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1-4-{[6-Amino-5-(4-Phenoxy-Phenyl)-Pyrimidin-4-Ylamino]-Methyl}-4-Fluoro-Piperidin-1-Yl)-Propenone

This article discusses clinical trials investigating 1-4-{[6-Amino-5-(4-Phenoxy-Phenyl)-Pyrimidin-4-Ylamino]-Methyl}-4-Fluoro-Piperidin-1-Yl)-Propenone, also known as TL-895. These trials evaluate the safety and effectiveness of this investigational drug in patients with blood cancers and mast cell disorders. The research includes studies in chronic lymphocytic leukemia, myelofibrosis, and systemic mastocytosis.

Table of Contents

Overview of Clinical Trials

1-4-{[6-Amino-5-(4-Phenoxy-Phenyl)-Pyrimidin-4-Ylamino]-Methyl}-4-Fluoro-Piperidin-1-Yl)-Propenone, also known by its research name TL-895, is being investigated in clinical trials for treating various blood disorders and mast cell conditions[1][2]. The substance is administered orally, making it a convenient treatment option for patients who may prefer pills over injections or infusions[1][2].

Two major clinical trials are evaluating this investigational drug across different disease types and patient populations[1][2]. These studies represent different stages of drug development, from early safety testing to more advanced effectiveness evaluation. The research includes both patients who have never received treatment for their condition and those whose disease has returned or not responded to previous therapies[1][2].

Trials in Blood Cancers

Study Design and Patient Population

A Phase 1/2 clinical trial (NCT02825836) investigated 1-4-{[6-Amino-5-(4-Phenoxy-Phenyl)-Pyrimidin-4-Ylamino]-Methyl}-4-Fluoro-Piperidin-1-Yl)-Propenone in patients with B-cell malignancies, including chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL)[2]. This trial has been completed and enrolled a total of 74 participants[2].

The study included several different patient groups[2]:

  • Relapsed or refractory B-cell malignancies: Patients whose cancer had returned after treatment or did not respond to previous therapies
  • Treatment-naïve CLL/SLL: Patients who had never received treatment for their chronic lymphocytic leukemia or small lymphocytic lymphoma
  • Relapsed/refractory CLL/SLL: Patients with chronic lymphocytic leukemia or small lymphocytic lymphoma that had returned or not responded to treatment

Monotherapy and Combination Approaches

The trial evaluated 1-4-{[6-Amino-5-(4-Phenoxy-Phenyl)-Pyrimidin-4-Ylamino]-Methyl}-4-Fluoro-Piperidin-1-Yl)-Propenone both as a single treatment (monotherapy) and in combination with another investigational drug called navtemadlin[2]. This approach allows researchers to understand how the drug works alone and whether combining it with other medications might improve outcomes.

The study was divided into different arms, with Arms 1 through 4 focusing on one set of patient populations and Arms 5 through 7 evaluating different treatment approaches[2]. This multi-arm design helps researchers gather comprehensive information about the drug’s effects across various clinical scenarios.

Measuring Success in Blood Cancer Trials

The primary way researchers measured whether 1-4-{[6-Amino-5-(4-Phenoxy-Phenyl)-Pyrimidin-4-Ylamino]-Methyl}-4-Fluoro-Piperidin-1-Yl)-Propenone was working in the blood cancer trial was through overall response rate (ORR)[2]. This measures the proportion of patients who achieved any type of positive response to treatment.

The trial used the International Workshop on Chronic Lymphocytic Leukemia (iwCLL) response criteria to define different types of responses[2]. These responses include:

  • Complete response (CR): All signs of cancer disappear
  • Complete response with incomplete blood count recovery (CRi): Cancer disappears but blood counts have not fully recovered
  • Nodular partial response (nPR): Cancer shrinks significantly but small clusters remain in bone marrow
  • Partial response (PR): Cancer shrinks by at least 50%
  • Partial response with lymphocytosis (PR-L): Cancer shrinks but white blood cell counts remain elevated

Investigators assessed these responses at any time while patients were participating in the study[2]. This flexible timing recognizes that different patients may respond at different rates to treatment.

Trials in Mast Cell Disorders and Myelofibrosis

Study Structure and Cohorts

A Phase 2 clinical trial (NCT04655118) is investigating 1-4-{[6-Amino-5-(4-Phenoxy-Phenyl)-Pyrimidin-4-Ylamino]-Methyl}-4-Fluoro-Piperidin-1-Yl)-Propenone in patients with myelofibrosis, indolent systemic mastocytosis, and mast cell activation syndrome[1]. This larger trial has been authorized and plans to enroll 277 participants[1].

The study is organized into six different cohorts, each focusing on specific patient populations and disease types[1]:

  • Cohorts 1-4: Include patients with myelofibrosis and various presentations of mast cell disorders
  • Cohort 5: Specifically focuses on patients with indolent systemic mastocytosis
  • Cohort 6: Evaluates patients with mast cell activation syndrome, including both monoclonal and non-monoclonal types

Multi-Part Study Design

The trial is divided into three parts (A, B, and C), each with different objectives[1]:

Part A focuses on determining the best dose and schedule for 1-4-{[6-Amino-5-(4-Phenoxy-Phenyl)-Pyrimidin-4-Ylamino]-Methyl}-4-Fluoro-Piperidin-1-Yl)-Propenone[1]. For Cohorts 1-4, researchers aim to identify the recommended phase 2 dose (RP2D)[1]. For Cohort 5, they determine the recommended dosing regimen based on safety, effectiveness, and how well patients tolerate the treatment[1]. For Cohort 6, researchers identify the recommended phase 3 dose using similar criteria[1].

Part B evaluates how well the drug improves symptoms[1]. In Cohorts 1-4, researchers measure the proportion of patients who achieve at least a 50% reduction in their Total Symptom Score (TSS) at Week 24 using the Myelofibrosis Symptom Assessment Form version 4.0 (MFSAF v4.0)[1]. For Cohort 5, the study assesses the mean change in the Indolent Systemic Mastocytosis Total Symptom Assessment Form (ISM-TSAF) TSS from the beginning of the study to Week 24[1]. Cohort 6 evaluates changes in mast cell activation syndrome symptoms[1].

Part C is specific to Cohort 5 and includes a comparison with placebo[1]. This part compares changes in indolent systemic mastocytosis symptoms between patients receiving 1-4-{[6-Amino-5-(4-Phenoxy-Phenyl)-Pyrimidin-4-Ylamino]-Methyl}-4-Fluoro-Piperidin-1-Yl)-Propenone and those receiving a placebo (inactive treatment)[1]. This comparison helps researchers understand whether symptom improvements are truly due to the drug rather than other factors.

Understanding the Conditions Being Studied

Myelofibrosis is a rare bone marrow disorder where scar tissue replaces normal bone marrow tissue, disrupting the production of blood cells. Patients often experience symptoms such as fatigue, night sweats, bone pain, and an enlarged spleen.

Indolent systemic mastocytosis is a condition where too many mast cells accumulate in various organs of the body. Mast cells are immune cells that release chemicals causing allergic reactions. When too many accumulate, patients may experience flushing, itching, abdominal pain, diarrhea, and other symptoms. The “indolent” designation means the condition progresses slowly.

Mast cell activation syndrome occurs when mast cells inappropriately release too many chemical mediators, causing symptoms similar to severe allergic reactions even without an allergic trigger. This can include skin reactions, gastrointestinal problems, cardiovascular symptoms, and neurological issues. The syndrome can be monoclonal (arising from a single abnormal cell line) or non-monoclonal.

Dose-Finding Approaches

Standard Dose Across Trials

In the clinical trials, 1-4-{[6-Amino-5-(4-Phenoxy-Phenyl)-Pyrimidin-4-Ylamino]-Methyl}-4-Fluoro-Piperidin-1-Yl)-Propenone is administered orally at a dose of 300 mg/kg[1]. The “mg/kg” designation means the dose is calculated based on the patient’s body weight in kilograms, allowing for personalized dosing that accounts for differences in patient size.

Adaptive Dose Selection

Both trials include important dose-finding components. The Phase 1/2 blood cancer trial was designed as a “first in human” dose escalation study, meaning it was the first time this drug was tested in people[2]. This type of study starts with low doses and gradually increases them to find the highest dose that patients can safely tolerate while still being effective.

The Phase 2 mast cell and myelofibrosis trial uses data on safety, effectiveness, and tolerability to determine optimal dosing[1]. Different cohorts may ultimately receive different recommended doses based on their specific condition and how they respond to treatment. This personalized approach recognizes that different diseases may require different dosing strategies.

Placebo Comparison

Part of the mast cell trial includes a placebo comparison, where some patients receive 1-4-{[6-Amino-5-(4-Phenoxy-Phenyl)-Pyrimidin-4-Ylamino]-Methyl}-4-Fluoro-Piperidin-1-Yl)-Propenone and others receive a matching placebo[1]. A placebo looks identical to the real medication but contains no active drug. This comparison is considered the gold standard in clinical research because it helps determine whether improvements are truly due to the drug’s effects rather than other factors like the natural course of disease or the placebo effect.

Measuring Treatment Success

Symptom-Based Assessments

For patients with myelofibrosis and mast cell disorders, the trials focus heavily on symptom improvement as a measure of success. The Myelofibrosis Symptom Assessment Form version 4.0 (MFSAF v4.0) is used to track symptoms in myelofibrosis patients[1]. This validated questionnaire asks patients to rate the severity of symptoms such as fatigue, night sweats, itching, abdominal discomfort, pain under the ribs on the left side, early satiety (feeling full quickly), and bone or muscle pain.

The trial considers treatment successful if patients achieve at least a 50% reduction in their Total Symptom Score by Week 24[1]. This represents a meaningful improvement in quality of life, as symptom burden significantly affects daily functioning in these patients.

For indolent systemic mastocytosis, researchers use the ISM-TSAF (Indolent Systemic Mastocytosis Total Symptom Assessment Form) to measure symptom changes[1]. This specialized form captures symptoms specific to mastocytosis, such as flushing, itching, abdominal cramping, diarrhea, brain fog, and fatigue. The trial measures the average change in scores from the beginning of the study to Week 24.

Response Criteria in Blood Cancers

As mentioned earlier, the blood cancer trial uses the iwCLL response criteria to define treatment success[2]. These standardized criteria allow researchers to objectively determine whether cancer is responding to treatment. The criteria consider factors such as:

  • Lymph node size (measured by physical examination and imaging)
  • Spleen and liver size
  • Blood counts (red blood cells, white blood cells, platelets)
  • Bone marrow findings
  • Presence or absence of disease symptoms

By using internationally recognized criteria, the results from this trial can be compared with other studies and help doctors understand how 1-4-{[6-Amino-5-(4-Phenoxy-Phenyl)-Pyrimidin-4-Ylamino]-Methyl}-4-Fluoro-Piperidin-1-Yl)-Propenone compares to existing treatments.

Timeline for Assessment

The mast cell and myelofibrosis trial uses a 24-week (approximately 6-month) timeframe for primary assessments[1]. This duration allows sufficient time for the drug to take effect and for symptom improvements to become apparent. The blood cancer trial assessed responses at any time during study participation, recognizing that responses may occur at different rates in different patients[2].

Patient Participation and Eligibility

Disease-Specific Requirements

Each trial enrolls patients with specific disease types. The blood cancer trial focused on patients with B-cell malignancies, particularly chronic lymphocytic leukemia and small lymphocytic lymphoma[2]. It included both patients who had received previous treatment (relapsed/refractory) and those who were treatment-naïve[2].

The mast cell and myelofibrosis trial enrolls patients with confirmed diagnoses of myelofibrosis, indolent systemic mastocytosis (both monoclonal and non-monoclonal), or mast cell activation syndrome[1]. The inclusion of different cohorts allows researchers to understand how the drug works across these related but distinct conditions.

Study Size and Scope

The completed blood cancer trial enrolled 74 participants[2], a typical size for a Phase 1/2 study that combines dose-finding with preliminary effectiveness evaluation. The ongoing Phase 2 mast cell and myelofibrosis trial is larger, with planned enrollment of 277 participants[1]. This larger size reflects the trial’s focus on confirming effectiveness rather than primarily establishing safety and dose.

Multi-Center Research

These trials represent interventional studies, meaning researchers actively administer treatment and measure outcomes[1][2]. This differs from observational studies where researchers simply observe patients receiving standard care. Interventional studies provide the strongest evidence for whether a new treatment works.

Current Trial Status

The blood cancer trial (NCT02825836) has been completed, meaning all patients have finished treatment and follow-up[2]. While the trial is complete, final results may still be under analysis or preparation for publication. The mast cell and myelofibrosis trial (NCT04655118) has been authorized and is actively enrolling or treating patients[1].

Trial ID Phase Condition Studied Status Enrollment Primary Endpoint
NCT04655118 Phase 2 Myelofibrosis, Indolent Systemic Mastocytosis, Mast Cell Activation Syndrome Authorised 277 Symptom reduction at Week 24; Recommended dose determination
NCT02825836 Phase 1/2 B-Cell Malignancies, Chronic Lymphocytic Leukemia, Small Lymphocytic Lymphoma Completed 74 Overall response rate based on iwCLL criteria

FAQ

  • What conditions are being studied in trials with 1-4-{[6-Amino-5-(4-Phenoxy-Phenyl)-Pyrimidin-4-Ylamino]-Methyl}-4-Fluoro-Piperidin-1-Yl)-Propenone? Clinical trials are investigating 1-4-{[6-Amino-5-(4-Phenoxy-Phenyl)-Pyrimidin-4-Ylamino]-Methyl}-4-Fluoro-Piperidin-1-Yl)-Propenone in several conditions including chronic lymphocytic leukemia, small lymphocytic lymphoma, myelofibrosis, indolent systemic mastocytosis, and mast cell activation syndrome. These trials aim to evaluate whether this investigational drug can help patients with these blood and mast cell disorders.
  • What phases are these clinical trials in? The trials investigating 1-4-{[6-Amino-5-(4-Phenoxy-Phenyl)-Pyrimidin-4-Ylamino]-Methyl}-4-Fluoro-Piperidin-1-Yl)-Propenone include both early and later-stage research. One completed trial was a Phase 1/2 study in blood cancers, while an ongoing trial is a Phase 2 study in myelofibrosis and mast cell disorders. These phases help researchers determine safe doses and evaluate effectiveness.
  • Who can participate in these clinical trials? Participants include patients with relapsed or refractory B-cell malignancies, treatment-naïve or relapsed chronic lymphocytic leukemia, myelofibrosis, indolent systemic mastocytosis, and mast cell activation syndrome. Specific eligibility depends on the individual trial, disease type, and previous treatments received.
  • How is 1-4-{[6-Amino-5-(4-Phenoxy-Phenyl)-Pyrimidin-4-Ylamino]-Methyl}-4-Fluoro-Piperidin-1-Yl)-Propenone administered in these trials? In these clinical trials, 1-4-{[6-Amino-5-(4-Phenoxy-Phenyl)-Pyrimidin-4-Ylamino]-Methyl}-4-Fluoro-Piperidin-1-Yl)-Propenone is given orally. The dose studied is 300 mg/kg, though trials include dose-finding components to determine the most appropriate dose for each condition.
  • What are the main goals of these trials? The trials aim to determine safe and effective doses of 1-4-{[6-Amino-5-(4-Phenoxy-Phenyl)-Pyrimidin-4-Ylamino]-Methyl}-4-Fluoro-Piperidin-1-Yl)-Propenone and measure how well it reduces disease symptoms. For blood cancers, researchers measure overall response rates, while for mast cell disorders, they assess symptom improvement using specific scoring systems.

Ongoing Clinical Trials on 1-4-{[6-Amino-5-(4-Phenoxy-Phenyl)-Pyrimidin-4-Ylamino]-Methyl}-4-Fluoro-Piperidin-1-Yl)-Propenone

  • Study of TL-895 for Patients with Relapsed or Refractory Myelofibrosis or Indolent Systemic Mastocytosis

    Recruiting

    1
    Investigated diseases:
    Investigated drugs:
    Belgium Bulgaria France Germany Italy The Netherlands +3

  • Study of TL-895 and Navtemadlin for Patients with Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma

    Not recruiting

    1 1
    Investigated diseases:
    Investigated drugs:
    Hungary Poland

Glossary

  • B-Cell Malignancies: Cancers that develop from B-cells, a type of white blood cell that normally helps fight infections by producing antibodies.
  • Chronic Lymphocytic Leukemia (CLL): A type of blood cancer that affects white blood cells called lymphocytes, causing them to grow slowly and accumulate in the blood and bone marrow.
  • Small Lymphocytic Lymphoma (SLL): A cancer closely related to chronic lymphocytic leukemia that primarily affects lymph nodes rather than blood and bone marrow.
  • Myelofibrosis: A rare bone marrow disorder that disrupts normal blood cell production, causing scar tissue to form in the bone marrow.
  • Indolent Systemic Mastocytosis: A condition where too many mast cells accumulate in various organs, progressing slowly and causing symptoms like flushing, itching, and abdominal pain.
  • Mast Cell Activation Syndrome (MCAS): A disorder where mast cells release too many chemical mediators, causing allergic-type symptoms throughout the body.
  • Relapsed/Refractory: Disease that has either returned after treatment (relapsed) or did not respond to previous treatment (refractory).
  • Overall Response Rate (ORR): The percentage of patients whose cancer shrinks or disappears after treatment, including complete and partial responses.
  • Total Symptom Score (TSS): A measurement tool that combines ratings of multiple symptoms to assess overall symptom burden in patients.
  • Recommended Phase 2 Dose (RP2D): The dose of an investigational drug determined to be safe and potentially effective for further testing in larger trials.
  • Treatment-Naïve: Patients who have not previously received treatment for their specific condition.
  • Complete Response (CR): The disappearance of all signs of cancer in response to treatment, though cancer may still be present in the body.

References