FaR-RMS: An overarching study for children and adults with Frontline and Relapsed RhabdoMyoSarcoma

Overview

Sponsor-declared trial summary

Key facts

Sponsor

The University Of Birmingham

Participant type

Pediatric, Patients

Age range

0-17 years, 18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

7 Oct 2020 → ongoing

Decision date (initial)

2024-11-19

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Loterie Nationale - 1 nieuwstraat - 1000 Brussel - Belgium · Swedish Childhood Cancer Fund, P.O Box 3426, S-103 68 Stockholm, Sweden · Aamu Lasten syöpäsäätiö, c/o Premium Group Kanavakatu 3 C, 00160 HELSINKI Finland · DFG - Deutsche Forschungsgemeinschaft, Germany · Kick Cancer - 24 dageraadstraat - 1000 Brussel - Belgium · CTAAC, Cancer Research UK · "Programme for Hospital Clinical Research in Cancer ""PHRC-K 2017" France · Danish Childhood Cancer Foundation · University Medical Center Ljubljana Slovenia · indirectly, Fundação Rui Osório de Castro (trial insurance) Portgual · National corefunding for academic first-line treatment trials -Netherlands · Bayer AG

External identifiers

EU CT number

2024-510579-40-00

EudraCT number

2018-000515-24

ClinicalTrials.gov

NCT04625907

ISRCTN

ISRCTN45535982

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Dose response, Pharmacokinetic, Efficacy, Pharmacogenomic

The primary objectives for this trial are related to each of the trial questions.

For the Phase I Dose Finding Studies, the aim is to determine the recommended phase II dose (RP2D) of new systemic therapy regimens. The first combination to be tested is irinotecan in combination with ifosfamide, vincristine and actinomycin D (IrIVA).

For the frontline chemotherapy questions, the objectives are:
• To compare systemic therapy regimens for patients with Very High Risk (VHR) disease at diagnosis. The first new combination regimens to be compared are IVADo and IrIVA in a dose intense schedule.
•To compare new systemic therapy regimens with standard chemotherapy for patients with High Risk (HR) disease at diagnosis. The standard chemotherapy is ifosfamide, vincristine, actinomycin D (IVA). The first new combination regime to be compared is irinotecan combined with IVA (IrIVA) in a dose intense schedule

For the radiotherapy questions, the objectives are as follows:
•To determine whether pre-operative or standard post-operative radiotherapy is better for patients with resectable disease
•To determine whether dose escalation of radiotherapy improves the outcome in patients with a higher local failure risk
•To determine whether radiotherapy treatment of all sites of disease, including metastatic sites, when compared to radiotherapy treatment to the primary site and involved regional lymph nodes alone, improves the outcome for patients with unfavourable metastatic disease

The objectives for the maintenance chemotherapy questions are as follows:
•To determine whether the addition of a further 12 cycles of vinorelbine and cyclophosphamide (VnC) to standard 12 cycles of maintenance chemotherapy (i.e. 24 cycles total) improves the clinical outcome for patients with Very High Risk disease at diagnosis
•To determine whether the addition of a further 6 cycles of VnC (intravenous vinorelbine, oral cyclophosphamide) to the standard 6 cycles (i.e. 12 cycles total) improves the outcome for patients with localised High Risk disease at diagnosis

The objectives for the relapsed disease questions are as follows:
•To determine whether new systemic therapy regimens improve outcome in relapsed RMS. The initial new systemic therapy combination to be tested is the addition of Regorafenib (R) to vincristine and irinotecan (VIr) (VIrR) compared with standard therapy Vincristine, irinotecan & temozolomide (VIrT)

Secondary objectives 8

1. To validate whether the use of fusion status (PAX3/PAX7-FOXO1) in place of histopathological diagnosis improves risk stratification
2. To determine whether assessment of fusion status is necessary in tumours classified as Embryonal RMS (ERMS) by histopathology
3. To determine whether immunohistochemistry (IHC) assessment for protein expression driven by the fusion protein is an accurate surrogate for fusion status
4. To determine whether FDG PET- CT response assessment following induction chemotherapy is a prognostic biomarker for local failure and/ or survival
5. Secondary Objectives (CT3) -To determine the tolerability of the regimens
6. Secondary Objectives (CT3) -To evaluate the anti-tumour activity and effect on overall survival of VIRR when compared to standard therapy
7. Secondary Objectives (CT3) -To evaluate the effect on quality of life of VIRR when compared to standard therapy
8. Secondary Objectives (CT3) -To evaluate the acceptability and palatability of regorafenib formulations To examine the pharmacokinetics of regorafenib

Conditions and MedDRA coding

Rhabdoyosarcoma

Regulatory references

EMA paediatric investigation plan (PIP)

EMEA-616451-PIP20-21

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 12

1. 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
2. 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
3. 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
4. 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
5. 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
6. 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
7. 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
8. 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
9. 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
10. 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
11. 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
12. 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 7

1. 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
2. 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
3. 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
4. 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
5. 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
6. 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
7. 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

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 3

1. Recommended Phase 2 Dose (RP2D) - Phase 1b
2. Event Free Survival for randomisations CT1a, CT1b, CT2, RT2 and CT3
3. Local failure free survival for randomisations RT1a, RT1b and RT1c

Secondary endpoints 16

1. Maximum Tolerated Dose for registration phase 1b
2. Dose Limiting Toxicity for registration phase 1b
3. Overall Survival for all patients, randomisations CT1a, CT1b, CT2, CT3, RT1a, RT1b, RT1c and also RT
4. Event Free Survival for all patients, randomisations RT1a, RT1b, RT1c and also the PET sub-study
5. Loco-regional failure-free survival for randomisations RT1a, RT1b, RT1c and RT2
6. Local failure free survival for the PET sub-study
7. Response for registration phase 1b and also randomisations CT1a, CT1b, and CT3
8. Best Response for randomisation CT3
9. Duration of response for randomisation CT3
10. Toxicity for registration phase 1b and also randomisations CT1a, CT1b, and CT3
11. Acute post-radiotherapy complications for randomisations RT1a, RT1b, RT1c and RT2
12. Late complications for randomisations RT1a, RT1b and RT1c
13. Acute post-operative complications for randomisations RT1a and RT1b
14. Wound complications for randomisations RT1a and RT1b
15. Health Related Quality of Life for randomisations RT1a and RT2
16. PET response for the PET sub-study

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 19

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

The University Of Birmingham

Sponsor organisation

The University Of Birmingham

Address

Vincent Drive

City

Birmingham

Postcode

B15 2TT

Country

United Kingdom

Scientific contact point

Organisation

The University Of Birmingham

Contact name

Senior Trial Manager

Public contact point

Organisation

The University Of Birmingham

Contact name

Senior Trial Manager

Third parties 15

Locations

16 EU/EEA countries · 174 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 667 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

1 submissions — initial application plus substantial / non-substantial modifications