Ruxolitinib for Bone Marrow Failure
Recruiting in Palo Alto (17 mi)
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 1 & 2
Recruiting
Sponsor: National Heart, Lung, and Blood Institute (NHLBI)
Must not be taking: Chemotherapy, Immunomodulatory, others
Disqualifiers: Fanconi anemia, MDS/MPN, others
No Placebo Group
Approved in 2 Jurisdictions
Trial Summary
What is the purpose of this trial?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.
Will I have to stop taking my current medications?
The trial information does not specify whether you need to stop taking your current medications. However, if you are on certain treatments like erythropoiesis-stimulating agents, hypomethylating agents, chemotherapy, or immunomodulatory therapy, you must not have taken them within 8 weeks prior to joining the study.
What evidence supports the effectiveness of the drug Ruxolitinib for bone marrow failure?
Ruxolitinib, a drug that blocks certain proteins (JAK1/2) involved in inflammation, has shown benefits in treating myelofibrosis, a condition related to bone marrow failure, by reducing spleen size and improving symptoms. However, it does not significantly affect the underlying bone marrow issues and can cause low blood cell counts.
12345What safety data exists for Ruxolitinib in humans?
Ruxolitinib is generally well tolerated in humans, but some common side effects include anemia (low red blood cell count), thrombocytopenia (low platelet count), and lymphopenia (low white blood cell count). Rare side effects include skin reactions and neurological symptoms like dizziness and headache. These side effects are usually manageable with dosage adjustments.
56789How is the drug Ruxolitinib unique for treating bone marrow failure?
Ruxolitinib is unique because it is an oral medication that specifically inhibits Janus Kinase (JAK) 1 and 2, which are involved in abnormal signaling pathways in bone marrow diseases. This mechanism helps reduce symptoms and improve blood cell counts, offering a novel approach compared to other treatments that may not target these pathways directly.
39101112Eligibility Criteria
Adults over 18 with immune bone marrow failure, willing to consent and use contraception if of childbearing potential. Excluded are those with certain genetic disorders, recent cancer treatments, uncontrolled infections or severe organ dysfunction, current pregnancy or breastfeeding, inability to swallow pills, or a history of acute thrombosis within the last 6 months.Inclusion Criteria
For females of childbearing potential, willingness to use accepted methods of contraception
Ability to understand and sign a written informed consent document
I am 18 years old or older.
+7 more
Exclusion Criteria
I am currently receiving treatment for cancer.
I have recently been treated with specific medications.
I do not have any severe illnesses that prevent me from daily activities.
+15 more
Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
2-4 weeks
1 visit (in-person)
Treatment
Participants receive ruxolitinib twice a day for up to 6 months
6 months
Weekly blood tests, clinic visits at 3 and 6 months
Follow-up
Participants are monitored for safety and effectiveness after treatment
3 years
Clinic visits at 1, 2, and 3 years
Extension
Participants who improve may continue treatment in an extension phase
Participant Groups
The trial is testing Ruxolitinib tablets taken twice daily for up to six months in patients with various types of immune bone marrow failure. It includes regular blood tests and clinic visits at specified intervals including after treatment completion to monitor effects.
5Treatment groups
Experimental Treatment
Group I: Subjects with hypoplastic MDSExperimental Treatment1 Intervention
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.
Group II: Subjects with TLGLExperimental Treatment1 Intervention
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.
Group III: Subjects with SAAExperimental Treatment1 Intervention
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.
Group IV: Subjects with PRCAExperimental Treatment1 Intervention
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.
Group V: Subjects with MAAExperimental Treatment1 Intervention
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.
Ruxolitinib is already approved in United States, European Union for the following indications:
🇺🇸 Approved in United States as Jakafi for:
- Intermediate or high-risk myelofibrosis
- Polycythemia vera
- Steroid-refractory acute graft-versus-host disease
- Chronic graft-versus-host disease
- Vitiligo
🇪🇺 Approved in European Union as Jakavi for:
- Intermediate or high-risk myelofibrosis
- Polycythemia vera
- Steroid-refractory acute graft-versus-host disease
- Chronic graft-versus-host disease
- Non-segmental vitiligo
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
National Institutes of Health Clinical CenterBethesda, MD
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Who Is Running the Clinical Trial?
National Heart, Lung, and Blood Institute (NHLBI)Lead Sponsor
References
Advances in potential treatment options for myeloproliferative neoplasm associated myelofibrosis. [2023]The Janus kinase (JAK)1/2 inhibitor ruxolitinib provides rapid, sustained and often dramatic benefits to patients with myelofibrosis, inducing spleen shrinkage and ameliorating symptoms, and improves survival. However, the drug has little effect on the underlying bone marrow fibrosis or on mutant allele burden, and clinical resistance eventually develops. Furthermore, ruxolitinib-induced cytopenias can be challenging in everyday practice.
Overall survival in the SIMPLIFY-1 and SIMPLIFY-2 phase 3 trials of momelotinib in patients with myelofibrosis. [2022]Janus kinase inhibitors (JAKi) approved for myelofibrosis provide spleen and symptom improvements but do not address anemia, a negative prognostic factor. Momelotinib, an inhibitor of ACVR1/ALK2, JAK1 and JAK2, demonstrated activity against anemia, symptoms, and splenomegaly in the phase 3 SIMPLIFY trials. Here, we report mature overall survival (OS) and leukemia-free survival (LFS) from both studies, and retrospective analyses of baseline characteristics and efficacy endpoints for OS associations. Survival distributions were similar between JAKi-naïve patients randomized to momelotinib, or ruxolitinib then momelotinib, in SIMPLIFY-1 (OS HR = 1.02 [0.73, 1.43]; LFS HR = 1.08 [0.78, 1.50]). Two-year OS and LFS were 81.6% and 80.7% with momelotinib and 80.6% and 79.3% with ruxolitinib then momelotinib. In ruxolitinib-exposed patients in SIMPLIFY-2, two-year OS and LFS were 65.8% and 64.2% with momelotinib and 61.2% and 59.7% with best available therapy then momelotinib (OS HR = 0.98 [0.59, 1.62]; LFS HR = 0.97 [0.59, 1.60]). Baseline transfusion independence (TI) was associated with improved survival in both studies (SIMPLIFY-1 HR = 0.474, p = 0.0001; SIMPLIFY-2 HR = 0.226, p = 0.0005). Week 24 TI response in JAKi-naïve, momelotinib-randomized patients was associated with improved OS in univariate (HR = 0.323; p
Peritransplantation Use of Ruxolitinib in Myelofibrosis. [2021]Ruxolitinib is an oral JAK1/2 inhibitor that is approved for use in patients with intermediate and high-risk myelofibrosis (MF) based on its proven spleen and symptom burden reduction. Its impact on hematopoietic stem cell transplantation (HSCT) outcomes is largely unknown, however. A significant number of patients proceeding to HSCT have been treated with ruxolitinib, and the specifics of its peritransplantation use vary widely in the published literature. Here we review the currently published data and experience to guide management of patients with MF on ruxolitinib proceeding to HSCT.
Ruxolitinib. [2021]Ruxolitinib, formerly known as INCB018424 or INC424, is a potent and selective oral inhibitor of JAK1 and JAK2. Ruxolitinib has been approved for the treatment of myelofibrosis, which is characterized, biologically, by the activation of the JAK-STAT pathway and, clinically, by bone marrow fibrosis, splenomegaly, abnormal blood counts, and poor quality-of-life through associated symptoms. Ruxolitinib treatment results in a meaningful reduction in spleen size and symptom burden in the majority of myelofibrosis patients, and it may also have a favorable effect on survival. Treatment response apparently does not depend on the presence of a JAK2 V617F mutation. The predominant toxicities are thrombocytopenia and anemia. The metabolization of ruxolitinib through CYP3A4 needs to be considered particularly if co-administered with potent CYP3A4 inhibitors. Several further JAK inhibitors are currently studied in myelofibrosis or other immuno-inflammatory diseases.
Interim analysis of safety and efficacy of ruxolitinib in patients with myelofibrosis and low platelet counts. [2021]Ruxolitinib, a Janus kinase 1 and 2 inhibitor, demonstrated improvements in spleen volume, symptoms, and survival over placebo and best available therapy in intermediate-2 or high-risk myelofibrosis patients with baseline platelet counts ≥100 × 109/L in phase III studies. The most common adverse events were dose-dependent anemia and thrombocytopenia, which were anticipated because thrombopoietin and erythropoietin signal through JAK2. These events were manageable, rarely leading to treatment discontinuation. Because approximately one-quarter of MF patients have platelet counts
Erythematous skin lesions with necrotic centers on lower extremities due to the use of ruxolitinib for primary myelofibrosis. [2021]Ruxolitinib is a small molecule JAK-2 inhibitor approved for the treatment of certain myeloproliferative neoplasms. Ruxolitinib-related skin toxicity is extremely rare. We report herein an unusual erythematous skin eruption with necrotic centers involving lower extremities in a patient with primary myelofibrosis treated with ruxolitinib. Awareness of this unusual skin toxicity with ruxolitinib becomes even more important as JAK-2 inhibition might soon find clinical applications in dermatology.
Ruxolitinib versus standard therapy for the treatment of polycythemia vera. [2022]Ruxolitinib, a Janus kinase (JAK) 1 and 2 inhibitor, was shown to have a clinical benefit in patients with polycythemia vera in a phase 2 study. We conducted a phase 3 open-label study to evaluate the efficacy and safety of ruxolitinib versus standard therapy in patients with polycythemia vera who had an inadequate response to or had unacceptable side effects from hydroxyurea.
Unexpected Neurological Symptoms of Ruxolitinib: A Case Report. [2023]Ruxolitinib is a highly potent JAK2 inhibitor approved for the treatment of myelofibrosis (idiopathic or post-polycythemia vera or post-essential thrombocythemia) and, more recently, for polycythemia vera with an inadequate response to or intolerant of hydroxyurea. The most common adverse events of ruxolitinib include immunosuppression with an increased risk of reactivation of silent infections and increased non-melanoma skin cancer. The known neurological side effects of ruxolitinib are dizziness and headache, but no neurological paroxysmal episodes have been recorded. This report deals with an 80-year-old outpatient woman with polycythemia vera turned into myelofibrosis who experienced neurological episodes of hypoesthesia and weakness of right arm and leg during ruxolitinib treatment.
Ruxolitinib: A Review in Polycythaemia Vera. [2021]Ruxolitinib (Jakavi(®), Jakafi(®)) is an orally administered, first-in-class Janus Kinase (JAK) 1 and 2 inhibitor that was recently approved for the treatment of patients with polycythaemia vera (PV) who have responded inadequately to or are intolerant of hydroxyurea. By inhibiting JAK 1 and 2, ruxolitinib reduces hyperactive JAK-signal transducers and activators of transcription (STAT) signalling that is implicated in the pathogenesis of PV. This article briefly reviews the pharmacology of the drug, focusing on its clinical use in patients with PV. In the phase III RESPONSE trial in PV patients who had an inadequate response to or unacceptable adverse effects from hydroxyurea, ruxolitinib was superior to best available therapy in reducing haematocrit without phlebotomy and reducing spleen size after 32 weeks of treatment. Ruxolitinib was also associated with reducing leukocyte and platelet counts and improving symptoms. Patient follow-up demonstrated that response to ruxolitinib was durable, including preliminary results after up to 80 weeks of treatment. The drug is generally well tolerated, although mild to moderate anaemia, thrombocytopenia and lymphopenia were common in the RESPONSE trial. These effects can usually be managed with dosage modification and did not lead to therapy discontinuation in the RESPONSE trial. Thus, for a subgroup of PV patients for whom few treatment options have existed previously, ruxolitinib provides a valid option.
Ruxolitinib for the treatment of myelofibrosis: its clinical potential. [2021]Ruxolitinib is an orally bioavailable, selective Janus kinase (JAK) 1 and 2 inhibitor approved for the treatment of myelofibrosis (MF), a bone marrow disease in which the JAK pathway is dysregulated, leading to impaired hematopoiesis and immune function. By inhibiting JAK1 and JAK2, ruxolitinib modulates cytokine-stimulated intracellular signaling. In a phase II clinical trial in patients with MF, ruxolitinib recipients exhibited durable reductions in spleen size, reductions in circulating pro-inflammatory cytokines, improvements in physical activity, weight gain, and alleviation of symptoms (including constitutional symptoms) in patients with and without JAK2 mutation. These findings were confirmed by two phase III clinical MF studies, in which a greater proportion of ruxolitinib recipients achieved a spleen volume reduction of ≥35% from baseline at week 24, compared with placebo in one study (41.9% versus 0.7%; P
New Concepts of Treatment for Patients with Myelofibrosis. [2023]Seven years after the approval of the Janus kinase 1/2 (JAK1/2) inhibitor ruxolitinib, it remains the only drug licensed for the treatment of myelofibrosis. Patients who discontinue ruxolitinib have a dismal outcome, and this is, therefore, an area of significant unmet need. Given the central role that JAK-signal transducer and activator of transcription (STAT) activation plays in disease pathogenesis, there have been many other JAK inhibitors tested, but most have been abandoned, for a variety of reasons. The JAK2-selective inhibitor fedratinib has recently been resurrected, and there has been a resurgence of interest in the failed JAK1/2 inhibitor momelotinib, which possibly improves anemia. Pacritinib, a non-myelosuppressive JAK2-selective inhibitor, is currently in a dose-ranging study mandated by regulatory authorities. A plethora of other targeted agents, most backed by preclinical data, are in various stages of investigation. These include epigenetic and immune therapies, agents targeting cellular survival, metabolic and apoptotic pathways, the cell cycle, DNA repair, and protein folding and degradation, among others. However, at this time, none of these is close to registration or even in a pivotal trial, illustrating the difficulties in recapitulating the clinical disease in preclinical models. Most current clinical trials are testing the addition of a novel agent to ruxolitinib, either in the frontline setting or in the context of an insufficient response to ruxolitinib, or attempting to study new drugs in the second-line, "ruxolitinib failure" setting. Emerging data supports the addition of azacitidine to ruxolitinib in some patients. Other strategies have focused on improving cytopenias, through amelioration of bone marrow fibrosis or other mechanisms. This is important, because cytopenias are the commonest reason for ruxolitinib interruption and/or dose reduction, and dose optimization of ruxolitinib is tied to its survival benefit. The activin receptor ligand trap, sotatercept, and the anti-fibrotic agent, PRM-151, have shown promise in this regard.
Fedratinib: a pharmacotherapeutic option for JAK-inhibitor naïve and exposed patients with myelofibrosis. [2022]Ruxolitinib is the most commonly used JAK-inhibitor (JAKi) for the management of symptoms related to splenomegaly and cytokine-mediated inflammation in patients with myelofibrosis (MF), but is limited by variable durability of response with most patients experiencing failure after 2-3 years. Long-term data on other approved JAKi, fedratinib and pacritinib, are not available due to the clinical hold put on pivotal trials for toxicity concerns.