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

Rhabdomyosarcoma (RMS) is a rare sarcoma, with 59% of cases presenting in
children and the rest occurring in adulthood, where the prognosis is poorer.
Although relatively rare, RMS is the commonest of the paediatric soft tissue
sarcomas, affecting about 15-20 children (0-18 years) per year in The
Netherlands. RMS arises in many different sites within the body and comprises
two major histological sub-groups: alveolar (ARMS) and embryonal (ERMS).
Because of its chemo-responsiveness, neoadjuvant chemotherapy is used in the
majority of patients with a response rate (RR) of around 80-85%. However,
despite its chemo-sensitivity, multimodality treatment including radiotherapy
or surgery or both radiotherapy and surgery is needed to achieve long term
local control and cure in the vast majority of cases. Patients with metastatic
disease can achieve remission with intensive chemotherapy and local therapy in
75% of cases but the vast majority relapse, often at distant sites, resulting
in a 3 year event-free survival (EFS) of only 27%. Unfortunately, at the time
of relapse, RMS is generally very refractory to treatment and has a 5 year
overall survival (OS) of less than 20%.

Chemotherapy is an integral component of multi-modality therapy for RMS.
Incremental improvements in outcome have been achieved over the last three
decades within clinical trials that have investigated stepwise modifications in
the intensity and combinations of these drugs. In low and SR disease, this has
proved very successful, with a current 3 year EFS rates of 95% and 77%
respectively. However, the greatest treatment challenges are in HR, VHR and
metastatic disease, as well as at relapse, where progress with currently
available agents has been inadequate; EFS remains below 70%, 45%, and 30%
respectively and novel approaches are needed.

Despite the significant improvements in outcomes for patients in the last 20
years, local control remains the principal challenge in localised RMS.
Radiotherapy is a key component of local therapy for RMS. It is proposed that
the effectiveness of radiotherapy in local control could be improved by
modifying the dose and/or the timing of radiotherapy. Within FaR-RMS both
strategies will be investigated.
There are conflicting data as to whether radiotherapy to metastatic sites truly
influences outcomes for RMS. To date, the standard of care for metastatic RMS
has been systematic irradiation of all metastatic sites whenever feasible.
FaR-RMS aims to investigate whether radiotherapy to metastatic sites improves
survival for patients with unfavourable metastatic RMS and evaluate the effects
on HRQoL of this treatment.

Since more than 90% of events in RMS appear > 12 months after diagnosis, i.e.
off-therapy, new approaches with longer low-dose treatments, so-called
maintenance or metronomic chemotherapy, have been developed. The optimal
duration of maintenance therapy for patients in the highest risk disease is
still unknown. The duration of maintenance therapy will be evaluated in
FaR-RMS, with a 12 vs 24 months maintenance randomisation for VHR RMS, and a 6
vs 12 months maintenance randomization for HR RMS.

This study has been transitioned to CTIS with ID 2024-510579-40-00 check the CTIS register for the current data.

PRIMARY OBJECTIVES
*Phase 1 Dose Finding Studies:
-To determine the recommended phase II dose (RP2D) of new systemic therapy
regimens.
*Frontline chemotherapy questions:
-To compare systemic therapy regimens for patients with VHR disease at
diagnosis (CT1A).
-To compare new systemic therapy regimens with standard chemotherapy for
patients with HR disease at diagnosis (CT1B).
*Radiotherapy questions:
-To determine whether pre-operative or standard post-operative radiotherapy is
better for patients with resectable disease (RT1A) .
-To determine whether dose escalation of radiotherapy improves the outcome in
patients with a higher local failure risk (RT1B/C).
-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 (RT2).
*Maintenance Chemotherapy Question:
-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 outcome for patients with VHR disease at
diagnosis (CT2A).
-To determine whether the addition of a further 6 cycles of VnC (intravenous
(i.v) vinorelbine, oral cyclophosphamide) to the standard 6 cycles (i.e. 12
cycles total) improves the outcome for patients with localised HR disease at
diagnosis (CT2B).
*Relapsed RMS Question:
-To determine whether new systemic therapy regimens improve event free survival
in relapsed RMS compared to standard therapy (VIrT) (CT3).

MAIN OVERARCHING SECONDARY OBJECTIVES
-To validate whether the use of fusion status (PAX3/PAX7-FOXO1) in place of
histopathological diagnosis improves risk stratification.
-To determine whether assessment of fusion status is necessary in tumours
classified as Embryonal RMS (ERMS) by histopathology.
-To determine whether immunohistochemistry (IHC) assessment for protein
expression driven by the fusion protein is an accurate surrogate for fusion
status.
-To determine whether FDG PET- CT response assessment following induction
chemotherapy is a prognostic biomarker for local failure and/ or survival.

SECONDARY OBJECTIVES (CT3)
- To determine the tolerability of the regimens
- To evaluate the anti-tumour activity and effect on overall survival of VIRR
when compared to standard therapy
- To evaluate the effect on quality of life of VIRR when compared to standard
therapy
- To evaluate the acceptability and palatability of regorafenib formulations
- To examine the pharmacokinetics of regorafenib

FaR-RMS is an over-arching study for patients with newly diagnosed and relapsed
RMS including multi-arm, multi-stage questions with three principal aims. These
are to evaluate:
-systemic therapy through the introduction of new agent regimens in the most
advanced disease states: Very High Risk (VHR), High Risk (HR) and Relapse
-the duration of maintenance therapy
-radiotherapy to improve local control in VHR, HR and Standard Risk (SR)
patients and to treat metastatic disease
In addition the study will evaluate:
-risk stratification through the use of PAX-FOXO1 fusion gene status instead of
histological subtyping
-the use of FDG PET-CT response assessment as a prognostic biomarker for
outcome following induction chemotherapy

FaR-RMS is intended to be a rolling programme of research with new treatment
arms being introduced dependant on emerging data and innovation, provided it is
within the pre-defined research remit of the trial. A maximum of three new arms
will be added to each of the frontline (VHR and HR) and relapse randomisations;
and a maximum of four new arms to the Phase 1b component

Phase 1b study:
-VHR: Treatment with IrIVA or other new systemic therapy regimens added later
on in dose finding study setting (with a maximum of 4 new arms).
Induction chemotherapy:
-VHR: Randomised treatment with IVADo, IrIVA and other new systemic treatment
regimens added later on (with a maximum of 3 new arms).
-HR: Randomises treatment with IVA, IrIVA and other new systemic treatment
regimens added later on (with a maximum of 3 new arms).
Maintenance chemotherapy:
-VHR: Randomised treatment with 12 or 24 cycles maintenance chemotherapy.
-HR: Randomised treatment with 6 or 12 cycles maintenance chemotherapy.
Radiotherapy:
-All patients with localized disease, resectable tumor: Randomised treatment
with pre-surgery or post surgery RT.
-All patients with local, resectable, high local-failure risk: Randomised
treatment with 41,4 Gy or 50,4 Gy RT.
-All patients with not-resectable, incomplete response, high local-failure
risk: Randomised treatment with 50,4 Gy or 59,4 Gy RT.
-All patients with *unfavourable* metastatic disease: Randomised RT treatment
all metastatic sites or primary tumor and loco-regional nodes only.
Relapsed RMS induction chemotherapy:
-Randomised treatment with VIrT, VIrRego or other systemic therapy regimens
(with a maximum of 3 new arms).

Patients participating in this study receive an intensive multimodal treatment,
with three or more cytotoxic drugs. They also receive this treatment or similar
treatment if the do not participate in the study. The intensive treatment is
necessary for the treatment of their rhabdomyosarcoma.

Some patients (HR, VHR, relapsed) receive extra or other drugs, added to the
current standard chemo backbone. This is justified because the overall survival
in these groups is poor. Safety and toxicity will be strictly monitored.

Some patients (HR and VHR) are randomized and receive 6 (HR) or 12 (VHR)
additional maintenance courses after induction treatment. Extension of
maintenance therapy may contribute to the improvement of overall-survival.
Toxicity and burden will be monitored.

Patients with a high local failure risk are randomized and receive an higher
dose radiotherapy on the primary tumor. This is justified because this could
contribute to a better local treatment result and survival. Acute toxicity,
late complications and quality of life (early and late) will be registered and
monitored.
These patients/parents are asked to complete a questionnaire four times.