Phase IV Rollover Study Evaluating Long-Term Safety of Ruxolitinib Alone or in Combination with Panobinostat, Siremadlin, or Rineterkib in Eligible Patients

The primary objective of this study is to evaluate the long-term safety data of **ruxolitinib** (RUX), specifically focusing on serious adverse events (SAEs) and adverse events (AEs). This is clinically relevant as it provides critical insights into the safety profile of RUX when used over extended periods, which is essential for understanding the risk-benefit balance in patients who have completed prior studies involving this medication.

Secondary objectives include evaluating the clinical benefit as assessed by the investigator. This assessment will help determine the therapeutic value of continued treatment with RUX in patients who have previously participated in global Novartis or Incyte-sponsored studies, or studies involving RUX in combination with other agents such as panobinostat, siremadlin, or rineterkib.

The clinical trial involves a total of **106 participants** who are currently enrolled in a Novartis-sponsored GDD or GMA study or an Incyte-sponsored study. The study population includes both **male and female subjects** across a range of age categories, specifically adults and adolescents. Participants are selected based on their current enrollment in the specified studies and their ongoing benefit from treatment with **ruxolitinib** monotherapy or its combinations with other agents such as panobinostat, siremadlin, or rineterkib. The trial population includes a vulnerable group, indicating that special considerations are in place for their participation. The study does not specify particular lifestyle considerations such as diet or physical activity. The selection criteria ensure that participants have fulfilled all requirements of the parent protocol and are benefiting from the treatment as determined by the investigator.

The clinical trial is designed as an open-label, multi-center, Phase IV rollover protocol aimed at evaluating the long-term safety of **ruxolitinib** monotherapy and its combination therapies. The trial will include patients who have completed a prior global Novartis or Incyte-sponsored study involving **ruxolitinib** or its combinations with either **panobinostat**, **siremadlin**, or **rineterkib**. The primary objective is to assess the frequency and severity of serious adverse events (SAEs) and adverse events (AEs), while secondary endpoints include the proportion of patients with clinical benefit as assessed by the investigator at scheduled visits. The trial is expected to conclude by September 16, 2027, with recruitment having started on July 10, 2015.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on the principal inclusion criteria. These criteria require that patients are currently enrolled in a Novartis or Incyte-sponsored study, receiving **ruxolitinib** or its combinations, and are benefiting from the treatment as determined by the investigator. Follow-up visits will be scheduled to monitor the safety and efficacy of the treatment, with assessments of SAEs and AEs conducted at each visit. The end-of-study visit will mark the conclusion of the participant's involvement, where final evaluations will be performed.

The expected length of participant involvement is contingent upon the maximum treatment period, which is set at 150 days for **ruxolitinib** and its combinations, and 40 days for **siremadlin**. Conditions that may lead to early termination from the study include the occurrence of unacceptable toxicity, disease progression, or withdrawal of consent by the participant. The trial's design ensures rigorous monitoring and evaluation to maintain participant safety and data integrity throughout the study duration.

The clinical trial involves the administration of several experimental medications, primarily focusing on **ruxolitinib** and its various formulations. **Jakavi** tablets, containing the active substance **ruxolitinib**, are available in dosages of 5 mg, 10 mg, 15 mg, and 20 mg. These tablets are administered orally, with a maximum daily dose of 50 mg and a total maximum dose of 7500 mg over a treatment period of up to 150 days. The tablets are provided by Novartis Europharm Limited and are packaged differently depending on the country, with clinical supplies in bottles and commercial presentations in blisters. The active substance, **ruxolitinib phosphate**, is chemically derived and is also known by synonyms such as INCB018424.

Another experimental medication used in the trial is **HDM201**, which contains the active substance **siremadlin**. This medication is provided in the form of hard capsules, also administered orally. The maximum daily dose for HDM201 is 40 mg, with a total maximum dose of 1600 mg over a treatment period of up to 40 days. The capsules are manufactured by Novartis Pharma AG, and the active substance is chemically derived, with synonyms including HDM201 and its chemical name.

Additionally, the trial includes the use of **Farydak** hard capsules, containing the active substance **panobinostat**. These capsules are available in dosages of 10 mg and 15 mg, administered orally. The maximum daily dose is 30 mg, with a total maximum dose of 2700 mg over a treatment period of up to 90 days. Farydak is provided by Pharmaand GmbH, and the active substance is chemically derived, with the descriptive name panobinostat.

Throughout the trial, participant compliance with the dosing schedules is monitored to ensure adherence to the prescribed treatment regimens. The trial aims to evaluate the long-term safety data, focusing on serious adverse events (SAEs) and adverse events (AEs) associated with these medications.

The efficacy of the clinical trial will be assessed through several key endpoints. The primary endpoint focuses on the frequency and severity of serious adverse events (SAEs) and adverse events (AEs). Secondary endpoints include the proportion of patients experiencing clinical benefit, as evaluated by the investigator during scheduled visits, and the frequency and severity of AEs/SAEs. These assessments will be conducted at predetermined intervals throughout the trial to ensure comprehensive data collection and analysis.

The trial involves the use of **ruxolitinib** as monotherapy or in combination with other agents such as panobinostat, siremadlin, or rineterkib. The evaluation of clinical benefit will be based on investigator assessments, which will be systematically recorded during scheduled visits. The trial is designed to gather long-term safety data, with a focus on the continued benefit of the treatment regimen for patients who have completed a prior study and are deemed to benefit from ongoing treatment.