalanine mustard, L-Sarcolysine, Melphalanum, Phenylalanine Mustard, Phenylalanine nitrogen mustard, Sarcoclorin, Sarkolysin, WR-19813
Intervention Description
Given IV
Intervention Type
Other
Intervention Name(s)
Pharmacological Study
Intervention Description
Correlative studies
Intervention Type
Drug
Intervention Name(s)
Ruxolitinib
Other Intervention Name(s)
INCB-18424, INCB18424, Oral JAK Inhibitor INCB18424
Intervention Description
Given PO
Intervention Type
Drug
Intervention Name(s)
Ruxolitinib Phosphate
Other Intervention Name(s)
INCB-18424 Phosphate, Jakafi
Intervention Description
Given PO
Intervention Type
Drug
Intervention Name(s)
Sirolimus
Other Intervention Name(s)
AY 22989, RAPA, Rapamune, Rapamycin, SILA 9268A, WY-090217
Intervention Description
Given PO
Intervention Type
Drug
Intervention Name(s)
Tacrolimus
Other Intervention Name(s)
FK 506, Fujimycin, Hecoria, Prograf, Protopic
Intervention Description
Given IV and PO
Primary Outcome Measure Information:
Title
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
Description
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.
Time Frame
Up to 45 days post stem cell infusion
Secondary Outcome Measure Information:
Title
Engraftment (recovery of granulopoiesis and megakaryopoiesis)
Description
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.
Time Frame
Up to 100 days post stem cell infusion
Title
Cumulative incidence of acute graft-versus-host disease (aGVHD), graded and staged according to the Consensus Grading
Description
Will be calculated using the Gray method with prior death or relapse considered competing events.
Time Frame
Up to 100 days post stem cell infusion
Title
Cumulative incidence of chronic GVHD, graded and staged according to the Consensus Grading
Description
Will be calculated using the Gray method with prior death or relapse considered competing events.
Time Frame
Up to 100 days post stem cell infusion
Title
Incidence of infections
Description
Will be reported by site of disease, date of onset, severity and resolution, if any.
Time Frame
Up to 100 days post stem cell infusion
Title
Overall survival
Description
Will be calculated using the Kaplan-Meier method.
Time Frame
From the day of stem cell infusion until death, or last follow-up, whichever occurs first, assessed for up to 2 years
Title
Progression-free survival
Description
Will be calculated using the Kaplan-Meier method.
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
Title
Cumulative incidence of relapse/progression
Description
Will be calculated as a competing risk using the Gray method.
Time Frame
Up to 2 years
Title
Non-relapse mortality, defined as death occurring in a patient from causes other than relapse or progression
Description
Will be calculated as a competing risk using the Gray method.
Time Frame
Up to 2 years

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
75 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Haris Ali
Organizational Affiliation
City of Hope Medical Center
Official's Role
Principal Investigator
Facility Information:
Facility Name
City of Hope Medical Center
City
Duarte
State/Province
California
ZIP/Postal Code
91010
Country
United States

12. IPD Sharing Statement

Citations:
PubMed Identifier
34581764
Citation
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.
Results Reference
derived

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Ruxolitinib Phosphate and Chemotherapy Given Before and After Reduced Intensity Donor Stem Cell Transplant in Treating Patients With Myelofibrosis

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