Amendment 1 was primarily written to increase recruitment by updating the inclusion/exclusion criteria in order to better reflect the actual patient population and to enlarge the patient population eligible to be enrolled in this study. Inclusion criterion 2 was changed in a manner that a histological confirmation of LC-NEC diagnosis for relapsing tumors was not necessarily needed anymore at time of recurrence. The histological diagnosis of LC-NEC was still necessary but could also be done during an earlier stage of disease. The diagnosis of LC-NEC depending on neuroendocrine differentiation was specified by including the requirement of non-small cell cytological characteristics (in order to exclude SCLC). The increased proliferation rate had to be demonstrated in histology by microscopic analysis (>11/10 HPF) and, if available, by the Ki67 proliferation marker (>50%). In the exclusion criteria, some ambiguous wordings were specified, especially for allowed prior chemotherapies and for radiotherapies of brain metastases. In addition, some inconsistencies in the protocol were amended: The allowed infusion time of the carboplatin infusion was now consistently 30 to 60 minutes and Figure 6-1 with the study treatment scheme was corrected accordingly. The description of RAD001 maintenance treatment after completion of combination treatment was shifted in a separate paragraph. An error in Table 6-4 was corrected. A wording in the paragraph “End of treatment” was amended. The allowed window for visit scheduling was clarified to +/- 3 days if not otherwise specified. Minor amendments in the visit evaluation schedule were made. Inconsistencies regarding the assessment of the primary and secondary efficacy parameters were corrected: The efficacy endpoints (with exception of overall survival) were assessed by the central imaging reviewer. In the statistical part of the protocol, the definition of the ITT set was corrected and the handling of the ITT set was clarified.

Amendment 2 was written for the purpose to terminate the enrollment to the trial. The termination was effective with approval of this protocol amendment by the Institutional Review Board (IRBs)/ Independent Ethics Committee (IECs) and Health Authorities. The reason for the termination was the low recruitment rate. Since the first patient was enrolled in April 2011, altogether only 48 patients (cut-off date 17-Nov-2014) could be recruited at 11 active study sites. Several actions were taken to improve the recruitment rate: implementation of protocol amendment 1 which updated the inclusion/exclusion criteria in order to better reflect the actual patient population and to enlarge the patient population eligible to be enrolled in this study; two investigator meetings including the site pathologists; a separate pathologist board; opening of two additional study sites; advertising for the trial in the internet; and several preliminary publications at scientific meetings. However, as the recruitment rate did not improve noteworthy, it could not be expected that the originally planned number of patients (71 evaluable patients) could be reached in a reasonable time.