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

University of Birmingham

Status and phase: Enrolling; Phase 2; Phase 1

Conditions: Rhabdomyosarcoma

Treatments: Drug: Doxorubicin; Radiation: radiotherapy; Drug: Irinotecan; Drug: Regorafenib; Drug: Temozolomide; Drug: Vinorelbine; Drug: Cyclophosphamide; Drug: Vincristine; Drug: Ifosfamide; Drug: Actinomycin D

Study type: Interventional

Funder types: Other

Identifiers

NCT04625907

2018-000515-24 (EudraCT Number)

RG_17-247

45535982 (Registry Identifier)

Details and patient eligibility

About

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

Full description

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.

Enrollment: 1,672 estimated patients

Sex: All

Volunteers: No Healthy Volunteers

Inclusion and exclusion 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. Very High Risk 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:

   1. Total bilirubin ≤ 1.5 times upper limit of normal (ULN) for age, unless the patient is known to have Gilbert's syndrome
   2. 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

Exclusion

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 Very High Risk - CT1a Inclusion

1. Entered in to the FaR-RMS study at diagnosis

2. Very High Risk 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

Exclusion

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 High Risk - CT1b Inclusion

1. Entered in to the FaR-RMS study at diagnosis

2. High Risk 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

Exclusion

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 Radiotherapy Note: eligible patients may enter multiple radiotherapy randomisations.

Radiotherapy Inclusion - for all radiotherapy randomisations

1. Entered in to the FaR-RMS study (at diagnosis or prior to radiotherapy randomisation)
2. Very High Risk, High Risk and Standard Risk disease
3. ≥ 2 years of age
4. 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
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

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

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 surgical resection (local decision).
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

RT1b Specific Inclusion

1. Primary tumour deemed resectable (predicted R0/R1 resection) after 3 cycles of induction chemotherapy (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:

   1. Unfavourable site
   2. 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:

   1. Unfavourable site
   2. 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 (Very High Risk) - 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. Very High Risk 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

Exclusion

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 (High Risk) - 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. High Risk 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

Exclusion

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

CT3 Relapsed Chemotherapy

Inclusion:

1. Entered in to the FaR-RMS study (at diagnosis or at any subsequent time point)
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:

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 design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

---

1,672 participants in 19 patient groups

Phase 1b Dose finding: VHR induction - IRIVA

Experimental group

Description:

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.

Treatment:

Drug: Actinomycin D

Drug: Ifosfamide

Drug: Irinotecan

Drug: Vincristine

CT1A: VHR induction - IVADO

Active Comparator group

Description:

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

Treatment:

Drug: Actinomycin D

Drug: Ifosfamide

Drug: Doxorubicin

Drug: Vincristine

CT1A: VHR Induction IRIVA

Experimental group

Description:

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.

Treatment:

Drug: Actinomycin D

Drug: Ifosfamide

Drug: Irinotecan

Drug: Vincristine

CT1B: HR Induction IVA

Active Comparator group

Description:

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.

Treatment:

Drug: Actinomycin D

Drug: Ifosfamide

Drug: Vincristine

CT1B: HR Induction IRIVA

Experimental group

Description:

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.

Treatment:

Drug: Actinomycin D

Drug: Ifosfamide

Drug: Irinotecan

Drug: Vincristine

RT1A: Preoperative Radiotherapy

Experimental group

Description:

To be given either 41.4 Gy or 50.4 Gy prior to surgery

Treatment:

Radiation: radiotherapy

RT1A: Post operative radiotherapy

Active Comparator group

Description:

To be given either 41.4 Gy or 50.4 Gy following surgery

Treatment:

Radiation: radiotherapy

RT1B: Radiotherapy for resectable disease: dose escalated

Experimental group

Description:

To receive 50.4 Gy

Treatment:

Radiation: radiotherapy

RT1B: Radiotherapy for resectable disease: standard dose

Active Comparator group

Description:

To receive 41.4 Gy

Treatment:

Radiation: radiotherapy

RT1C: Radiotherapy for unresectable disease: dose escalated

Experimental group

Description:

To receive 59.4 Gy

Treatment:

Radiation: radiotherapy

RT1C: Radiotherapy for unresectable disease: standard dose

Active Comparator group

Description:

To receive 50.4 Gy

Treatment:

Radiation: radiotherapy

RT2: Radiotherapy to primary tumour and involved lymph nodes

Experimental group

Description:

Radiotherapy to the primary tumour and involved regional lymph nodes only

Treatment:

Radiation: radiotherapy

RT2: Radiotherapy to all metastatic sites

Experimental group

Description:

Radiotherapy given to all metastatic sites

Treatment:

Radiation: radiotherapy

CT2A: VHR Maintenance - VC

Experimental group

Description:

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

Treatment:

Drug: Cyclophosphamide

Drug: Vinorelbine

CT2A: Maintenance -Stop treatment

No Intervention group

Description:

To stop treatment at the point of randomisation

CT2B: HR Maintenance - VC

Experimental group

Description:

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

Treatment:

Drug: Cyclophosphamide

Drug: Vinorelbine

CT2B: HR Maintenance - Stop Treatment

No Intervention group

Description:

To stop treatment at the point of randomisation

CT3: Relpased Chemotherapy - VIRT

Active Comparator group

Description:

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

Treatment:

Drug: Temozolomide

Drug: Irinotecan

Drug: Vincristine

CT3: Relapsed Chemotherapy - VIRR

Experimental group

Description:

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.

Treatment:

Drug: Regorafenib

Drug: Irinotecan

Drug: Vincristine