- The criterion for evaluability was changed from having received a minimum of 4 courses to having received a minimum of 2 courses. - The following secondary endpoint was added: Bone marrow transplant (BMT)/ peripheral blood stem cell transplant (PBSCT) rate was to be determined by dividing the number of subjects receiving BMT/PBSCT by the total number of subjects evaluable for response. - The following was added to the preamble to the inclusion criteria: The trial would recruit subjects who had failed to achieve remission by standard first line therapy or following first relapse, failed to achieve remission by standard relapse therapy. Subjects with multiple relapses would be eligible provided their prior salvage therapy did not include BMT or PBSCT. - Following Inclusion criterion was removed: National and local ethical approval for the protocol. - The criterion for subject discontinuation was changed from “lead investigator’s discretion” to “investigator’s discretion”. - It was specified that off-study (end of study) assessments were to be performed within 14 days of the last dose of clofarabine. No time-frame had been specified in version 1 of the protocol. - A definition of “end of study” for analysis purposes was added, being the completion of course 4 of clofarabine treatment, including the bone marrow aspirate (BMA) taken at the end of course 4 to assess disease status and response to clofarabine treatments. - The confidence interval for characterising the overall response (OR) was changed from 99% to 95%.

- The lead Clinical Research Organization (Tessman Technology Limited) was removed. - The preamble to the inclusion criteria was amended to specify that: Children who had received an allogeneic progenitor cell transplant must be at least 6 months post-transplant. - Following inclusion criterion was amended to: Subjects with 2 or more relapses of acute lymphoblastic leukaemia (ALL) Children who had received an allogeneic progenitor cell transplant, must be a. At least 6-months post transplant b. Had good organ function c. Stable with no major complications. - The requirement that subjects’ prior salvage therapy did not include BMT or PBSCT was deleted from inclusion criterion. - Exclusion criterion was amended to allow the inclusion of subjects with prior BMT or PBSCT provided this happened more than 6 months previously. As a result, a new exclusion criterion was added, with all subsequent criteria being renumbered, to exclude subjects with prior BMT or PBSCT and poor organ function.

- Overall remission, complete remission, partial remission, etc were changed to OR, etc. However the term “duration of remission” was not changed. - Secondary objective “To document an OR rate of ≥ 20% in children with refractory or relapsed ALL” was removed. - The following new secondary objective was inserted with all subsequent secondary objectives being renumbered; the modified overall response (MOR) rate was also defined as a secondary endpoint. To document the MOR rate in paediatric subjects with refractory or relapsed ALL. The MOR rate was defined as the sum of the number of subjects with either complete response (CR), complete response in the absence of platelet recovery (CRp) or partial response (PR) divided by the total number of subjects evaluable for response. - The option to reduce the dose in the event of “significant haematological toxicity” was introduced. - Exclusion criterion was amended to read: Had an active or uncontrolled systemic infection considered opportunistic, life threatening, or clinically significant at the time of treatment. Subjects who had a recent (< 30 days) history of fungal or bacterial infection or who were receiving therapeutic doses of antibiotics or antifungals. - A new exclusion criterion was introduced: Had recent history of significant renal, hepatic or pulmonary dysfunction, or cardiac dysfunction, or on treatment to support cardiac function. - A new criterion for subject discontinuation was introduced: No MOR after 4 courses of clofarabine treatment. - Metabolism studies (urine sampling) were added for the subset of subjects that consented to these investigations. - The definition of serious adverse events (SAEs) was changed to include “any medically important event” and all National Cancer Institute common toxicity criteria (NCI-CTC) grade 4 events. - Information on capillary leak syndrome and instructions to the investigators in the event of such a case occurring were added.

- The primary objective was amended to determine OR only in subjects that had completed at least one full course of clofarabine treatment. -Determination of OR after 2 or more courses, which was the primary objective in the previous versions, was changed to secondary objective. - Secondary endpoint was amended to: The OR rate after 2 courses or more will be determined by the sum of the number of subjects with either a CR or CRp with 2 courses or more of clofarabine divided by the total number of subjects who received 2 courses or more of clofarabine. - The inclusion of subjects without primary refractory disease was permitted if they had relapsed or refractory disease after a minimum of 2 prior blocks of treatment.- Inclusion criterion was reworded to include definitions of adequate cardiac function. - The definition of adequate hepatic function for inclusion were amended to specify AST and ALT of ≤ 5 x ULN. - Reasons for discontinuation were amended to remove the option for discontinuation at the investigator’s discretion, and to remove the exclusion from discontinuation due to non-haematological toxicities for elevated liver function tests.- Dosage, Administration, and Storage section was amended to state that the diluted clofarabine was to be used immediately or that if not used immediately, would normally not exceed 24 hours at 2 to 8°C unless reconstitution/dilution (etc) had taken place in controlled and validated aseptic conditions.- Repetition of clofarabine courses was to be at 21 ± 7 day intervals, and that subjects were to receive a minimum of 1 course and a maximum of 12 courses.- Criteria for dose reduction in subjects experiencing haematological toxicities were introduced.- The requirement for absolute neutrophil count (ANC) recovery to 0.75 × 10 9 /L for the third and subsequent courses of treatment was removed.- Criteria for bone marrow or blood sampling for molecular pharmacology studies were added.