This substantial amendment was generated to include dexamethasone as prophylactic medication required before infusion with plitidepsin. Therefore, standard premedication for hypersensitivity reactions with anti H1 and H2 receptor antagonists and glucocorticoids had to be given intravenously before each plitidepsin infusion; this is mandatory in all ongoing studies with plitidepsin as stated in the Investigator Brochure. In v.1.0 of this protocol, dexamethasone was not part of the premedication regimen due to an omission at the time of writing the document. Additionally, the following changes, corrections, and clarifications were also included in this substantial amendment: - Clarifications to some of the parts of the text regarding the prior treatment, LVEF and hypersensitivity eligibility criteria were included to ensure patient safety - Muscular toxicity criteria for treatment continuation and dose reduction were revised to ensure patient safety - The list of excipients of plitidepsin was added to the study drug formulation information - Clarifications to some assessments and procedures windows were included as follow: tumor assessment timing after Cycle 3 was changed to avoid delays in starting Cycle 4; the frequency of follow-up until disease progression during the first year of follow-up was corrected in line with standard clinical practice; laboratory analyses required in the event of grade 3/4 nausea/vomiting or a treatment-related SAE were corrected to require only biochemistry-A laboratory tests. - The use of National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) grade 5 was revised to align with current Pharmacovigilance Department standard practice. - ICH Topic E6 Guideline for Good Clinical Practice reference to R1 was removed in anticipation of a revised version (R2). - Study contact details were updated and some minor typographical errors were corrected

This substantial amendment was generated to: - Implement additional information on imaging requirements and periods for radiological tumor assessment with PET-CT in combination with diagnostic quality CT. - Modify the exclusion criterion #5 to allow the inclusion of patients concurrently treated with low doses of corticosteroids (an equivalent prednisone dose of ≤10 mg daily) for controlling symptoms derived from the disease. - Modify section referred to prohibited medications/therapies to clarify that patients were allowed to receive hydrocortisone treatment by any administration, not only by single bolus, and also to be consistent with the amended Exclusion criterion #5 (see above). - Simplify the follow-up procedures and periods for patients discontinuing treatment with or without disease progression, to be similar to the procedures used in clinical practice for monitoring these patients. Therefore, both groups of patients would be followed up ‘every four months during the first two years and then once every six months’. - Update the study contacts and correct some minor typographical errors.

Additionally, according to an FDA request, a new Substantial Amendment No. 3 (7 May 2018) was issued to include several changes as additional precautionary measures to mitigate any likely rhythm abnormality. This amendment was based on the occurrence of one episode of grade 4 cardiac arrest due to Torsades de pointes (TdP) reported in one patient during Cycle 4 that resolved but led to treatment discontinuation. Precautionary measures to avoid TdP risk were to be implemented in this ongoing phase II study, including more stringent eligibility criteria, continuation of treatment criteria, prohibited medications (excluding prophylactic antiemetic ondansetron), and more extensive cardiac monitoring. Furthermore, as preliminary data from the APL-C-001-09 ADMYRE study showed that the greatest increases in QTcF, although being below the safety threshold of 20 milliseconds (ms), occurred 30 and 60 min after the end of infusion, thus the FDA requested that protocol of APL-B-021-13 study had to be modified to check ECGs 30 and 60 min post-infusion, timed with pharmacokinetic sample collections. Nevertheless, the study APL-B-021-13 was closed before this new substantial amendment was implemented.