Evaluation of Navitoclax Monotherapy and Combination with Ruxolitinib in Myeloproliferative Neoplasms: Safety, Tolerability, and Pharmacokinetics

The primary objective of this study is to evaluate the **safety** and tolerability, preliminary efficacy, and pharmacokinetics of **navitoclax** when administered as monotherapy and in combination with **ruxolitinib** in subjects with Myeloproliferative Neoplasms (MPN) and Chronic Myelomonocytic Leukemia (CMML). This includes assessing the effect of navitoclax on the corrected QT interval by Fridericia's correction formula (QTcF) in these subjects. Additionally, the study aims to evaluate the effect of navitoclax, a CYP2C9 inhibitor, on the pharmacokinetics, safety, and tolerability of a single dose of **celecoxib**, a sensitive CYP2C9 substrate, in subjects with MPN or CMML. Furthermore, the study will assess the effect of navitoclax on the pharmacokinetics, safety, and tolerability of ruxolitinib in subjects with first-line and relapsed/refractory Myelofibrosis (MF). These objectives are clinically relevant as they aim to understand the interaction and safety profile of navitoclax in combination with other treatments, which is crucial for optimizing therapeutic strategies for MPN and CMML.

The secondary objectives are to evaluate the preliminary efficacy of navitoclax when administered as monotherapy and in combination with ruxolitinib. Safety evaluations will include monitoring of adverse events, physical examinations, vital signs measurements, electrocardiogram variables, and clinical laboratory testing. Pharmacokinetic samples will be collected and analyzed for navitoclax, ruxolitinib, and celecoxib, with plasma concentrations used to compute their pharmacokinetic parameters as applicable. These evaluations are important for determining the potential benefits and risks associated with the treatment regimens, thereby informing clinical decision-making and patient management.

The clinical trial involves a total of **31 participants** diagnosed with **myelofibrosis** or other **myeloproliferative neoplasms**. The study population includes both male and female subjects aged **18 years and older**. Participants were selected based on specific inclusion criteria, such as requiring treatment and having failed or being intolerant to at least one prior therapy, and being ineligible for allogeneic stem cell transplantation. The trial does not include a vulnerable population. Participants are expected to have an Eastern Cooperative Oncology Group (ECOG) performance status of 2 or less, indicating they are ambulatory and capable of all self-care but unable to carry out any work activities. The study does not specify particular lifestyle considerations such as diet or physical activity. The selection process ensures that participants meet laboratory parameters for bone marrow reserves, platelet count, neutrophil count, renal function, hepatic function, and other relevant health indicators. The trial aims to evaluate the safety, tolerability, and pharmacokinetics of navitoclax, both as a monotherapy and in combination with ruxolitinib, in this specific patient population.

The clinical trial is designed to evaluate the **safety** and tolerability, as well as the pharmacokinetics of **navitoclax** when administered as monotherapy and in combination with **ruxolitinib** in subjects with **myeloproliferative neoplasms** (MPN). This study is structured as a Phase 1, open-label trial, incorporating multiple parts to assess different objectives. The trial is expected to conclude by June 2025, with recruitment having commenced in April 2021. The study is not conducted within the EEA for Parts 1 and 2, while Parts 3 to 6 involve subjects from the US, Europe, and specific regions such as France and Bulgaria.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to determine eligibility based on criteria such as prior treatment history, performance status, and laboratory parameters. Follow-up visits will be scheduled to monitor safety endpoints, including adverse event monitoring, physical examinations, and laboratory testing. The end-of-study visit will conclude the participant's involvement, assessing the overall impact of the treatment regimen. The expected length of participant involvement varies depending on the part of the study they are enrolled in, with conditions for early termination including failure to meet inclusion criteria or adverse reactions to the treatment.

The trial employs a controlled design, with specific parts focusing on the effect of navitoclax on the pharmacokinetics of other drugs, such as **celecoxib**, a CYP2C9 substrate. The primary endpoints include evaluating the effect of navitoclax on the corrected QTc interval and its interaction with other medications. Secondary endpoints involve safety evaluations, pharmacodynamic assessments, and preliminary efficacy evaluations. Participants are required to have a documented diagnosis of MPN or related conditions and must meet specific laboratory and clinical criteria to be eligible for the study.

The clinical trial involves the administration of several experimental medications, each with specific characteristics and roles in the study. **Celecoxib** is utilized as a sensitive CYP2C9 substrate to evaluate the effect of navitoclax on its pharmacokinetics, safety, and tolerability. Celecoxib is a **COX-2 inhibitor** and is administered orally in a pharmaceutical form identified as PHF00005MIG. The dosage and frequency of administration are determined based on the study protocol, and participant compliance is monitored throughout the trial.

**Ruxolitinib**, marketed as Jakavi, is a **Janus Associated Kinases (JAKs) JAK1 and JAK2 inhibitor**. It is provided in tablet form, with available dosages of 5 mg and 10 mg. Ruxolitinib is administered orally, and its role in the trial is to assess its pharmacokinetics, safety, and tolerability when used in combination with navitoclax in subjects with myeloproliferative neoplasms (MPN) or chronic myelomonocytic leukemia (CMML). The administration schedule is designed to ensure optimal therapeutic outcomes, and adherence is closely monitored.

**Navitoclax**, also known by its sponsor product code ABT-263, is a **BCL-2 family protein inhibitor**. It is administered in tablet form and is taken orally. Navitoclax is evaluated both as a monotherapy and in combination with ruxolitinib. The study aims to assess its safety, tolerability, and pharmacokinetics in subjects with MPN or CMML. The dosing schedule is tailored to the study's objectives, and participant compliance is tracked to ensure accurate data collection.

Throughout the trial, the administration of these medications is conducted under strict adherence to the study protocol, with careful monitoring of participant compliance and any potential adverse effects. The trial does not include any non-experimental treatments such as standard-of-care therapy or placebo. The focus remains on evaluating the experimental medications' effects on the specified conditions.

The efficacy of the clinical trial will be assessed through several endpoints, focusing on the effects of **navitoclax** in combination with other treatments. The primary endpoints include evaluating the effect of navitoclax on the corrected QTc interval by Fridericia's correction formula (QTcF) in subjects with Myeloproliferative Neoplasms (MPN) or Chronic Myelomonocytic Leukemia (CMML) in the US and Europe. Additionally, the trial will assess the impact of navitoclax, a potential CYP2C9 inhibitor, on the pharmacokinetics, safety, and tolerability of a single dose of celecoxib, a sensitive CYP2C9 substrate, in subjects with MPN or CMML. Furthermore, the effect of navitoclax on the pharmacokinetics, safety, and tolerability of ruxolitinib in subjects with Myelofibrosis (MF) in the US and Europe will be evaluated.

Secondary endpoints include safety evaluations through adverse event monitoring, physical examinations, vital sign measurements, electrocardiogram (ECG) variables, and clinical laboratory testing. Pharmacodynamic assessments will focus on ECG variables such as QTcF, heart rate, PR interval, QRS duration, and waveform composition. Pharmacokinetic samples will be collected at specified time points to analyze navitoclax levels. Preliminary efficacy will also be evaluated as part of the secondary endpoints. The trial is designed to provide comprehensive data on the safety, tolerability, and efficacy of navitoclax in combination with other treatments for MPN and CMML.