A Phase I/II Study of the JAK1/2 Inhibitor Ruxolitinib for Relapsed / Refractory Immune Bone Marrow Failure
试验速览
- 阶段
- 1 期
- 状态
- 进行中（未招募）
- 入组人数
- 13
- 试验地点
- 1
- 主要终点
- The number of patients who complete a full course of ruxolitinib without cessation is required by hematologic toxicity.
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 99 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •INCLUSION/
排除标准
- •Participants of both sexes will be considered for inclusion in this study. There will be no racial, ethnic, or sex 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
- •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.
- •Patients who have a documented historic diagnosis of SAA and have received an ATG-based therapy in the past and are now relapsed / refractory may be included in this cohort even if documentation of original CBC and bone marrow are unavailable.
- •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 bone marrow with absent or reduced red cell precursors
- •Platelet lineage: Thrombocytopenia <= 30 x 10^9/L or platelet transfusion dependence and bone marrow with absent or reduced megakaryocytes
- •Granulocyte lineage: Neutropenia <= 0.5 x 10^9/L and bone marrow for 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);
- •Severe thrombocytopenia (<= 20 x 10^9/L), or moderate thrombocytopenia (<= 50 x 10^9/L) with active bleeding;
- •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
- 另有 26 项未显示
研究组 & 干预措施
Cohort 2: Participants with Moderate Aplastic Anemia (MAA)
Participants diagnosed with Moderate Aplastic Anemia (MAA) will be administered ruxolitinib 5 mg by mouth twice daily. The dose will be increased weekly in 5 mg twice-daily increments, up to a maximum dose of 20 mg by mouth twice daily.
干预措施: Ruxolitinib (Drug)
Cohort 3: Participants with Unilineage Bone Marrow Failure Disorder
Participants diagnosed with Unilineage Bone Marrow Failure Disorder will be administered ruxolitinib 5 mg by mouth twice daily. The dose will be increased weekly in 5 mg twice-daily increments, up to a maximum dose of 20 mg by mouth twice daily.
干预措施: Ruxolitinib (Drug)
Cohort 4: Participants with T-cell large granular lymphocyte (T-LGL) leukemia
Participants diagnosed with T-cell large granular lymphocyte (T-LGL) will be administered ruxolitinib 5 mg by mouth twice daily. The dose will be increased weekly in 5 mg twice-daily increments, up to a maximum dose of 20 mg by mouth twice daily
干预措施: Ruxolitinib (Drug)
Cohort 5: Participants with hypoplastic myelodysplastic syndrome (hMDS)
Participants diagnosed with hypoplastic myelodysplastic syndrome (hMDS) will be administered ruxolitinib 5 mg by mouth twice daily. The dose will be increased weekly in 5 mg twice-daily increments, up to a maximum dose of 20 mg by mouth twice daily.
干预措施: Ruxolitinib (Drug)
Cohort 1: PParticipants with Severe Aplastic Anemia (SAA)
Participants diagnosed with Severe Aplastic Anemia (SAA) will be administered ruxolitinib 5 mg by mouth twice daily. The dose will be increased weekly in 5 mg twice-daily increments, up to a maximum dose of 20 mg by mouth twice daily.
干预措施: Ruxolitinib (Drug)
结局指标
主要结局
The number of patients who complete a full course of ruxolitinib without cessation is required by hematologic toxicity.
时间窗: 6 months
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.
时间窗: 6 months
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.
Number of Participants Who Completed a Full Course of Ruxolitinib Without Discontinuation Due to Hematologic Toxicity
时间窗: 6 months
Numbers of participants who complete a full course of ruxolitinib without discontinuation due to hematologic toxicity in the 6 months following treatment initiation. Discontinuation due to hematologic toxicity is defined as those participants that remain off drug for 6 consecutive weeks due to ongoing hematologic toxicity. Hematologic toxicity for this study will be defined as follows: * Greater than 50% increase in transfusion needs in participants who were transfusion dependent prior to ruxolitinib therapy, lasting for more than 12 weeks * Need for any transfusion for more than 12 weeks in participants who were transfusion independent prior to ruxolitinib therapy. This excludes transfusions given for Hb \>7g/dL or platelets \>10 x 109 or those given for procedures. * Worsening in peripheral cytopenias \>50% compared to pre-treatment levels in participants with a pre-treatment ANC \>500 or platelets \>50 Drop in ANC to \<200 in participants with a pre-treatment ANC \<500
Number of Participants Who Achieved an Overall Response
时间窗: 6 months
Participants who had a CR at 3 months and discontinued study drug were considered responders, even if they subsequently relapsed. • Cohort 1: Response: No Camitta SAA criteria; ≥2 of ANC ≥0.5 × 10⁹/L, platelets ≥20 × 10⁹/L, reticulocytes ≥60 × 10⁹/L on 2 counts ≥1 week apart Complete Response (CR): ANC ≥1 × 10⁹/L, platelets ≥100 × 10⁹/L, Hb ≥10 g/dL Partial Response (PR): Response but not CR • Cohorts 3: Response: ≥1 evaluable lineage response Erythroid: Hb ↑ \>1.5 g/dL, ≥4 fewer RBC transfusions/8 weeks, or reticulocytes \>60 × 10⁹/L Platelet: ↑ ≥30 × 10⁹/L if baseline ≥20 × 10⁹/L, or \<20 to \>20 × 10⁹/L and ≥100% ↑ Neutrophil: ≥100% ↑ and absolute ↑ \>0.5 × 10⁹/L CR: ANC ≥1 × 10⁹/L, platelets ≥100 × 10⁹/L, Hb ≥10 g/dL • Cohort 4: Response: ≥1 evaluable lineage response CHR: ANC \>1.5 × 10⁹/L, platelets \>150 × 10⁹/L, lymphocytes \<4 × 10⁹/L PHR: Improvement in ≥1 affected parameter but not CHR CMR: No clonal T-cell detection and CHR CR: CHR and CMR
次要结局
- Time to transfusion independence(Variable)
- Hematological response(3, 12 months, and yearly thereafter)
- Rate of clonal evolution(Variable)
- Rate of relapse(Variable)
- Percent of patients tolerating 20 mg ruxolitinib BID.(Variable)
- Overall survival(Variable)
- Hematological response of relapse subjects that re-start treatment(Variable)
- Depth of response(3, 6 months)
- Hematological Response of Relapse Subjects That Re-start Treatment(Variable)
- Percent of Patients Tolerating 20 mg Ruxolitinib BID.(Variable)
- Time to Transfusion Independence(Variable)
- Hematological Response(3, 12 months, and yearly thereafter)
- Depth of Response(3, 6 months)
- Rate of Clonal Evolution(Variable)
- Rate of Relapse(Variable)
- Overall Survival(Variable)