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2-((4S)-6-(4-Chlorophenyl)-1-Methyl-4H-Benzo[C]Isoxazolo[4,5-E]Azepin-4-Yl)Acetamide Monohydrate

This article discusses two clinical trials investigating the use of pelabresib (CPI-0610), a novel drug for treating myelofibrosis and essential thrombocythemia. These studies aim to evaluate the safety and efficacy of pelabresib, either alone or in combination with other treatments, for patients with these rare blood disorders. The trials focus on assessing improvements in symptoms, spleen size, and overall patient outcomes.

Table of Contents

What is Pelabresib?

Pelabresib, also known as CPI-0610, is an investigational medication being developed for the treatment of certain blood disorders[1]. It is a small molecule drug that belongs to a class of medications called bromodomain and extra-terminal (BET) protein inhibitors[2]. Pelabresib is currently being studied in clinical trials to evaluate its effectiveness and safety in treating myelofibrosis and essential thrombocythemia, which are types of myeloproliferative neoplasms.

Medical Conditions Treated

Pelabresib is being investigated for the treatment of two main conditions:

  • Myelofibrosis: A rare blood cancer that affects the bone marrow, leading to scarring and impaired blood cell production[1].
  • Essential Thrombocythemia: A condition characterized by an overproduction of platelets in the bone marrow[2].

These conditions are part of a group of disorders called myeloproliferative neoplasms, which affect the production of blood cells in the bone marrow.

How Pelabresib Works

Pelabresib works by inhibiting bromodomain and extra-terminal (BET) proteins[2]. BET proteins play a role in regulating gene expression, and by inhibiting these proteins, pelabresib may help to control the abnormal cell growth and function associated with myelofibrosis and essential thrombocythemia. This mechanism of action is different from currently available treatments, potentially offering a new approach to managing these conditions.

Clinical Trials

Pelabresib is currently being evaluated in several clinical trials:

  1. MANIFEST-2 Study: This is a Phase 3 clinical trial comparing the combination of pelabresib and ruxolitinib (a currently approved medication for myelofibrosis) to placebo and ruxolitinib in patients with myelofibrosis who have not previously received JAK inhibitor treatment[1]. The study aims to determine if adding pelabresib to ruxolitinib can improve outcomes for patients.
  2. Extension Study: This is an open-label, multicenter study for patients who have previously participated in pelabresib clinical trials[2]. The primary objectives of this study are to evaluate the long-term safety of pelabresib and to assess overall survival and leukemia-free survival in patients receiving the drug.

These clinical trials are designed to assess various aspects of pelabresib’s effectiveness and safety, including its impact on spleen size, symptom burden, bone marrow fibrosis, and quality of life for patients with myelofibrosis and essential thrombocythemia.

Dosage and Administration

In the clinical trials, pelabresib is administered orally in the form of tablets[1][2]. The exact dosing regimen may vary depending on the specific trial and patient characteristics. In the MANIFEST-2 study, for example, pelabresib is given daily for 14 consecutive days followed by a 7-day break, which is considered one cycle of treatment (21 days total)[1]. The maximum daily dose being studied is 225 mg[2].

It’s important to note that as pelabresib is still an investigational drug, the optimal dosing regimen may be subject to change based on ongoing research findings.

Side Effects and Safety

As with any medication, pelabresib may cause side effects. The ongoing clinical trials are carefully monitoring patients for any adverse events. Some potential side effects and safety considerations include:

  • Gastrointestinal effects such as nausea, vomiting, or diarrhea[2]
  • Changes in blood cell counts
  • Potential interactions with other medications, particularly strong CYP3A4 inhibitors or inducers[2]

The clinical trials also have specific eligibility criteria to ensure patient safety, including restrictions on recent vaccinations, other medical conditions, and concomitant medications[1][2].

Conclusion

Pelabresib (CPI-0610) represents a promising new approach to treating myelofibrosis and essential thrombocythemia. As a BET inhibitor, it offers a novel mechanism of action that may complement or enhance existing therapies. The ongoing clinical trials will provide crucial information about its effectiveness, safety, and potential role in the treatment of these challenging blood disorders. Patients interested in learning more about pelabresib should consult with their healthcare providers and consider whether participation in a clinical trial might be appropriate for their individual situation.

Aspect MANIFEST-2 Trial Extension Study
Study Type Phase 3, randomized, double-blind Open-label, multicenter
Primary Objective Evaluate efficacy of pelabresib + ruxolitinib vs placebo + ruxolitinib Evaluate long-term safety and survival
Patient Population JAK inhibitor-naive myelofibrosis patients Patients previously enrolled in pelabresib studies
Primary Endpoint Splenic response at Week 24 TEAEs, overall survival, leukemia-free survival
Treatment Duration Up to 36 months Up to 60 months
Key Eligibility Criteria DIPSS risk Intermediate-1 or higher, spleen volume ≥450 cm3 Ongoing clinical benefit from pelabresib in parent study

FAQ

  • What is pelabresib and how does it work? Pelabresib (CPI-0610) is a small molecule inhibitor that targets bromodomain and extra-terminal (BET) proteins. It is being studied as a potential treatment for myelofibrosis and essential thrombocythemia, which are rare blood disorders. Pelabresib works by modulating gene expression and potentially reducing inflammation and fibrosis in the bone marrow.
  • What are the main objectives of the MANIFEST-2 trial? The MANIFEST-2 trial aims to compare the efficacy of pelabresib combined with ruxolitinib versus placebo with ruxolitinib in patients with myelofibrosis who have not previously received JAK inhibitors. The primary objective is to determine the splenic response at Week 24. Secondary objectives include assessing changes in total symptom score, bone marrow fibrosis, and overall survival.
  • Who is eligible to participate in the extension study? The extension study is open to patients who have previously participated in clinical trials involving pelabresib. Eligible participants must be at least 18 years old, still receiving treatment with pelabresib in a parent study, and experiencing clinical benefit as assessed by their investigator. They must also be willing to comply with the study procedures and contraception requirements.
  • What are the primary endpoints of the extension study? The primary endpoints of the extension study are: 1) The occurrence and severity of treatment-emergent adverse events (TEAEs) and serious TEAEs among patients receiving pelabresib, 2) Overall survival and leukemia-free survival, and 3) Time to event endpoints such as duration of response and progression-free survival in patients who are receiving or have received pelabresib.
  • How long can patients receive treatment in these studies? In the MANIFEST-2 trial, patients may receive treatment until disease progression or discontinuation, for up to 36 months. In the extension study, the maximum treatment period with pelabresib is 60 months. However, patients will be followed for disease progression and overall survival even after discontinuing treatment.

Ongoing Clinical Trials on 2-((4S)-6-(4-Chlorophenyl)-1-Methyl-4H-Benzo[C]Isoxazolo[4,5-E]Azepin-4-Yl)Acetamide Monohydrate

  • Study on Long-Term Safety of Pelabresib for Patients with Myelofibrosis or Essential Thrombocythemia

    Recruiting

    3 1 1
    Investigated diseases:
    Investigated drugs:
    Belgium Italy The Netherlands

  • Study of pelabresib (DAK539) plus ruxolitinib versus placebo plus ruxolitinib in adult patients with myelofibrosis who are JAK‑inhibitor‑naive

    Not yet recruiting

    3 1 1
    Investigated drugs:
    Austria Belgium Czechia France Germany Italy +3

Glossary

  • Myelofibrosis: A rare blood cancer where scar tissue forms in the bone marrow, interfering with normal blood cell production and causing various symptoms including enlarged spleen and anemia.
  • Essential Thrombocythemia: A rare blood disorder characterized by the overproduction of platelets in the bone marrow, which can lead to blood clots or bleeding problems.
  • JAK inhibitor: A type of medication that blocks the action of Janus kinase (JAK) enzymes, which are involved in blood cell production and immune function. Ruxolitinib is an example of a JAK inhibitor used in treating myelofibrosis.
  • Splenic response: A measure of treatment effectiveness in myelofibrosis, typically defined as a reduction in spleen size by a certain percentage or volume.
  • Total Symptom Score (TSS): A measure of the severity of myelofibrosis symptoms, including fatigue, night sweats, itching, abdominal discomfort, pain under ribs on left side, and feeling of fullness when eating little food.
  • Progression-free survival (PFS): The length of time during and after treatment that a patient lives with the disease without it worsening.
  • Overall survival (OS): The length of time from the start of treatment or diagnosis that patients are still alive.
  • Leukemia-free survival: The length of time after treatment during which no signs of leukemia are found in patients previously diagnosed with a blood disorder.
  • Treatment-emergent adverse events (TEAEs): Side effects or undesirable experiences that occur after starting a treatment and were not present before or have worsened since treatment began.
  • DIPSS risk category: Dynamic International Prognostic Scoring System, a tool used to assess the risk and prognosis of patients with myelofibrosis.

References

  1. http://clinicaltrials.eu/trial/study-to-compare-pelabresib-and-ruxolitinib-with-placebo-and-ruxolitinib-in-patients-with-myelofibrosis-who-have-not-previously-received-jak-inhibitors/
  2. http://clinicaltrials.eu/trial/study-on-long-term-safety-of-pelabresib-for-patients-with-myelofibrosis-or-essential-thrombocythemia/