FLUJO FLUJO DE OPERACIONES DE IMEC S.A.

A choice has been made for this study to rely on volume measurements for tumour response assessment. Tumours do not necessarily grow or shrink in a rounded fashion and 3D evaluation may be more accurate than uni or bidimensional criteria.

It is planned to also measure the maximum unidimensional measurement as suggested by the RECIST guidelines and later compare the volume with unidimensional measurements in terms of tumour response. The maximum lesion diameter in any plane should be recorded as the longest tumour diameter, and measurements may be taken from CT or MRI (contrary to the formal RECIST guidance) but the maximum tumour measurement must always be in the same plane (axial, coronal or sagittal).

The presence or absence of a post-therapeutic residue should be stated in the radiology report. Very good partial response and minor partial response criteria are not recognised international criteria but have been added for this protocol.

A clinical assessment of tumour response should be made at each visit in order to detect tumour progression at any point during treatment. This should be supplemented by radiological examination as appropriate.

For the patients in standard and high risk group with evidence of macroscopical residues after initial surgery a formal reassessment of Tumour Response is undertaken at week 9, after the initial 3 cycles of chemotherapy.

Assessment must include a detailed clinical examination with external tumour measurements where relevant and radiology using comparable techniques to those used at diagnosis (MRI and/or CT scan).

Tumour dimensions should be recorded in three diameters and can be compared choosing, as far as possible, the diameters selected at diagnosis.

Tumour volume (V) calculation:

a= length (in cm)

b= width (in cm) V = π/6 x a x b x c = 0.52 x a x b x c in cm3 c= thickness (in cm)

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19.1 RESPONSE EVALUATION CRITERIA

Response in patients with macroscopic residual disease after initial surgery (IRS group III) will be evaluated as follow:

Complete Response (CR) Complete disappearance of all visible disease

Very Good Partial Response (VGPR) Tumour volume reduction > 90% but < 100%

Partial Response (PR>2/3) Tumour volume reduction > 66% but < 89%

Minor Partial Response (PR<2/3) Tumour volume reduction > 33% but < 66%

Stable disease (SD) No criteria for PR or PD (< 33% tumour volume

reduction)

Progressive Disease (PD) Any increase of more than 40% in volume (or > 25% in

area) of any measurable lesion, or appearance of new lesions.

All response must last at least 4 weeks without evidence of tumour progression or relapse

Residual disease should be defined as macroscopic measurable residue. Residual ill-defined areas of high density on CT-scan, or residual signal abnormalities on MR such as low intensity on T1WI, high intensity on T2WI and ill-defined margins of enhancement areas are commonly observed after chemotherapy. If no measurable mass, these may be regarded as post-therapeutic residue, and should not exclude the classification as CR.

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20. Second line therapy

A poor response to initial chemotherapy appears correlated with a poor prognosis in RMS patients. Data from the CWS-81 and CWS-86 studies demonstrated a significantly worse prognosis for children with a poor response after the initial three blocks of chemotherapy.

Therefore the current management of patients with evidence of poor response after the initial chemotherapy phase includes the administration of drugs not previously administered and the implementation of local treatment measures (surgery and/or radiotherapy).

In this protocol, we suggest to treat such patients with alternative chemotherapy combinations along with surgery and radiotherapy. Chemotherapy regimen should be chosen taking into account chemotherapy previously administered and patient tolerance. We suggest different chemotherapy regimens that could be used by the responsible clinicians.

Local treatment must be considered at any time when an unsatisfying response to initial chemotherapy is evident.

When more chemotherapy treatment is thought appropriate by the responsible clinician before local control measures (surgery and/or radiotherapy) chemotherapy response evaluation will be possible. A proper phase II study is not part of this protocol, however we ask centres to record the response to the regimen administered to collect more information.

Patients eligible to second line chemotherapy response evaluation may be for instance: - young patients for whom local treatment is thought to be excessively toxic or not possible - patients in good condition with stable tumour for whom a second chemotherapy test is retained

appropriate

- patients for whom surgery or irradiation is not possible in a short time (i.e. within 6-8 wks)

20.1 SECOND LINE CHEMOTHERAPY

Drugs not administered during first line therapy should be used.

- Topotecan has been demonstrated to be active in paediatric malignancies including RMS. Carboplatin has been part of previously used regimens (CEVAIE) that proved to be effective against RMS. It has also been used alone in a window study conducted by the UKCCSG (unpublished data). A phase II trial has been performed at the Bambino Gesù Hospital in Rome showing the feasibility of the proposed regimen. The Topo-Carbo combination is also used as window treatment in the current CWS protocol for metastatic RMS.

- Doxorubicin may be used instead of Topotecan in patients if they have not received anthracyclines in the initial treatment.

After 2 cycles there will be a tumour response evaluation and decisions will be taken accordingly: a) Good response (including CR, VGPR and PR): the initial chemotherapy will continue: see

second line treatment schema.

b) No response (stable or progressive disease): local treatment must be evaluated and a new chemotherapy regimen may be considered.

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20.1.1 SECOND LINE TREATMENT SCHEMA

Topo - Carbo Regimen

Topo Topo Good Topo VP16 Topo VP16

Carbo Carbo Response Cyclo Carbo Cyclo Carbo

weeks 1 4

_×

Tumour response evaluation

Topotecan: 2 mg/m2/day on day 1 to 3 (total dose 6 mg/m2/course) in 30 minutes.

Carboplatin: 250 mg/m2/day in 1 hour on day 4 and 5 when given with topotecan, on day 1 and 2 when given with VP16 (total dose 500 mg/m2 course).

Cyclophosphamide: 1500 mg/m2 /day on day 1 and 2 (total dose 3000 mg/m2 course) in 4 hours. VP16: 100 mg/m2/day on day 1 to 3 (total dose 300 mg/m2 course) in 1 hour.

Doxo – Carbo Regimen

Doxo Doxo Good Doxo Doxo Doxo Doxo

Carbo Carbo Response Cyclo Carbo Cyclo Carbo

weeks 1 4

_×

Tumour response evaluation

Doxorubicin: 60 mg/m2/day on day 1 (total dose 60 mg/m2/course) 1 to 6 hours according institutional policies.

Carboplatin: 250 mg/m2_{/day on day 1 and 2 (total dose 500 mg/m}2 _{course) in 1 hour.} Cyclophosphamide: 1500 mg/m2 /day on day 1 and 2 (total dose 3000 mg/m2 course) in 4 hours.

Chemotherapy modulation

The interval between courses should be 21 days and the following chemotherapy course should not be started unless all these conditions are present:

- 2 x109/l WBC, or 1 x109/l neutrophils - 80 x109/l platelets are reached.

- absence of any relevant organ dysfunction

Response assessment

This should be done according to the same recommendations and criteria adopted for the first line treatment (see paragraph 19.1). However the tumour volume after the initial two courses of second line chemotherapy must be compared to the tumour evaluated at week 9th and not at diagnosis.

Important note: please remember that patients in CR after second line chemotherapy are still

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21. Adequate Local Therapy Diagram

(for details see surgical and radiotherapy guidelines)