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JAK1/2 Inhibitor Ruxolitinib for Relapsed/Refractory Immune Bone Marrow Failure

Primary Purpose

Severe Aplastic Anemia, Single Lineage Cytopenias, T-LGL, Hypoplastic MDS

Status
Not yet recruiting
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
Ruxolitinib
Sponsored by
National Heart, Lung, and Blood Institute (NHLBI)
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Severe Aplastic Anemia focused on measuring Hematologic toxicity, Ruxolitinib

Eligibility Criteria

18 Years - 99 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

INCLUSION/EXCLUSION CRITERIA: Participants of both sexes will be considered for inclusion in this study. There will be no racial, ethnic, or gender discrimination. To be eligible to participate in the treatment portion of this study, an individual must meet all of the following inclusion criteria and none of the following exclusion criteria: INCLUSION CRITERIA: ALL COHORTS: Ability of the participant or legally authorized representative (LAR) to understand and be willing to sign a written informed consent document Age 18 or older For females of childbearing potential, stated willingness to use an accepted method of contraception for the duration of the study. Accepted methods of contraception are: Total abstinence Use of an implanted or intrauterine hormonal device for at least 30 consecutive days before study drug administration Use of oral, patch or injectable contraceptives or a vaginal hormonal device for at least 30 consecutive days before study drug infusion Use of a non-hormonal intrauterine device for at least 30 consecutive days before study drug administration Two barrier methods such as a diaphragm with spermicide or a condom with spermicide For sexually active males with a female partner of childbearing potential, stated willingness to agree to use a condom with spermicide for the duration of the study. Diagnosis of immune bone marrow failure (see specific cohort) COHORT 1: RELAPSED/REFRACTORY SAA: Meet all 3 criteria below: Severe aplastic anemia: -Bone marrow cellularity <30% excluding lymphocytes AND At least two of the following: Absolute neutrophil count < 0.5 x 10^9/L Platelet count < 20 x 10^9/L Absolute Reticulocyte count < 60 x 10^9/L Relapsed or refractory disease as evidenced by a course of at least 1 prior therapy. Not suitable for transplant due to age, co-morbidities, lack of suitable donor, or participant choice. COHORT 2: RELAPSED/REFRACTORY MODERATE AA: Moderate AA: Aplastic anemia (hypocellular bone marrow for age) with no evidence for other disease processes causing marrow failure, and depression of at least two out of three blood counts below the normal values but not fulfilling the criteria for SAA: Absolute neutrophil count <= l.2 x 10^9/L Platelet count <= 70 x 10^9/L Anemia with hemoglobin <= 9 g/dL and absolute reticulocyte count < 60 x 10^9/L or transfusion dependence Relapsed or refractory disease as evidenced by a course of at least 1 prior therapy. COHORT 3: RELAPSED/REFRACTORY UNILINEAGE BONE MARROW FAILURE DISORDERS: Cytopenia in lineage as below: -Erythroid lineage: Hemoglobin <= 9 g/dL and reticulocyte count < 60 x 10^9/L or red cell transfusion dependence and hypocellular bone marrow for age with absent or reduced red cell precursors OR Platelet lineage: Thrombocytopenia <= 30 x 10^9/L or platelet transfusion dependence and hypocellular bone marrow for age with absent or reduced megakaryocytes OR Granulocyte lineage: Neutropenia <= 0.5 x 10^9/L and hypocellular bone marrow for age with absent or reduced granulopoiesis No evidence of viral or drug suppression of the marrow, T-LGL, dysplasia, or underproduction anemias secondary to B12, folate, iron or other reversible causes. Relapsed or refractory disease as evidenced by a course of at least 1 prior therapy. COHORT 4: RELAPSED/REFRACTORY T-LGL WITH CYTOPENIAS: Clinical history supportive of the diagnosis of T-LGL leukemia (i.e., a history of cytopenias with peripheral blood morphologic evidence of LGLs). Immunophenotypic studies of peripheral blood showing an increased population of T-LGLs (suggested by staining with CD3+, CD8+ and CD16+ or CD57+) or gamma-delta T cells. Restricted or clonal rearrangement of the T-cell receptor by PCR AND cytopenia as follows: Severe neutropenia (< 0.5 x 10^9/L); OR Severe thrombocytopenia (<= 20 x 10^9/L), or moderate thrombocytopenia (<= 50 x 10^9/L) with active bleeding; OR Symptomatic anemia with a hemoglobin <= 9 g/dL or red blood cell transfusion dependence -Relapsed or refractory disease as evidenced by a course of at least 1 prior therapy. COHORT 5: HYPOPLASTIC MDS: -A diagnosis of hypoplastic MDS by WHO 2016, WHO 2022, or ICC criteria with significant cytopenias defined as: Bone marrow hypocellular for age AND Either morphologic dysplasia or cytogenetic abnormality AND At least one of the following: Neutropenia: Absolute neutrophil count < 0.5 x 10^9/L Thrombocytopenia: Platelet count < 30 x 10^9/L or platelet transfusion dependence Anemia: Hemoglobin < 9g/dL or red cell transfusion-dependence or absolute reticulocyte count <60 x 10^9/L Relapsed or refractory disease as evidenced by a course of at least 1 prior therapy EXCLUSION CRITERIA: An individual who meets any of the following criteria will be excluded from participation in this study: Known diagnosis or high suspicion of Fanconi anemia or other constitutional marrow failure syndrome Evidence of a clonal disorder with poor risk cytogenetics per R-IPSS criteria involving chromosome 7 (-7del/-7), chromosome 3 (inv 3/del3/t(3)) or three or more chromosomal abnormalities (complex). MDS with EB-1, EB-2, AML, chronic myelomonocytic leukemia (CMML), MDS/MPN. For MDS: Has received erythropoiesis-stimulating agent (ESA), hypomethylating agent, chemotherapy, or immunomodulatory therapy within 8 weeks prior to study entry. History of progressive multifocal leuko-encephalopathy (PML) Infection not adequately responding to appropriate therapy Participants with untreated or poorly controlled HIV, Hepatitis B or C Participants with cancer who are on active chemotherapeutic treatment Presence of severely impaired renal function defined by CrCl (as calculated by eGFR) less than 15 mL/min not requiring renal dialysis Current pregnancy, or unwillingness to take oral contraceptives or use a barrier method of birth control or practice abstinence to refrain from pregnancy if of childbearing potential during this study Moribund status or concurrent hepatic, renal, cardiac, neurologic, pulmonary, infectious, or metabolic disease of such severity that it would preclude the participant s ability to tolerate protocol therapy, or that death within 7-10 days is likely Inability to understand the investigational nature of the study or to give informed consent or does not have a legally authorized representative or surrogate that can provide informed consent Hypersensitivity to ruxolitinib or its components Inability to swallow pills Currently breastfeeding Active non-melanoma skin cancer Acute thrombosis (myocardial infarction, ischemic heart disease requiring stents, stroke, pulmonary embolism, or deep venous thrombosis) within the last 6 months Patients with a PNH clone >50% who are not taking anticoagulation or anticomplement therapy

Sites / Locations

  • National Institutes of Health Clinical Center

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm 5

Arm Type

Experimental

Experimental

Experimental

Experimental

Experimental

Arm Label

Subjects with hypoplastic MDS

Subjects with MAA

Subjects with PRCA

Subjects with SAA

Subjects with TLGL

Arm Description

Subjects are defined as patients with a diagnosis of hMDS clinically confirmed by a licensed physician or an advanced practitioner who meets the inclusion and exclusion criteria and can provide informed consent.

Subjects are defined as patients with a diagnosis of MAA clinically confirmed by a licensed physician or an advanced practitioner who meets the inclusion andexclusion criteria and can provide informed consent.

Subjects are defined as patients with a diagnosis of PRCA clinically confirmed by a licensed physician or advanced practitioners who meet the inclusion and exclusion criteria and can provide informed consent.

Subjects are defined as patients with a diagnosis of SAA clinically confirmed by a licensed physician oran advanced practitioner who meets the inclusion andexclusion criteria and can provide informed consent.

Subjects are defined as patients with a diagnosis of TLGL clinically confirmed by a licensed physician or advanced practitioner who meets the inclusion and exclusion criteria and can provide informed consent.

Outcomes

Primary Outcome Measures

The number of patients who complete a full course of ruxolitinib without cessation is required by hematologic toxicity.
The primary safety endpoint will be the number of patients who complete a full course of ruxolitinib without cessation required by hematologic toxicity in the 6 months following treatment initiation.
Overall Response Rate. Patients who develop a Complete response at 3 months and stop the drug will also be deemed responders even if they subsequently relapse.
The primary efficacy endpoint is the OR rate by 6 months. Patients who develop CR at 3 months and stop the drug will also be deemed responders even if they subsequently relapse.

Secondary Outcome Measures

Hematological response
Depth of response
Rate of clonal evolution
Rate of relapse
Time to transfusion independence
Overall survival
Hematological response of relapse subjects that re-start treatment
Percent of patients tolerating 20 mg ruxolitinib BID.

Full Information

First Posted
August 17, 2023
Last Updated
October 24, 2023
Sponsor
National Heart, Lung, and Blood Institute (NHLBI)
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1. Study Identification

Unique Protocol Identification Number
NCT05998408
Brief Title
JAK1/2 Inhibitor Ruxolitinib for Relapsed/Refractory Immune Bone Marrow Failure
Official Title
A Phase I/II Study of the JAK1/2 Inhibitor Ruxolitinib for Relapsed/Refractory Immune Bone Marrow Failure
Study Type
Interventional

2. Study Status

Record Verification Date
August 22, 2023
Overall Recruitment Status
Not yet recruiting
Study Start Date
October 30, 2023 (Anticipated)
Primary Completion Date
June 3, 2030 (Anticipated)
Study Completion Date
June 3, 2032 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
National Heart, Lung, and Blood Institute (NHLBI)

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No

5. Study Description

Brief Summary
Background: Immune bone marrow failure is a condition that occurs when a person s immune system attacks the cells of the bone marrow. This can lead to diseases including different types of anemias and blood cancers. Some of these diseases can be deadly. Better treatments are needed. Objective: To test a drug (ruxolitinib) in people with different types of immune bone marrow failure. Eligibility: Adults aged 18 and older with an immune bone marrow failure. Design: Participants will be screened. They will have a physical exam. They will give samples of blood and saliva. They will have a bone marrow biopsy: A large needle will be inserted into a small cut to remove a sample of the soft tissue inside the bone. Some participants may have a skin biopsy: A small piece of skin will be removed. Some may have a computed tomography (CT) scan: They will lie on a table that slides into a donut-shaped machine that uses X-rays to make pictures of the inside of the body. Ruxolitinib is a tablet taken by mouth. Participants will take the drug twice a day for up to 6 months. Participants will have blood tests every week while they are taking the drug. These tests can be done by the participant s own physician and the results sent to the researchers. Participants will have clinic visits after taking the drug for 3 months and 6 months and then after 1, 2, and 3 years. The blood tests and bone marrow biopsy will be repeated. Participants who improve while taking the drugs may go on to an extension phase of the study.
Detailed Description
Study description: This is a prospective, non-randomized, phase I/II study in which participants with relapsed/refractory immune marrow failure (severe aplastic anemia, moderate aplastic anemia, single lineage cytopenias, T-LGL, and hypoplastic MDS) will be treated with the JAK1/2 inhibitor ruxolitinib. Our hypothesis is that JAK1/2 inhibition with ruxolitinib will result in hematologic improvement in participants with immune marrow failure. Objectives: The primary objectives are to assess safety and efficacy of the JAK1/2 inhibitor ruxolitinib in immune marrow failure. The secondary objectives are to assess early and long-term hematologic response, depth of response, development of transfusion independence, rate of relapse, rate of clonal evolution to myeloid malignancy and Paroxysmal Nocturnal Hemoglobinuria (PNH), 3-year overall survival, response after re-initiation of therapy in relapsed participants, maximum tolerated dose. Endpoints: The primary endpoints are: (a) the primary safety endpoint will be number of participants who complete a full course of ruxolitinib without cessation required by hematologic toxicity in the 6 months following treatment initiation; (b) The primary efficacy endpoint is overall response (OR) rate by 6 months. The secondary endpoints are time to OR, OR at 3 months, development of transfusion independence at 3 and 6 months, type of response at 3 and 6 months, rate of relapse up to 3 years, rate of clonal evolution up to 3 years, 3-year overall survival (OS), and number of participants tolerating maximum ruxolitinib dose.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Severe Aplastic Anemia, Single Lineage Cytopenias, T-LGL, Hypoplastic MDS
Keywords
Hematologic toxicity, Ruxolitinib

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
145 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Subjects with hypoplastic MDS
Arm Type
Experimental
Arm Description
Subjects are defined as patients with a diagnosis of hMDS clinically confirmed by a licensed physician or an advanced practitioner who meets the inclusion and exclusion criteria and can provide informed consent.
Arm Title
Subjects with MAA
Arm Type
Experimental
Arm Description
Subjects are defined as patients with a diagnosis of MAA clinically confirmed by a licensed physician or an advanced practitioner who meets the inclusion andexclusion criteria and can provide informed consent.
Arm Title
Subjects with PRCA
Arm Type
Experimental
Arm Description
Subjects are defined as patients with a diagnosis of PRCA clinically confirmed by a licensed physician or advanced practitioners who meet the inclusion and exclusion criteria and can provide informed consent.
Arm Title
Subjects with SAA
Arm Type
Experimental
Arm Description
Subjects are defined as patients with a diagnosis of SAA clinically confirmed by a licensed physician oran advanced practitioner who meets the inclusion andexclusion criteria and can provide informed consent.
Arm Title
Subjects with TLGL
Arm Type
Experimental
Arm Description
Subjects are defined as patients with a diagnosis of TLGL clinically confirmed by a licensed physician or advanced practitioner who meets the inclusion and exclusion criteria and can provide informed consent.
Intervention Type
Drug
Intervention Name(s)
Ruxolitinib
Intervention Description
Subjects will be instructed to take ruxolitinib at up to 20mg (total) BID for up to 6 months (with or without food)
Primary Outcome Measure Information:
Title
The number of patients who complete a full course of ruxolitinib without cessation is required by hematologic toxicity.
Description
The primary safety endpoint will be the number of patients who complete a full course of ruxolitinib without cessation required by hematologic toxicity in the 6 months following treatment initiation.
Time Frame
6 months
Title
Overall Response Rate. Patients who develop a Complete response at 3 months and stop the drug will also be deemed responders even if they subsequently relapse.
Description
The primary efficacy endpoint is the OR rate by 6 months. Patients who develop CR at 3 months and stop the drug will also be deemed responders even if they subsequently relapse.
Time Frame
6 months
Secondary Outcome Measure Information:
Title
Hematological response
Time Frame
3, 12 months, and yearly thereafter
Title
Depth of response
Time Frame
3, 6 months
Title
Rate of clonal evolution
Time Frame
Variable
Title
Rate of relapse
Time Frame
Variable
Title
Time to transfusion independence
Time Frame
Variable
Title
Overall survival
Time Frame
Variable
Title
Hematological response of relapse subjects that re-start treatment
Time Frame
Variable
Title
Percent of patients tolerating 20 mg ruxolitinib BID.
Time Frame
Variable

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
99 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
INCLUSION/EXCLUSION CRITERIA: Participants of both sexes will be considered for inclusion in this study. There will be no racial, ethnic, or gender discrimination. To be eligible to participate in the treatment portion of this study, an individual must meet all of the following inclusion criteria and none of the following exclusion criteria: INCLUSION CRITERIA: ALL COHORTS: Ability of the participant or legally authorized representative (LAR) to understand and be willing to sign a written informed consent document Age 18 or older For females of childbearing potential, stated willingness to use an accepted method of contraception for the duration of the study. Accepted methods of contraception are: Total abstinence Use of an implanted or intrauterine hormonal device for at least 30 consecutive days before study drug administration Use of oral, patch or injectable contraceptives or a vaginal hormonal device for at least 30 consecutive days before study drug infusion Use of a non-hormonal intrauterine device for at least 30 consecutive days before study drug administration Two barrier methods such as a diaphragm with spermicide or a condom with spermicide For sexually active males with a female partner of childbearing potential, stated willingness to agree to use a condom with spermicide for the duration of the study. Diagnosis of immune bone marrow failure (see specific cohort) COHORT 1: RELAPSED/REFRACTORY SAA: Meet all 3 criteria below: Severe aplastic anemia: -Bone marrow cellularity <30% excluding lymphocytes AND At least two of the following: Absolute neutrophil count < 0.5 x 10^9/L Platelet count < 20 x 10^9/L Absolute Reticulocyte count < 60 x 10^9/L Relapsed or refractory disease as evidenced by a course of at least 1 prior therapy. Not suitable for transplant due to age, co-morbidities, lack of suitable donor, or participant choice. COHORT 2: RELAPSED/REFRACTORY MODERATE AA: Moderate AA: Aplastic anemia (hypocellular bone marrow for age) with no evidence for other disease processes causing marrow failure, and depression of at least two out of three blood counts below the normal values but not fulfilling the criteria for SAA: Absolute neutrophil count <= l.2 x 10^9/L Platelet count <= 70 x 10^9/L Anemia with hemoglobin <= 9 g/dL and absolute reticulocyte count < 60 x 10^9/L or transfusion dependence Relapsed or refractory disease as evidenced by a course of at least 1 prior therapy. COHORT 3: RELAPSED/REFRACTORY UNILINEAGE BONE MARROW FAILURE DISORDERS: Cytopenia in lineage as below: -Erythroid lineage: Hemoglobin <= 9 g/dL and reticulocyte count < 60 x 10^9/L or red cell transfusion dependence and hypocellular bone marrow for age with absent or reduced red cell precursors OR Platelet lineage: Thrombocytopenia <= 30 x 10^9/L or platelet transfusion dependence and hypocellular bone marrow for age with absent or reduced megakaryocytes OR Granulocyte lineage: Neutropenia <= 0.5 x 10^9/L and hypocellular bone marrow for age with absent or reduced granulopoiesis No evidence of viral or drug suppression of the marrow, T-LGL, dysplasia, or underproduction anemias secondary to B12, folate, iron or other reversible causes. Relapsed or refractory disease as evidenced by a course of at least 1 prior therapy. COHORT 4: RELAPSED/REFRACTORY T-LGL WITH CYTOPENIAS: Clinical history supportive of the diagnosis of T-LGL leukemia (i.e., a history of cytopenias with peripheral blood morphologic evidence of LGLs). Immunophenotypic studies of peripheral blood showing an increased population of T-LGLs (suggested by staining with CD3+, CD8+ and CD16+ or CD57+) or gamma-delta T cells. Restricted or clonal rearrangement of the T-cell receptor by PCR AND cytopenia as follows: Severe neutropenia (< 0.5 x 10^9/L); OR Severe thrombocytopenia (<= 20 x 10^9/L), or moderate thrombocytopenia (<= 50 x 10^9/L) with active bleeding; OR Symptomatic anemia with a hemoglobin <= 9 g/dL or red blood cell transfusion dependence -Relapsed or refractory disease as evidenced by a course of at least 1 prior therapy. COHORT 5: HYPOPLASTIC MDS: -A diagnosis of hypoplastic MDS by WHO 2016, WHO 2022, or ICC criteria with significant cytopenias defined as: Bone marrow hypocellular for age AND Either morphologic dysplasia or cytogenetic abnormality AND At least one of the following: Neutropenia: Absolute neutrophil count < 0.5 x 10^9/L Thrombocytopenia: Platelet count < 30 x 10^9/L or platelet transfusion dependence Anemia: Hemoglobin < 9g/dL or red cell transfusion-dependence or absolute reticulocyte count <60 x 10^9/L Relapsed or refractory disease as evidenced by a course of at least 1 prior therapy EXCLUSION CRITERIA: An individual who meets any of the following criteria will be excluded from participation in this study: Known diagnosis or high suspicion of Fanconi anemia or other constitutional marrow failure syndrome Evidence of a clonal disorder with poor risk cytogenetics per R-IPSS criteria involving chromosome 7 (-7del/-7), chromosome 3 (inv 3/del3/t(3)) or three or more chromosomal abnormalities (complex). MDS with EB-1, EB-2, AML, chronic myelomonocytic leukemia (CMML), MDS/MPN. For MDS: Has received erythropoiesis-stimulating agent (ESA), hypomethylating agent, chemotherapy, or immunomodulatory therapy within 8 weeks prior to study entry. History of progressive multifocal leuko-encephalopathy (PML) Infection not adequately responding to appropriate therapy Participants with untreated or poorly controlled HIV, Hepatitis B or C Participants with cancer who are on active chemotherapeutic treatment Presence of severely impaired renal function defined by CrCl (as calculated by eGFR) less than 15 mL/min not requiring renal dialysis Current pregnancy, or unwillingness to take oral contraceptives or use a barrier method of birth control or practice abstinence to refrain from pregnancy if of childbearing potential during this study Moribund status or concurrent hepatic, renal, cardiac, neurologic, pulmonary, infectious, or metabolic disease of such severity that it would preclude the participant s ability to tolerate protocol therapy, or that death within 7-10 days is likely Inability to understand the investigational nature of the study or to give informed consent or does not have a legally authorized representative or surrogate that can provide informed consent Hypersensitivity to ruxolitinib or its components Inability to swallow pills Currently breastfeeding Active non-melanoma skin cancer Acute thrombosis (myocardial infarction, ischemic heart disease requiring stents, stroke, pulmonary embolism, or deep venous thrombosis) within the last 6 months Patients with a PNH clone >50% who are not taking anticoagulation or anticomplement therapy
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Ivana Darden, R.N.
Phone
(301) 827-2988
Email
ivana.darden@nih.gov
First Name & Middle Initial & Last Name or Official Title & Degree
Emma M Groarke, M.D.
Phone
(301) 496-5093
Email
emma.groarke@nih.gov
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Emma M Groarke, M.D.
Organizational Affiliation
National Heart, Lung, and Blood Institute (NHLBI)
Official's Role
Principal Investigator
Facility Information:
Facility Name
National Institutes of Health Clinical Center
City
Bethesda
State/Province
Maryland
ZIP/Postal Code
20892
Country
United States
Facility Contact:
First Name & Middle Initial & Last Name & Degree
NIH Clinical Center Office of Patient Recruitment (OPR)
Phone
800-411-1222
Ext
TTY dial 711
Email
ccopr@nih.gov

12. IPD Sharing Statement

Plan to Share IPD
No
Links:
URL
https://clinicalstudies.info.nih.gov/cgi/detail.cgi?B_001667-H.html
Description
NIH Clinical Center Detailed Web Page

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JAK1/2 Inhibitor Ruxolitinib for Relapsed/Refractory Immune Bone Marrow Failure

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