Phase I/II Multicenter Evaluation of Ribociclib with Topotecan and Temozolomide in Pediatric Patients with Relapsed or Refractory Neuroblastoma and Solid Tumors

The primary objective of this Phase I/II multicenter study is to evaluate the **maximum tolerated dose (MTD)** and/or recommended Phase II dose (RP2D) of **ribociclib** in combination with topotecan and temozolomide (TOTEM) in pediatric patients with relapsed or refractory neuroblastoma and other solid tumors. This is clinically relevant as determining the MTD and RP2D is crucial for ensuring the safety and efficacy of the treatment regimen in this vulnerable patient population.

Secondary objectives include:

• Phase I – Part A: Characterizing the safety and tolerability of ribociclib in combination with TOTEM, and characterizing the pharmacokinetics (PK) of ribociclib+TOTEM.
• Phase I – Part B: Assessing the antitumor activity of ribociclib+TOTEM as measured by Duration of Response (DOR), Progression-Free Survival (PFS), Time to Response (TTR), and Overall Survival (OS). Additionally, characterizing the safety, tolerability, and PK of ribociclib+TOTEM.
• Phase II: Evaluating the treatment effect of ribociclib+TOTEM as assessed by PFS and DOR versus placebo plus TOTEM, and by TTR, Clinical Benefit Rate, and OS versus placebo plus TOTEM. Further objectives include characterizing the PK, safety, and tolerability of ribociclib+TOTEM, and describing the effect on Patient Reported Outcomes (PRO).

The clinical trial involves a total of **42 participants** diagnosed with **relapsed or refractory neuroblastoma** and other solid tumors, including medulloblastoma, high-grade glioma, malignant rhabdoid tumors, and rhabdomyosarcoma. The study population comprises both male and female subjects, aged between 12 months and 21 years. Participants were selected based on their histologically or cytologically confirmed solid tumors that have progressed despite standard therapy or for which no effective standard therapy exists. The trial includes individuals with a life expectancy of at least 12 weeks and adequate bone marrow, organ, and cardiac function. Participants are required to have measurable disease per specific criteria and must be able to provide informed consent. The trial population includes vulnerable groups, and lifestyle factors such as diet and physical activity are not specified. The sponsor has not provided additional information regarding lifestyle considerations.

The clinical trial is designed as a **randomized**, **double-blind**, and **controlled** study to evaluate the efficacy and safety of **ribociclib** in combination with **topotecan hydrochloride** and **temozolomide** in pediatric patients with relapsed or refractory neuroblastoma and other solid tumors. The trial is divided into two phases: Phase I and Phase II. Phase I aims to determine the maximum tolerated dose (MTD) and recommended Phase II dose (RP2D) of ribociclib in combination with the TOTEM regimen, while Phase II focuses on evaluating the treatment effect as assessed by the Overall Response Rate (ORR) of ribociclib in combination with TOTEM versus placebo plus TOTEM. The trial is expected to run from December 27, 2022, to July 16, 2029.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on criteria such as age, confirmed diagnosis of specific solid tumors, and adequate organ function. Following the screening, participants will be enrolled in the study and will attend regular follow-up visits to monitor safety, efficacy, and pharmacokinetics. These visits will include assessments of adverse events, laboratory tests, and imaging studies to evaluate tumor response. The end-of-study visit will occur after the completion of the treatment regimen or upon early termination from the study.

The expected length of participant involvement varies depending on individual response and tolerance to the treatment, with a minimum life expectancy of 12 weeks required at enrollment. Conditions that may lead to early termination from the study include significant adverse events, disease progression, or withdrawal of consent. The study will adhere to rigorous ethical standards, ensuring informed consent is obtained from all participants or their guardians prior to participation.

The clinical trial involves the administration of several experimental medications, each with specific pharmaceutical forms, dosages, and routes of administration. **Topotecan Hydrochloride** is utilized in two distinct forms within the study. The first form is a concentrate for solution for infusion, administered via **intravenous use**. The second form is administered as an **intravenous slow bolus injection**. The specific dosage and frequency of administration for both forms are determined based on the trial protocol, aiming to evaluate the efficacy and safety in combination with other treatments.

**Temozolomide** is another experimental medication used in this trial. It is provided in capsule form and administered orally. The dosing schedule is designed to optimize therapeutic outcomes while minimizing potential adverse effects. The trial protocol specifies the dosage and frequency, ensuring adherence to the study's objectives and safety guidelines.

**Ribociclib**, also known by its sponsor product code LEE011, is included in the trial as a powder for oral solution. This medication is administered orally, with the dosage and frequency tailored to achieve the desired therapeutic effect in combination with the other study drugs. The trial aims to determine the maximum tolerated dose and evaluate the antitumor activity of ribociclib in combination with the other treatments.

Participant compliance with the dosing schedules is monitored throughout the trial to ensure adherence to the protocol. The study also includes a comparator treatment, which may involve a placebo, to assess the efficacy of the experimental medications. The trial's design and execution are guided by rigorous scientific and ethical standards to ensure the validity and reliability of the results.

The efficacy of the clinical trial will be assessed through several primary and secondary endpoints. The primary endpoints include the **Overall Response Rate (ORR)**, which is defined as the percentage of participants with a confirmed best overall response of complete response (CR) or partial response (PR). This will be evaluated by a Blinded Independent Review Committee (BIRC) using specific criteria: Revised Assessment in Neuro-Oncology (RANO) for high-grade glioma, International Neuroblastoma Response Criteria (INRC) for neuroblastoma, and Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 for medulloblastoma, malignant rhabdoid tumor, and rhabdomyosarcoma.

Secondary endpoints will include progression-free survival (PFS), duration of response (DOR), and time to response (TTR) as assessed by BIRC using the same criteria as the primary endpoints. Additionally, the trial will measure plasma concentrations of ribociclib, topotecan, and temozolomide, along with derived pharmacokinetic parameters such as area under the curve (AUC) and maximum concentration (Cmax). Safety assessments will be conducted, including the incidence, type, and severity of adverse events per the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Tolerability will be evaluated through dose interruptions, reductions, dose intensity, and duration of exposure for all treatment components. Patient-reported outcomes (PRO) will be measured using the Pediatric Quality of Life Inventory (PedsQL) questionnaire.