The protocol was revised to address the FDA recommendations. Section 8.3, Adverse events and serious adverse events was updated to reflect changes in the haematologic toxicity dose modifications management and to provide additional clarity on the management of non-haematologic toxicities, with detailed information on dose modifications for the management of gastrointestinal (GI) toxicities. Section 4.1 Overall design and section 8.6.1.1 Tumour tissue, were updated to clarify that all diagnostic tumor tissue samples should be submitted, not only if the diagnostic sample is different from the biomarker sample. Section 4.1 Overall design, Figure 2 was updated to reflect a change in tumor assessment frequency. Section 4.1.1 Study Conduct Mitigation During Study Disruptions Due to Cases of Civil Crisis, Natural Disaster, or Public Health Crisis and Appendix J Changes Related to Mitigation of Study Disruptions Due to Cases of Civil Crisis, Natural Disaster, or Public Health Crisis were added to include guidance on how the study could continue in the event of a serious disruption. Section 9.5.1 Safety Review Committee was updated to add additional detail regarding the Safety Review Committee. Appendix A Guidelines for Evaluation of Objective Tumour Response using RECIST v1.1 Criteria (Response Evaluation Criteria in Solid Tumours), was updated to remove reference to CT/MRI of the liver and adrenal glands, as this is not applicable for this study.

The protocol was revised to address the recommendations of the Safety Review Committee. Additional safety haematology and clinical chemistry assessment, review of the Toxicity Management Guidelines for participants with CTCAE Grade 4 infection with Grade 4 neutropenia, to allow participants who recover and have clear clinical benefit that outweighs the risks to continue dosing (at a reduced dose), only after sponsor approval and additional guidance in Toxicity Management Guidelines for the G-CSF use in severe neutropenia were the 3 recommendations which were reflected through the updates made to sections 1.3 Schedule of activities, section 8.2.4. Clinical Safety Laboratory Assessments and section 8.3.13.1 Haematologic Toxicity Dose Modifications. Section 8 was updated in view of the additional laboratory assessments required, to increase the amount of blood collected from each participant accordingly.

The protocol was revised in line with the urgent safety measures implemented, based on a preliminary analysis which identified an association between reduced renal function and the risk of Grade 4 neutropenia. Section 1.3 Schedule of Activities and section 8.2.4 Clinical Safety Laboratory Assessments updated to include creatinine clearance calculation at each study visit where clinical chemistry is assessed. Section 2.3.1 Risk Assessment was updated to include sepsis as an identified risk. Section 5.1 Inclusion criteria was updated with the threshold for creatinine clearance. Section 5.2 Exclusion criteria was updated with supplemental exclusion criteria relating to infection. Section 8.3.13 Mangement of Adavosertib related toxicities, was updated with Toxicity management guidelines for Blood neutrophil count decrease and for moderate/severe renal impairment (low creatinine clearance). Gastrointestinal toxicity management (title was updated) and renal function monitoring reference were also added in the same section.

Additional risk mitigation strategies were implemented through this protocol amendment following the safety events of sepsis cases. Sections 1.1 Synopsis, 1.2 Schema, 1.3 Schedule of activities, 4.1 Overall design, 6.1 Study intervention administered, 6.6 Dose modification and Figure 2 Study flow chart were updated with the starting dose being changed from 300mg to 250 mg QD adavosertib for the remaining participants to be recruited to the study. Two cohorts were defined Cohorts A and B: Cohort A with participants dosed at starting dose of 300mg QD, and Cohort B with participants dosed at a starting dose of 250 mg QD. No further participants would be enrolled to Cohort A. The relevant sections were updated to provide clarity on the data from which primary analysis and final analysis will be arrived at and also to include eligibility criteria and cohort A and cohort B. Section 1.3 Schedule of Activities and section 8 Study Assessments and Procedures were updated with additional safety on-site visits. Section 4 Study Design was updated with rationale for starting dose of 250mg QD adavosertib for Cohort B and end of study definition in view of introduction of Cohort B. Section 5.1 Inclusion criteria 11 was updated to clarify the definition of postmenopausal women and section 5.2 Exclusion criteria 4 was updated for participants with refractory nausea and vomiting. Section 5.3.3 Contraception was updated to include permanent sterilization as a highly effective method of contraception.Table 9 Dose Levels for Adavosertib was updated for dose reduction levels for new starting dose of 250mg QD. Section 7.1.2 Study Intervention Interruption was updated to clarify onset of 21-day drug interruption period. Section 8.3.13 Management of Adavosertib-related Toxicities, was updated with Toxicity Management Guidelines. Section 9.4 Statistical Analyses was updated to reflect that efficacy and safety endpoints will be summarised by starting dose.

Throughout the protocol all reference to Cohorts (A and B), and 250 mg dose was removed. Section 8.3.13 Management of Adavosertib-related Toxicities, was updated with Toxicity Management Guidelines. The final analysis data cut-off was removed from section 4 Overall design, section 8 Study assessments and Procedures and section 9 Statistical considerations. Section 4.4 was updated with end of study definition. Section 9.4 Statistical Analyses was updated to reflect the removal of Cohort B.