Protocol v 1.1 (Amendment 1) was dated 20 April 2020 and amended to incorporate FDA feedback on Protocol v 1.0, the changes in Administrative Letter #1, and other minor or administrative changes. Protocol v 1.1 was not executed, and no patients were enrolled under this version. The other key changes in Protocol v 1.1 included the following:  Clarified that the SMC should utilize all available clinical data and information to determine the RP2D, not only the information from the first 4 weeks of treatment for each patient; and  Provided guidance based on the potential that NM21-1480 might impact cytochrome P enzyme production and activity via cytokine modulation.

Protocol v 1.2 (Amendment 2) was dated 27 April 2020 and amended to incorporate FDA feedback on Protocol v 1.1 and other minor or administrative changes. Protocol v 1.2 was executed as the final version and patients were enrolled. The key changes in Protocol v 1.2 included the following:  Modified the definition of a DLT; and  Provided guidance that any patient who experienced Grade 4 toxicity must have been permanently discontinued.

Protocol v 2.0 (Amendment 3) was dated 04 June 2020 and amended to incorporate the following key changes and other minor or administrative changes:  Updated wording regarding definition of criteria to be fulfilled by patients to qualify as DLT-evaluable patients;  Provided more detailed specification of washout periods for different types of previous therapies in the eligibility criteria;  Introduced a new patient population (EAS) for statistical analyses of efficacy parameters;  Increased tolerated time windows for clinical visits;  Revised wording of Inclusion Criterion 1 to allow enrollment of patients aged 20 years and above in Taiwan, in accordance with local regulations;  Revised wording of Inclusion Criterion 3 to provide clarity on requirements for baseline biopsy;  Revised Inclusion Criteria 8 and 11 to provide clarity in regard of washout periods following previous systemic vs. focal RT;  Revised Inclusion Criterion 15 on WOCBP;  Revised wording of Exclusion Criteria 3 to 6 to provide more detailed guidance on necessary washout periods for different types of previous pharmaceutical treatments;  Revised Exclusion Criterion 23 to clarify use of systemically active versus topical CBD; Removed Exclusion Criterion 26 due to redundancy with other eligibility criteria;  Revised wording on study procedures following occurrence of repeated delayed DLTs;  Revised wording for continued treatment of patients with clinical benefit from treatment who had infusion delays of >35 days; and  Included DLTs and infusion reactions of any grade in the definition of AESIs. Administrative Letter #2 dated 08 July 2020 for Protocol v 2.0 was released to update the required duration for the use of a reliable contraception from 7 months to 6 months after the end of study treatment.

Protocol v 3.0 (Amendment 4) was dated 15 January 2021 and amended to incorporate the changes in Administrative Letter #2, the following key changes, and other minor or administrative changes:  Clarified the number of study sites and geographical location of study sites in Part A and Part B;  Introduced the option to conduct a small intermediate dose-expansion cohort (Cohort A-2) between Part A and Part B to further characterize the dose/PD relationship in support of dose selection for Part B;  Revised to determine final RP2D in Part B rather than in Part A, by studying up to 4 different dose levels based on Part A data for which full PD-L1 target occupancy on peripheral T cells during the dosing interval had been demonstrated;  Replaced description of duration of DLT evaluation period from weeks to number of days;  Clarified definition of criteria to be fulfilled by patients to qualify as DLT-evaluable patients in some instances;  Revised response assessment intervals for the first 24 weeks in Part B of the study from every 8 weeks to every 6 weeks;  Revised Part B study design and patient eligibility criteria (ie, Inclusion Criteria 2 and 8 and Exclusion Criteria 3 and 6; all only applicable for Part B) for Cohorts B1 through B3;  Introduced additional Inclusion Criterion 19 (for optional Cohort A-2 only);  Clarified countries in which respective Part B Cohorts were conducted;  Increased the maximum number of patients treated in Part B cohorts from 25 to 40 and adjusted the BOP2 interim analysis approach accordingly;  Introduced a 2-step screening process for Cohort B3;  Provided more flexibility for timing of PK sampling;  Revised Exclusion Criterion 10 to allow patients with controlled psoriasis not requiring systemic therapy to be enrolled;  Clarified the preferred timepoints for post-treatment initiation biopsies; Clarified that for patients who withdraw early from the study for reasons other than disease progression, e

Protocol v 4.0 (Amendment 5) was dated 17 May 2021 and amended to incorporate the changes in Protocol Clarification Memorandum #1, the following key changes, and other minor or administrative changes:  Updated Inclusion Criterion 3 to incorporate recent guidance from Protocol Clarification Memorandum #1 distributed to study sites (18 March 2021);  Clarified DLT classification criteria pertaining to toxicities leading to study/treatment discontinuation and infusion related reactions (IRRs); and  Clarified AESI reporting guidance for IRRs.

Protocol v 5.0 (Amendment 6) was dated 01 September 2021 and amended to incorporate the changes in Administrative Letter #3, Administrative Letter #4, the following key changes, and other minor or administrative changes:  Increased the number of expansion cohorts from 3 cohorts to 7 cohorts (Cohorts B1 through B7) and increased the number of study sites in Part B to accommodate for enrollment in all of the Part B expanded cohorts;  Added details to Inclusion Criteria 2 and 8 and Exclusion Criterion 3 to describe the new tumor specific Cohorts B4-B7;  Revised the wording of the Inclusion Criteria 3 to provide clarity on requirements for baseline archival tissue;  Revised Inclusion Criterion 13 to clarify the waiting period for minor surgical procedures conducted prior to dosing of NM21-1480;  Added new Inclusion Criterion 20 to ensure patients were at low risk to develop symptoms of COVID-19 infection while on study;  Revised Exclusion Criterion 10 to provide granularity on potential eligibility of patients who had a history of autoimmune disease;  Revised Exclusion Criteria 11 and 14 to allow for inclusion of patients who had been cured from previous Hepatitis C infection; Revised statistical analysis text to include Cohort B5 evaluation;  Included an initial 3+3 dose-escalation design to determine optimal safe dose levels of NM21-1480 in the combinatorial setting (Cohort B5);  Added the determination of disease control rate (DCR) as per RECIST 1.1 and BOR, DCR, ORR, Duration of Response, and PFS as per iRECIST as secondary endpoints in Part B;  Included analysis of T-cell receptor clonality in tumor tissue samples;  Introduced the option for the SMC to assign a longer dosing interval (approximately 3 weeks) to given dose levels selected for Part B than previously defined in the Protocol for Part A (approximately 2 weeks);  Updated the Schedule of Assessments (Table 7-1 to Table 7-1a) and Blood Sampling Schedule (Table 7-2 to

Protocol v 6.0 (Amendment 7) was dated 29 October 2021 and amended to incorporate the following key changes and other minor or administrative changes:  Removed Dose Level 8, 1400 mg flat dose from Part A and updated corresponding statistical section and operational characteristics of the BOIN design as applicable;  Removed full PK blood draw requirements for Part B patients in Taiwan; and  Provided additional details on analysis of ADA assessments. Protocol Letter of Amendment dated 13 December 2021 for Protocol v 6.0 was released to update PK/PD parameter sampling time points for Part A and optional Part A-2.

Protocol v 7.0 (Amendment 8) was dated 28 February 2022 and amended to incorporate the following key changes and other minor or administrative changes:  Updated Contract Research Organization information for overall project oversight and safety processing and reporting;  Expanded optional Part A-2 to allow up to 40 patients to enroll in a broader range of countries/sites than originally planned, with possibility to dose NM21-1480 either bi-weekly or every 3 weekRevised to allow for possible parallel conduct of Part A-2 with Part B;  Added Cohort B8 (mCRC) to Part B;  Added time to response to exploratory endpoints in Part A and Part A-2 and secondary anti-tumor endpoints in Part B; and  Updated Section 8.5.1, Permitted Medications and added a new Section 8.5.2, Prohibited Medications. Administrative Letter #5 dated 24 May 2022 for Protocol v 7.0 was released to update telephone contact for SAE reporting. Protocol Letter of Amendment dated 11 July 2022 for Protocol v 7.0 was released to include the following:  Updated to include completion of enrollment into Part A and SMC determination of the MTD from Part A;  Updated dose level to be initially evaluated in Part B; and  Revised to study the 1400 mg flat dose in up to 10 patients under Part A-2.s;

Protocol v 8.0 (Amendment 9) was dated 11 July 2022 and amended to incorporate the changes described above in Administrative Letter #5 dated 24 May 2022, Protocol Letter of Amendment dated 11 July 2022, the following key changes, and other minor or administrative changes:  Updated countries in which Part B8 may be conducted;  Updated primary objectives of Part A-2;  Updated dose level to be initially evaluated in Part B;  Updated safety run-in design for Cohort B5;  Updated eligibility criteria for Cohort B8;  Updated permitted and prohibited medications;  Updated Schedule of Assessments, Tables 7-1 to 7-4;  Updated Follow-up Procedures for patients with abnormal liver function tests; and  Updated list of required laboratory assessments by panel.

Protocol v 9.0 (Amendment 10) was dated 17 November 2022 and amended to incorporate the following key changes and other minor or administrative changes:  Updated Sponsor address;  Updated status of Part A;  Updated countries in which Cohorts B5 and B6 may be conducted;  Updated eligibility criteria for Cohorts B1, B7, and B8; and  Clarified requirements for scans during Follow-up period. Protocol Letter of Amendment dated 12 January 2023 for Protocol v 9.0 was released to allow archival tissue utilization to satisfy Cohort B8 patient eligibility and screening requirements. Protocol Clarification Letter dated 09 August 2023 for Protocol v 9.0 was released to provide clarification on the events to be classified as an AESI under hepatobiliary disorders.