Efficacy of Nintedanib in Reducing Total Lesion Glycolysis in Adult Unicentric Hyalino-Vascular Castleman's Disease Over 6-Month Treatment Period

The primary objective of this study is to evaluate the efficacy of **nintedanib** in decreasing Total Lesion Glycolysis (TLG) of the Unicentric Castleman Disease (UCD) lesion over a 6-month treatment period. This is clinically relevant as it aims to assess the potential of nintedanib to reduce metabolic activity in UCD lesions, which could translate into improved patient outcomes.

Secondary objectives include:

• Evaluation of the safety profile of nintedanib.
• Assessment of the size and metabolism of the UCD lesion under treatment.
• Determination of the resectability of the lesion after a 6-month nintedanib treatment.
• Evaluation of the evolution and occurrence of autoimmune-related complications under treatment.
• Analysis of the mutational status of PDGFRB of the lesion using NGS technology.
• Assessment of nintedanib residual plasma concentration and its correlation with response to treatment.

The clinical trial involves **adult patients** aged 18 and over diagnosed with unicentric hyalino-vascular Castleman's disease. The study population includes both male and female participants, with no specific gender restrictions. Participants are required to have a biopsy-proven diagnosis of hyaline-vascular Unicentric Castleman disease and must be either unable or unwilling to undergo surgical resection of the UCD lesion. The trial population is selected based on their ability to provide written informed consent and their affiliation with the National French social security system. The sponsor has not provided information regarding the total number of participants. The study does not specify any particular lifestyle considerations such as diet or physical activity. The trial includes a vulnerable population, indicating that special considerations may be in place to ensure the safety and ethical treatment of participants.

The clinical trial is designed to evaluate the efficacy of **nintedanib** in decreasing Total Lesion Glycolysis (TLG) in patients with unicentric hyalino-vascular Castleman's disease over a six-month treatment period. This study is a Phase 4, randomized, double-blind, controlled trial. Participants will be administered either Ofev 100 mg or 150 mg soft capsules, with a maximum daily dose of 200 mg or 300 mg, respectively, taken orally. The trial is expected to commence recruitment in September 2024 and conclude by July 2030.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age (18 years or older), biopsy-proven diagnosis, and availability of the oral route. Following the screening, participants will attend follow-up visits at months 1, 3, 6, and 9. The primary endpoint will be assessed by measuring the best response over six months, defined as a greater than 30% decrease from baseline in TLG, using 18F FDG PET/CT scans at months 3 and 6. Secondary endpoints include the number of adverse events, changes in lesion size, and evaluation of autoimmune-related complications.

The expected length of participant involvement is up to nine months, with the treatment phase lasting six months. Conditions that may lead to early termination from the study include significant adverse events or participant withdrawal of consent. The end-of-study visit will occur at month 9, where final assessments will be conducted, including the evaluation of nintedanib residual plasma concentration and the mutational status of PDGFRB of the lesion. This trial aims to provide valuable insights into the therapeutic potential of nintedanib for this rare disease.

The clinical trial involves the administration of **nintedanib**, an experimental medication, in the form of soft capsules. Two dosages of the medication are utilized: Ofev 100 mg soft capsules and Ofev 150 mg soft capsules. Both formulations are manufactured by Boehringer Ingelheim International GmbH. The active substance, nintedanib, is of chemical origin and is also known by the synonym BIBF 1120. The pharmaceutical form of the medication is a soft capsule, and the route of administration is oral. The maximum daily dose for the 100 mg capsules is 200 mg, with a total maximum dose of 36,600 mg over the treatment period. For the 150 mg capsules, the maximum daily dose is 300 mg, with a total maximum dose of 54,900 mg over the treatment period. The treatment period for both dosages is set at six months.

In this study, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are mentioned. The trial's main objective is to evaluate the efficacy of nintedanib in decreasing Total Lesion Glycolysis (TLG) of the Unicentric Castleman Disease (UCD) lesion over a six-month treatment period. Participant compliance with the dosing schedule will be monitored throughout the trial to ensure adherence to the prescribed regimen. The trial does not involve any pediatric formulations, and the medication is not classified as an orphan drug. The study is conducted under the authorization of the European Union, with marketing authorization numbers EU/1/14/979/001 for the 100 mg capsules and EU/1/14/979/003 for the 150 mg capsules.

The efficacy of **nintedanib** in the treatment of Unicentric Castleman Disease (UCD) will be assessed by evaluating the decrease in Total Lesion Glycolysis (TLG) of the UCD lesion over a 6-month treatment period. The primary endpoint is defined as a best response over 6 months, characterized by a greater than 30% decrease from baseline in TLG, as measured by 18F FDG PET/CT scans conducted at Month 3 (M3) and Month 6 (M6).

Secondary endpoints include the number of adverse events (AEs) and serious AEs, as well as the discontinuation of nintedanib up to Month 9 (M9). Additional assessments will involve variations from baseline in the size, standardized uptake value (SUV), and TLG percentage of the lesion at M3 and M6. The change in the status of non-resectability of the UCD lesion at M6 will also be evaluated. The evolution of autoimmune-related complications, such as paraneoplastic pemphigus and bronchiolitis obliterans, will be monitored through specific indices and lung function tests at M1, M3, M6, and M9. The occurrence of paraneoplastic pemphigus and/or myasthenia gravis during follow-up up to M9 will be recorded. The mutational status of PDGFRB of the lesion will be evaluated using NGS technology, and its correlation with treatment response will be analyzed. Additionally, nintedanib residual plasma concentration will be measured at M1, M3, and M6.