Tag Archives: clinical trial

Pelabresib Plus Ruxolitinib Improves Spleen Responses in Myelofibrosis

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By Roman Fabbricatore
Fact checked by Russ Conroy

Pelabresib (CPI 0610) in combination with ruxolitinib (Jakafi) significantly improved spleen responses and elicited robust clinical activity compared with placebo/ruxolitinib in patients with JAK inhibitor-naïve myelofibrosis, according to results from the phase 3 MANIFEST-2 trial (NCT04603495) published in Nature Medicine.1

Efficacy data from the trial revealed that the primary end point of spleen volume reduction of at least 35% at week 24 favored the investigational combination vs the placebo arm: 65.9% vs 35.2%, respectively (difference, 30.4%; 95% CI, 21.6%-39.3%; P <.001). Additionally, the mean percent change at week 24 in the respective arms was –50.6% (95% CI, –53.2% to –48.0%) vs –30.6% (95% CI, –33.7% to –27.5%). Spleen volume response was consistently higher with pelabresib vs placebo across predefined subgroups.

Furthermore, the hemoglobin response rate, defined as a 1.5 g/dl or greater mean increase, occurred in in 10.7% of the pelabresib arm (95% CI, 6.60%-14.90%) vs 6.0% of the placebo arm (95% CI, 2.85%-9.19%). Transfusions were received in the first 24 weeks of treatment in 27.6% and 37.5% of respective arms.

Greater reductions in NF-κB-regulated cytokines (–32.1% [95% CI, –34.9% to –29.2%] vs –19.4% [95% CI, –22.5% to –16.2%]), tumor necrosis factor (TNF; –43.5% [95% CI, –47.0% to –39.8%] vs –26.4% [95% CI, –30.5% to –22.1%]), and interleukin-6 (IL-6; –35.4% [95% CI, –44.2% to –25.2%] vs –14.5% [95% CI, –25.2% to –2.3%]) were seen in the investigational arm vs the placebo arm. Of note, a reduction in IL-8 levels was observed with pelabresib (–14.3% [95% CI, –22.3% to –5.5%]), but an increase was observed in the placebo arm (31.2% [95% CI, 17.5%-46.5%).

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Promising New Treatment for Myelofibrosis Blood Cancer Using a Combination Targeted Therapy 

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By Julie Grisham

An international phase 3 clinical trial of a new drug combination for treating the blood cancer myelofibrosis found that adding a second, experimental drug to standard treatment was more effective than the standard treatment alone. Further, adding the second drug did not significantly increase side effects. Memorial Sloan Kettering Cancer Center (MSK) enrolled the most patients in the trial.

“This is one of the largest myelofibrosis clinical trials to date,” says MSK leukemia specialist Raajit Rampal, MD, PhD, lead author of the study, published March 10 in Nature Medicine. “There is a real unmet need for patients with this disease, and the findings from this trial represent an exciting advance.”

This study looked at adding an experimental drug called pelebresib to the drug ruxolitinib (Jakafi®), which is the current treatment for myelofibrosis. Both drugs are targeted therapies. Pelebrisib blocks the action of proteins involved in inflammation and cancer; ruxolitinib blocks a protein called JAK. This combination approach was based on ongoing research from the lab of MSK leukemia specialist and physician-scientist Ross Levine, MD.

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New MF Study Recruiting Participants for Its Phase 3 Portion

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Özge Özkaya, MSc, PhD
Publish Date

A phase 1/3 clinical trial testing the safety and efficacy of selinexor plus ruxolitinib in patients with myelofibrosis (MF) who are Janus kinase (JAK) inhibitor-naïve is now recruiting participants for its phase 3 portion.

The global, multicenter, 2-part study aims to recruit an estimated 350 participants with MF. Participants were all at least 18 years of age.

The study consists of an experimental phase 1a, experimental phase 1b, and experimental phase 3 portion.

In the experimental phase 1a portion, 1 group of patients were given 40 mg of oral selinexor once a week on days 1, 8, 15, and 22 of each 28-day cycle together with 15 or 20 mg of ruxolitinib twice a day based on their platelet count at baseline while another group was given 60 mg of oral selinexor on the same days and the same dose of ruxolitinib as the first group.

In the experimental phase 1b, patients were given either 40 or 60 mg of oral selinexor once a week on days 1, 8, 15, and 22 of each 28-day cycle and the same dose of ruxolitinib.

In the experimental phase 3 portion, patients will either be given a fixed starting dose of 60 mg of oral selinexor or a placebo once a week on days 1, 8, 15, and 22 of each 28-day cycle together with the same dose of ruxolitinib.

The primary outcome measures of the phase 1 portion of the trial was the maximum tolerated dose and recommended phase 2 dose of selinexor and the number of participants with adverse events by severity, nature, and occurrence.

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Protagonist and Takeda Announce Positive Topline Results from Phase 3 VERIFY Study of Rusfertide in Patients with Polycythemia Vera

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March 3, 2025

− Study met the primary endpoint, with a significantly higher proportion of clinical responders on rusfertide compared to placebo

− All four key secondary endpoints were met, including EU primary endpoint and patient-reported outcomes

− Rusfertide was generally well tolerated; no new safety findings were observed in the study

NEWARK, Calif. & OSAKA, Japan & CAMBRIDGE, Mass.–(BUSINESS WIRE)–Protagonist Therapeutics, Inc. (“Protagonist”) (NASDAQ:PTGX) and Takeda (TSE:4502/NYSE:TAK) today announced positive topline results for the Phase 3 VERIFY study, in which phlebotomy-dependent patients with polycythemia vera (PV) were randomized to treatment with either rusfertide or placebo, as an add-on to standard of care treatment. The study met its primary endpoint and all four key secondary endpoints. Rusfertide is a first-in-class investigational hepcidin mimetic peptide therapeutic, which has received Orphan Drug designation and Fast Track designation from the U.S. Food & Drug Administration (FDA).

Key findings from the study include:

  • The primary endpoint of the study was met, with a significantly higher proportion of clinical responders1 among rusfertide-treated patients with PV (77%) compared to those who received placebo (33%) during weeks 20-32; p<0.0001. The primary endpoint of the study was the proportion of patients achieving a response, which was defined as the absence of phlebotomy eligibility.
  • The first key secondary endpoint, which is the pre-specified primary endpoint for European Union (EU) regulators, was also met, with a mean of 0.5 phlebotomies per patient in the rusfertide arm compared to 1.8 phlebotomies per patient in the placebo arm during weeks 0-32; p<0.0001.
  • The other three pre-specified key secondary endpoints, namely hematocrit control2 and patient-reported outcomes using PROMIS Fatigue SF-8a3 and MFSAF TSS-74, were also achieved with statistical significance.
  • Rusfertide was generally well tolerated in the Phase 3 VERIFY trial, and safety was in line with previous rusfertide clinical studies. No new safety findings were observed in the study. The majority of adverse events were grade 1-2 injection site reactions and all serious adverse events reported were deemed to be not drug related. There was no evidence of an increased risk of cancer in rusfertide-treated patients compared to those on placebo.

“The positive results of the Phase 3 VERIFY study across the primary and all key secondary endpoints provide compelling evidence of the potential for rusfertide as a first-in-class erythrocytosis-specific agent to address unmet medical needs in patients with PV who are unable to achieve adequate hematocrit control despite standard of care treatments,” said Arturo Molina, M.D., M.S., Chief Medical Officer of Protagonist. “We plan to submit additional details of these promising results for presentation at upcoming medical conferences in 2025. We are immensely grateful to the patients, study staff and principal investigators who made the VERIFY study possible.”

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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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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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