Category Archives: Clinical Trial

Phase 3 Trial of Bomedemstat in Essential Thrombocythemia Begins Enrollment

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By Sabrina Serani
Fact checked by Jordyn Sava

A pivotal phase 3 trial (NCT06456346) has initiated to evaluate bomedemstat (MK-3543; IMG-7289), an investigational agent for the treatment of patients with essential thrombocythemia (ET) who have previously not received cytoreductive therapy.1

“The standard of care in essential thrombocythemia has remained unchanged for decades, and patients are in need of new options that have the potential to not only improve disease control, but also improve their quality of life,” said Gregory Lubiniecki, MD, vice president, global clinical development, Merck Research Laboratories, in a press release. “We are rapidly advancing our clinical development programs with the goal of helping to address these unmet needs and bring more options to patients living with myeloproliferative neoplasms.”

The Shorespan-007 trial will compare the orally available LSD1 inhibitor bomedemstat with standard-of-care hydroxyurea in patients with treatment-naive ET, the most common myeloproliferative neoplasm. LSD1 is an enzyme that is potentially important for regulating the proliferation of hematopoietic stem cells, as well as the maturation of progenitor cells.

The study’s primary end point is durable clinicohematologic response rate, and secondary end points include duration of hematologic remission, event-free survival, incidence of adverse events, and disease progression rate. Additionally, investigators will be patient-reported outcomes, including fatigue and symptoms.

The FDA previously granted orphan drug and fast track designations to bomedemstat in ET and myelofibrosis, as well as orphan drug designation in acute myeloid leukemia.

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Dr Grunwald on the Patient Population and Limitations of the REVEAL Study in PV

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September 4, 2024

Author(s): Michael R. Grunwald, MD, FACP

Michael R. Grunwald, MD, FACP, hematologist/oncologist, chief, Leukemia Division; director, Transplantation and Cellular Therapy Program, Levine Cancer Institute, Atrium Health, discusses the key characteristics of patients with polycythemia vera (PV) enrolled onto the real-world, observational REVEAL study (NCT02252159), as well as thelimitations of the investigation.

This observational study represents the largest prospective cohort study of patients with PV conducted to date, Grunwald begins. Patients were not uniformly enrolled at the time of diagnosis; rather, they could be enrolled at any stage of their disease progression. A total of 2510 patients were included in the study, with 2023 having a confirmed diagnosis of PV, ensuring the accuracy of their inclusion in the study, he explains. The remaining patients may or may not have had PV, which introduces a level of uncertainty regarding their inclusion, Grunwald adds.

The analysis focused those who exhibited signs of progression to myelofibrosis, he continues. By comparing the characteristics of patients in the transformed group with those in the non-transformed group, it was observed that patients in the transformed group had a longer duration between their initial diagnosis and enrollment in the study, Grunwald elucidates.

Although the study offers valuable insights, it has limitations, according to Grunwald. Although its findings are effective in generating hypotheses, they do not provide definitive guidance on therapeutic interventions, he explains. Real-world data can offer insights into the outcomes of patients with low-risk disease treated with various therapies, Grunwald says. However, the true validation of a therapy’s effectiveness, particularly for low-risk disease, lies in clinical trials, Grunwald reports.

Looking ahead, there is a need for clinical trials that focus on early intervention in patients classified as low risk, who may harbor features indicating a higher risk of disease progression, he continues. Early intervention may alter the disease course, though this must be balanced against the risk of introducing toxicity prematurely or exhausting treatment options too early, Grunwald says. Fortunately, the treatment paradigm for myeloproliferative neoplasms is evolving, with a significant increase in drug development and approvals over the past decade, he notes. It is anticipated that concerns about exhausting treatment options prematurely will diminish as more therapies become available for patients, he concludes.

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Essential Thrombocythemia Trial Launched Evaluating Bomedemstat

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By Alex Biese
Fact checked by Ashley Chan

A second phase 3 clinical trial has been launched for the investigational oral drug bomedemstat as a potential new treatment for patients with essential thrombocythemia.

The Shorespan-007 clinical trial, according to a news release from bomedemstat manufacturer Merck, will investigate the use of the drug among patients with essential thrombocythemia who have not previously received cytoreductive therapy.

The global trial, which is currently recruiting, will compare bomedemstat to the current standard of care chemotherapy, hydroxyurea. The trial, with 300 participants, is expected to be concluded in May 2029, according to its listing on clinicaltrials.gov.

Essential thrombocythemia, part of a group of blood cancers known as myeloproliferative neoplasms (MPNs), is a rare disease in which the bone marrow produces too many platelets, according to The Leukemia & Lymphoma Society. This disease, The Leukemia & Lymphoma Society explained, can cause blood clots to form in a patient’s blood vessels, in turn resulting in serious health issues such as stroke, heart attack or pulmonary embolism.

“The standard of care in essential thrombocythemia has remained unchanged for decades, and patients are in need of new options that have the potential to not only improve disease control but also improve their quality of life,” said Dr. Gregory Lubiniecki, vice president of global clinical development for Merck Research Laboratories, in the company’s news release. “We are rapidly advancing our clinical development programs with the goal of helping to address these unmet needs and bring more options to patients living with myeloproliferative neoplasms.”

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Merck Announces Phase 3 Trial Initiation for Bomedemstat, an Investigational Candidate for the Treatment of Certain Patients With Essential Thrombocythemia

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August 27, 2024 6:45 am ET

The initiation of a second Phase 3 clinical trial for bomedemstat demonstrates company’s commitment to advancing research in myeloproliferative neoplasms (MPNs)

RAHWAY, N.J.–(BUSINESS WIRE)– Merck (NYSE: MRK), known as MSD outside of the United States and Canada, today announced the initiation of Shorespan-007, a pivotal Phase 3 clinical trial evaluating bomedemstat, an investigational orally available lysine-specific demethylase 1 (LSD1) inhibitor, for the treatment of patients with essential thrombocythemia (ET) who have previously not received cytoreductive therapy. Essential thrombocythemia is a chronic, rare blood disorder and is the most common type of myeloproliferative neoplasm. Global recruitment of the Shorespan-007 trial has begun, with patients now enrolling.

“The standard of care in essential thrombocythemia has remained unchanged for decades, and patients are in need of new options that have the potential to not only improve disease control, but also improve their quality of life,” said Dr. Gregory Lubiniecki, vice president, global clinical development, Merck Research Laboratories. “We are rapidly advancing our clinical development programs with the goal of helping to address these unmet needs and bring more options to patients living with myeloproliferative neoplasms.”

Shorespan-007 is a Phase 3, randomized, double-blind, active comparator-controlled clinical trial ( NCT06456346 ) evaluating bomedemstat compared to the current standard of care chemotherapy, hydroxyurea, for treatment of patients with ET who have previously not received cytoreductive therapy. The trial will enroll approximately 300 patients globally. The primary endpoint of the study is durable clinicohematologic response rate (CHR). Key secondary endpoints include Myelofibrosis Symptom Assessment Form version 4.0 (MFSAF v4.0) individual fatigue symptom item score, Patient-reported Outcomes Measurement Information System (PROMIS) Fatigue SF-7a total fatigue score and MFSAF v4.0 total symptom score. Additional secondary endpoints include duration of hematologic remission, event-free survival and disease progression rate.

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Observational MOST Trial Reveals Progression Trends in Low-Risk Myelofibrosis

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July 11, 2024

Author(s):Jax DiEugenio

Findings from the prospective, observational MOST trial (NCT02953704) showed that 58.5% of patients with low- or intermediate-1–risk myelofibrosis enrolled in cohort A (n = 205) met at least 1 criterion for disease progression after a median follow-up of less than 53 months, which was a higher rate than investigators expected, according to Aaron Gerds, MD.

Cohort A included patients with low-risk or intermediate-1–risk disease, where patients were considered to have intermediate-1–risk myelofibrosis based on age only. Cohort B (n = 27) featured patients with intermediate-1–risk disease with other Dynamic International Prognostic Scoring System (DIPSS) risk factors beyond age.

Findings presented at the 2024 EHA Congress showed that of the 120 patients in cohort A who experienced disease progression, 64 (53.3%) met 1 criterion for progression, 27 (22.5%) met 2 criteria, and 29 (24.2%) met at least 3 disease progression criteria. The most common progression criteria met in cohort A included a hemoglobin level of less than 10 g/dL (47.5%) and a platelet count of less than 100 x 109/L (31.7%). For Cohort B, 25 patients (92.6%) met 1 progression criterion, 1 patient (3.7%) met 2 progression criteria, and 1 patient (3.7%) met 3 progression criteria.

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Mascarenhas on the SENTRY Trial Design and Goals

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By John Mascarenhas, MD

John Mascarenhas, MD, professor, medicine, Icahn School of Medicine, Mount Sinai, director, Center of Excellence for Blood Cancers and Myeloid Disorders, member, The Tisch Cancer Institute, Mount Sinai, discusses the methods, design, and inclusion criteria of the phase 3 SENTRY trial (NCT04562389) for patients with JAK inhibitor treatment-naive myelofibrosis.

SENTRY is a global, multicenter, phase 1/3 study where investigators are assessing the efficacy and safety of selinexor (Xpovio) combined with ruxolitinib (Jakafi) in this patient population.

According to Mascarenhas, the primary end points of phase 3 of the trial include the proportion of patients with spleen volume reduction of greater than or equal to 35% at week 24 (SVR35), and the proportion of patients with a total symptom score reduction of greater than or equal to 50% at week 24 (TSS50), as measured by the myelofibrosis symptom assessment form V4.0.

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Dr Kishtagari on JAK Inhibitor Selection for Myelofibrosis in the Community Setting

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John Mascarenhas, MD

John Mascarenhas, MD, professor, medicine, Icahn School of Medicine, Mount Sinai, director, Center of Excellence for Blood Cancers and Myeloid Disorders, member, The Tisch Cancer Institute, Mount Sinai, discusses phase 3 of the SENTRY (NCT04562389) trial, a global, multicenter, phase 1/3 study evaluating the efficacy and safety of selinexor (Xpovio) when given in combination with ruxolitinib (Jakafi) in patients with JAK inhibitor treatment-naive myelofibrosis.

The study is being conducted in 2 phases. In phase 1, the open-label portion of the study, enrollment has been completed and the safety and recommended dose of selinexor plus ruxolitinib was studied. Phase 1a utilized a standard 3+3 design, and phase 1b was the dose-expansion part. Phase 3 of the trial is enrolling patients with JAK inhibitor treatment-naive myelofibrosis and randomizing them 2:1 to receive the combination therapy of selinexor with ruxolitinib or placebo with ruxolitinib.

In phase 3, the primary end points are the proportion of patients with spleen volume reduction of greater than or equal to 35% at week 24, and the proportion of patients with a total symptom score reduction of greater than or equal to 50% at week 24, as measured by the myelofibrosis symptom assessment form V4.0.

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Ajax Therapeutics Announces FDA Clearance of IND Application for AJ1-11095, a First-in-Class Type II JAK2 inhibitor, for the Treatment of Myelofibrosis

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

– Phase 1 dose escalation study expected to begin in 2H 2024 –

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 that it has received clearance for its Investigational New Drug (IND) application from the U.S. Food and Drug Administration (FDA) to initiate a Phase 1clinical study of AJ1‑11095, a first-in-class Type II JAK2 inhibitor, for the treatment of patients with myelofibrosis.

“This is an important milestone for our company and our first program to enter the clinic and the first clinical study to ever evaluate a Type II JAK2 inhibitor in patients.”

“We are thrilled to obtain clearance to advance AJ1-11095 into the clinic and excited to bring this innovative new medicine to patients with myelofibrosis,” said Martin Vogelbaum, co-founder and CEO of Ajax Therapeutics. “This is an important milestone for our company and our first program to enter the clinic and the first clinical study to ever evaluate a Type II JAK2 inhibitor in patients.”

“We look forward to the clinical development of AJ1-11095 in myelofibrosis and to initiating our Phase 1 dose escalation study, AJX-101, later this year,” said David Steensma, MD, FACP, Chief Medical Officer at Ajax. “As a first-in-class therapy with a unique mechanism as a Type II inhibitor of JAK2, AJ1-11095 was developed to provide a much-needed new treatment for patients with myelofibrosis by offering the potential for improved efficacy with disease modifying effects compared to existing therapies.”

About AJ1-11095

AJ1-11095 was designed by Ajax, through our collaboration with Schrödinger, to be a next generation JAK2 inhibitor by using structure-based drug design and computational methods at scale to selectively bind the Type II conformation of the JAK2 kinase and to provide greater efficacy with disease modification compared to all currently approved JAK2 inhibitors which bind the Type I conformation of JAK2. Additionally, AJ1-11095 has been shown in preclinical studies to reverse marrow fibrosis, reduce mutant allele burden and maintain efficacy against MPN cells that become resistant to chronic Type I JAK2 inhibition.

About Myelofibrosis

Myelofibrosis (MF) is a rare blood cancer that affects approximately 20,000 patients in the United States. The disease is characterized by spleen enlargement, scarring (fibrosis) in the bone marrow, progressive anemia, and debilitating symptoms, such as fatigue, night sweats, itching, and abdominal discomfort, which can impair a patient’s’ quality of life. The most widely used treatment for MF patients are Type I JAK2 inhibitors which can reduce spleen size and provide symptomatic improvement but have little effect on the underlying cause of disease. Over time, most MF patients stop Type I JAK2 inhibitor therapy. The most common causes for treatment discontinuation include a lack of benefit or loss of response, adverse events, and disease progression, leaving significant unmet treatment needs for these patients.

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How the PERSIST-2 Results Show The Benefit of Pacritinib in MF

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Targeted Oncology Staff

Targeted Oncology: What was the make-up of the PERSIST-2 trial (NCT02055781) looking at pacritinib (Vonjo) in patients with myelofibrosis (MF)?

JOHN MASCARENHAS, MD: This was the more interesting of the 2 PERSIST studies. PERSIST-2 looked at patients with platelets of 100,000/µL or less.1 So, the cytopenic patient with MF could have been given a Janus kinase [JAK] inhibitor before being enrolled, and half did in this study…but these are patients that were hard to treat, which was opposite to the set-up of the COMFORT-1 [NCT00952289] and COMFORT-2 [NCT00934544] studies.2 [Patients in PERSIST-2 study] were given either 400 mg daily or 200 mg of twice daily pacritinib vs patients on best available therapy [BAT], which could also include ruxolitinib [Jakafi], with a coprimary end point of spleen volume reduction of 35% or more and reduction of the total symptom score at week 24.1

What stood out among patients enrolled in either arm of the study?

I think what’s important to appreciate is when asking the investigator what they would give to patients who were randomly assigned to the BAT arm is that there is a lack of options available. In the BAT arm, 45% of patients got low-dose ruxolitinib, 19% had no options, while some patients were getting hydroxyurea [19%], steroids [13%], and even interferons [2%], which I would argue don’t work in this setting.1 These were patients who had higher-risk disease, and half of them had hemoglobin counts less than 10 g/dL, and the median platelet count was somewhere around 50,000/µL [in a majority of patients in both arms].

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Parsaclisib Added to Ruxolitinib Decreases Spleen Volume and Improves Symptom Scores in Myelofibrosis

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Kyle Doherty

The PI3Kδ inhibitor parsaclisib added to a stable dose of ruxolitinib (Jakafi) reduced spleen volume and improved symptom scores for patients with myelofibrosis who experienced a suboptimal response to ruxolitinib, according to findings from a phase 2 study (NCT02718300) published in Blood Adv.

Final results of the study revealed that patients who received daily-to-weekly dosing of parsaclisib (n = 32) and those who received all-daily dosing of parsaclisib (n = 42) achieved a decrease in spleen volume of at least 10% at 12 weeks at rates of 28.0% and 59.5%, respectively. Moreover, patients achieved a 50% decrease or more at week 12 in Myelofibrosis Symptom Assessment Form symptom scores at rates of 14% and 28%, respectively; the rates of at least a 50% decrease at week 12 in Myeloproliferative Neoplasms Symptom Assessment Form symptom scores were 18% and 32%, respectively.

“Ruxolitinib reduces spleen volume, improves symptoms, and increases survival in patients with intermediate- or high-risk myelofibrosis. However, suboptimal response may occur, potentially because of signaling via the PI3K/protein kinase B pathway,” Abdulraheem Yacoub, MD, professor of Hematologic Malignancies and Cellular Therapeutics at KU Medical Center in Kansas City, Kansas, and coauthors wrote. “The addition of parsaclisib to stable-dose ruxolitinib can reduce splenomegaly and improve symptoms, with manageable toxicity in patients with myelofibrosis with suboptimal response to ruxolitinib.”

The study authors added that parsaclisib was designed with a different molecular structure than earlier-generation PI3K inhibitors—the orally bioavailable, potent, and highly selective next-generation inhibitor may in turn be able to limit both on- and off-target toxicities that were previously seen.

Additional findings from the study demonstrated that in the overall population evaluable for the primary end point (n = 65), the median change in spleen volume was −163.6 cm3 (range, −735.6 to 10173 cm3), with a median percentage change of −11% (range, −47% to 444%). At week 24, these figures were −192.0 cm3 (range, −2040 to 761.4 cm3) and −10% (range, −89% to 34%) among 49 evaluable patients. The median percentage change was greater among patients who received all-daily dosing compared with those who received daily-to-weekly dosing both at 12 weeks (−15.0% vs −2.0%) and 24 weeks (−19.0% vs −2.5%, respectively).

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