Imatinib for Bone Marrow Failure Syndrome

Overseen By Lea C Cunningham, M.D.

Age: 18+

Sex: Any

Trial Phase: Phase 1

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 All trial participants will receive the active study treatment (no placebo)

Approved in 5 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 12

78 Participants Needed

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. ^{1 2 3 4 5}

Is 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. ^{6 7 8 9 10}

How 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. ^{11 12 13 14 15}

Research Team

Lea C Cunningham, M.D.

Principal Investigator

National Cancer Institute (NCI)

Eligibility 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.

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.

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)

Treatment Details

Interventions

• Imatinib

Trial Overview 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.

Participant Groups

Group I: Dose Expansion Experimental Treatment 2 Interventions

Imatinib at the MTD

Group II: Dose Escalation Experimental Treatment 2 Interventions

Escalating doses of imatinib to determine the MTD

Group III: No Treatment Active Control 1 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

Who Is Running the Clinical Trial?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

Findings from Research

Imatinib (Gleevec) has been shown to be highly effective in treating all stages of chronic myelogenous leukemia (CML), with over 12,000 patients treated during its clinical development.

In a randomized study, first-line imatinib therapy demonstrated superior efficacy and safety compared to traditional treatments involving interferon and cytarabine, highlighting its role as a targeted anticancer agent.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Imatinib: a targeted clinical drug development. Capdeville, R., Silberman, S.[2021]

Imatinib mesylate (Gleevec) is highly effective in treating chronic myeloid leukemia (CML) due to its specificity, although some patients may develop resistance.

Combining imatinib with other chemotherapeutic agents or inhibitors targeting key signaling pathways in CML may help prevent resistance and improve treatment outcomes, as suggested by various in vitro studies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Imatinib mesylate in combination with other chemotherapeutic drugs: in vitro studies. Tipping, AJ., Melo, JV.[2015]

Imatinib Mesylate has significantly improved outcomes for chronic myeloid leukemia (CML) patients in the chronic phase, leading to high rates of complete hematologic and cytogenetic responses.

Long-term studies indicate that while Imatinib is effective, there is a need for early molecular markers to identify which patients will benefit most from this treatment, especially with the availability of generic options and newer therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Imatinib mesylate in chronic myeloid leukemia: frontline treatment and long-term outcomes. Stagno, F., Stella, S., Spitaleri, A., et al.[2016]

Imatinib mesylate is a highly effective tyrosine kinase inhibitor specifically targeting the BCR-ABL fusion protein in chronic myeloid leukemia, leading to high rates of hematological and cytogenetic remission, making it the gold standard treatment for patients without a bone marrow donor.

Despite its effectiveness, caution is advised due to the potential for resistance mechanisms and the risk of patients progressing to more severe disease stages, highlighting the importance of considering curative options like bone marrow transplantation when appropriate.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Imatinib mesylate--gold standards and silver linings. Peggs, K.[2021]

Imatinib mesylate is an effective treatment for chronic myelogenous leukemia (CML) across all disease stages, targeting the Bcr-Abl fusion gene responsible for the disease.

Resistance to imatinib mesylate, particularly in advanced-phase CML, poses a significant challenge, prompting exploration of combination therapies, including arsenic trioxide, to enhance treatment efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Recent advances in Philadelphia chromosome-positive malignancies: the potential role of arsenic trioxide. O'Dwyer, ME., La Rosée, P., Nimmanapalli, R., et al.[2019]

Imatinib, a tyrosine kinase inhibitor, has significantly improved the prognosis for patients with chronic myeloid leukaemia (CML) and gastrointestinal stromal tumours (GIST), showing high rates of cytogenetic and molecular responses across all phases of CML.

The drug is well tolerated, with only mild adverse effects such as joint pain and gastrointestinal symptoms, primarily occurring in the first two years of treatment, making it a safe and effective oral option for these cancers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A benefit-risk assessment of imatinib in chronic myeloid leukaemia and gastrointestinal stromal tumours. Wolf, D., Rumpold, H.[2021]

Imatinib mesylate is the standard first-line treatment for chronic myeloid leukaemia (CML) and gastrointestinal stromal tumour (GIST), effectively targeting specific tyrosine kinases and significantly improving patient prognosis.

The treatment is generally well tolerated with a low risk of severe side effects, and long-term use shows excellent tolerability, with concerns like cardiotoxicity being largely exaggerated.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The safety profile of imatinib in CML and GIST: long-term considerations. Thanopoulou, E., Judson, I.[2015]

Imatinib mesylate (IM) is the preferred treatment for chronic myeloid leukemia (CML) and has also shown effectiveness in other conditions, such as gastrointestinal stromal tumors, due to its ability to target multiple kinases.

While IM is generally associated with mild to moderate toxicity that can often be managed by adjusting the dose, long-term adverse effects are increasingly recognized, particularly those that may arise after the first two years of treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Principal long-term adverse effects of imatinib in patients with chronic myeloid leukemia in chronic phase. Mughal, TI., Schrieber, A.[2021]

Imatinib (Gleevec) has shown high efficacy in treating chronic myelogenous leukemia (CML) and gastrointestinal stromal tumors (GIST), with over 12,000 patients involved in clinical trials, indicating its effectiveness as a treatment option.

The drug is generally well tolerated, with manageable common side effects such as nausea and rash, and ongoing studies have helped identify rarer toxicities and predictors of common side effects, as well as its impact on male fertility and pregnancy outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Imatinib treatment: specific issues related to safety, fertility, and pregnancy. Hensley, ML., Ford, JM.[2022]

Asciminib, a new treatment for chronic myeloid leukemia (CML), shows a good safety profile with a lower rate of adverse effects compared to previous tyrosine kinase inhibitors (TKIs), with 55% of patients reporting side effects and only 18% experiencing severe effects.

Despite its unique mechanism of action, asciminib does carry a risk of cross-toxicity with traditional TKIs, particularly for side effects like thrombocytopenia and anemia, indicating careful monitoring is still necessary.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Toxicity of Asciminib in Real Clinical Practice: Analysis of Side Effects and Cross-Toxicity with Tyrosine Kinase Inhibitors. Pérez-Lamas, L., Luna, A., Boque, C., et al.[2023]

Momelotinib, a JAK1/JAK2 inhibitor, has shown promising results in improving hemoglobin levels and reducing the need for blood transfusions in myelofibrosis patients suffering from anemia, which is a common and debilitating symptom of the disease.

In addition to enhancing hemoglobin, momelotinib also reduces spleen size and alleviates overall symptoms, indicating its potential as a comprehensive treatment option for myelofibrosis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Momelotinib for the treatment of myelofibrosis with anemia. Tremblay, D., Mesa, R.[2022]

Ruxolitinib, a JAK 1/2 inhibitor, is a key treatment for myelofibrosis (MF), providing significant benefits in reducing spleen size and improving symptoms, but it does not address all disease aspects and patients may eventually lose response to it.

The introduction of fedratinib offers a new treatment option for patients who do not respond to ruxolitinib, and ongoing research into various novel agents may further enhance treatment options for MF in the future.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

SOHO State of the Art Updates and Next Questions: Identifying and Treating "Progression" in Myelofibrosis. Bose, P., Verstovsek, S.[2023]

Myelofibrosis (MF) is a serious blood cancer that leads to anemia and poor quality of life, with limited treatment options available, especially since only a few patients can undergo curative stem cell transplantation.

Emerging treatments for MF-related anemia include luspatercept and KER-050, which target specific pathways, as well as various inhibitors like momelotinib and pacritinib, indicating a need for new strategies to manage this condition effectively.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Anemia in myelofibrosis: Current and emerging treatment options. Passamonti, F., Harrison, CN., Mesa, RA., et al.[2022]

JAK inhibitors have shown some effectiveness in treating myelofibrosis, but their benefits are limited, highlighting the need for new treatment options.

The identification of Aurora Kinase A as a novel therapeutic target could lead to new single-agent and combination therapies that may help restore normal bone marrow function in patients with myelofibrosis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Aurora Kinase A Inhibition: A Mega-Hit for Myelofibrosis Therapy? Piszczatowski, RT., Steidl, U.[2020]

In a phase II trial involving 34 patients with myelofibrosis who were not responding adequately to ruxolitinib, the addition of the BCL-XL/BCL-2 inhibitor navitoclax led to a 26.5% spleen volume reduction at week 24, with a median duration of this response lasting 13.8 months.

The treatment also resulted in significant improvements in symptoms and hemoglobin levels, with 30% of patients achieving a 50% reduction in total symptom score, and 64% showing an anemia response, indicating that navitoclax can enhance the efficacy of ruxolitinib in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Addition of Navitoclax to Ongoing Ruxolitinib Therapy for Patients With Myelofibrosis With Progression or Suboptimal Response: Phase II Safety and Efficacy. Harrison, CN., Garcia, JS., Somervaille, TCP., et al.[2023]

References

1. United States pubmed.ncbi.nlm.nih.gov

Imatinib: a targeted clinical drug development. [2021]

2. United States pubmed.ncbi.nlm.nih.gov

Imatinib mesylate in combination with other chemotherapeutic drugs: in vitro studies. [2015]

3. England pubmed.ncbi.nlm.nih.gov

Imatinib mesylate in chronic myeloid leukemia: frontline treatment and long-term outcomes. [2016]

4. Italy pubmed.ncbi.nlm.nih.gov

Imatinib mesylate--gold standards and silver linings. [2021]

5. United States pubmed.ncbi.nlm.nih.gov

Recent advances in Philadelphia chromosome-positive malignancies: the potential role of arsenic trioxide. [2019]

6. New Zealand pubmed.ncbi.nlm.nih.gov

A benefit-risk assessment of imatinib in chronic myeloid leukaemia and gastrointestinal stromal tumours. [2021]

7. Germany pubmed.ncbi.nlm.nih.gov

The safety profile of imatinib in CML and GIST: long-term considerations. [2015]

8. New Zealand pubmed.ncbi.nlm.nih.gov

Principal long-term adverse effects of imatinib in patients with chronic myeloid leukemia in chronic phase. [2021]

9. United States pubmed.ncbi.nlm.nih.gov

Imatinib treatment: specific issues related to safety, fertility, and pregnancy. [2022]

10. Switzerland pubmed.ncbi.nlm.nih.gov

Toxicity of Asciminib in Real Clinical Practice: Analysis of Side Effects and Cross-Toxicity with Tyrosine Kinase Inhibitors. [2023]

11. England pubmed.ncbi.nlm.nih.gov

Momelotinib for the treatment of myelofibrosis with anemia. [2022]

12. United States pubmed.ncbi.nlm.nih.gov

SOHO State of the Art Updates and Next Questions: Identifying and Treating "Progression" in Myelofibrosis. [2023]

13. Netherlands pubmed.ncbi.nlm.nih.gov

Anemia in myelofibrosis: Current and emerging treatment options. [2022]

14. United States pubmed.ncbi.nlm.nih.gov

Aurora Kinase A Inhibition: A Mega-Hit for Myelofibrosis Therapy? [2020]

15. United States pubmed.ncbi.nlm.nih.gov

Addition of Navitoclax to Ongoing Ruxolitinib Therapy for Patients With Myelofibrosis With Progression or Suboptimal Response: Phase II Safety and Efficacy. [2023]