Imetelstat for Myelofibrosis
Recruiting in Palo Alto (17 mi)
+247 other locations
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 3
Recruiting
Sponsor: Geron Corporation
Must be taking: JAK-inhibitors
Must not be taking: Chemotherapy, Corticosteroids, others
Disqualifiers: High blood blast count, Malignancy, others
No Placebo Group
Pivotal Trial (Near Approval)
Prior Safety Data
Trial Summary
What is the purpose of this trial?The purpose of the study is to evaluate the overall survival of participants treated with imetelstat compared to best available therapy with intermediate-2 or high-risk Myelofibrosis (MF) who are relapsed/refractory (R/R) to Janus Kinase (JAK)-Inhibitor treatment.
Will I have to stop taking my current medications?
The trial requires that you stop any chemotherapy or myelofibrosis-directed therapy, including JAK-inhibitors, at least 14 days before starting the study. Other medications may need to be stopped as well, but the protocol does not specify all details.
What data supports the effectiveness of the drug imetelstat for treating myelofibrosis?
Research shows that imetelstat, when used for myelofibrosis patients who did not respond to previous treatments, led to a longer overall survival of about 30 months compared to 12 months with the best available therapy. This suggests that imetelstat may be more effective in extending life for these patients.
12345Is imetelstat safe for humans?
In a study with patients who had myelofibrosis, imetelstat was associated with longer overall survival compared to other treatments, suggesting it may be safe for use in humans. However, more research is needed to fully understand its safety profile.
24678How is the drug Imetelstat different from other treatments for myelofibrosis?
Imetelstat is unique because it is a telomerase inhibitor, which means it targets the enzyme telomerase that helps cancer cells keep dividing. Unlike other treatments, it has shown potential to improve overall survival in patients with myelofibrosis who have not responded to standard JAK inhibitor treatments.
12469Eligibility Criteria
This trial is for adults with intermediate-2 or high-risk Myelofibrosis who haven't improved after treatment with JAK-inhibitor drugs. They should not be eligible for a stem cell transplant, have symptoms of MF, and meet certain blood test criteria. People can't join if they've had recent major surgery, other cancers (with some exceptions), uncontrolled infections, liver disease unrelated to MF, or previous imetelstat treatment.Inclusion Criteria
Participants should follow protocol defined contraceptives procedures
A woman of childbearing potential must have a negative serum or urine pregnancy test at screening
My spleen has grown after JAK inhibitor treatment and I can't have more of this treatment.
+10 more
Exclusion Criteria
I have no active cancer except for treated skin cancer or cervical carcinoma in situ.
I haven't taken any cancer drugs, steroids over 30 mg/day, or JAK inhibitors in the last 14 days.
I have HIV or a current severe infection needing IV antibiotics.
+6 more
Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
4 weeks
1 visit (in-person)
Treatment
Participants receive imetelstat or best available therapy until disease progression or unacceptable toxicity
Up to 3 years
Every 21 days (±3 days) for imetelstat group
Follow-up
Participants are monitored for safety and effectiveness after treatment
Until death, lost to follow-up, withdrawal of consent, or study end
Crossover
Participants on BAT who meet progressive disease criteria may crossover to receive imetelstat treatment
Participant Groups
The study compares the effectiveness of Imetelstat versus Best Available Therapy (BAT) in improving overall survival rates in patients whose Myelofibrosis hasn't responded to JAK-inhibitors. Participants will either receive Imetelstat or their doctor's choice of another therapy deemed best available.
2Treatment groups
Experimental Treatment
Active Control
Group I: ImetelstatExperimental Treatment1 Intervention
Participants will receive imetelstat sodium at 9.4 mg/kg intravenous (IV) every 21 days (±3 days), until disease progression or unacceptable toxicity, treatment discontinuation or study end.
Group II: Best Available Therapy (BAT)Active Control1 Intervention
Participants will receive BAT (investigator-selected non-JAK-inhibitor treatment), until disease progression or unacceptable toxicity, treatment discontinuation or study end.
Participants on BAT who meet protocol-defined criteria for progressive disease may crossover to receive imetelstat treatment after sponsor's approval.
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
University of Kansas Medical Center Research Institute, Inc.Westwood, KS
Weill Cornell Medical CollegeNew York, NY
Mercy HealthSaint Louis, MO
UCLA David Geffen School of MedicineLos Angeles, CA
More Trial Locations
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Who Is Running the Clinical Trial?
Geron CorporationLead Sponsor
References
Randomized, Single-Blind, Multicenter Phase II Study of Two Doses of Imetelstat in Relapsed or Refractory Myelofibrosis. [2021]Patients with myelofibrosis who are relapsed or refractory (R/R) to Janus-associated kinase inhibitors (JAKis) have poor clinical outcomes including dismal overall survival (OS) that ranges between 13 and 16 months. Imetelstat, a telomerase inhibitor, was evaluated in patients with intermediate-2 or high-risk myelofibrosis R/R to JAKi in a phase II multicenter study (ClinicalTrials.gov identifier: NCT02426086).
Favorable overall survival with imetelstat in relapsed/refractory myelofibrosis patients compared with real-world data. [2022]In the MYF2001 trial, treatment of Janus kinase (JAK) inhibitor-relapsed/refractory intermediate-2 or high-risk myelofibrosis (MF) with imetelstat 9.4 mg/kg every 3 weeks demonstrated encouraging median overall survival of 29.9 months. To provide historical context, external real-world data (RWD) were collected from a study of 96 patients who had discontinued ruxolitinib and were subsequently treated with best available therapy (BAT) at Moffitt Cancer Center. A closely matched cohort was identified using the MYF2001 eligibility criteria, including patients with MF who had discontinued ruxolitinib due to lack or loss of response. Overall survival was measured from time of JAK inhibitor discontinuation to death or censored at last follow-up. To improve comparability, propensity score weighting approaches using average treatment effect for overlap population (ATO) and stabilized inverse probability treatment weighting (sIPTW) were used for 10 critical baseline covariates. Fifty-seven patients treated with imetelstat 9.4 mg/kg from MYF2001 and 38 patients treated with BAT from RWD were analyzed with improved balanced baseline covariates after propensity score adjustment, showing significantly lower risk of death with imetelstat compared with BAT (hazard ratio: 0.35; p = 0.0019). With sIPTW, results were similar. Results of sensitivity analyses were consistent with the primary analysis. In conclusion, treatment with imetelstat was associated with longer overall survival compared to BAT (30 vs 12 months, respectively) in closely matched patients with MF after JAK inhibitor failure, warranting further evaluation of imetelstat in this poor-prognosis patient population.
JAK inhibition in myelofibrosis: how to sequence treatment in this new era of multiple options. [2023]The management of myelofibrosis has improved following approval of the JAK1/JAK2 inhibitor, ruxolitinib. This agent laid the foundation for JAK inhibitor therapy, yet limitations have included myelosuppression and other adverse events (skin cancer, weight gain, and infection), as well as loss of response. Recently, two additional JAK inhibitors were approved for use in myelofibrosis. Fedratinib can be used front-line and has demonstrated impressive responses as a salvage option after ruxolitinib loss of response. Previously, patients with severe thrombocytopenia had limited treatment options; approval of pacritinib offers an option to address splenomegaly and/or symptoms in these patients. A significant unmet need has been the treatment of anemia; momelotinib (not approved at the time of writing) has demonstrated spleen, symptom, and anemia responses. The possibility of having four approved options for myelofibrosis may be soon realized. This speaks to progress in the past decade, though achieving clinical and molecular remissions remain paramount.
Momelotinib versus best available therapy in patients with myelofibrosis previously treated with ruxolitinib (SIMPLIFY 2): a randomised, open-label, phase 3 trial. [2021]The Janus kinase (JAK) inhibitor ruxolitinib is the only approved therapy for patients with symptomatic myelofibrosis. After ruxolitinib failure, however, there are few therapeutic options. We assessed the efficacy and safety of momelotinib, a JAK 1 and JAK 2 inhibitor, versus best available therapy (BAT) in patients with myelofibrosis who had suboptimal responses or haematological toxic effects with ruxolitinib.
How I treat myelofibrosis after failure of JAK inhibitors. [2021]The introduction of JAK inhibitors, leading to regulatory approval of ruxolitinib, represents a major therapeutic advance in myelofibrosis (MF). Most patients experience reduction in splenomegaly and improved quality of life from symptom improvement. It is a paradox, however, that, despite inhibition of signaling downstream of disease-related driver mutations, JAK inhibitor treatment is not associated with consistent molecular or pathologic responses in MF. Furthermore, there are important limitations to JAK inhibitor therapy including development of dose-limiting cytopenias and/or nonhematological toxicities such as neuropathy or opportunistic infections. Over half of the patients discontinue treatment within 3 years of starting treatment. Although data are sparse, clinical outcome after JAK inhibitor "failure" is likely poor; consequently, it is important to understand patterns of failure to select appropriate salvage treatment(s). An algorithmic approach, particularly one that incorporates cytogenetics/molecular data, is most helpful in selecting stem cell transplant candidates. Treatment of transplant-ineligible patients relies on a problem-based approach that includes use of investigational drugs, or consideration of splenectomy or radiotherapy. Data from early phase ruxolitinib combination studies, despite promising preclinical data, have not shown clear benefit over monotherapy thus far. Development of effective treatment strategies for MF patients failing JAK inhibitors remains a major unmet need.
A Pilot Study of the Telomerase Inhibitor Imetelstat for Myelofibrosis. [2022]Current drugs for myeloproliferative neoplasm-associated myelofibrosis, including Janus kinase (JAK) inhibitors, do not induce complete or partial remissions. Imetelstat is a 13-mer lipid-conjugated oligonucleotide that targets the RNA template of human telomerase reverse transcriptase.
Evaluating the Safety, Efficacy, and Therapeutic Potential of Momelotinib in the Treatment of Intermediate/High-Risk Myelofibrosis: Evidence to Date. [2020]Myelofibrosis is a heterogeneous disorder with regard to both molecular pathogenesis and clinical phenotype, ranging from an initial fairly indolent condition in some through to an aggressive and debilitating scenario with profound constitutional symptoms, cytopenia frequently requiring transfusional support, and massive splenomegaly. Many advances have been made within the therapeutic arena, and an increasing array of novel agents are now available for disease management. Within this review, we focus on the current and predicted role of the JAK inhibitor momelotinib (Sierra Oncology) in myelofibrosis, with an emphasis on clinical trial evaluation, drug efficacyand safety, and discuss the suggested place in the therapeutic paradigm of myelofibrosis in 2020 and beyond.
JAK inhibitors in the treatment of myelofibrosis. [2022]Myelofibrosis (MF) is a myeloproliferative neoplasm driven by constitutive activation of the JAK/STAT pathway, resulting in clonal hematopoiesis, fibrotic replacement of the bone marrow, extramedullary hematopoiesis, splenomegaly, and debilitating constitutional symptoms. The advent of JAK inhibitors has changed the landscape of treatment options for patients with MF, providing relatively tolerable drug options that control symptoms, reduce splenomegaly, and improve quality of life, but often at the expense of worsening cytopenias. JAK inhibitors do not appear to halt the progression of disease or prevent leukemic transformation, and their effect on survival is debated. Here, we review both the US Food and Drug Administration-approved JAK inhibitors and those in late-phase clinical trials, with a focus on clinical activity and unique adverse effects. We also provide a schema for choosing among these options for patients with MF.
Imetelstat in intermediate-2 or high-risk myelofibrosis refractory to JAK inhibitor: IMpactMF phase III study design. [2022]Imetelstat, a first-in-class telomerase inhibitor, demonstrated meaningful clinical benefit including a robust symptom response rate and potential overall survival benefit in IMbark, a phase II study in intermediate-2 or high-risk myelofibrosis (MF) patients who have relapsed after or are refractory to JAK inhibitors. We describe the rationale and design for the phase III trial, IMpactMF (NCT04576156), an open-label evaluation of imetelstat versus best available therapy, excluding JAK inhibitors, in MF patients refractory to JAK inhibitor. Imetelstat 9.4 mg/kg is administered as an intravenous infusion every 21 days. Primary objective is to assess overall survival. Secondary objectives include symptom and spleen responses, progression-free survival, clinical response assessment, bone marrow fibrosis reduction, safety and pharmacokinetics. Biomarker, cytogenetics and mutation analyses will be performed.