REGORAFENIB for Rhabdomyosarcoma

Inclusion criteria

• {"criterion_text":"- Inclusion Criteria for study entry – Mandatory at first point of study entry 1.\tHistologically confirmed diagnosis of RMS (except pleomorphic RMS) 2.\tWritten informed consent from the patient and/or the parent/legal guardian\n- Maintenance chemotherapy (VHR) - CT2A Inclusion Randomisation must take place during the 12th cycle of maintenance chemotherapy. 1.\tEntered in to the FaR-RMS study (at diagnosis or at any subsequent time point) 2.\tVHR disease 3.\tReceived frontline induction chemotherapy as part of the FaR-RMS trial or with a IVA/IVADo based chemotherapy regimen a.\tPatients for whom ifosfamide has been replaced with cyclophosphamide will be eligible 4.\tCompleted 11 cycles of VnC maintenance treatment (either oral or IV regimens) 5.\tNo evidence of progressive disease 6.\tAbsence of severe vincristine neuropathy – i.e. requiring discontinuation of vincristine treatment) 7.\tMedically fit to continue to receive treatment 8.\tPatient 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.\tWritten informed consent from the patient and/or the parent/legal guardian\n- Maintenance chemotherapy (HR) - CT2B Randomisation must take place during the 6th cycle of maintenance chemotherapy. Inclusion 1.\tEntered in to the FaR-RMS study (at diagnosis or at any subsequent time point) 2.\tHR disease 3.\tReceived 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.\tCompleted 5 cycles of VnC maintenance treatment 5.\tNo evidence of progressive disease 6.\tAbsence of severe vincristine neuropathy i.e. requiring discontinuation of vincristine treatment 7.\tMedically fit to continue to receive treatment 8.\tPatient 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.\tWritten informed consent from the patient and/or the parent/legal guardian\n- Relapse randomisation CT3: VIRR compared to VIRT: Inclusion 1.\tEntered in to the FaR-RMS study (at diagnosis or at any subsequent time point including at relapse) 2.\tFirst or subsequent relapse of histologically verified RMS 3.\tAge ≥ 6 months 4.\tMeasurable or evaluable disease 5.\tNo cytotoxic chemotherapy or other investigational medicinal product (IMP) within previous three weeks: within two weeks for vinorelbine and cyclophosphamide maintenance chemotherapy 6.\tMedically fit to receive trial treatment 7.\tDocumented negative pregnancy test for female patients of childbearing potential within 7 days of planned randomisation 8.\tPatient 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.\tWritten informed consent from the patient and/or the parent/legal guardian\n- Phase 1b Dose Finding - IRIVA Inclusion 1.\tEntered in to the FaR-RMS study at diagnosis 2.\tVHR disease 3.\tAge >12 months and ≤25 years 4.\tNo prior treatment for RMS other than surgery 5.\tMedically fit to receive treatment 6.\tAdequate hepatic function: a.\tTotal bilirubin ≤ 1.5 times upper limit of normal (ULN) for age, unless the patient is known to have Gilbert’s syndrome b.\tALT or AST < 2.5 X ULN for age 7.\tAbsolute neutrophil count ≥1.0x 109/L 8.\tPlatelets ≥ 80 x 109/L 9.\tAdequate renal function: estimated or measured creatinine clearance ≥60 ml/min/1.73 m2 10.\tDocumented negative pregnancy test for female patients of childbearing potential 11.\tPatient 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.\tWritten informed consent from the patient and/or the parent/legal guardian\n- Frontline chemotherapy randomisation VHR - CT1A Inclusion 1.\tEntered in to the FaR-RMS study at diagnosis 2.\tVHR disease 3.\tAge ≥ 6 months 4.\tAvailable for randomisation ≤60 days after diagnostic biopsy/surgery 5.\tNo prior treatment for RMS other than surgery 6.\tMedically fit to receive treatment 7.\tAdequate hepatic function : a.\tTotal bilirubin ≤ 1.5 times upper limit of normal (ULN) for age, unless the patient is known to have Gilbert’s syndrome 8.\tAbsolute neutrophil count ≥1.0x 109/L (except in patients with documented bone marrow disease) 9.\tPlatelets ≥ 80 x 109/L (except in patients with documented bone marrow disease) 10.\tFractional Shortening ≥ 28% 11.\tDocumented negative pregnancy test for female patients of childbearing potential 12.\tPatient 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.\tWritten informed consent from the patient and/or the parent/legal guardian\n- Frontline chemotherapy randomisation HR - CT1B Inclusion 1.\tEntered in to the FaR-RMS study at diagnosis 2.\tHR disease 3.\tAge ≥ 6 months 4.\tAvailable for randomisation ≤60 days after diagnostic biopsy/surgery 5.\tNo prior treatment for RMS other than surgery 6.\tMedically fit to receive treatment 7.\tAdequate hepatic function : a.\tTotal bilirubin ≤ 1.5 times upper limit of normal (ULN) for age, except if the patient is known to have Gilbert’s syndrome 8.\tAbsolute neutrophil count ≥1.0x 109/L 9.\tPlatelets ≥ 80 x 109/L 10.\tDocumented negative pregnancy test for female patients of childbearing potential 11.\tPatient 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.\tWritten informed consent from the patient and/or the parent/legal guardian\n- Radiotherapy Inclusion – for all radiotherapy randomisations 1.\tEntered in to the FaR-RMS study (at diagnosis or prior to radiotherapy randomisation) 2.\tVHR, HR and SR disease 3.\t ≥ 2 years of age 4.\tReceiving 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 cyclofosfamide will be eligible 5.\tPatient assessed as medically fit to receive the radiotherapy 6.\tDocumented negative pregnancy test for female patients of childbearing potential 7.\tPatient 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.\tWritten informed consent from the patient and/or the parent/legal guardian\n- RT1A Specific Inclusion 1.\tPrimary tumour deemed resectable (predicted R0/ R1 resection feasible) after 3 cycles of induction chemotherapy (6 cycles for metastatic disease) 2.\tAdjuvant radiotherapy required in addition to delayed surgical resection of the primary tumour (local decision) 3.\tAvailable 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\n- RT1B Specific Inclusion 1.\tPrimary tumour deemed resectable (predicted R0/R1 resection) after 3 cycles of induction chemotherapy1 (6 cycles for metastatic disease). 2.\tAdjuvant radiotherapy required in addition to surgical resection (local decision) 3.\tHigher Local Failure Risk (HLFR) based on presence of either of the following criteria: a.\tUnfavourable site b.\tAge ≥ 18yrs 4.\tAvailable 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\n- RT1C Specific Inclusion 1.\tPrimary radiotherapy indicated (local decision) 2.\tHigher Local Failure Risk (HLFR) based on either of the following criteria: a.\tUnfavourable site b.\tAge ≥ 18yrs 3.\tAvailable 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\n- RT2 1.\tAvailable for randomisation after cycle 6 and before the start of cycle 9 of induction chemotherapy. 2.\tUnfavourable metastatic disease, defined as Modified Oberlin Prognostic Score 2-4"}

Exclusion criteria

• {"criterion_text":"- Phase 1b Dose Finding - IRIVA 1.\tWeight <10kg 2.\tActive > grade 2 diarrhoea 3.\tPrior allo- or autologous Stem Cell Transplant 4.\tUncontrolled inter-current illness or active infection 5.\tPre-existing medical condition precluding treatment 6.\tUrinary outflow obstruction that cannot be relieved prior to starting treatment 7.\tActive inflammation of the urinary bladder (cystitis) 8.\tKnown hypersensitivity to any of the treatments or excipients 9.\tSecond malignancy 10.\tPregnant or breastfeeding women\n- Frontline chemotherapy randomisation VHR - CT1A 1.\tActive > grade 2 diarrhoea 2.\tPrior allo- or autologous Stem Cell Transplant 3.\tUncontrolled inter-current illness or active infection 4.\tPre-existing medical condition precluding treatment 5.\tUrinary outflow obstruction that cannot be relieved prior to starting treatment 6.\tActive inflammation of the urinary bladder (cystitis) 7.\tKnown hypersensitivity to any of the treatments or excipients 8.\tSecond malignancy 9.\tPregnant or breastfeeding women\n- Frontline chemotherapy randomisation HR - CT1B 1.\tActive > grade 2 diarrhoea 2.\tPrior allo- or autologous Stem Cell Transplant 3.\tUncontrolled inter-current illness or active infection 4.\tPre-existing medical condition precluding treatment 5.\tUrinary outflow obstruction that cannot be relieved prior to starting treatment 6.\tActive inflammation of the urinary bladder (cystitis) 7.\tKnown hypersensitivity to any of the treatments or excipients 8.\tSecond malignancy 9.\tPregnant or breastfeeding women\n- Radiotherapy Exclusion – for all radiotherapy randomisations 1.\tPrior allo- or autologous Stem Cell Transplant 2.\tSecond malignancy 3.\tPregnant or breastfeeding women 4.\tReceiving radiotherapy as brachytherapy\n- Maintenance chemotherapy (VHR) - CT2A 1.\tPrior allo- or autologous Stem Cell Transplant 2.\tUncontrolled intercurrent illness or active infection 3.\tUrinary outflow obstruction that cannot be relieved prior to starting treatment 4.\tActive inflammation of the urinary bladder (cystitis) 5.\tSecond malignancy 6.\tPregnant or breastfeeding women\n- Maintenance chemotherapy (HR) - CT2B 1.\tPrior allo- or autologous Stem Cell Transplant 2.\tUncontrolled inter current illness or active infection 3.\tUrinary outflow obstruction that cannot be relieved prior to starting treatment 4.\tActive inflammation of the urinary bladder (cystitis) 5.\tSecond malignancy 6.\tPregnant or breastfeeding women\n- Relapse randomisation CT3: VIRR compared to VIRT:1.\tProgression during frontline therapy without previous response (=Refractory to first line treatment) 2.\tPrior regorafenib or temozolomide 3.\tActive > grade 1 diarrhoea 4.\tALT or AST >3.0 x upper limit normal (ULN) 5.\tBilirubin, Total >1.5 x ULN; total bilirubin is allowed up to 3 x ULN if Gilbert’s syndrome is documented 6.\tPatients 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.\tUncontrolled hypertension > 95th centile for age and gender 8.\tPrior allo- or autologous Stem Cell Transplant 9.\tUncontrolled inter current illness or active infection 10.\tPre-existing medical condition precluding treatment 11.\tKnown hypersensitivity to any of the treatments or excipients 12.\tSecond malignancy 13.\tPregnant or breastfeeding women"}

Primary endpoints

• {"endpoint_text":"- Recommended Phase 2 Dose (RP2D) - Phase 1b","definition_or_measurement_approach":""}
• {"endpoint_text":"- Event Free Survival for randomisations CT1a, CT1b, CT2, RT2 and CT3","definition_or_measurement_approach":""}
• {"endpoint_text":"- Local failure free survival for randomisations RT1a, RT1b and RT1c","definition_or_measurement_approach":""}

Secondary endpoints

• {"endpoint_text":"- Maximum Tolerated Dose for registration phase 1b","definition_or_measurement_approach":""}
• {"endpoint_text":"- Dose Limiting Toxicity for registration phase 1b","definition_or_measurement_approach":""}
• {"endpoint_text":"- Overall Survival for all patients, randomisations CT1a, CT1b, CT2, CT3, RT1a, RT1b, RT1c and also RT","definition_or_measurement_approach":""}
• {"endpoint_text":"- Event Free Survival for all patients, randomisations RT1a, RT1b, RT1c and also the PET sub-study","definition_or_measurement_approach":""}
• {"endpoint_text":"- Loco-regional failure-free survival for randomisations RT1a, RT1b, RT1c and RT2","definition_or_measurement_approach":""}
• {"endpoint_text":"- Local failure free survival for the PET sub-study","definition_or_measurement_approach":""}
• {"endpoint_text":"- Response for registration phase 1b and also randomisations CT1a, CT1b, and CT3","definition_or_measurement_approach":""}
• {"endpoint_text":"- Best Response for randomisation CT3","definition_or_measurement_approach":""}
• {"endpoint_text":"- Duration of response for randomisation CT3","definition_or_measurement_approach":""}
• {"endpoint_text":"- Toxicity for registration phase 1b and also randomisations CT1a, CT1b, and CT3","definition_or_measurement_approach":""}
• {"endpoint_text":"- Acute post-radiotherapy complications for randomisations RT1a, RT1b, RT1c and RT2","definition_or_measurement_approach":""}
• {"endpoint_text":"- Late complications for randomisations RT1a, RT1b and RT1c","definition_or_measurement_approach":""}
• {"endpoint_text":"- Acute post-operative complications for randomisations RT1a and RT1b","definition_or_measurement_approach":""}
• {"endpoint_text":"- Wound complications for randomisations RT1a and RT1b","definition_or_measurement_approach":""}
• {"endpoint_text":"- Health Related Quality of Life for randomisations RT1a and RT2","definition_or_measurement_approach":""}
• {"endpoint_text":"- PET response for the PET sub-study","definition_or_measurement_approach":""}

Primary sponsor

Full Name

The University Of Birmingham

Organisation Type

Educational Institution

Country Of Registered Address

United Kingdom

Contract research organisations

Name

Premier Research Group Limited

Responsibilities

Sponsor duties code: [1] (operational CRO functions listed among sponsorDuties)

Name

Julius Clinical International B.V.

Responsibilities

Sponsor duties code: [1] (operational CRO functions listed among sponsorDuties)

Third parties

• {"country":"Ireland","full_name":"Eramol Limited","duties_or_roles":"sponsorDuties codes: [14]","organisation_type":"Pharmaceutical company"}
• {"country":"United Kingdom","full_name":"Eramol (UK) Limited","duties_or_roles":"sponsorDuties codes: [14]","organisation_type":"Pharmaceutical company"}
• {"country":"Greece","full_name":"Coronis Research S.A.","duties_or_roles":"sponsorDuties codes: [1, 15 (Quartet Imaging program value: Greece), 5]","organisation_type":"Pharmaceutical company"}
• {"country":"Belgium","full_name":"European Organisation for Research and Treatment of Cabcer","duties_or_roles":"sponsorDuties codes: [15 (Quartet Imaging program)]","organisation_type":"Health care"}
• {"country":"Sweden","full_name":"Apoteket AB","duties_or_roles":"sponsorDuties codes: [14, 15 (Sweden)]","organisation_type":"Pharmaceutical company"}
• {"country":"Sweden","full_name":"Viedoc Technologies AB","duties_or_roles":"sponsorDuties codes: [7]","organisation_type":"Non-Pharmaceutical company"}
• {"country":"Denmark","full_name":"Frederiksberg Hospital","duties_or_roles":"sponsorDuties codes: [1, 15 (Denmark)]","organisation_type":"Hospital/Clinic/Other health care facility"}
• {"country":"United Kingdom","full_name":"Premier Research Group Limited","duties_or_roles":"sponsorDuties codes: [1]","organisation_type":"Pharmaceutical company (CRO)"}
• {"country":"Belgium","full_name":"European Society for Paediatric Oncology","duties_or_roles":"sponsorDuties codes: [15 (Quartet Imaging program)]","organisation_type":"Health care"}
• {"country":"Belgium","full_name":"Pierre Fabre Sante Benelux","duties_or_roles":"sponsorDuties codes: [14, 15 (Belgium)]","organisation_type":"Pharmaceutical company"}
• {"country":"Belgium","full_name":"Health, Innovation and Research Institute - HIRUZ","duties_or_roles":"sponsorDuties codes: [1, 15 (Belgium)]","organisation_type":"SME"}
• {"country":"Belgium","full_name":"BSPHO - Belgian Society of Paediatric Haematology Oncology","duties_or_roles":"sponsorDuties codes: [15 (Belgium), 5]","organisation_type":"Health care"}
• {"country":"Czechia","full_name":"Masarykova Univerzita","duties_or_roles":"sponsorDuties codes: [12, 15 (Czech Republic)]","organisation_type":"Educational Institution"}
• {"country":"Netherlands","full_name":"Julius Clinical International B.V.","duties_or_roles":"sponsorDuties codes: [1, 15 (Netherlands)]","organisation_type":"Pharmaceutical company (CRO)"}
• {"country":"Belgium","full_name":"UZ GENT","duties_or_roles":"sponsorDuties codes: [15 (Belgium), 4]","organisation_type":"Health care"}

Co-sponsors

• European Organisation for Research and Treatment of Cabcer
• European Society for Paediatric Oncology
• Bayer AG