Imetelstat + Ruxolitinib for Myelofibrosis

Recruiting at 5 trial locations

Overseen By Michelle Mudge-Riley, DO

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Geron Corporation

Must be taking: Ruxolitinib

Must not be taking: JAK inhibitors, Hydroxyurea

Disqualifiers: HIV, Cardiovascular disease, others

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

Compensation: Varies

Number of Visits: Unknown

36 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a combination of two drugs, imetelstat (also known as Rytelo or GRN163L) and ruxolitinib (also known as Jakafi, Jakavi, or Opzelura), to determine a safe and effective dose for treating myelofibrosis, a type of bone marrow cancer that disrupts blood cell production. The trial aims to evaluate the efficacy and safety of this combination for people with myelofibrosis. It includes participants who have been on ruxolitinib for at least 12 weeks or those new to JAK inhibitors, a type of medication that reduces inflammation and other symptoms. Participants should have symptoms like an enlarged spleen and should not be candidates for a stem cell transplant. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this new combination therapy.

Do I have to stop taking my current medications for the trial?

The trial does not specify if you need to stop taking your current medications, but you cannot have taken any investigational drugs, hydroxyurea, chemotherapy, immunomodulatory or immunosuppressive therapy, or high-dose corticosteroids within 14 days before enrolling.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that using imetelstat and ruxolitinib together to treat myelofibrosis is generally safe. Studies found that patients could handle the treatment without needing to lower the dose due to severe side effects. The main side effects included low red blood cell count (anemia), low platelet count (thrombocytopenia), and diarrhea. These side effects were common but manageable. Early results suggest that patients tolerate this combination well. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about imetelstat combined with ruxolitinib for myelofibrosis because it offers a fresh approach to tackling this challenging condition. Unlike standard treatments that primarily focus on alleviating symptoms, imetelstat targets the underlying disease mechanism by inhibiting the enzyme telomerase, which is crucial for the survival of cancerous cells. This unique mechanism of action could potentially slow disease progression and improve outcomes for patients. Additionally, the combination with ruxolitinib, a JAK inhibitor already used in this context, might enhance overall efficacy, offering hope for more robust and durable responses.

What evidence suggests that this trial's treatments could be effective for myelofibrosis?

Research has shown that combining imetelstat and ruxolitinib may help treat myelofibrosis. In this trial, participants will receive this combination treatment. Specifically, patients in earlier studies noticed improvements, such as smaller spleens and less overall discomfort. Studies indicate that this combination is generally safe, with no major side effects limiting dosage. The most common side effects were low red blood cell count (anemia) and low platelet count (thrombocytopenia), affecting about 40% of patients. Overall, early results are positive, suggesting this treatment could be effective. ^{1 3 4 5 6}

Who Is on the Research Team?

Michelle Mudge-Riley, DO

Principal Investigator

Geron Corporation

Are You a Good Fit for This Trial?

This trial is for adults with a condition called myelofibrosis, who are either already on ruxolitinib treatment or haven't been treated with JAK inhibitors. They should have symptoms like an enlarged spleen or other related issues and must not be candidates for stem cell transplant. Participants need to meet certain blood and biochemical test criteria, have a performance status score of 0-2, and agree to use contraception.

Inclusion Criteria

I can take care of myself and am up and about more than half of my waking hours.

Participants should follow protocol defined contraceptives procedures

A woman of childbearing potential must have a negative serum or urine pregnancy test at screening

Exclusion Criteria

I have HIV or a severe infection needing IV antibiotics.

Peripheral blood blast count of ≥10% or bone marrow blast count of ≥10%

I have had surgery to remove all or part of my spleen.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment Part 1

Participants who have received ruxolitinib for at least 12 weeks prior to Screening will initiate imetelstat therapy. Dose levels of imetelstat may include 4.7, 6, 7.5, 9.4mg, until a RP2D is established.

24 weeks

Regular visits for dose adjustments and monitoring

Treatment Part 2

JAK inhibitor naïve participants will receive initial treatment with ruxolitinib for at least 12 weeks, including 4 weeks at a stable dose, followed by imetelstat treatment at the RP2D in combination with ruxolitinib.

24 weeks

Regular visits for monitoring and assessment

Follow-up

Participants are monitored for safety and effectiveness after treatment

30 days after the last dose

What Are the Treatments Tested in This Trial?

Interventions

• Imetelstat
• Ruxolitinib

Trial Overview

The study tests the combination of two drugs: Imetelstat and Ruxolitinib in people with myelofibrosis. The first part determines the best dose of Imetelstat when used with Ruxolitinib, while the second part assesses safety and how well this combined dose works.

How Is the Trial Designed?

Group I: Part 2: Imetelstat sodium + Ruxolitinib Experimental Treatment 2 Interventions

Cohort A: Janus Kinase (JAK) inhibitor naive participants will receive initial treatment with ruxolitinib on study for at least 12 weeks, including 4 consecutive weeks at a stable dose, prior to the addition of imetelstat sodium. Participants can begin imetelstat sodium treatment after sponsor review and approval and meet the following requirements: platelet value is ≥75 x 10\^9/L for two consecutive measurements, at least 1 week apart, and the participant does not meet criteria for dose delay. Note that the study will no longer recruit participants into Cohort A. Cohort B: Participants will receive treatment with ruxolitinib for 12 weeks with at least 4 consecutive weeks at a stable dose prior to enrollment and will start combination treatment with imetelstat on study.

Group II: Part 1: Imetelstat sodium + Ruxolitinib Experimental Treatment 2 Interventions

Participants who have received ruxolitinib orally (PO) as part of standard of care (SOC) for at least 12 weeks prior to Screening will be enrolled. After enrollment, participants will initiate imetelstat sodium therapy. Dose levels of imetelstat sodium may include 4.7, 6, 7.5, 9.4 mg/kg, until a RP2D is established.

Imetelstat is already approved in United States for the following indications:

Approved in United States as Rytelo for:

• Transfusion-dependent low- to intermediate-risk myelodysplastic syndromes

Who Is Running the Clinical Trial?

Geron Corporation

Lead Sponsor

Trials

20

Recruited

1,500+

Published Research Related to This Trial

In a study of 219 patients with myelofibrosis, ruxolitinib significantly improved health-related quality of life (HRQoL) and reduced disease-related symptoms over 48 weeks compared to best available therapy (BAT).

Ruxolitinib treatment led to notable enhancements in physical functioning, fatigue, and appetite, with significant improvements observed as early as week 8 and continuing throughout the study, supporting its efficacy as a treatment for symptomatic myelofibrosis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Health-related quality of life and symptoms in patients with myelofibrosis treated with ruxolitinib versus best available therapy. Harrison, CN., Mesa, RA., Kiladjian, JJ., et al.[2021]

In a study of 219 patients with myelofibrosis, ruxolitinib demonstrated a significant efficacy advantage over the best available therapy, with 28% of patients achieving at least a 35% reduction in spleen volume at 48 weeks, compared to 0% in the control group.

Ruxolitinib not only reduced spleen size but also improved overall quality of life and disease symptoms, with manageable side effects, primarily hematologic issues like thrombocytopenia and anemia, indicating it is a safe and effective treatment option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

JAK inhibition with ruxolitinib versus best available therapy for myelofibrosis. Harrison, C., Kiladjian, JJ., Al-Ali, HK., et al.[2022]

Ruxolitinib, a JAK-inhibitor, has been successfully used to treat 12 Danish patients with myelofibrosis, even those with low platelet counts (< 50 × 10(9)/L).

The majority of patients showed significant clinical improvement, and serious side effects were rare, occurring in only one patient, suggesting that ruxolitinib is a safe and effective option for symptomatic patients with low platelet counts.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ruxolitinib is manageable in patients with myelofibrosis and severe thrombocytopenia: a report on 12 Danish patients. Bjørn, ME., Holmström, MO., Hasselbalch, HC.[2021]

In the MYF2001 trial, patients with relapsed or refractory myelofibrosis treated with imetelstat showed a median overall survival of 29.9 months, indicating its potential efficacy in this challenging condition.

When compared to best available therapy (BAT) in a closely matched cohort, imetelstat significantly reduced the risk of death (hazard ratio: 0.35), suggesting it may offer a substantial survival advantage over traditional treatments after JAK inhibitor failure.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Favorable overall survival with imetelstat in relapsed/refractory myelofibrosis patients compared with real-world data. Kuykendall, AT., Sun, L., Mascarenhas, J., et al.[2022]

Ruxolitinib is commonly used for managing myelofibrosis symptoms, but many patients experience treatment failure after 2-3 years, highlighting the need for alternative therapies like fedratinib.

Fedratinib has shown efficacy in reducing spleen volume and symptoms in patients with myelofibrosis, and ongoing trials are focused on understanding its long-term effects and managing potential gastrointestinal toxicity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Fedratinib: a pharmacotherapeutic option for JAK-inhibitor naïve and exposed patients with myelofibrosis. England, JT., Gupta, V.[2022]

In a phase II study involving patients with myelofibrosis who were resistant to JAK inhibitors, the higher dose of imetelstat (9.4 mg/kg) showed significant clinical benefits, including a median overall survival of 29.9 months and improved spleen and symptom response rates compared to the lower dose (4.7 mg/kg).

Imetelstat treatment led to notable improvements in bone marrow fibrosis and reductions in driver mutation frequencies, indicating its potential effectiveness in targeting the underlying disease mechanisms, while maintaining an acceptable safety profile with manageable side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Randomized, Single-Blind, Multicenter Phase II Study of Two Doses of Imetelstat in Relapsed or Refractory Myelofibrosis. Mascarenhas, J., Komrokji, RS., Palandri, F., et al.[2021]

In a phase II study, ruxolitinib, starting at a low dose of 5 mg twice daily, showed significant efficacy in myelofibrosis patients with low platelet counts (50-100 × 10^9/L), with 62% of patients achieving stable doses of 10 mg twice daily by week 24, and median reductions in spleen volume and symptoms of 24.2% and 43.8%, respectively.

While some patients experienced thrombocytopenia requiring dose adjustments, the treatment was generally manageable, with mean hemoglobin levels remaining stable, indicating that ruxolitinib can be safely administered to this subset of patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Interim analysis of safety and efficacy of ruxolitinib in patients with myelofibrosis and low platelet counts. Talpaz, M., Paquette, R., Afrin, L., et al.[2021]

Ruxolitinib, the first JAK1/2 inhibitor for myelofibrosis, has significantly improved patient outcomes, including better spleen size reduction, symptom relief, quality of life, and overall survival.

Despite its benefits, there are still unmet needs in managing myelofibrosis patients, such as the need for clear resistance criteria and guidelines for handling complications like anemia and infections during ruxolitinib treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Management of Myelofibrosis during Treatment with Ruxolitinib: A Real-World Perspective in Case of Resistance and/or Intolerance. Breccia, M., Palandri, F., Guglielmelli, P., et al.[2022]

In a study of 104 patients with intermediate- and high-risk myelofibrosis, ruxolitinib demonstrated significant efficacy, with over 62% of patients showing a reduction in spleen size after 24 weeks, and high survival rates at 48 weeks (91% progression-free survival).

While ruxolitinib was effective, it was associated with notable safety concerns, including a high incidence of adverse events (62.5% of patients experienced serious AEs) and a 19.2% occurrence of second malignancies, indicating the need for careful monitoring during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A subgroup analysis of JUMP, a phase IIIb, expanded-access study evaluating the safety and efficacy of ruxolitinib in patients with myelofibrosis in a Brazilian cohort. Tavares, R., Souza, CA., Paley, C., et al.[2021]

Ruxolitinib, a JAK1/JAK2 inhibitor, was evaluated in a large phase 3b study (N = 2233) for treating myelofibrosis, including patients with low platelet counts, showing significant reductions in spleen size and symptoms.

The safety profile of ruxolitinib was consistent with previous studies, with common adverse events like anemia and thrombocytopenia, but these rarely led to treatment discontinuation, indicating it is a viable option for patients with low platelet counts.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Primary analysis of JUMP, a phase 3b, expanded-access study evaluating the safety and efficacy of ruxolitinib in patients with myelofibrosis, including those with low platelet counts. Al-Ali, HK., Griesshammer, M., Foltz, L., et al.[2021]

Ruxolitinib, an oral JAK1/JAK2 inhibitor, has been the standard treatment for intermediate or high-risk myelofibrosis (MF) since its FDA approval in 2011, demonstrating significant efficacy in improving patient outcomes based on data from the phase 3 COMFORT trials.

The review highlights the importance of dose optimization and management of common side effects, such as anemia and thrombocytopenia, to maximize the safety and clinical benefits of ruxolitinib, supported by findings from subsequent trials like JUMP, ROBUST, EXPAND, and REALISE.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ten years of treatment with ruxolitinib for myelofibrosis: a review of safety. Verstovsek, S., Mesa, RA., Livingston, RA., et al.[2023]

Citations

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The combination of imetelstat and ruxolitinib showed a consistent safety profile with no dose-limiting toxicities in myelofibrosis patients.

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Patients receiving imetelstat achieved a reduction in TSS from baseline to up to 24 weeks, as well as a decrease in spleen volume. The ...

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Press Release Details

The early results from IMproveMF support the potential tolerability of imetelstat and ruxolitinib as a combination therapy and could have significant ...

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NCT05371964 | A Study to Evaluate the Safety, ...

The purpose of the study is to identify the recommended Part 2 dose (R2PD) of imetelstat sodium in combination with ruxolitinib in participants with ...