• Section 2.1 (ganetespib) – updated in line with v8.0 of the IB: no. of patients being treated with ganetespib and the number of new studies. Adverse Events has also been updated with new events and the percentages reported has now changed as the sample size increased. • Section 4.1 updated e – sites must assess a patient’s ability to understand verbal explanations and written information in English. If local interpreters are not available and fully informed consent is not deemed possible, the patient should not be considered for the trial • Section 7.3.1 – updated in line with v8.0 of the IB: (Events of special interest), updated instructions for investigators regarding neutropenia. • Section 7.5 – Ganetespib administration – ‘D5W’ American terminology changed to ‘5% Glucose’ to concentration of solution when making infusion. • Section 7.14.1 – Management of severe or complicated neutropenia – recommendation of GCSF prophylactic use during subsequent treatment cycles in cases of Neutropenia lasting more than 7 days • Section 7.14.2 - Ganetespib pre-medication and management of hypersensitivity reactions – minor edits in line with IB: upon recover patients may also or re-schedule patient for re-treatment • Section 9.0 updated – data in CRFs should be verifiable by source date • Section 9.1 and 9.4 – instruction regarding CRF corrections and update regarding the use of query sheets • Section 10.0 updated in line with CTC template: UCL CTC will consider events evaluated as possibly, probably or definitely related to be adverse reactions • Section 10.0 updated - ‘Exemptions from SAE Report Submission’ updated to include events that occur after 30 days post last trial treatment administration that are not considered to be side-effects of the trial treatment and are not AEs of special interest. • Section 12.2 updated – Central Monitoring – Data received at UCL CTC will be subject to review in accordance with section 9

•Updated with Clinicaltrials.gov number •Section 1.1 & 5.4– Units for Haemoglobin changed from g/dL to g/L in accordance with the new national units •Section 1.2 – Trial Schema – Mosteller formula for calculation of BSA changed to Dubois and Dubois •Section 4.0 – Sites must assess a patient’s ability to understand verbal and written information in English •Section 5.3 – Patient Eligibility -Ensuring patient eligibility is the responsibility of the PI or other delegated Investigator(s). •Section 7.3 – Phase I trial - Mosteller formula for calculation of BSA changed to Dubois and Dubois. Randomised Phase II trial - Mosteller formula for calculation of BSA changed to Dubois and Dubois •Section 7.5 - Ganetespib infusion now supplied in 2 different vials sizes; 300mg and 400mg. Container and Storage conditions added for 300mg vial. •Section 7.5 - The DuBois and DuBois formula is the recommended method to be used for the calculation of BSA. •Section 7.11.1 – Ganetespib dose reductions – ANC values for Haematological Toxicity clarified •Section 7.11.3 - The dose modification schedules should be followed as closely as possible but clinical judgement should be used in individual cases. •Section 9 – Some data will be recorded directly on the CRFs and it will be considered to be the source document. •Section 12.1 – Key areas for assessment during on site monitoring removed altogether and referenced to the trial monitoring plan document. •Section 12.2 – Ensuring patient eligibility is the responsibility of the PI or other delegated Investigator(s). •Section 13 – Withdrawals – update to language •Section 16 – Ethical and Regulatory Approvals – updated in line with new CTC template. •Section 16.3 - updated in line with new CTC template - Site Approvals reference to Lead CLRN removed •Section 17.1 – Sponsor Details updated •Section 20 – Translational Research – Address for diagnostic tissue samples updated.

• Change in Trial Coordinator’s name • 7.3 – clarification loperamide is administered prior to day 1 and 15 ganetespib administration • 7.11 clarification the two dose reductions that can occur before a patient must be withdrawn refers to ganetespib only • 7.14.2 - chlorphenamine added as an alternative to diphenhydramine • 7.15 - correction to the telephone number for drug-specific advice for ganetespib, and alternative numbers added • 8.1, 8.2 & 8.3 – typographical errors amended • Appendix 2 – table corrected to match protocol

•Change in title from cisplatin to platinum to reflect option of using carboplatin in phase II •Change in TMG members •Section 1.1 - Summary of trial design updated •Sections 1.2, 2.2, 7.3 - details added to include additional patients to be registered to receive ganetespib, pemetrexed and carboplatin in the phase I. This group will be recruited concurrently with the group of patients used to confirm the MTD. •Section 1.2.3, 2.2.2, 7.3.2. - updated to reflect the option of using carboplatin in the phase II •Section 2.1 – Clinical experience and Adverse Events updated in line with new version of IB for ganetespib •Sections 2.2.3, 8.1, 8.3, 8.4, 20 and Appendix 2 – update to schedule of blood sample collection for translational research •Section 5.5 – Patient Exclusion criteria updated in line with version 9.0 of IB for ganetespib •Section 6.3 – updated to include carboplatin (to be supplied from hospital stock) •Section 7 – update to include carboplatin as IMP •Section 7.3.1 – updated to clarify definition of DLTs •Section 7.3.1 – updated to clarify accelerated titrated phase I design •Section 7.3.1, 7.15.1, 7.15.2, 7.15.3 – Management of events of special interest updated in line with version 9.0 of IB for ganetespib •Section 7.5 – ganetespib storage conditions updated •Section 7.12.1 – dose modifications for ganetespib •Section 7.13.2 drug interaction section updated for ganetespib in line with version 9.0 of IB •Section 7.14, 7.14.1 – Medications used with caution updated in line with version 9.0 of IB for ganetespib •Section 8.2, Appendices 2 and 3 – Schedule of ECG and dose modifications in the event of QTc prolongation updated in line with version 9.0 of IB for ganetespib •Section 15 – Statistical considerations updated to reflect the option of using carboplatin in phase II •Section 21 – references updated to incSynta studies •Appendix 5 – new appendix listing drugs with a risk of Torsades de Pointes

• Change to Trial Coordinator • Update to exclusion criteria to reflect new safety data • Section 2.1 - Background clinical information and adverse effects for ganetespib have been updated to reflect new data. • Section 2.2.3 – Changes to translational blood sample evaluation and use of results affecting future sample analysis. • Section 7.3 – clarification – DLT assessments for the carboplatin arm will be made after 1 cycle • Section 7.3.1 – Update and additional information for ocular, liver and gastrointestinal perforation toxicities • Section 7.7 – Symptom review for cisplatin added prior to treatment • Section 7.12.3.7 – Information on use of local guidelines for dose reduction of carboplatin • Section 7.13.1 – Instructions on availability of equipment for anaphylaxis • Section 7.15.1 – New information for prophylactic use of Loperamide • Section 7.15.4 – addition of information for premedication regimen • Section 8.2 – change to required ANC value at Day 1 assessment and additional information explaining requirement to take Day 15 bloods. • Section 10.1 – Updated to reflect use of RSI in defining SUSARs • Section 15.4.2 – Additional information relating to interim analysis and timing of IDMC. • Appendix 5 – information relating to Torsades de pointes updated to reflect new data since last update • Appendix 6 – Additional appendix added to protocol outlining meso-modified criteria and what is required when reporting trial CT scans.

• Change in trial statistician • Change in trial oversight • Change in trial coordinator • Change in drug company name from Synta Pharmaceuticals Corp to Madrigal Pharmaceuticals Inc. following reverse merger • Decision by not to proceed with continuing the phase II of the trial included in relevant sections of protocol as follows: 1.1 Summary of trial design; 1.2. Trial Schema; 2.2 Trial Design; 6.2 Randomisation to the phase II trial; 15.3 Safety Monitoring during the phase II trial; and 15.4.2 Randomised phase II trial • Section 2.1 – number of patients exposed to ganetespib updated in line with IB version 11, 13Nov2015 • Section 7.16 Out-of-hours drug advice contact numbers for ganetespib updated • Section 7.3 – loperamide guidance in line with IB v11 – to allow treatment to continue for up to 24 hours • Section 7.3 and 7.12.1 – Dose modifications and frequency of ECG recordings relating to QTc prolongation updated in line with IB v11 • Appendix 2 – Scheduling of CT assessments reworded to reflect that outlined in section 8.2 • Appendix 2 – Additional wording regarding the frequency of ECG assessments in case of QTc prolongation • Appendix 5 – updated in line with IB v11

• Section 7.5 Drug company information updated to reflect change in IMP sourcing information for gantespib • Sections 8.1, 8.2 and 8.4 – additional information regarding the sharing of pseudo-anonymised CT scan images for selected trial participants • Section 9.2 – new section on Imaging • Section 16 – updated in line with General Data Protection Regulation (GDPR) 2018 and Data Protection Legislation 2018 • Sections 1.1 and 14.1 - End of trial definition updated • New reference added for modified RECIST 1.1