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RecruitingLast updated: 3 January 2024

FaR-RMS: This study is evaluating the impact of new cancer treatments in both newly diagnosed and relapsed rhabdomyosarcoma patients; it will determine whether changing the duration of maintenance therapy affects outcome; and whether changes to dose, extent and timing of radiotherapy improve outcomes and quality of life for patientsAn overarching study for children and adults with Frontline and Relapsed RhabdoMyoSarcoma

Clinical summary

Summary

The first part of this study will be a phase Ib dose-finding trial, open to newly diagnosed patients. This study will investigate the addition of irinotecan to IVA (ifosfamide, vincristine and actinomycin D) chemotherapy (IrIVA) and support the identification of a recommended phase II dose. Once the recommended phase II dose has been determined, patients will be randomised, according to whether they are newly diagnosed or high risk, into the next part of the study.

In this part of the study, newly diagnosed patients will be randomised to receive either IVADo (Ifosfamide, Vincristine, Actinomycin D, Doxorubicin) or IrIVA; and high risk patients will be randomised to IVA or IrIVA. Cycles of chemotherapy will be given at 21-day intervals. The next part of the study will contain several radiotherapy randomisations for patients with newly diagnosed and high risk rhabdomyosarcoma, followed by maintenance chemotherapy.

Following the completion of treatment, the frequency of follow-up assessments will be guided by local practice. However, every 3 months for the first 3 years and every 6 months thereafter is suggested. Patients will be followed-up for a minimum of 3 years, until the last patient has been followed-up for 3 years.

Conditions

This trial is treating patients with Rhabdomyosarcoma

Cancer

Sarcoma Cancers Sarcoma

Age

People0+

Phase

I/II

Trial Acronym

FaR-RMS

More information

Trial Identifiers

Use the hyperlinks, where available to access additional clinical trial information.

Trial sponsor

University of Birmingham & Cancer Research UK,Australian and New Zealand Children's Haematology and Oncology Group (ANZCHOG)

Scientific Title

An overarching study for children and adults with Frontline and Relapsed RhabdoMyoSarcoma

Eligibility

Inclusion

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

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

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

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

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

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

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

Phase 1b Dose Finding - IRIVA 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 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 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

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 (Very High Risk) - CT2a 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 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 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

Exclusion

  • You have been diagnosed with a prior or secondary type of cancer.
  • You have certain types of non-cancer medical conditions.
  • You have had certain treatments, surgical procedures or drugs.
Message

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Ask your doctor if this trial could be right for you.

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