Imatinib for Bone Marrow Failure Syndrome
Recruiting in Palo Alto (17 mi)
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 1
Recruiting
Sponsor: National Cancer Institute (NCI)
Must not be taking: Aspirin, Anti-platelet, CYP3A4 inhibitors, others
Disqualifiers: Pregnancy, Hematologic therapy, Cardiac conditions, others
No Placebo Group
Approved in 5 Jurisdictions
Trial Summary
What is the purpose of this trial?Background:
Runt-related transcription factor 1 (RUNX1) gene regulates the formation of blood cells. People with mutations of this gene may bleed or bruise easily; they are also at higher risk of getting cancers of the blood, bone marrow, and lymph nodes.
Objective:
To test a drug (imatinib) in people with RUNX1 mutations that cause symptoms.
Eligibility:
Adults aged 18 and older with RUNX1 mutations. Healthy people without this mutation, including family members of affected participants, are also needed.
Design:
Participants with the RUNX1 mutation will be screened. They will have a physical exam with blood and urine tests. They will have a test of their heart function. They may need a new bone marrow biopsy: A sample of soft tissue will be removed from inside a bone.
Imatinib is a tablet taken by mouth once a day, every day, at home. Affected participants in different parts of the study will take imatinib for either 28 days or up to 84 days.
Participants will visit the clinic once a week for the first 28 days that they are taking the imatinib. Then they will come once every 2 weeks if they are taking the drug for 84 days. Blood, urine, and tests of heart function will be repeated. They may opt to have the bone marrow biopsy repeated after they finish their course of imatinib.
Participants will have a follow-up visit 30 days after they stop taking imatinib.
Participants who do not have the RUNX1 mutation will have 1 clinic visit. They will have blood tests. They will fill out questionnaires. They may opt to have a bone marrow biopsy....
Do I need to stop my current medications to join the trial?
The trial requires that you do not take medications that affect platelet number or function, like aspirin, or those that interact with imatinib, such as certain HIV and hepatitis medications. If you are on such medications, you may need to stop them before joining the trial.
What data supports the effectiveness of the drug Imatinib for treating bone marrow failure syndrome?
Imatinib has been highly effective in treating chronic myelogenous leukemia (CML) and gastrointestinal stromal tumors by targeting specific proteins involved in these diseases. Its success in these conditions suggests potential benefits for other disorders involving similar biological pathways.
12345Is imatinib generally safe for humans?
Imatinib, also known as Gleevec, is generally well tolerated in humans, with most side effects being mild to moderate, such as nausea, rash, and muscle cramps. Serious side effects are rare and often occur early in treatment, but long-term use has shown excellent tolerability.
678910How is the drug Imatinib unique for treating bone marrow failure syndrome?
Imatinib is unique because it specifically targets certain proteins involved in cell growth, which can help manage conditions like bone marrow failure syndrome by potentially addressing the underlying causes of the disease, unlike other treatments that may only alleviate symptoms.
1112131415Eligibility Criteria
Adults over 18 with RUNX1 mutations causing symptoms like easy bleeding, and healthy relatives without the mutation. Participants must have certain blood cell counts, no significant organ dysfunction, and not be on conflicting medications or treatments for other conditions. Pregnant women and those unable to take oral medication are excluded.Inclusion Criteria
- platelets >= 65,000/mcL (without transfusion support)
Breastfeeding participants must be willing to discontinue breastfeeding from study treatment initiation through 30 days after the last administration of study drug.
Ability of participant to understand and the willingness to sign a written informed consent document.
+22 more
Exclusion Criteria
You are currently taking any experimental medications.
Participants without access to medical care at home.
I have received treatment for blood cancer before.
+8 more
Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
2-4 weeks
1 visit (in-person)
Dose Escalation
Participants receive escalating doses of imatinib to determine the maximum tolerated dose (MTD) for 28 days
4 weeks
4 visits (in-person)
Dose Expansion
Participants receive imatinib at the MTD for 12 weeks to evaluate safety and pharmacokinetics
12 weeks
6 visits (in-person)
Follow-up
Participants are monitored for safety and effectiveness after treatment
4 weeks
1 visit (in-person)
Participant Groups
The trial is testing imatinib, a daily oral tablet taken at home for up to 84 days by people with RUNX1 gene mutations. It aims to see if it can improve their condition. The study includes regular clinic visits for monitoring through physical exams, blood tests, heart function tests, and optional bone marrow biopsies.
3Treatment groups
Experimental Treatment
Active Control
Group I: Dose ExpansionExperimental Treatment2 Interventions
Imatinib at the MTD
Group II: Dose EscalationExperimental Treatment2 Interventions
Escalating doses of imatinib to determine the MTD
Group III: No TreatmentActive Control1 Intervention
Collection of blood or marrow only. No treatment.
Imatinib is already approved in European Union, United States, Canada, Japan, Switzerland for the following indications:
🇪🇺 Approved in European Union as Gleevec for:
- Chronic myeloid leukemia
- Gastrointestinal stromal tumors
- Dermatofibrosarcoma protuberans
- Systemic mastocytosis
- Hypereosinophilic syndrome
🇺🇸 Approved in United States as Gleevec for:
- Chronic myeloid leukemia
- Gastrointestinal stromal tumors
- Dermatofibrosarcoma protuberans
- Systemic mastocytosis
- Hypereosinophilic syndrome
🇨🇦 Approved in Canada as Glivec for:
- Chronic myeloid leukemia
- Gastrointestinal stromal tumors
- Dermatofibrosarcoma protuberans
- Systemic mastocytosis
- Hypereosinophilic syndrome
🇯🇵 Approved in Japan as Glivec for:
- Chronic myeloid leukemia
- Gastrointestinal stromal tumors
- Dermatofibrosarcoma protuberans
- Systemic mastocytosis
- Hypereosinophilic syndrome
🇨🇭 Approved in Switzerland as Gleevec for:
- Chronic myeloid leukemia
- Gastrointestinal stromal tumors
- Dermatofibrosarcoma protuberans
- Systemic mastocytosis
- Hypereosinophilic syndrome
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 Cancer Institute (NCI)Lead Sponsor
References
Imatinib: a targeted clinical drug development. [2021]Imatinib (Gleevec) (formerly STI571) is an orally bioavailable rationally developed inhibitor of the tyrosine kinases Bcr-Abl, Kit, and platelet-derived growth factor receptor (PDGFR). In 4 years of clinical development, more than 12,000 patients have been treated in the clinical development program. Imatinib was first shown to be highly effective in the treatment of all stages of chronic myelogenous leukemia (CML). Moreover, preliminary results of a randomized study have demonstrated superior efficacy and safety of first-line imatinib therapy compared with a combination of interferon and cytarabine. Imatinib has also been shown to be the only effective drug therapy in the treatment of patients with metastatic gastrointestinal stromal tumors expressing the stem cell factor (SCF) receptor Kit. This review outlines the successive steps in the clinical development of this new, targeted anticancer agent.
Imatinib mesylate in combination with other chemotherapeutic drugs: in vitro studies. [2015]Imatinib mesylate (Gleevec) (formerly STI571) has secured a definitive role in the treatment of chronic myeloid leukemia (CML) due to its specificity and efficacy. Although some patients become resistant to the drug, it may still be possible to control the leukemia with imatinib-containing regimens. Front-line treatment with such combinations may indeed minimize the risk that resistance, and hence relapse, occurs. In this review, we discuss the published data on in vitro studies that address this question in a variety of models, and attempt to predict efficacious combinations for future clinical trials. These represent regimens where imatinib is combined with conventional chemotherapeutic drugs or with inhibitors of other key signal transduction molecules that may be preferentially activated in CML cells.
Imatinib mesylate in chronic myeloid leukemia: frontline treatment and long-term outcomes. [2016]The tyrosine kinase inhibitor Imatinib Mesylate has dramatically improved the clinical outcome of chronic myeloid leukemia (CML) patients in the chronic phase of the disease, generating unprecedented rates of complete hematologic and cytogenetic responses and sustained reductions in BCR-ABL transcripts. Here, we present an overview on the efficacy and safety of Imatinib and describe the most important clinical studies employing this drug for the frontline treatment of chronic phase CML. We also discuss recent reports describing the long-term outcome of patients receiving Imatinib for their disease. The imminent availability of generic forms of Imatinib coupled with the approval of expensive second-generation tyrosine kinase inhibitors underlines an unmet need for early molecular parameters that may distinguish CML patients likely to benefit from the drug from those that should receive alternative forms of treatment.
Imatinib mesylate--gold standards and silver linings. [2021]Imatinib mesylate represents the first of a new generation of molecularly targeted therapies engineered to disrupt signal transduction pathways. It is a tyrosine kinase inhibitor with relatively selective activity against the Abelson (ABL) proto-oncogene, platelet-derived growth factor receptor, and c-KIT receptor. Deregulated tyrosine kinase activity has been implicated as a central pathogenic event in a number of human malignancies, most notably chronic myeloid leukemia. In this myeloproliferative disorder the t(9;22) reciprocal translocation results in the generation of a novel fusion oncoprotein, BCR-ABL, with constitutive tyrosine kinase activity. Imatinib inhibits this activity, inducing remarkable rates of hematological and cytogenetic remission in excess of those seen with alternative medical therapies. Following a large phase III study comparing its efficacy with the combination of interferon alpha and low-dose cytarabine, it has emerged as the current gold standard therapy for patients with chronic-phase disease without a potential bone marrow donor and those considered unsuitable for bone marrow transplantation. Its integration into the management of those patients who might be considered for transplantation, which has historically been considered the only potentially curative approach, remains a major challenge. The increasing recognition and subsequent molecular characterization of resistance mechanisms has reinforced the need to exercise caution against deferring a proven curative therapy in favor of a treatment approach that is still investigational, with the spectre of increased numbers of patients progressing to sudden-onset blast crisis remaining the potential dark cloud in the silver lining for imatinib.
Recent advances in Philadelphia chromosome-positive malignancies: the potential role of arsenic trioxide. [2019]Chronic myelogenous leukemia (CML) is characterized by the presence of the Bcr-Abl fusion gene, which encodes a constitutively active tyrosine kinase that has been strongly implicated as the sole oncogenic abnormality in early-stage CML. Treatment with the specific tyrosine kinase inhibitor imatinib mesylate has achieved excellent results in CML, at all stages of the disease. However, limitations to the successful use of imatinib mesylate as a single agent include the problem of resistance, seen chiefly in patients with advanced-phase disease. This review summarizes the clinical results to date with imatinib mesylate and briefly discusses the problem of resistance before describing potential strategies, including the use of combination therapy. In particular, the rationale for combination therapy with arsenic trioxide will be examined.
A benefit-risk assessment of imatinib in chronic myeloid leukaemia and gastrointestinal stromal tumours. [2021]Targeting constitutively activated tyrosine kinases, such as BCR-ABL, in chronic myeloid leukaemia (CML) and c-KIT in gastrointestinal stromal tumours (GIST) has substantially changed the clinical management of both diseases. The introduction of imatinib, a tyrosine kinase inhibitor mainly targeting BCR-ABL, c-KIT and PDGFR, has profoundly improved the prognosis of both entities, while being surprisingly well tolerated. This article summarizes recent data on clinical efficacy as well as safety aspects of imatinib for treatment of CML and GIST, including a final benefit-risk assessment. Imatinib induces high rates of cytogenetic and molecular responses in all phases of CML and also has substantial activity in GIST patients. In both diseases, only a few adverse effects, such as musculoskeletal and joint pain, muscle cramps, oedema and gastrointestinal symptoms, occur. Most of these are grade I or II toxicities and generally occur during the early phase of treatment (i.e. within the first 2 years). Thus, in view of the low rates of severe toxicities and the extraordinary efficacy of the drug in both diseases, imatinib represents an oral drug with a high benefit-risk ratio for the treatment of CML and GIST.
The safety profile of imatinib in CML and GIST: long-term considerations. [2015]Imatinib mesylate is considered the standard first-line systemic treatment for patients with chronic myeloid leukaemia (CML) and gastrointestinal stromal tumour (GIST) by targeting BCR-ABL and c-KIT tyrosine kinases, respectively. Indeed, imatinib has substantially changed the clinical management and improved the prognosis of both diseases. Treatment with imatinib is generally well tolerated, and the risk for severe adverse effects is low, generally occurring during the early phase of treatment and correlating with imatinib dose, phase of disease and patient's characteristics. This article summarises recent data on safety profile of imatinib for the treatment of CML and GIST, including long-term side effects. Prolonged treatment with imatinib in both diseases demonstrates excellent tolerability. There are few significant concerns and those that have emerged, like cardiotoxicity, have far turned out to be exaggerated.
Principal long-term adverse effects of imatinib in patients with chronic myeloid leukemia in chronic phase. [2021]Imatinib mesylate (IM), an original Abl tyrosine kinase inhibitor, entered the clinics in 1998 for the treatment of patients with chronic myeloid leukemia (CML). The drug is universally considered the treatment of choice for most, if not all, patients with CML. Importantly, lessons learned from patients with CML have been applied successfully for the treatment of patients with other disorders where IM has since been found to be active by virtue of its ability to target other kinases, such as c-kit in patients with gastrointestinal stromal tumors. IM is associated with mild to moderate toxicity, mostly reversible by dose reduction or discontinuation of the drug. Most adverse effects occur within the first 2 years of starting therapy; however, late effects, many being unique, are now being recognized. In this report, we assess the toxicity associated with IM, with an emphasis on the long-term adverse effects.
Imatinib treatment: specific issues related to safety, fertility, and pregnancy. [2022]Imatinib (Gleevec) (formerly STI571) has demonstrated high levels of efficacy in chronic myelogenous leukemia (CML) and gastrointestinal stromal tumors (GIST) and has been used in more than 12,000 patients participating in clinical trials. Experience from clinical trials with imatinib has largely demonstrated the drug to be well tolerated in humans. Common side effects, usually manageable, include nausea, rash, superficial edema, myelosuppression, muscle cramps, and elevated liver transaminases. With longer follow-up and with further experience with the treatment of patients outside of clinical trials, we are able to report on rarer toxicities, the identification of certain predictors of common toxicities, and the clinical experience with male fertility and pregnancy outcomes.
Toxicity of Asciminib in Real Clinical Practice: Analysis of Side Effects and Cross-Toxicity with Tyrosine Kinase Inhibitors. [2023](1) Background: Despite the prognostic improvements achieved with tyrosine kinase inhibitors (TKIs) in chronic myeloid leukemia (CML), a minority of patients still fail TKIs. The recent introduction of asciminib may be a promising option in intolerant patients, as it is a first-in-class inhibitor with a more selective mechanism of action different from the ATP-competitive inhibition that occurs with TKIs. Therefore, our goal was to analyze toxicities shown with asciminib as well as to study cross-toxicity with previous TKIs. (2) Methods: An observational, multicenter, retrospective study was performed with data from 77 patients with CML with therapeutic failure to second-generation TKIs who received asciminib through a managed-access program (MAP) (3) Results: With a median follow-up of 13.7 months, 22 patients (28.5%) discontinued treatment: 32% (7/22) due to intolerance and 45% (10/22) due to resistance. Fifty-five percent of the patients reported adverse effects (AEs) with asciminib and eighteen percent grade 3-4. Most frequent AEs were: fatigue (18%), thrombocytopenia (17%), anemia (12%), and arthralgias (12%). None of the patients experienced cardiovascular events or occlusive arterial disease. Further, 26%, 25%, and 9% of patients required dose adjustment, temporary suspension, or definitive discontinuation of treatment, respectively. Toxicities under asciminib seemed lower than with prior TKIs for anemia, cardiovascular events, pleural/pericardial effusion, diarrhea, and edema. Cross-toxicity risk was statistically significant for thrombocytopenia, anemia, neutropenia, fatigue, vomiting, and pancreatitis. (4) Conclusion: Asciminib is a molecule with a good safety profile and with a low rate of AEs. However, despite its new mechanism of action, asciminib presents a risk of cross-toxicity with classical TKIs for some AEs.
Momelotinib for the treatment of myelofibrosis with anemia. [2022]Myelofibrosis is a myeloproliferative neoplasm characterized by splenomegaly, debilitating constitutional symptoms and bone marrow failure. Disease-related anemia is common and associated with an inferior quality of life and survival. Unfortunately, few therapies exist to improve hemoglobin in myelofibrosis patients. Momelotinib is a JAK1/JAK2 inhibitor that also antagonizes ACVR1, leading to downregulation of hepcidin expression and increased availability of iron for erythropoiesis. In clinical testing, momelotinib has demonstrated a unique ability to improve hemoglobin and reduce transfusion burden in myelofibrosis patients with baseline anemia, while producing reductions in spleen size and symptom burden. This review explores the preclinical rationale, clinical trial data and future role of momelotinib in the evolving therapeutic landscape of myelofibrosis.
SOHO State of the Art Updates and Next Questions: Identifying and Treating "Progression" in Myelofibrosis. [2023]Over the last decade, the Janus kinase (JAK) 1/2 inhibitor ruxolitinib has become widely established as the cornerstone of pharmacologic therapy for most patients with myelofibrosis (MF), providing dramatic and durable benefits in terms of splenomegaly and symptoms, and prolonging survival. Ruxolitinib does not address all aspects of the disease, however; notably cytopenias, and its ability to modify the underlying biology of the disease remains in question. Furthermore, patients eventually lose response to ruxolitinib. Multiple groups have reported the median overall survival of MF patients after ruxolitinib discontinuation to be 13 to 14 months. While consensus criteria only recognize splenic and blast progression as "progressive disease" in patients with MF, disease progression can occur in a variety of ways. Besides increasing splenomegaly and progression to accelerated phase/leukemic transformation, patients may develop worsening disease-related symptoms, cytopenias, progressive leukocytosis, extramedullary hematopoiesis, etc. As in the frontline setting, treatment needs to be tailored to the clinical needs of the patient. Current treatment options for patients with MF who fail ruxolitinib remain unsatisfactory, and this continues to represent an area of major unmet medical need. The regulatory approval of fedratinib has introduced an important option in the postruxolitinib setting. Fortunately, a plethora of novel agents, both new JAK inhibitors and drugs from other classes, eg, bromodomain and extraterminal (BET), murine double minute 2 (MDM2) and telomerase inhibitors, activin receptor ligand traps, BH3-mimetics and more, are poised to greatly expand the therapeutic armamentarium for patients with MF if successful in pivotal trials.
Anemia in myelofibrosis: Current and emerging treatment options. [2022]Myelofibrosis (MF) is a clonal hematologic malignancy with progressive bone marrow fibrosis. Clinical manifestations of MF include splenomegaly, constitutional symptoms, and anemia, whose pathogenesis is multifactorial and largely due to ineffective erythropoiesis and is clinically associated with poor quality of life and reduced overall survival. The only curative treatment for MF is allogenic stem cell transplantation; however, few patients are eligible. Disease management strategies for MF-related anemia have limited effectiveness, and Janus kinase (JAK) inhibitors may induce or worsen related anemia. Thus, there is a significant unmet need for the treatment of patients with MF-related anemia. This review summarizes current and emerging treatments for anemia in MF, including luspatercept and KER-050 (transforming growth factor-β ligand traps), momelotinib and pacritinib (JAK inhibitors), pelabresib (a bromodomain extra-terminal domain inhibitor), PRM-151 (an antifibrotic agent), imetelstat (a telomerase inhibitor), and navitoclax (a BCL-2/BCL-xL inhibitor). Therapeutic combinations with ruxolitinib may offer another treatment approach.
Aurora Kinase A Inhibition: A Mega-Hit for Myelofibrosis Therapy? [2020]The positive but limited efficacy of JAK inhibitors has sparked the need for alternative therapeutic targets in the treatment of myelofibrosis. The discovery of novel targets, like Aurora Kinase A, may provide new avenues of single-agent and combinatorial therapy for myelofibrosis and restoration of normal bone marrow function.See related article by Gangat et al., p. 4898.
Addition of Navitoclax to Ongoing Ruxolitinib Therapy for Patients With Myelofibrosis With Progression or Suboptimal Response: Phase II Safety and Efficacy. [2023]Label="PURPOSE">Targeting the BCL-XL pathway has demonstrated the ability to overcome Janus kinase inhibitor resistance in preclinical models. This phase II trial investigated the efficacy and safety of adding BCL-XL/BCL-2 inhibitor navitoclax to ruxolitinib therapy in patients with myelofibrosis with progression or suboptimal response to ruxolitinib monotherapy (ClinicalTrials.gov identifier: NCT03222609).