This substantial protocol amendment incorporated changes to clarify patient inclusion criteria and to avoid inconsistencies or discrepancies through the document regarding dose adjustment guidance, as follows: 1) potential misinterpretation was avoided by erasing a coma in a sentence describing patient inclusion requirements, and 2) the scheme of ifosfamide consecutive reductions was corrected according to the initial dose range for ifosfamide administration. Additionally, the time of prophylactic dexamethasone before trabectedin administration was adjusted to 30 min, to be in concordance to the Summary of Product Characteristics specifications

This substantial protocol amendment included changes with respect to: 1) issues affecting the medical management of alveolar rhabdomyosarcoma patients, which led to the exclusion of this subgroup from the study population; 2) a better definition of the study termination (clinical cutoff) period was required; 3) to clarify the reference document for evaluation of AEs in patients under treatment with investigational drugs; 4) to better explain the measures taken for international transfers of personal data, and 5) other changes and additions have been included to disambiguate some unclear statements.

This substantial protocol amendment included changes with respect to: 1) inclusion criteria: to add progressive disease prior to study entry as well as to allow inclusion of patients with Gilbert’s syndrome with total bilirubin > ULN; 2) to modify the frequency of tumor assessments in order to allow close monitoring of disease response to treatment but to decrease the exposure to irradiation of patients; 3) to clarify the times for confirmation of tumor response; 4) some changes in hematology laboratory test schedule in case of neutropenia to make it less restrictive and more practical; 5) to update information on concomitant therapy according to more recent reports of toxicity; 6) to update the study contacts, and 7) minor changes to eliminate grammatical errors and to clarify ambiguous statements in the Time and Events Schedule Table.

This substantial protocol amendment included changes with respect to: 1) the wording of inclusion criterion No.3 was changed to clarify that recruitment was restricted to only those patients who had any of the tumor subtypes listed in this criterion [in the particular case of endometrial stromal sarcoma, only patients with low grade disease were allowed to enter the study, as translocation t(7;17)(p15;p21) has been found associated with this variant]; 2) a new inclusion criteria (No.5) was added stating that patients had to have measurable disease as defined by RECIST v.1.0; 3) in the case of alveolar soft part sarcoma, due to the absence of available probe to perform FISH, patients with externally confirmed pathological diagnosis of this subtype were also allowed to be included in the efficacy population; 4) some clarifications were added with respect to AEs/SAEs reporting, including guidelines to report laboratory disorders, exclusion of disease progression as an AE, and rewording of sentences about deaths in SAE reporting, and 5) other changes, including update of study contacts, the number of investigational sites, and the planned enrollment period.