MetroWILMS-1906: Phase 1-2 trial evaluating metronomic chemotherapy in patients with relapsed or refractory Wilms tumor

The primary objective of this study is to evaluate the **safety** and feasibility of a metronomic chemotherapy regimen, consisting of Vincristine, Irinotecan, Etoposide, Temozolomide, and Cis-Retinoic acid, in children and teenagers with relapsed or refractory **Wilms tumor**. This is crucial for determining the regimen's potential as a viable treatment option for this patient population. Additionally, the study aims to assess the efficacy of the metronomic chemotherapy in terms of disease control after two cycles, approximately over a period of six months.

Secondary objectives include:

• Evaluating disease control in terms of progression-free survival (PFS) and overall survival (OS).
• Assessing quality of life using the kidKindl® Quality of Life questionnaire at baseline and approximately at weeks 7 and 13 of treatment.
• Evaluating early response after one cycle of metronomic treatment.
• Assessing the best tumor response over the entire duration of the metronomic treatment.
• Evaluating the safety of the proposed metronomic chemotherapy.
• Assessing the feasibility of the proposed metronomic chemotherapy.

The clinical trial involves a study population comprising **children and teenagers** aged between 18 months and 18 years, diagnosed with relapsed or refractory **Wilms tumor**. Both male and female participants are included, and the trial specifically targets a vulnerable population. The sponsor has not provided the total number of participants. Participants were selected based on their medical condition, with a requirement for histologically proven diagnosis and prior treatment with at least two lines of chemotherapy, or one line in cases of high-risk relapse. The trial considers lifestyle factors such as the ability to take oral medication and requires participants to adhere to specific contraceptive measures if sexually active. Participants must have a performance status of at least 70% on the Karnofsky or Lansky Play score, depending on age, and meet certain biological criteria, including adequate neutrophil and platelet counts, liver function, and renal function. The trial does not provide additional information on the general health status or specific lifestyle habits of the participants.

The clinical trial is designed to evaluate the safety, feasibility, and efficacy of a metronomic chemotherapy regimen in patients with relapsed or refractory **Wilms tumor**. This trial is structured as a Phase 1-2 study and employs a randomized, double-blind, controlled design. The trial is expected to span approximately six years, with an estimated recruitment start date in September 2022 and an anticipated end date in September 2028.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on specific criteria, such as age, performance status, and previous treatment history. The inclusion criteria require patients to be between 18 months and 18 years old, with a histologically proven relapsed or refractory Wilms tumor, and to have undergone at least two lines of chemotherapy. Following the screening, eligible participants will be enrolled in the trial and will receive the investigational treatment regimen, which includes **vincristine**, **irinotecan**, **etoposide**, **temozolomide**, and **isotretinoin**.

Study visits will occur at regular intervals to monitor the participants' response to treatment and to assess any adverse events. The primary endpoints include dose-limiting toxicity over the first cycle and disease control after two cycles of treatment, approximately six months post-inclusion. Secondary endpoints will evaluate progression-free survival, overall survival, health-related quality of life, tumor response, and the feasibility of the therapy. Participants will be involved in the trial for the duration of the treatment cycles, with follow-up visits scheduled to assess long-term outcomes.

The expected length of participant involvement is approximately six months, with conditions for early termination including significant adverse events, disease progression, or withdrawal of consent. The trial will adhere to rigorous ethical standards, ensuring that all participants provide informed consent and that their health and safety are prioritized throughout the study.

The clinical trial involves the administration of several experimental medications, each with specific pharmaceutical forms, dosages, and routes of administration. **Isotretinoin**, a retinoid for acne treatment of chemical origin, is administered orally. The pharmaceutical form is denoted as PHF00095MIG. The dosage and frequency of administration are determined based on the trial protocol, ensuring participant safety and compliance.

**Vincristine**, an antineoplastic agent of chemical origin, is administered intravenously. The pharmaceutical form is PHF675. This medication is part of the metronomic chemotherapy regimen being evaluated for its safety and efficacy in patients with relapsed or refractory Wilms tumor.

**Irinotecan**, another antineoplastic agent of chemical origin, is administered orally. The pharmaceutical form is PHF00230MIG. It is included in the trial to assess its role in the metronomic chemotherapy regimen, contributing to the overall treatment strategy for the targeted patient population.

**Temozolomide**, classified as an alkylating agent of chemical origin, is also administered orally. The pharmaceutical form is PHF00005MIG. Its inclusion in the trial aims to evaluate its impact on disease control when used in combination with other agents in the regimen.

**Etoposide**, a podophyllotoxin derivative of chemical origin, is administered orally with the pharmaceutical form PHF675. It is part of the comprehensive treatment approach being tested for its potential benefits in managing relapsed or refractory Wilms tumor.

Throughout the trial, participant compliance with the dosing schedules is closely monitored to ensure adherence to the protocol. The trial does not include any non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatment. The primary objective is to evaluate the safety, feasibility, and efficacy of the metronomic chemotherapy regimen in the specified patient population.

The efficacy of the metronomic chemotherapy regimen in patients with relapsed or refractory **Wilms tumor** will be assessed through a series of primary and secondary endpoints. The primary endpoints include dose-limiting toxicity (DLT) over the first cycle, which spans 12 weeks or longer if there is a temporary discontinuation, and disease control, defined as complete response, partial response, or stable disease, after two cycles of treatment. This will be measured by progression-free survival (PFS) approximately six months after inclusion.

Secondary endpoints will further evaluate efficacy through several parameters. Progression-free survival will be calculated as the time from trial entry to disease progression or death from any cause, with patients still alive without progression being censored at their last visit. Overall survival will be measured from trial entry to death from any cause, with similar censoring rules applied. Health-Related Quality of Life (HRQoL) will be assessed using the Kindl® Quality of Life questionnaires at baseline and approximately at weeks 7 and 13. Tumor response will be evaluated using CT-scan or MRI imaging, following RECIST 1.1 criteria, after each treatment cycle, approximately every three months. The early response will be based on evaluation after one cycle, and the best response will be measured over the entire treatment duration.

Adverse events will be reported and graded using the NCI-CTCAE v5.0 classification, excluding those clearly related to the underlying disease or its progression. The feasibility of the therapy will be assessed by the frequency of dose reductions or temporary treatment stops, summarized by the relative dose intensity for each drug, and reasons for permanent discontinuation.