Protocol v2.0 (Amendment 1): ● To provide details on the sensitivity and supportive analyses of the primary efficacy endpoint. ● To clarify the computation of some QoL scores. ● The endpoint “Change in FAACT total score from baseline to Week 9” was changed from an exploratory endpoint to a secondary endpoint.

Protocol v3.0 (Amendment 2): ● Methylphenidate was removed because this drug may induce reduction of appetite; therefore, it was not consistent with Exclusion Criterion #5. ● The term “medical” was removed because the Sponsor did not want to differentiate between medical and recreational marijuana. Marijuana had to be avoided independently of the intended use, i.e., medical or recreational. ● Blinding procedure was clarified according to a specific request by the German Ministry of Health about Clinical Study Protocol ANAM-17-21. ● Duration of contraception period was specified for completeness of information. ● Vital signs measurements were reported consistently throughout the entire protocol where applicable. ● Pregnancy reporting and related follow-up was extended to the female partner of male patients in the study for clarification and accurate follow-up.

Protocol v4.0 (Amendment 3): ● Section 1.5 of the study protocol provides a rationale for the amendment: “Further to FDA advice obtained on the primary endpoints analysis, the Sponsor re-defined the primary efficacy endpoints to duration of treatment benefit from baseline to Week 12 for body weight and anorexia (5-IASS). Based on this new approach a re-definition of the secondary and exploratory endpoints was also included. In order to measure duration of treatment benefit, a definition of a threshold of the relevant changes in body weight and anorexia (5-IASS) was needed. To determine clinically meaningful thresholds for body weight, similarly to what was currently planned for anorexia, the Sponsor was to use an anchor-based method using PGIS and PGIC as anchors.” ● Assessment of primary and secondary endpoints was shifted from Week 9 to Week 12. ● An estimand approach based on ICH E9(R1) was introduced to handle data in case of study drug discontinuation and death. The section on statistics was entirely rewritten to account for the changed primary, secondary, and exploratory endpoints. This included expanded considerations on sample size, missing data, and multiplicity, formulation of new hypotheses for primary, supportive, and secondary efficacy analyses, specification of analysis models for exploratory efficacy endpoints, specification of process order, i.e., first threshold determination then unblinding, and determination of the clinically meaningful responder threshold in weight change in a new section. ● Specified the visit considered as end of study regarding overall survival. ● Specified use of corticosteroids and prohibited medication as beta-blockers, and olanzapine and mirtazapine during study. ● Added a more detailed description of assessment instruments PGIS and PGIC considering added questionnaires on weight perception. ● Clarified role of Investigator for CT procedures.

Protocol v4.A (Amendment 4.A): ● Further to FDA advice obtained on the primary endpoints analysis, the Sponsor re-defined the primary efficacy endpoints to duration of treatment benefit from baseline to Week 12 for body weight and anorexia (5-IASS). Based on this new approach, a re-definition of the secondary and exploratory endpoints was also included. ● Methods were added to determine clinically meaningful thresholds for body weight increase and anorexia symptoms improvement through patient interviews conducted within 14 days after Week 12 (Visit 6). Up to 50 interviews were planned to be conducted with patients only in selected countries. ● The SF-12 questionnaire was added, which was to be used to collect QoL assessments. This was administered to patients at Week 1 (Visit 2), Week 6 (Visit 4), and Week 12 (Visit 6). The questionnaire was to be administered to patients only in selected countries, and was to be evaluated outside the study following a dedicated analysis plan.

Protocol v5.0 (Amendment 4) and v5.A (Amendment 5.A): ● During the course of the study, an error was discovered in the algorithm used to determine the statistical power for the evaluation of the duration of treatment benefit from baseline to Week 12 for body weight and anorexia (5-IASS) co-primary endpoints. Corrected calculations revealed that each trial, with the current planned sample size of 316 patients, would be underpowered for the 5-IASS endpoint. Based on corrected simulations and calculations, obtaining an acceptable power would require at least doubling the sample size. At the current stage of the studies, such a huge change in sample size would be of great impact for cachectic cancer patients who are currently looking at anamorelin as the only promising investigational agent in development for treating the 2 important unmet needs of malignancy associated weight loss and anorexia and hoping in its prompt approval. The Sponsor endorses the importance of having 2 adequate and well controlled trials, each achieving statistical significance. To achieve proper power for the analysis of the 5-IASS co-primary endpoint, the Sponsor decided to perform the analysis by adopting the same methodological approach and same variables, i.e., 2 co-primary endpoints, still keeping body weight and 5-IASS as efficacy variables; however, measuring the mean change from baseline in replacement of the duration of treatment benefit, as defined based on scientific and clinical experts’ feedback and confirmed as a feasible endpoint by sample size calculations.