FaR-RMS: An Overarching Study for Children and Adults With Frontline and Relapsed RhabdoMyoSarcoma (FaR-RMS)

FaR-RMS is an over-arching study for children and adults with newly diagnosed and relapsed rhabdomyosarcoma (RMS)

FaR-RMS is an over-arching study for children and adults with newly diagnosed and relapsed rhabdomyosarcoma (RMS). It is a multi-arm, multi-stage format, involving several different trial questions. FaR-RMS is intended to be a rolling programme of research with new treatment arms being introduced dependant on emerging data and innovation. This study has multiple aims. It aims to evaluate the impact of new agent regimens in both newly diagnosed and relapsed RMS; whether changing the duration of maintenance therapy affects outcome; and whether changes to dose, extent (in metastatic disease) and timing of radiotherapy improve outcome and quality of life. In addition the study will evaluate risk stratification through the use of PAX-FOXO1 fusion gene status instead of histological subtyping and explore the use of FDG PET-CT response assessment as a prognostic biomarker for outcome following induction chemotherapy. Newly diagnosed patients should, where possible, be entered into the FaR-RMS study at the time of first diagnosis prior to receiving any chemotherapy. However, patients can enter at the point of radiotherapy or maintenance, and those with relapsed disease can enter the study even if not previously entered at initial diagnosis. Patients may be entered into more than one randomisation/registration, dependant on patient risk group and disease status.

Irinotecan: an i.v. infusion over 1 hour on days 8,9,10,11 and 12 . For the phase 1b registration, starting dose of 20 mg/m2. Ifosfamide: 3g/m2 as an i.v. infusion over 3 hours on days 1 and 2 Vincristine: 1.5 mg/m2 as an As per local practice: recommended as a short infusion (maximum dose 2mg). Administered days 1,8,15 on cycles 1-2 and on days 1 and 8 on cycles 3-9. Actinomycin: 1.5 mg/m2 as an i.v. bolus injection (maximum dose 2mg) on day 1.

Ifosfamide: 3g/m2 as an i.v. infusion over 3 hours on days 1 and 2 Vincristine: 1.5 mg/m2 As per local practice: recommended as a short infusion (maximum dose 2mg). Administered days 1,8,15 on cycles 1-2 and on day 1 on cycles 3-9. Actinomycin: 1.5 mg/m2 as an i.v. bolus injection (maximum dose 2mg) on day 1. Doxorubicin: 30 mg/m2 as an i.v infusion over 1 hour on days 1 and 2 on cycles 1-4

Irinotecan: an i.v. infusion over 1 hour on days 8,9,10,11 and 12 . Phase 2 recommended dose as determined by IRIVA dose finding arm Ifosfamide: 3g/m2 as an i.v. infusion over 3 hours on days 1 and 2 Vincristine: 1.5 mg/m2 As per local practice: recommended as a short infusion (maximum dose 2mg). Administered days 1,8,15 on cycles 1-2 and on days 1 and 8 on cycles 3-9. Actinomycin: 1.5 mg/m2 as an i.v. bolus injection (maximum dose 2mg) on day 1.

Ifosfamide: 3g/m2 as an i.v. infusion over 3 hours on days 1 and 2 Vincristine: 1.5 mg/m2 As per local practice: recommended as a short infusion (maximum dose 2mg). Administered days 1,8,15 on cycles 1-2 and on day 1 on cycles 3-9. Actinomycin: 1.5 mg/m2 as an i.v. bolus injection (maximum dose 2mg) on day 1.

Irinotecan: an i.v. infusion over 1 hour on days 8,9,10,11 and 12 . Phase 2 recommended dose as determined by IRIVA dose finding arm Ifosfamide: 3g/m2 as an i.v. infusion over 3 hours on days 1 and 2 Vincristine: 1.5 mg/m2 As per local practice: recommended as a short infusion (maximum dose 2mg). Administered days 1,8,15 on cycles 1-2 and on days 1 and 8 on cycles 3-9. Actinomycin: 1.5 mg/m2 as an i.v. bolus injection (maximum dose 2mg) on day 1.

Vinorelbine: 25 mg/m2 i.v. or 60 mg/m2 orally on days 1,8 and 15 Cyclophosphamide 25 mg/m2 orally daily for 28 days

Vincristine: 1.5 mg/m2 As per local practice: recommended as a short infusion (maximum dose 2mg) on days 1 and 8 Irinotecan: 50 mg/m2 as an i.v. infusion over 1 hour on days 1-5 Temozolomide: 125 mg/m2 (Escalate to 150mg/m2/day in Cycle 2 if no toxicity > grade 3) as an oral tablets prior to vincristine and irinotecan on days 1-5

Vincristine: 1.5 mg/m2 As per local practice: recommended as a short infusion (maximum dose 2mg) on days 1 and 8 Irinotecan: 50 mg/m2 as an i.v. infusion over 1 hour on days 1-5 Regorafenib: Children between 6 and 24 months = 65 mg/m2, children less than 12 and/or less than 40kg dose = 82 mg/m2 Maximum 120 mg, Fixed dose of 120 mg for patients over 12 years of age AND ≥ 40 kg, as an oral tablets on days 8 to 21.

chemotherapeutic agent chemically related to the nitrogen mustards and is a synthetic analog of cyclophosphamide

Oral multi-kinase inhibitor that targets a broad range of angiogenic, stromal and oncogenic kinases, including vascular endothelial growth factor receptors (VEFGR) 1, 2 and 3, tyrosine kinase with immunoglobulin and epidermal growth factor homology domain 2 (TIE2), platelet-derived growth factor receptor (PDGFR), fibroblast growth factor receptors (FGFR), c-KIT, RET, RAF-1 and BRAF (wild-type and V600E mutant).

Failure events are: Relapse or progression of existing disease, or occurrence of disease at new sites, Death from any cause without disease progression, Second malignant neoplasm

Failure events are: Relapse or progression of existing disease, or occurrence of disease at new sites, Death from any cause without disease progression, Second malignant neoplasm

Failure events are: Relapse or progression of existing disease, or occurrence of disease at new sites, Death from any cause without disease progression, Second malignant neoplasm

Failure events are: Relapse or progression of existing disease, or occurrence of disease at new sites, Death from any cause without disease progression, Second malignant neoplasm

Failure events are: Relapse or progression of existing disease, or occurrence of disease at new sites, Death from any cause without disease progression, Second malignant neoplasm

To determine whether new systemic therapy regimens improve event free survival in relapsed RMS compared to standard therapy (VIRT) (CT3): Initial new systemic therapy combination to be tested: o Regorafenib (R) added to vincristine and irinotecan (VIR) (VIRR)

Patients will be followed up for a minimum of 6 years from trial entry (or 5 years from end of relapsed trial treatment, whichever comes later). Patients will be followed up for progression and death until the end of trial definition has been met.

A local failure event is relapse or progression of tumour at the primary site at any time even if there has been a prior /concurrent, regional or distant failure

A local failure event is relapse or progression of tumour at the primary site at any time even if there has been a prior /concurrent, regional or distant failure

Based on tolerability, where tolerability is evaluated through the occurrence of dose limiting toxicity (DLT).

From first patient first visit in dose finding study until appropriate dose level found, estimated 9 months

Dose level at which no or one participant experiences a DLT when at least two of three to six participants experience a DLT at the next highest dose.

Diarrhoea: Grade 3 for >3 days despite loperamide therapy Diarrhoea: Grade 4 despite loperamide therapy. Enterocolitis: Grade 3 or above Ileus: Grade 3 or above for more than 3 days Oral mucositis: Grade 3 above for >3 days despite optimal supportive care Persistent neutropenia or thrombocytopenia leading to delay of start of next course by >7 days; i.e. starting > day 28 Any grade 3 or 4 toxicity resulting in discontinuation of the new combination Any grade 5 toxicity

defined as complete (CR) or partial response (PR) and is clinically defined. Patients who are not assessable for response - e.g. because of early stopping of treatment or death - will be assumed to be non-responders.

To evaluate the anti-tumour activity and effect on overall survival of VIRR when compared to standard therapy

Patients will be followed up for a minimum of 6 years from trial entry (or 5 years from end of relapsed trial treatment, whichever comes later). Patients will be followed up for progression and death until the end of trial definition has been met.

specific grade 3 and above complications according to CTCAE v 4 and Clavien Dindo scale. Specific wound complications within the same time frame will also be collected

A local failure event is relapse or progression of tumour at the primary site at any time even if there has been a prior concurrent local, regional or distant failure. A regional event is relapse or progression of tumour at regional lymph nodes at any time even if there has been a prior distant failure.

will be assessed using Pediatric quality of life questionnaire (PedsQL) for the paediatric population (under 18 years). The minimum score is 0 where quality of life is completely unaffected by the intervention to 4 where quality of life is severely affected.

4 timepoints: 1) 1 day of start of radiotherapy, 2) at completion of radiotherapy, average 5 weeks after start of radiotherapy, 3) 3 months and 4) 24 months following radiotherapy

will be assessed using European Organisation for Research and Treatment of Cancer, Quality of Life Questionnaire 30 (EORTC QLQ-C30) for patients 18 years of age and over. The minimum score is 0 where quality of life is completely unaffected by the intervention to 4 where quality of life is severely affected.

4 timepoints: 1) 1 day of start of radiotherapy, 2) at completion of radiotherapy, average 5 weeks after start of radiotherapy, 3) 3 months and 4) 24 months following radiotherapy

will be assessed using Pediatric quality of life questionnaire (PedsQL) for the paediatric population (under 18 years). The minimum score is 0 where quality of life is completely unaffected by the intervention to 4 where quality of life is severely affected.

3 timepoints: Each Cycle is 28 days. Timepoint 1: Day 0 of cycle 1 (prior to starting treatment), Timepoint 2 day 0 cycle 3, Timepoint 3) day 0 cycle 5

will be assessed using European Organisation for Research and Treatment of Cancer, Quality of Life Questionnaire 30 (EORTC QLQ-C30) for patients 18 years of age and over. The minimum score is 0 where quality of life is completely unaffected by the intervention to 4 where quality of life is severely affected.

3 timepoints: Each Cycle is 28 days. Timepoint 1: Day 0 of cycle 1 (prior to starting treatment), Timepoint 2 day 0 cycle 3, Timepoint 3) day 0 cycle 5

"Acceptability and Palatability Questionnaire" To evaluate the acceptability and palatability of regorafenib formulations

Failure events are: Relapse or progression of existing disease, or occurrence of disease at new sites, Death from any cause without disease progression, Second malignant neoplasm

Failure events are: Relapse or progression of existing disease, or occurrence of disease at new sites, Death from any cause without disease progression, Second malignant neoplasm

A local failure event is relapse or progression of tumour at the primary site at any time even if there has been a prior /concurrent, regional or distant failure

Inclusion Criteria for study entry - Mandatory at first point of study entry Histologically confirmed diagnosis of RMS (except pleomorphic RMS) Written informed consent from the patient and/or the parent/legal guardian Phase 1b Dose Finding - IRIVA Inclusion Entered in to the FaR-RMS study at diagnosis Very High Risk disease Age >12 months and ≤25 years No prior treatment for RMS other than surgery Medically fit to receive treatment Adequate hepatic function: Total bilirubin ≤ 1.5 times upper limit of normal (ULN) for age, unless the patient is known to have Gilbert's syndrome ALT or AST < 2.5 X ULN for age Absolute neutrophil count ≥1.0x 109/L Platelets ≥ 80 x 109/L Adequate renal function: estimated or measured creatinine clearance ≥60 ml/min/1.73 m2 Documented negative pregnancy test for female patients of childbearing potential 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 Written informed consent from the patient and/or the parent/legal guardian Exclusion Weight <10kg Active > grade 2 diarrhoea Prior allo- or autologous Stem Cell Transplant Uncontrolled inter-current illness or active infection Pre-existing medical condition precluding treatment Urinary outflow obstruction that cannot be relieved prior to starting treatment Active inflammation of the urinary bladder (cystitis) Known hypersensitivity to any of the treatments or excipients Second malignancy Pregnant or breastfeeding women Frontline chemotherapy randomisation Very High Risk - CT1a Inclusion Entered in to the FaR-RMS study at diagnosis Very High Risk disease Age ≥ 6 months Available for randomisation ≤60 days after diagnostic biopsy/surgery No prior treatment for RMS other than surgery Medically fit to receive treatment 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 Absolute neutrophil count ≥1.0x 109/L (except in patients with documented bone marrow disease) Platelets ≥ 80 x 109/L (except in patients with documented bone marrow disease) Fractional Shortening ≥ 28% Documented negative pregnancy test for female patients of childbearing potential 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 Written informed consent from the patient and/or the parent/legal guardian Exclusion Active > grade 2 diarrhoea Prior allo- or autologous Stem Cell Transplant Uncontrolled inter-current illness or active infection Pre-existing medical condition precluding treatment Urinary outflow obstruction that cannot be relieved prior to starting treatment Active inflammation of the urinary bladder (cystitis) Known hypersensitivity to any of the treatments or excipients Second malignancy Pregnant or breastfeeding women Frontline chemotherapy randomisation High Risk - CT1b Inclusion Entered in to the FaR-RMS study at diagnosis High Risk disease Age ≥ 6 months Available for randomisation ≤60 days after diagnostic biopsy/surgery No prior treatment for RMS other than surgery Medically fit to receive treatment 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 Absolute neutrophil count ≥1.0x 109/L Platelets ≥ 80 x 109/L Documented negative pregnancy test for female patients of childbearing potential 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 Written informed consent from the patient and/or the parent/legal guardian Exclusion Active > grade 2 diarrhoea Prior allo- or autologous Stem Cell Transplant Uncontrolled inter-current illness or active infection Pre-existing medical condition precluding treatment Urinary outflow obstruction that cannot be relieved prior to starting treatment Active inflammation of the urinary bladder (cystitis) Known hypersensitivity to any of the treatments or excipients Second malignancy Pregnant or breastfeeding women Frontline Radiotherapy Note: eligible patients may enter multiple radiotherapy randomisations. Radiotherapy Inclusion - for all radiotherapy randomisations Entered in to the FaR-RMS study (at diagnosis or prior to radiotherapy randomisation) Very High Risk, High Risk and Standard Risk disease ≥ 2 years of age Receiving frontline induction treatment as part of the FaR-RMS trial or with a IVA/IVADo based chemotherapy regimen patients for whom. Note that patients for whom ifosfamide has been replaced with cyclophosphamide will be eligible Patient assessed as medically fit to receive the radiotherapy Documented negative pregnancy test for female patients of childbearing potential 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 Written informed consent from the patient and/or the parent/legal guardian Radiotherapy Exclusion - for all radiotherapy randomisations Prior allo- or autologous Stem Cell Transplant Second malignancy Pregnant or breastfeeding women Receiving radiotherapy as brachytherapy RT1a Specific Inclusion Primary tumour deemed resectable (predicted R0/ R1 resection feasible) after 3 cycles of induction chemotherapy (6 cycles for metastatic disease) Adjuvant radiotherapy required in addition to surgical resection (local decision). 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 RT1b Specific Inclusion Primary tumour deemed resectable (predicted R0/R1 resection) after 3 cycles of induction chemotherapy (6 cycles for metastatic disease). Adjuvant radiotherapy required in addition to surgical resection (local decision) Higher Local Failure Risk (HLFR) based on presence of either of the following criteria: Unfavourable site Age ≥ 18yrs 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 Primary radiotherapy indicated (local decision) Higher Local Failure Risk (HLFR) based on either of the following criteria: Unfavourable site Age ≥ 18yrs 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 Available for randomisation after cycle 6 and before the start of cycle 9 of induction chemotherapy. 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 (Very High Risk) - CT2a Inclusion Randomisation must take place during the 12th cycle of maintenance chemotherapy. Entered in to the FaR-RMS study (at diagnosis or at any subsequent time point) Very High Risk disease 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 Completed 11 cycles of VnC maintenance treatment (either oral or IV regimens) No evidence of progressive disease Absence of severe vincristine neuropathy - i.e requiring discontinuation of vincristine treatment) Medically fit to continue to receive treatment 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 Written informed consent from the patient and/or the parent/legal guardian Exclusion Prior allo- or autologous Stem Cell Transplant Uncontrolled intercurrent illness or active infection Urinary outflow obstruction that cannot be relieved prior to starting treatment Active inflammation of the urinary bladder (cystitis) Second malignancy Pregnant or breastfeeding women Maintenance chemotherapy (High Risk) - CT2b Randomisation must take place during the 6th cycle of maintenance chemotherapy. Inclusion Entered in to the FaR-RMS study (at diagnosis or at any subsequent time point) High Risk disease 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 Completed 5 cycles of VnC maintenance treatment No evidence of progressive disease Absence of severe vincristine neuropathy i.e. requiring discontinuation of vincristine treatment Medically fit to continue to receive treatment 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 Written informed consent from the patient and/or the parent/legal guardian Exclusion Prior allo- or autologous Stem Cell Transplant Uncontrolled inter current illness or active infection Urinary outflow obstruction that cannot be relieved prior to starting treatment Active inflammation of the urinary bladder (cystitis) Second malignancy Pregnant or breastfeeding women CT3 Relapsed Chemotherapy Inclusion: Entered in to the FaR-RMS study (at diagnosis or at any subsequent time point) First or subsequent relapse of histologically verified RMS Age ≥ 6 months Measurable or evaluable disease No cytotoxic chemotherapy or other investigational medicinal product (IMP) within previous three weeks: within two weeks for vinorelbine and cyclophosphamide maintenance chemotherapy Medically fit to receive trial treatment Documented negative pregnancy test for female patients of childbearing potential within 7 days of planned randomisation 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 Written informed consent from the patient and/or the parent/legal guardian Exclusion: Progression during frontline therapy without previous response (=Refractory to first line treatment) Prior regorafenib or temozolomide Active > grade 1 diarrhoea ALT or AST >3.0 x upper limit normal (ULN) Bilirubin, Total >1.5 x ULN; total bilirubin is allowed up to 3 x ULN if Gilbert's syndrome is documented 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) Uncontrolled hypertension > 95th centile for age and gender Prior allo- or autologous Stem Cell Transplant Uncontrolled inter-current illness or active infection Pre-existing medical condition precluding treatment Known hypersensitivity to any of the treatments or excipients Second malignancy Pregnant or breastfeeding women