Imetelstat + Ruxolitinib for Myelofibrosis

Recruiting at 7 trial locations

Overseen By Judy Ho

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

51 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial is testing a combination of two drugs, imetelstat and ruxolitinib, in patients with myelofibrosis, a type of bone marrow cancer. Imetelstat works by stopping cancer cells from multiplying, while ruxolitinib slows their growth. The study aims to find the best dose and evaluate the safety and effectiveness of this combination. Ruxolitinib is a targeted drug approved for treating myelofibrosis, known for reducing spleen size and improving survival rates.

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 the combination of Imetelstat and Ruxolitinib safe for treating myelofibrosis?

Ruxolitinib, used for myelofibrosis, has been studied for over a decade and is generally safe, though it can cause anemia (low red blood cell count) and thrombocytopenia (low platelet count). These side effects are usually manageable and rarely lead to stopping treatment. ^{1 2 3 4 5}

How is the drug combination of Imetelstat and Ruxolitinib unique for treating myelofibrosis?

The combination of Imetelstat and Ruxolitinib is unique because Imetelstat, a telomerase inhibitor, has shown to significantly improve overall survival in patients with myelofibrosis who have not responded to other treatments, like Ruxolitinib alone, which is a common JAK inhibitor. This combination offers a novel approach for patients with limited options after JAK inhibitor failure. ^{6 7 8 9 10}

What data supports the effectiveness of the drug combination Imetelstat and Ruxolitinib for treating myelofibrosis?

Research shows that Imetelstat improved overall survival in myelofibrosis patients who had stopped responding to other treatments, with a median survival of 30 months compared to 12 months for those on other therapies. Ruxolitinib has been shown to improve symptoms and quality of life in myelofibrosis patients, making the combination potentially beneficial. ^{2 3 5 6 11}

Who Is on the Research Team?

Shyamala Navada, MD

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 or other JAK inhibitor Experimental Treatment 5 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 ≥100 x 109/L for two consecutive measurements, at least 1 week apart, and the participant does not meet criteria for dose delay. Cohort B: Participants will receive treatment with ruxolitinib or other JAK inhibitor for 12 weeks (maximum 48 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, 9.4mg, 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 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]

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 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]

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, 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]

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]

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]

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 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]

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]

Citations

1. Germany pubmed.ncbi.nlm.nih.gov

Favorable overall survival with imetelstat in relapsed/refractory myelofibrosis patients compared with real-world data. [2022]

2. England pubmed.ncbi.nlm.nih.gov

Health-related quality of life and symptoms in patients with myelofibrosis treated with ruxolitinib versus best available therapy. [2021]

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

Interim analysis of safety and efficacy of ruxolitinib in patients with myelofibrosis and low platelet counts. [2021]

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

JAK inhibition with ruxolitinib versus best available therapy for myelofibrosis. [2022]

5. Switzerland pubmed.ncbi.nlm.nih.gov

Management of Myelofibrosis during Treatment with Ruxolitinib: A Real-World Perspective in Case of Resistance and/or Intolerance. [2022]

6. England 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. [2021]

7. England pubmed.ncbi.nlm.nih.gov

Ten years of treatment with ruxolitinib for myelofibrosis: a review of safety. [2023]

8. England pubmed.ncbi.nlm.nih.gov

Fedratinib: a pharmacotherapeutic option for JAK-inhibitor naïve and exposed patients with myelofibrosis. [2022]

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

Ruxolitinib is manageable in patients with myelofibrosis and severe thrombocytopenia: a report on 12 Danish patients. [2021]

10. Brazil 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. [2021]

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

Randomized, Single-Blind, Multicenter Phase II Study of Two Doses of Imetelstat in Relapsed or Refractory Myelofibrosis. [2021]