Evaluation of Irinotecan, Ifosfamide, Vincristine, and Dactinomycin in Frontline and Relapsed Rhabdomyosarcoma in Pediatric and Adult Populations
- Trial ID
- 2024-510579-40-00
- Protocol
- RG_17-247
- Sponsor
- The University Of Birmingham
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate the efficacy of various systemic therapy regimens and radiotherapy strategies in patients with **Rhabdomyosarcoma** (RMS). This includes determining the recommended phase II dose (RP2D) of new systemic therapy regimens, such as irinotecan combined with ifosfamide, vincristine, and actinomycin D (IrIVA). The study aims to compare these new regimens with standard chemotherapy for patients with Very High Risk (VHR) and High Risk (HR) disease at diagnosis. Additionally, the study seeks to assess the impact of different radiotherapy approaches, including pre-operative versus post-operative radiotherapy, dose escalation, and treatment of all disease sites, on patient outcomes. For maintenance chemotherapy, the study evaluates whether extending the number of cycles improves clinical outcomes in VHR and HR patients. In relapsed RMS, the study investigates the potential benefits of new systemic therapy combinations, such as the addition of Regorafenib to vincristine and irinotecan (VIrR), compared to standard therapy.
Secondary objectives include:
- Validating whether the use of fusion status (PAX3/PAX7-FOXO1) instead of histopathological diagnosis enhances risk stratification.
- Determining the necessity of fusion status assessment in tumors classified as Embryonal RMS (ERMS) by histopathology.
- Evaluating if immunohistochemistry (IHC) for protein expression driven by the fusion protein is an accurate surrogate for fusion status.
- Assessing whether FDG PET-CT response following induction chemotherapy serves as a prognostic biomarker for local failure and/or survival.
- Determining the tolerability of the regimens.
- Evaluating the anti-tumor activity and effect on overall survival of VIRR compared to standard therapy.
- Assessing the effect on quality of life of VIRR compared to standard therapy.
- Evaluating the acceptability and palatability of regorafenib formulations and examining the pharmacokinetics of regorafenib.
Participants
The clinical trial involves a total of **400 participants** diagnosed with **rhabdomyosarcoma**. The study population includes both male and female subjects, with an age range from 6 months to 25 years. Participants were selected based on a histologically confirmed diagnosis of rhabdomyosarcoma, excluding pleomorphic types, and must have provided written informed consent. The trial includes individuals with Very High Risk (VHR), High Risk (HR), and Standard Risk (SR) disease categories. Participants are required to be medically fit to receive treatment, with adequate hepatic and renal function, and must agree to use contraception during and after the trial period. The trial population is considered vulnerable due to the inclusion of minors and individuals with a serious health condition. Lifestyle considerations such as diet and physical activity are not specified in the trial data provided. Key inclusion criteria include the absence of prior treatment for rhabdomyosarcoma other than surgery and the ability to undergo chemotherapy and radiotherapy as part of the trial protocol.
Plans and Procedures
The clinical trial is designed to evaluate the efficacy and safety of various systemic therapy regimens in patients with **rhabdomyosarcoma**. This trial employs a multi-arm, multi-stage design, incorporating randomized, double-blind, and controlled methodologies to ensure robust and unbiased results. The trial is expected to span from October 2024 to September 2030, with participant involvement varying based on the specific treatment arm and disease stage.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as histologically confirmed diagnosis and informed consent. Subsequent visits will include regular follow-up assessments to monitor treatment response and adverse events. The end-of-study visit will conclude the participant's involvement, assessing overall outcomes and any long-term effects of the treatment.
The expected length of participant involvement will depend on the treatment regimen and disease progression, with some participants potentially receiving up to 24 cycles of maintenance chemotherapy. Conditions that may lead to early termination from the study include evidence of progressive disease, severe adverse reactions, or withdrawal of consent. The trial aims to determine the recommended phase II dose of new regimens, compare new and standard therapies, and evaluate the impact of radiotherapy strategies on patient outcomes.
Treatment
The clinical trial involves the administration of several experimental medications, each with specific pharmaceutical forms, routes, and frequencies of administration. **Irinotecan** is utilized in the form of a concentrate for solution for infusion. It is a cytostatic topoisomerase I inhibitor, administered via infusion. The dosing schedule and frequency are determined based on the trial protocol, with compliance monitored through regular assessments.
**Cyclophosphamide** is employed in multiple forms: powder for solution for injection, coated tablet, and injection. As an alkylating agent, it is administered either orally or via injection, depending on the formulation used. The dosing regimen is tailored to the specific needs of the trial, ensuring optimal therapeutic outcomes while monitoring participant adherence.
**Regorafenib** is provided as granules and film-coated tablets, functioning as an oral multi-kinase inhibitor. It is administered orally, with the dosing schedule designed to maximize efficacy while minimizing potential adverse effects. Participant compliance is closely monitored throughout the trial.
**Ifosfamide** is available as a powder for solution for injection or infusion, classified as an antineoplastic agent. It is administered intravenously, with the dosing frequency and schedule adjusted according to the trial's requirements. Compliance is ensured through systematic monitoring.
**Temozolomide** is administered in the form of hard capsules, categorized under antineoplastic agents, specifically other alkylating agents. It is taken orally, with the dosing regimen structured to align with the trial's objectives. Participant adherence is tracked through regular follow-ups.
**Doxorubicin** is utilized as a concentrate for solution for infusion, belonging to the anthracyclines and related substances category. It is administered intravenously, with the dosing schedule carefully calibrated to achieve the desired therapeutic effect while monitoring for compliance.
**Dactinomycin** is provided as a solution for injection, functioning as a cytotoxic antibiotic. It is administered via intravenous bolus use, with the dosing frequency and schedule tailored to the trial's specific needs. Participant adherence is monitored to ensure consistent administration.
**Vinorelbine Tartrate** is available as a concentrate for solution for infusion and soft capsule, classified under antineoplastic and immunomodulating agents, specifically vinca alkaloids. It is administered either intravenously or orally, with the dosing regimen designed to optimize therapeutic outcomes. Compliance is tracked through systematic assessments.
**Vincristine Sulfate** is administered as a solution for injection, categorized as an antineoplastic agent. It is delivered via injection, with the dosing schedule and frequency determined by the trial protocol. Participant adherence is ensured through regular monitoring and follow-up.
Efficacy
The efficacy of the clinical trial will be assessed using a range of primary and secondary endpoints. The primary endpoints include the determination of the Recommended Phase 2 Dose (RP2D) for Phase 1b, **Event Free Survival** for various randomizations including CT1a, CT1b, CT2, RT2, and CT3, and Local Failure Free Survival for randomizations RT1a, RT1b, and RT1c. Secondary endpoints encompass a broader spectrum of measures such as Maximum Tolerated Dose and Dose Limiting Toxicity for the registration phase 1b, Overall Survival for all patients across multiple randomizations, and Loco-regional Failure-Free Survival for specific radiotherapy randomizations.
Additional secondary endpoints include Response and Best Response for certain randomizations, Duration of Response, and various toxicity assessments. The trial will also evaluate acute and late complications post-radiotherapy and post-operative, as well as Health Related Quality of Life for specific randomizations. The efficacy parameters will be collected and analyzed at designated timepoints throughout the trial, ensuring a comprehensive evaluation of the therapeutic regimens being tested.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Inclusion Criteria for study entry – Mandatory at first point of study entry 1. Histologically confirmed diagnosis of RMS (except pleomorphic RMS) 2. Written informed consent from the patient and/or the parent/legal guardian
- Phase 1b Dose Finding - IRIVA Inclusion 1. Entered in to the FaR-RMS study at diagnosis 2. VHR disease 3. Age >12 months and ≤25 years 4. No prior treatment for RMS other than surgery 5. Medically fit to receive treatment 6. Adequate hepatic function: a. Total bilirubin ≤ 1.5 times upper limit of normal (ULN) for age, unless the patient is known to have Gilbert’s syndrome b. ALT or AST < 2.5 X ULN for age 7. Absolute neutrophil count ≥1.0x 109/L 8. Platelets ≥ 80 x 109/L 9. Adequate renal function: estimated or measured creatinine clearance ≥60 ml/min/1.73 m2 10. Documented negative pregnancy test for female patients of childbearing potential 11. Patient agrees to use contraception during therapy and for 12 months after last trial treatment (females) or 6 months after last trial treatment (males), where patient is sexually active 12. Written informed consent from the patient and/or the parent/legal guardian
- Frontline chemotherapy randomisation VHR - CT1A Inclusion 1. Entered in to the FaR-RMS study at diagnosis 2. VHR disease 3. Age ≥ 6 months 4. Available for randomisation ≤60 days after diagnostic biopsy/surgery 5. No prior treatment for RMS other than surgery 6. Medically fit to receive treatment 7. Adequate hepatic function : a. Total bilirubin ≤ 1.5 times upper limit of normal (ULN) for age, unless the patient is known to have Gilbert’s syndrome 8. Absolute neutrophil count ≥1.0x 109/L (except in patients with documented bone marrow disease) 9. Platelets ≥ 80 x 109/L (except in patients with documented bone marrow disease) 10. Fractional Shortening ≥ 28% 11. Documented negative pregnancy test for female patients of childbearing potential 12. Patient agrees to use contraception during therapy and for 12 months after last trial treatment (females) or 6 months after last trial treatment (males), where patient is sexually active 13. Written informed consent from the patient and/or the parent/legal guardian
- Frontline chemotherapy randomisation HR - CT1B Inclusion 1. Entered in to the FaR-RMS study at diagnosis 2. HR disease 3. Age ≥ 6 months 4. Available for randomisation ≤60 days after diagnostic biopsy/surgery 5. No prior treatment for RMS other than surgery 6. Medically fit to receive treatment 7. Adequate hepatic function : a. Total bilirubin ≤ 1.5 times upper limit of normal (ULN) for age, except if the patient is known to have Gilbert’s syndrome 8. Absolute neutrophil count ≥1.0x 109/L 9. Platelets ≥ 80 x 109/L 10. Documented negative pregnancy test for female patients of childbearing potential 11. Patient agrees to use contraception during therapy and for 12 months after last trial treatment (females) or 6 months after last trial treatment (males), where patient is sexually active 12. Written informed consent from the patient and/or the parent/legal guardian
- Radiotherapy Inclusion – for all radiotherapy randomisations 1. Entered in to the FaR-RMS study (at diagnosis or prior to radiotherapy randomisation) 2. VHR, HR and SR disease 3. ≥ 2 years of age 4. Receiving frontline induction treatment as part of the FaR-RMS trial or with an IVA/IVADo based chemotherapy regimen.. Note that, patients for whom ifosfamide has been replaced with cyclophosphamide will be eligible 5. Patient assessed as medically fit to receive the radiotherapy 6. Documented negative pregnancy test for female patients of childbearing potential 7. Patient agrees to use contraception during therapy and for 12 months after last trial treatment (females) or 6 months after last trial treatment (males), where patient is sexually active 8. Written informed consent from the patient and/or the parent/legal guardian
- RT1A Specific Inclusion 1. Primary tumour deemed resectable (predicted R0/ R1 resection feasible) after 3 cycles of induction chemotherapy (6 cycles for metastatic disease) 2. Adjuvant radiotherapy required in addition to delayed surgical resection of the primary tumour (local decision) 3. Available for randomisation after cycle 3 and prior to the start of cycle 5 of induction chemotherapy for localised disease, or after cycle 6 and prior to the start of cycle 8 for metastatic disease
- RT1B Specific Inclusion 1. Primary tumour deemed resectable (predicted R0/R1 resection) after 3 cycles of induction chemotherapy1 (6 cycles for metastatic disease). 2. Adjuvant radiotherapy required in addition to surgical resection (local decision) 3. Higher Local Failure Risk (HLFR) based on presence of either of the following criteria: a. Unfavourable site b. Age ≥ 18yrs 4. Available for randomisation after cycle 3 and prior to the start of cycle 6 of induction chemotherapy for localised disease, or after cycle 6 and prior to the start of cycle 9 for metastatic disease
- RT1C Specific Inclusion 1. Primary radiotherapy indicated (local decision) 2. Higher Local Failure Risk (HLFR) based on either of the following criteria: a. Unfavourable site b. Age ≥ 18yrs 3. Available for randomisation after cycle 3 and prior to the start of cycle 6 of induction chemotherapy for localised disease, or after cycle 6 and prior to the start of cycle 9 for metastatic disease
- RT2 1. Available for randomisation after cycle 6 and before the start of cycle 9 of induction chemotherapy. 2. Unfavourable metastatic disease, defined as Modified Oberlin Prognostic Score 2-4 *Note: Definition of metastatic lesions for RT2 eligibility Modified Oberlin Prognostic Score (1 point for each adverse factor): • Age ≥10y • Extremity, Other, Unidentified Primary Site • Bone and/ or Bone Marrow involvement • ≥3 metastatic sites Unfavourable metastatic disease: 2- 4 adverse factors Favourable metastatic disease: 0-1 adverse factors
- Maintenance chemotherapy (VHR) - CT2A Inclusion Randomisation must take place during the 12th cycle of maintenance chemotherapy. 1. Entered in to the FaR-RMS study (at diagnosis or at any subsequent time point) 2. VHR disease 3. Received frontline induction chemotherapy as part of the FaR-RMS trial or with a IVA/IVADo based chemotherapy regimen a. Patients for whom ifosfamide has been replaced with cyclophosphamide will be eligible 4. Completed 11 cycles of VnC maintenance treatment (either oral or IV regimens) 5. No evidence of progressive disease 6. Absence of severe vincristine neuropathy – i.e. requiring discontinuation of vincristine treatment) 7. Medically fit to continue to receive treatment 8. Patient agrees to use contraception during therapy and for 12 months after last trial treatment (females) or 6 months after last trial treatment (males), where patient is sexually active 9. Written informed consent from the patient and/or the parent/legal guardian
- Maintenance chemotherapy (HR) - CT2B Randomisation must take place during the 6th cycle of maintenance chemotherapy. Inclusion 1. Entered in to the FaR-RMS study (at diagnosis or at any subsequent time point) 2. HR disease 3. Received frontline induction chemotherapy as part of the FaR-RMS trial or with a IVA based chemotherapy regimen. Note that patients for whom ifosfamide has been replaced with cyclophosphamide will be eligible 4. Completed 5 cycles of VnC maintenance treatment 5. No evidence of progressive disease 6. Absence of severe vincristine neuropathy i.e. requiring discontinuation of vincristine treatment 7. Medically fit to continue to receive treatment 8. Patient agrees to use contraception during therapy and for 12 months after last trial treatment (females) or 6 months after last trial treatment (males), where patient is sexually active 9. Written informed consent from the patient and/or the parent/legal guardian
- Relapse randomisation CT3: VIRR compared to VIRT: Inclusion 1. Entered in to the FaR-RMS study (at diagnosis or at any subsequent time point including at relapse) 2. First or subsequent relapse of histologically verified RMS 3. Age ≥ 6 months 4. Measurable or evaluable disease 5. No cytotoxic chemotherapy or other investigational medicinal product (IMP) within previous three weeks: within two weeks for vinorelbine and cyclophosphamide maintenance chemotherapy 6. Medically fit to receive trial treatment 7. Documented negative pregnancy test for female patients of childbearing potential within 7 days of planned randomisation 8. Patient agrees to use contraception during therapy and for 12 months after last trial treatment (females) or 6 months after last trial treatment (males), where patient is sexually active 9. Written informed consent from the patient and/or the parent/legal guardian
Exclusion Criteria
- Phase 1b Dose Finding - IRIVA 1. Weight <10kg 2. Active > grade 2 diarrhoea 3. Prior allo- or autologous Stem Cell Transplant 4. Uncontrolled inter-current illness or active infection 5. Pre-existing medical condition precluding treatment 6. Urinary outflow obstruction that cannot be relieved prior to starting treatment 7. Active inflammation of the urinary bladder (cystitis) 8. Known hypersensitivity to any of the treatments or excipients 9. Second malignancy 10. Pregnant or breastfeeding women
- Frontline chemotherapy randomisation VHR - CT1A 1. Active > grade 2 diarrhoea 2. Prior allo- or autologous Stem Cell Transplant 3. Uncontrolled inter-current illness or active infection 4. Pre-existing medical condition precluding treatment 5. Urinary outflow obstruction that cannot be relieved prior to starting treatment 6. Active inflammation of the urinary bladder (cystitis) 7. Known hypersensitivity to any of the treatments or excipients 8. Second malignancy 9. Pregnant or breastfeeding women
- Frontline chemotherapy randomisation HR - CT1B 1. Active > grade 2 diarrhoea 2. Prior allo- or autologous Stem Cell Transplant 3. Uncontrolled inter-current illness or active infection 4. Pre-existing medical condition precluding treatment 5. Urinary outflow obstruction that cannot be relieved prior to starting treatment 6. Active inflammation of the urinary bladder (cystitis) 7. Known hypersensitivity to any of the treatments or excipients 8. Second malignancy 9. Pregnant or breastfeeding women
- Radiotherapy Exclusion – for all radiotherapy randomisations 1. Prior allo- or autologous Stem Cell Transplant 2. Second malignancy 3. Pregnant or breastfeeding women 4. Receiving radiotherapy as brachytherapy
- Maintenance chemotherapy (VHR) - CT2A 1. Prior allo- or autologous Stem Cell Transplant 2. Uncontrolled intercurrent illness or active infection 3. Urinary outflow obstruction that cannot be relieved prior to starting treatment 4. Active inflammation of the urinary bladder (cystitis) 5. Second malignancy 6. Pregnant or breastfeeding women
- Maintenance chemotherapy (HR) - CT2B 1. Prior allo- or autologous Stem Cell Transplant 2. Uncontrolled inter current illness or active infection 3. Urinary outflow obstruction that cannot be relieved prior to starting treatment 4. Active inflammation of the urinary bladder (cystitis) 5. Second malignancy 6. Pregnant or breastfeeding women
- Relapse randomisation CT3: VIRR compared to VIRT:1. Progression during frontline therapy without previous response (=Refractory to first line treatment) 2. Prior regorafenib or temozolomide 3. Active > grade 1 diarrhoea 4. ALT or AST >3.0 x upper limit normal (ULN) 5. Bilirubin, Total >1.5 x ULN; total bilirubin is allowed up to 3 x ULN if Gilbert’s syndrome is documented 6. Patients with unstable angina or new onset angina (within 3 months of planned date of randomisation), recent myocardial infarction (within 6 months of randomisation) and those with cardiac failure New York Heart Association (NYHA) Classification 2 or higher Cardiac abnormalities such as congestive heart failure (Modified Ross Heart Failure Classification for Children = class 2) and cardiac arrhythmias requiring antiarrhythmic therapy (beta blockers or digoxin are permitted) 7. Uncontrolled hypertension > 95th centile for age and gender 8. Prior allo- or autologous Stem Cell Transplant 9. Uncontrolled inter current illness or active infection 10. Pre-existing medical condition precluding treatment 11. Known hypersensitivity to any of the treatments or excipients 12. Second malignancy 13. Pregnant or breastfeeding women
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Austria | Recruiting | 10 Oct 2024 | 50 |
 Belgium | Recruiting | 10 Oct 2024 | 50 |
 Czechia | Recruiting | 10 Oct 2024 | 50 |
 Denmark | Recruiting | 10 Oct 2024 | 50 |
 Finland | Not Yet Recruiting | 10 Oct 2024 | 25 |
 France | Recruiting | 10 Oct 2024 | 200 |
 Germany | Recruiting | 10 Oct 2024 | 200 |
 Greece | Recruiting | 10 Oct 2024 | 50 |
 Ireland | Recruiting | 10 Oct 2024 | 25 |
 Italy | Recruiting | 10 Oct 2024 | 150 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
TEMOZOLOMIDE | Test | — | ORAL | — | — | SUB10889MIG |
VINORELBINE TARTRATE | Test | — | INTRAVENOUS INFUSION | — | — | SUB20777 |
DACTINOMYCIN | Test | — | INTRAVENOUS BOLUS USE | — | — | SUB13528MIG |
IFOSFAMIDE | Test | — | INTRAVENOUS | — | — | SUB08125MIG |
CYCLOPHOSPHAMIDE | Test | — | ORAL | — | — | SUB06859MIG |
Regorafenib_PIP | Test | GRANULES | ORAL | — | — | PRD1610899 |
VINORELBINE TARTRATE | Test | — | ORAL | — | — | SUB20777 |
IRINOTECAN | Test | — | INFUSION | — | — | SUB08295MIG |
Regorafenib_PIP | Test | GRANULES | ORAL | — | — | PRD1610900 |
TEMOZOLOMIDE | Test | — | ORAL | — | — | SUB10889MIG |