Category Archives: Clinical Trial

Ropeginterferon Alfa-2b Effective in Phase 3 Essential Thrombocythemia Trial

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By Jordyn Sava
Fact checked by Jason Broderick

The SURPASS-ET trial (NCT04285086), evaluating ropeginterferon alfa-2b (Besremi) in patients with essential thrombocythemia (ET), has achieved its primary endpoint, demonstrating a durable clinical response as defined by modified European Leukemia Net (ELN) criteria.1

In the intent-to-treat (ITT) population, 42.9% (39/91) of patients treated with ropeginterferon alfa-2b had durable responses at 9 and 12 months vs 6.0% (5/83) of patients enrolled in the comparator arm who were treated with anagrelide (Agrylin) (P =.0001).

For the secondary end point, the JAK2 V617F allele burden decreased from 33.7% to 25.3% (-8.4%) in the ropeginterferon alfa-2b group over 12 months, compared with a reduction from 39.7% to 37.3% (-2.4%) in the anagrelide group. These findings indicate that ropeginterferon alfa-2b may provide a more pronounced effect on mitigating the underlying disease pathology relative to anagrelide.

“We are extremely proud of the SURPASS-ET phase 3 study outcome, which shows the potential of [ropeginterferon alfa-2b] as an important new treatment option for patients with ET, a rare blood cancer that drastically increases the risk of heart attack or stroke,” said Ko-Chung Lin, PhD, founder and chief executive officer of PharmaEssentia, in a press release. “The data highlight the broad potential to apply our innovative monopegylated, long-acting interferon technology as a significant step forward for treating ET, and potentially other myeloproliferative neoplasms, with non-chemotherapy treatments.”

For safety, ropeginterferon alfa-2b did not lead to any treatment-related serious adverse events. Overall, the agent had a manageable safety profile.

Full trial results, including additional pharmacokinetics and biomarker data, are expected to be presented at a later date.

“The results of the SURPASS-ET trial are significant,” said Albert Qin, MD, PhD, chief medical officer, PharmaEssentia, in a press release. “ET is a challenging condition associated with symptoms and risks of thrombosis and disease progression. These encouraging results highlight the potential of [ropeginterferon alfa-2b] to provide an effective and tolerable new treatment option that we believe could provide a substantial clinical benefit for patients with ET. We plan to submit these results to the FDA and other regulatory agencies as soon as possible in hopes of providing this potential new treatment option to patients with ET.”

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Ruxolitinib Combinations in MPNs: Updates From ASH

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January 8, 2025

Author(s): Mary Caffrey

Following its approval in 2011 for myelofibrosis (MF), ruxolitinib (Jakafi, Incyte) became the backbone of treatment for MF and later for polycythemia vera (PV), 2 of the 3 common myeloproliferative neoplasms (MPNs).

But although ruxolitinib improves survival outcomes and quality of life, some patients may not respond to therapy, while others may stop due to genetic mutations, disease progression, or other factors. For years now, investigators have been studying the Janus kinase (JAK) inhibitor in combination with other drugs, both in first-line treatment and refractory disease. Abstracts and oral presentations at the recent 66th American Society of Hematology (ASH) Annual Meeting and Exposition, held December 7-10, 2024, in San Diego, California, offered updates on several combinations in the pipeline:

MANIFEST-2. Previous results from this phase 3 study (NCT04603495) of pelabresib, a selective bromodoman and extraterminal domain (BET) inhibitor, with ruxolitinib show it met its primary end point; in patients with MF not treated with a JAK inhibitor, a statistically significant higher proportion showed at least 35% reduction in spleen volume from baseline at week 24 with the combination vs ruxolitinib and placebo. Results presented at ASH showed those results were maintained after a median follow-up of 72 weeks, with a 48-week response rate of 57.0% for the combination vs 37.5% for ruxolitinib and placebo. An improvement in the Myelofibrosis Symptom Assessment Form total symptom score (TSS) by at least 50% was seen in 45.3% of patients receiving the combination vs 39.4% in the placebo group.1

Bomedemstat. An abstract at ASH reported on an ongoing phase 2 study (NCT05569538) involving bomedemstat combined with ruxolitinib in patients with advanced MF.2 Bomedemstat is an irreversible inhibitor of lysine-specific demethylase 1 (LSD1), which plays a role in gene regulation; blocking this enzyme alters cell differentiation and growth. In August 2024, Merck announced the second phase 3 trial of bomedemastat in another MPN, essential thrombocythemia (ET).

The abstract authors noted that about 50% of patients with MF stop ruxolitinib after 3 years, mostly due to disease progression or cytopenia; median OS after discontinuation is 14 months.2 LSD1, they write, is “critical for self-renewal” of cancerous stem cells, and has shown promise as a single agent. This study reported on 2 cohorts: Cohort A had a suboptimal response to ruxolitinib, and cohort B patients had MF and were treatment naive. Patients in cohort A remained on the entry dose of ruxolitinib while cohort B started 10 mg twice per day; all patients received a starting dose of 0.4 mg/kg/day of bomedemstat. Dose adjustments were permitted every 4 weeks to achieve an optimal platelet count; downward titrations were done at any time for safety reasons. After a median of 61.7 weeks, in 40 evaluable patients, at week 24, 11 patients had at least a 50% improvement in TSS, with 25.9% in cohort A and 30.7% in cohort B; 17.5% had at least 35% spleen volume reduction, with 7.4% in cohort A and 38.5% in cohort B; and 50% of patients had stable or improved hemoglobin (51.9% in cohort A and 46.3% in cohort B). There were no safety signals or deaths related to the drug, the authors said.2

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Bromodomain and BET Inhibitor INCB057643 Shows Benefit for Patients With Myelofibrosis

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12/19/24

Emily Estrada

According to research presented by Justin Watts, MD, Sylvester Cancer Center Institute, University of Miami, Miami, Florida at the 2024 American Society of Hematology (ASH) Annual Meeting & Exposition in San Diego, California, INCB057643 may improve patient outcomes in the treatment of hematologic malignancies, including myelofibrosis (MF).

A small-molecular bromodomain and extra-terminal BET protein inhibitor, INCB057643, has shown safety and tolerability as monotherapy and combination with Janus kinase (JAK) 1 and 2 inhibitors among patients with MF in previous phases of the ongoing phase 1/2 clinical trial. In this dose-escalation and expansion portion of the trial, the dose of INCB057643 in patients with MF receiving monotherapy was increased from 4mg to 12mg and for patients with MF who had an inadequate response to ruxolitinib, combination therapy dosage was increased from 4mg to total maximum dosage.

The primary end points were safety and tolerability, as well as dose-limiting toxicities of INCB057643 at 24 weeks. The secondary end points included spleen volume reduction greater than 35% from baseline (SVR35), symptom reduction by greater than 50% from baseline via MPN-Symptom Assessment Form (TSS50), and anemia response of a hemoglobin increase at least 1.5 g/dL from baseline in patients that were not receiving transfusions or transfusion-free for at least 12 weeks for patients dependent on transfusions at baseline.

Patients with relapsed/refractory MF (84.1%%), essential thrombocythemia ([ET]; 4.5%), myelodysplastic syndromes (MDS), or myeloproliferative neoplasm (MPN) syndromes (11.4%). were included in the study. In total, 18 patients were treated with a monotherapy dose escalation and 10 patients received dose expansion. Combination therapy dose escalation was received by 16 patients whose median age was 71 years and whose median ruxolitinib dose was 22.4mg per day. The median duration of INCB057643 exposure was 195.5 days for patients in the monotherapy dose-escalation cohort and 139.0 days for patients in the dose-expansion cohort. As for patients who were in the combination therapy dose-escalation cohort, median INCB057643 exposure was 194.0  days.

At 24 weeks, 3 out of 16 patients who received monotherapy achieved SVR35 and 5 out of 14 achieved TSS50 with any dose of INCB057643, of which 3 received a dose of at least 10 mg. During any time of treatment, improvements in spleen volume and TSS50 best response were demonstrated by 13/19 and 12/15 patients, respectively. Among patients who received combination therapy of INCB057643 and ruxolitinib, 3 out of 12 patients achieved SVR35 and 6 out of 11 achieved TSS50 at any combo dose. Improvements were seen at any time during treatment for both SVR35 and TSS50 in 13 out of 16 and 10 out of 15 patients, respectively. Of patients not dependent on blood transfusions, an anemia response was demonstrated by 3 patients in both the monotherapy and the combination group. Additionally, of 6 patients who were blood transfusion dependent at BL, 2 achieved transfusion independence.

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JAB-8263 Monotherapy Demonstrates Early Promise in Myelofibrosis

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December 13, 2024

Author(s): Kristi Rosa

The investigative BET inhibitor JAB-8263 was found to be well tolerated and to demonstrate preliminary efficacy in patients with myelofibrosis, according to data from a phase 1/2 study (NCT04686682) presented during the 2024 ASH Annual Meeting.1

Any treatment-emergent adverse effects (TEAEs) occurred in 93.8% of those who received the agent at any dose level (n = 16), with 37.5% experiencing grade 3 or higher TEAEs and 25.0% experiencing a serious TEAEs. Treatment-related AEs (TRAEs) occurred in 87.5% of patients, with 31.3% experiencing grade 3 or higher TRAEs, and 18.8% experiencing serious TRAEs. TRAEs led to dose interruption and reduction for 43.8% and 25.0% of patients, respectively. One patient experienced a TRAE that led to discontinuation of JAB-8263. No treatment-related events proved to be fatal.

Notably, 1 dose-limiting toxicity occurred in a patient who received the agent at a dose of 0.4 mg; this patient experienced grade 3 increases in alanine and aspartate aminotransferase levels.

In all evaluable patients (n = 13), the mean spleen volume reduction (SVR) was –19.95% (range, –39.4% to 3.6%) at week 24 and –26.16% (range, 56.6% to –11.0%) at best response. Notably, 2 patients achieved an SVR of 35% or higher, and 1 patient experienced an SVR of –34.9%. Moreover, at week 24, 60% of 10 patients had a tumor symptom score reduction of at least 50% (TSS50). Two of 8 patients who had received JAK inhibitors experienced a best response of SVR of –41.2% and 34.9%, respectively. Moreover, 50% of 6 evaluable patients who had received JAK inhibitors achieved TSS50 at week 24.

“JAB-8263 at 0.125 mg [once daily to] 0.3 mg [once daily] was well tolerated…Hematological and gastrointestinal AEs are mild with JAB-8263 continuous dosing [compared with] other BET inhibitors,” Junyuan Qi, MD, of the Institute of Hematology and Blood Disease Hospital, Chinese Academy of Medical Sciences, in Tianjin, China, and coauthors, wrote in the poster of the data. “The preliminary efficacy data in myelofibrosis for JAB-8263 monotherapy is promising. Most patients showed spleen reduction and TSS reduction.”

The early-phase study enrolled patients with confirmed primary myelofibrosis (PMF), post–polycythemia vera myelofibrosis (PV-MF), or post–essential thrombocytopenia myelofibrosis (ET-MF). Patients were at least 18 years of age, had spleen volume of at least 450 cm3, a Dynamic International Prognostic Score (DIPSS) of at least intermediate-1, and an ECOG performance status up to 2.

The median age in the 16 total patients was 62 years (range, 36-69) and 56.3% were female. All patients were Asian. Regarding ECOG performance status, 31.3% had a status of 0, 62.5% had a status of 1, and 6.3% had a status of 2. Regarding disease subtype, 68.8% of patients had PMF, 18.8% had PV-MF, and 12.5% had ET-MF. Half of patients had prior exposure to a JAK inhibitor. Most patients had a JAK2 mutation (93.8%). Regarding DIPSS, 68.8% had intermediate-1 disease and 25.0% had intermediate-2 disease. The median time since initial diagnosis was 13.5 months (range, 0.9-76.6).

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Ruxolitinib Plus Pegylated Interferon Alfa-2a Show Promise in Newly Diagnosed Polycythemia Vera

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November 1, 2024

Author(s): Alexandra Gerlach, Associate Editor

Ruxolitinib (Jakafi; Incyte Corp) in combination with pegylated interferon alfa-2a demonstrated efficacy and tolerability in patients with newly diagnosed polycythemia vera (PV). According to the 2-year end-of-study results from the phase 2 COMBI 2 clinical trial (EudraCT2018-004150-13), the treatment improved cell counts, bone marrow cellularity, and fibrosis in patients with PV.1

In the phase 2 COMBI 2 trial, researchers evaluated the safety and efficacy of ruxolitinib and low-dose peg-IFN-α2a in patients with newly diagnosed PV.

Image Credit: © MdBabul – stock.adobe.com

PV is a chronic, progressive myeloproliferative neoplasm characterized by the overproduction of red blood cells. The excess cells thicken the blood, slowing its flow and contributing to serious complications, such as blood clots. Almost all patients with PV have the JAK2V617F mutations, and the JAK2V617F variant allele frequency (VAF) is key for determining outcomes, including thrombosis and progression to myelofibrosis.2-4

Ruxolitinib is a Janus kinase inhibitor approved by the FDA in 2011 and is indicated for the treatment of patients with high-risk MF with reduced abnormal expression of PF4, which can lead to decreased fibrosis. It is additionally indicated as a second-line treatment of PV for patients who have an inadequate response to or cannot tolerate hydroxyurea. In the COMBI 2 trial, researchers assessed the efficacy of ruxolitinib in combination with pegylated interferon alfa-2a (peg-IFN-α2a) (Pegasys ProClick; Genentech), an injection commonly used to treat hepatitis B and C infections. According to data from prior studies, peg-IFN-α2a has been shown to induce durable hematologic and molecular remissions in patients with PV. However, approximately 20% to 40% of patients are intolerant or show limited response to peg-IFN-α2a.5-8

In the phase 2 COMBI 2 trial, researchers evaluated the safety and efficacy of ruxolitinib and low-dose peg-IFN-α2a in patients with newly diagnosed PV in an effort to counterbalance intolerance to peg-IFN-α2a. The primary end point was safety, with secondary end points including efficacy, based on hematologic parameters, quality-of-life measurements, and JAK2V617F variant allele frequency (VAF).8

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Ajax Therapeutics Announces First Patient Dosed in Phase 1 Clinical Trial Evaluating AJ1-11095, a First-in-Class Type II JAK2 inhibitor, for the Treatment of Myelofibrosis

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October 30, 2024

– AJ1-11095 is the first Type II JAK2 Inhibitor to enter the clinic –

– Preclinically, AJ1-11095 has demonstrated superior efficacy to Type I JAK2 inhibitors, such as ruxolitinib, with disease modifying effects on mutant allele burden and fibrosis –

NEW YORK & CAMBRIDGE, Mass.–(BUSINESS WIRE)–Ajax Therapeutics, Inc., a biopharmaceutical company developing next generation JAK inhibitors for patients with myeloproliferative neoplasms (MPNs), today announced the first patient has been dosed in its Phase 1 clinical trial evaluating AJ1‑11095, a first-in-class Type II JAK2 inhibitor, for the treatment of patients with myelofibrosis.

“We’re excited to announce dosing of the first patient enrolled in our first-in-human study with AJ1-11095” said David Steensma, MD, FACP, Chief Medical Officer at Ajax. “As a first-in-class therapy with a unique mechanism of action as a Type II inhibitor of JAK2, AJ1-11095 was developed to provide a much-needed new treatment for patients with myeloproliferative neoplasms by offering the potential for improved efficacy compared to existing therapies.”

AJ1-11095 is the first JAK2 inhibitor to enter the clinic that binds the Type II conformation of the JAK2 kinase as opposed to all the other approved JAK2 inhibitors, including ruxolitinib, that bind the Type I conformation. The advancement of AJ1-11095 into this Phase 1 clinical trial was based on preclinical studies in which AJ1-11095 showed superior efficacy when compared to Type I JAK2 inhibitors with significant disease modifying effects on mutant allele burden and fibrosis, two of the main hallmarks of myelofibrosis.

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INCA033989 May Address Need for Disease-Modifying Therapies in Myelofibrosis

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October 25, 2024

Author(s): Courtney Flaherty

Fact checked by: Megan Hollasch

Unlike the array of JAK inhibitors available for the treatment of patients with myelofibrosis, the novel monoclonal antibody INCA033989 may have disease-modifying potential among those expressing CALR type 1 mutations, potentially addressing an area of need in myeloproliferative neoplasm (MPN) management, according to Daniel J. DeAngelo MD, PhD.

“With the 4 [FDA-approved] JAK inhibitors, we see clear improvements in symptoms, reduction in spleen [volume], and decreased counts for patients with polycythemia or essential thrombocytopenia, but we’re not seeing eradication and normalization of the bone marrow,” DeAngelo said in an interview with OncLive®. “We don’t know if this agent is going to change that, but the hypothesis is that [INCA033989] may be getting at the heart of the disease, although only for patients with CALR type 1 mutations.”

In engineered cell lines and primary CD34-positive cells from patients with MPN, INCA033989 was shown to antagonize mutant CALR–driven signaling and cellular proliferation. Moreover, in a mouse model of MPN with mutant CALR, administration of an INCA033989 mouse surrogate antibody prevented the development of thrombocytosis and accumulation of platelet-producing megakaryocytes in the bone marrow. The agent’s disease-modifying potential is supported by its reduction of pathogenic self-renewal among MPN cells expressing CALR mutations in both primary and secondary transplantations.1

These preclinical data support the agent’s ongoing investigation in a phase 1 study (NCT06034002) for patients with MPN.2

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Recognizing Symptoms of Myeloproliferative Neoplasms and Clinical Trial Challenges

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October 24, 2024

Author(s): Mary Caffrey, Laura Joszt, MA

The symptoms of myeloproliferative neoplasms can be variable and common, which can make it difficult to diagnose if you aren’t looking for the right thing, said Ruben Mesa, MD, FACP, executive director of Atrium Health Wake Forest Baptist Comprehensive Cancer Center and president of Atrium Health Levine Cancer.

He also discusses the challenges with getting patients enrolled in clinical trials, such as the limited availability of them and patient factors that make it difficult to participate.

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FREEDOM2 Trial Shows Fedratinib’s Efficacy and Safety in Myelofibrosis

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By Jordyn Sava
Fact checked by Sabrina Serani

When given as a second-line JAK inhibitor option in patients with myelofibrosis, fedratinib (Inrebic) showed its effectiveness in achieving spleen volume reduction (SVR) while highlighting strategies for managing gastrointestinal adverse effects (AEs) and thiamine deficiency, according to findings from the FREEDOM2 study (NCT03952039).1

The FREEDOM2 study, a multicenter, open-label, randomized controlled trial, involved 316 patients with intermediate-2 or high-risk myelofibrosis who were either relapsed, refractory, or intolerant to ruxolitinib (Jakafi).2 The median follow-up for survival at the data cutoff on December 27, 2022, was 64.5 weeks (IQR, 37.9-104.9). The primary end point was the proportion of patients achieving an SVR of at least 35% (SVR35) at the end of cycle 6.

Results from the study demonstrated a significant difference in SVR35 between the fedratinib and best available therapy (BAT) groups, with 36% of patients in the fedratinib group achieving the primary end point compared with only 6% in the BAT group (30% difference; 95% CI 20%-39%; 1-sided P <.0001).1

“Findings from FREEDOM2 support fedratinib as a second-line Janus kinase inhibitor option to reduce spleen size after ruxolitinib failure or intolerance in patients with myelofibrosis,” wrote study authors in findings published in The Lancet Hematology.

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Dr Scandura on the SENTRY-2 Trial of Single-Agent Selinexor in JAK Inhibitor–Naive Myelofibrosis

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October 16, 2024

Author(s): Joe Scandura, MD, PhD

Fact checked by: Ryan Scott, Courtney Flaherty

Joseph M. Scandura, MD, PhD, associate attending physician, NewYork-Presbyterian Hospital; associate professor, medicine, Weill Cornell Medical College, Cornell University, discusses the phase 2 SENTRY-2 study (XPORT-MF-044; NCT05980806) evaluating single-agent selinexor (Xpovio) in JAK inhibitor–naive myelofibrosis.

The FDA granted fast track designation to single-agent selinexor for the treatment of patients with primary myelofibrosis, post-essential thrombocythemia myelofibrosis, and post-polycythemia vera myelofibrosis in July 2023. Notably, selinexor will be assessed in combination with ruxolitinib (Jakafi) in the phase 3 portion of the SENTRY trial (NCT04562389) and as a monotherapy in the phase 2 SENTRY-2 study for JAK inhibitor–naive patients.

The primary aim of the SENTRY-2 study is to evaluate the efficacy of selinexor as a standalone treatment for patients with myelofibrosis who have not previously been treated with a JAK inhibitor, Scandura begins. Currently, JAK inhibitors are the only FDA-approved class of drugs for this condition, complicating the ability to test alternative treatments like selinexor independently, he states. However, evidence suggests that selinexor demonstrates activity, prompting the FDA to permit the study’s initiation, Scandura says. In SENTRY-2, patients will start treatment with selinexor, and responses will be measured based on spleen volume reduction and symptom improvement, particularly anemia, he details.

An innovative aspect of the study is its flexibility, Scandura notes. If a patient shows some degree of response but it is not deemed significant, they may have a JAK inhibitor added to their treatment regimen, he explains. This could include ruxolitinib or newer agents such as pacritinib (Vonjoy), which does not suppress platelet counts, making it suitable for patients with low platelets. Momelotinib (Ojjaara), known for its efficacy in improving anemia, will be added if patients are anemic and maintain adequate platelet counts.

The importance of safety and rigorous science is emphasized in clinical trials, especially when evaluating new treatments, Scandura continues. With selinexor already recognized as safe, the focus shifts to optimizing its use in the treatment landscape of myelofibrosis, he says. If selinexor gains FDA approval for myelofibrosis, it could play a significant role in a more nuanced treatment approach, reflecting the complexities of managing this condition amidst financial considerations and the availability of multiple JAK inhibitors, Scandura concludes.

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