Personalized Treatment of Rhabdomyosarcomas: A Comparison of New Drugs, Radiation Therapies, and Maintenance Strategies

Rhabdomyosarcomas (RMS) belong to a group of soft-tissue tumors that arise from so-called embryonic mesenchymal cells. These cells are not yet fully mature and therefore have the ability to differentiate into various cell types of connective tissue, such as bone, cartilage, and fat cells—or, as in the case of RMS, muscle cells. In RMS, these cells undergo malignant transformation, causing them to proliferate uncontrollably and form a tumor. RMS can develop in various parts of the body, as embryonic mesenchymal cells are found throughout the body. However, the most common sites are the head, neck, urogenital tract, and extremities. There are various histological types of RMS, including embryonal, alveolar, and pleomorphic RMS, which differ in their growth patterns and aggressiveness. While embryonal and alveolar RMS predominate in children, pleomorphic RMS are more common in adults. Treatment for embryonal and alveolar RMS involves a combination of surgery, chemotherapy, and radiation therapy, with the exact approach depending on various factors such as tumor stage, location, and the patient’s age. Treatment for RMS typically involves surgical removal of the tumor. If complete removal is not possible, chemotherapy and/or radiation therapy are used to shrink the tumor. Depending on the risk group (e.g., location, metastases, and genetic characteristics), the intensity of treatment is adjusted. Patients with alveolar RMS or a specific genetic mutation—a so-called PAX-FOXO1 fusion—are considered high-risk cases and receive more intensive treatment. Despite intensive standard treatment, the cure rate for rhabdomyosarcomas—particularly in cases of advanced disease or recurrence—remains poor. Furthermore, current treatment is highly standardized, meaning that more individualized treatment approaches based on risk factors such as tumor biology (e.g., PAX-FOXO1 fusion) or response to therapy (e.g., monitoring imaging using positron emission tomography) still need to be further developed in order to treat high-risk patients more intensively and low-risk patients more gently. It is currently unclear whether maintenance therapy following primary treatment can actually prevent relapses.

The goal of this Phase 1/2 study is to improve the efficacy of treatments, avoid unnecessary side effects, and increase the long-term chance of cure. It aims to evaluate the effects of new drug combinations in both newly diagnosed and recurrent RMS, investigate whether changing the duration of maintenance therapy affects the outcome, and examine whether changes in the dose, extent (in metastatic disease), and timing of radiation therapy can improve patient outcomes and quality of life.

The FaR-RMS study is divided into several treatment phases (so-called “modules”) with multiple comparison groups. This structure allows the study to conduct a highly targeted investigation of various treatment approaches—each tailored to the individual risk profile of the patients. In each group, a new therapy is compared with the current standard of care. Patients are assigned to an appropriate group based on their disease stage and risk profile. In this study, risk stratification is performed using the PAX-FOXO1 fusion gene status instead of the previously used microscopic subtyping.

Module 1: Dose-finding for the study induction therapy The standard chemotherapy regimen consisting of ifosfamide, vincristine, and actinomycin D is supplemented with the study drug irinotecan. To date, this drug has only been approved for other types of cancer and is not specifically approved for RMS. In Phase 1b of the study, the dose of the drug will be gradually increased to determine the maximum tolerated dose, which will then be further investigated in the subsequent module.

Module 2: Induction Therapy for Patients at Very High Risk (CT1A) and High Risk (CT1B): This module investigates whether adding the drug irinotecan to standard chemotherapy can increase the treatment’s effectiveness. For each risk group (CT1A or CT1B), two groups are formed at random (randomized). The control groups receive the current standard therapy (CT1A: ifosfamide, vincristine, actinomycin D, and doxorubicin; CT1B: ifosfamide, vincristine, and actinomycin D). The study groups receive the drug irinotecan in addition to standard therapy (CT1B), or irinotecan is administered in place of doxorubicin (CT1A). The goal of this module is to reduce the risk of relapse by adding irinotecan.

Module 3: Radiation Therapy Comparison (RT1A, RT1B, RT1C): The effectiveness of different radiation doses and timing is being evaluated. For patients at high risk of recurrence (RT1A), radiation therapy is administered before surgery in the study group and after surgery in the control group. For completely resectable tumors (RT1B), the standard dose is compared with a higher dose (41.4 Gy vs. 50.4 Gy). For inoperable tumors (RT1C), the study examines whether high-dose radiation (59.4 Gy) is more effective than the standard dose (50.4 Gy).

Module 4: Radiation Targeting (RT2): This module investigates whether it is sufficient to irradiate only the primary tumor and affected lymph nodes—or whether all visible metastases should also be irradiated. This could improve the chances of cure in cases of widespread disease.

Module 5: Adjuvant Therapy After Completion of Primary Treatment (CT2A & CT2B): The goal is to determine whether adjuvant therapy with vinorelbine and cyclophosphamide further reduces the risk of relapse. Patients will be randomly assigned again into two groups within their risk group (CT2A or CT2B) and will either receive this maintenance therapy (study group) or complete treatment at this point (control group). This drug combination is already being used in studies for maintenance therapy in RMS. Vinorelbine is not yet approved for this use, and cyclophosphamide is used as standard in first-line therapy for RMS.

Module 6: Relapse Treatment (CT3): In the event of a relapse, the study will investigate whether adding regorafenib, a targeted therapy, to standard chemotherapy can improve relapse treatment. The study drug is already approved for other types of cancer but not yet for RMS. The study compares two randomly assigned groups: the control group receives the standard treatment VIRT (vincristine, irinotecan, and temozolomide), and the study group receives the new combination therapy VIRR (vincristine, irinotecan, and regorafenib).

Patients with newly diagnosed or recurrent, histologically confirmed rhabdomyosarcoma (RMS)—excluding pleomorphic RMS—are eligible to participate. Additional specific eligibility criteria depend on the phase of the study in which patients are enrolled—such as during maintenance therapy or relapse. Newly diagnosed patients should, if possible, be enrolled in the FaR-RMS study at the time of initial diagnosis, before starting chemotherapy; however, they may also be enrolled at the time of radiation therapy or maintenance therapy. If patients with relapses were not enrolled in the study at the time of their initial diagnosis, they may still be enrolled. Depending on their risk group and disease status, patients may be assigned to more than one randomization group.